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Oral-facial-digital (OFD) type 2 is characterized by hand and feet deformities, facial deformities, midline cleft of the upper lip and tongue hamartomas. ## Epidemiology Less than 20 cases have been reported so far. ## Clinical description Main clinical features include bilateral preaxial polydactyly of hands and feet, partial duplication of hallux, brachydactyly, syndactyly, scoliosis, pectus excavatums, short stature, muscular hypotonia, conductive hearing loss. Facial dysmorphism may include midface hypoplasia, hypertelorism, antimongoloid slant, broad nasal root, bifid nasal tip, cleft palate, microglossia, lobulated tongue, thick frenulum and low set ears. Microcephaly, porencephaly and internal hydrocephalus are also observed. Intelligence is normal in the majority of cases. Intellectual deficit and increased susceptibility to respiratory infections have been described in some patients. Involvement of the central nervous system (cerebellar atrophy) seems to be a clinical feature of OFD2. ## Etiology The causative gene has not yet been identified. ## Genetic counseling Autosomal recessive inheritance has been suggested. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Orofaciodigital syndrome type 2	c0026363	5,200	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2751	2021-01-23T18:17:28	{"gard": ["3701"], "mesh": ["C538585", "D009958"], "omim": ["252100"], "umls": ["C0026363", "C2931889"], "icd-10": ["Q87.0"], "synonyms": ["Mohr syndrome", "OFD2", "Oral-facial-digital syndrome type 2"]}
A number sign (#) is used with this entry because of evidence that renal hypomagnesemia-4 (HOMG4) is caused by homozygous mutation in the EGF gene (131530) on chromosome 4q25. One such family has been reported. For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014. Clinical Features Geven et al. (1987) described 2 Dutch sisters, born of second-cousin parents, who had isolated hypomagnesemia due to renal loss. Serum calcium levels and urinary calcium excretion were normal. The sisters had seizures, mild to moderate psychomotor retardation, and brisk tendon reflexes. Mapping Groenestege et al. (2007) performed homozygosity mapping in the consanguineous Dutch family originally described by Geven et al. (1987) and obtained a lod score of 2.66 on chromosome 4 at an 18.4-cM interval between markers D4S2623 and D4S1575. Molecular Genetics Meij et al. (2003) analyzed the FXYD2 (601814), CLDN16 (603959), and SLC12A3 (600968) genes in 2 Dutch sisters with renal hypomagnesemia, originally reported by Geven et al. (1987), but found no mutations. Following mapping studies in the Dutch family that showed linkage to chromosome 4, Groenestege et al. (2007) analyzed the candidate EGF gene (131530) and identified homozygosity for a mutation (P1070L; 131530.0001) in the 2 affected sisters. The unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in 126 ethnically matched controls. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYPOMAGNESEMIA 4, RENAL	c2673648	5,201	omim	https://www.omim.org/entry/611718	2019-09-22T16:03:03	{"doid": ["0060882"], "mesh": ["C567127"], "omim": ["611718"], "orphanet": ["34527"], "synonyms": ["Alternative titles", "HYPOMAGNESEMIA, RENAL, NORMOCALCIURIC"]}
Lennert lymphoma Other namesLymphoepithelioid lymphoma SpecialtyDermatology Lennert lymphoma is a systemic T-cell lymphoma that presents with cutaneous skin lesions roughly 10% of the time.[1]:739 It is also known as "lymphoepithelioid variant of peripheral T-cell lymphoma".[2] It was first characterized in 1952.[3][4] ## See also[edit] * Cutaneous T-cell lymphoma * Pleomorphic T-cell lymphoma * Skin lesion * Peripheral T-cell lymphoma-Not-Otherwise-Specified ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ Summers, TA.; Rush, W.; Aguilera, N.; Lupton, G. (Oct 2009). "Cutaneous involvement in the lymphoepithelioid variant of peripheral T-cell lymphoma, unspecified (Lennert lymphoma). Report of a case and review of the literature". J Cutan Pathol. 36 Suppl 1: 25–30. doi:10.1111/j.1600-0560.2008.01203.x. PMID 19775391. 3. ^ Feller, AC.; Griesser, GH.; Mak, TW.; Lennert, K. (Sep 1986). "Lymphoepithelioid lymphoma (Lennert's lymphoma) is a monoclonal proliferation of helper/inducer T cells". Blood. 68 (3): 663–7. PMID 2943330. 4. ^ Lennert K: Zur Histologischen Diagnose der Lymphogranulomatose. Frankfurt, FRG, Habil-Schrift, 1952 This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lennert lymphoma	c1621719	5,202	wikipedia	https://en.wikipedia.org/wiki/Lennert_lymphoma	2021-01-18T18:43:39	{"umls": ["C1621719"], "wikidata": ["Q6522771"]}
Wilson disease is an inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes. The signs and symptoms of Wilson disease usually first appear between the ages of 6 and 45, but they most often begin during the teenage years. The features of this condition include a combination of liver disease and neurological and psychiatric problems. Liver disease is typically the initial feature of Wilson disease in affected children and young adults; individuals diagnosed at an older age usually do not have symptoms of liver problems, although they may have very mild liver disease. The signs and symptoms of liver disease include yellowing of the skin or whites of the eyes (jaundice), fatigue, loss of appetite, and abdominal swelling. Nervous system or psychiatric problems are often the initial features in individuals diagnosed in adulthood and commonly occur in young adults with Wilson disease. Signs and symptoms of these problems can include clumsiness, tremors, difficulty walking, speech problems, impaired thinking ability, depression, anxiety, and mood swings. In many individuals with Wilson disease, copper deposits in the front surface of the eye (the cornea) form a green-to-brownish ring, called the Kayser-Fleischer ring, that surrounds the colored part of the eye. Abnormalities in eye movements, such as a restricted ability to gaze upwards, may also occur. ## Frequency Wilson disease is a rare disorder that affects approximately 1 in 30,000 individuals. ## Causes Wilson disease is caused by mutations in the ATP7B gene. This gene provides instructions for making a protein called copper-transporting ATPase 2, which plays a role in the transport of copper from the liver to other parts of the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The copper-transporting ATPase 2 protein is particularly important for the elimination of excess copper from the body. Mutations in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional protein, excess copper is not removed from the body. As a result, copper accumulates to toxic levels that can damage tissues and organs, particularly the liver and brain. Research indicates that a normal variation in the PRNP gene may modify the course of Wilson disease. The PRNP gene provides instructions for making prion protein, which is active in the brain and other tissues and appears to be involved in transporting copper. Studies have focused on the effects of a PRNP gene variation that affects position 129 of the prion protein. At this position, people can have either the protein building block (amino acid) methionine or the amino acid valine. Among people who have mutations in the ATP7B gene, it appears that having methionine instead of valine at position 129 of the prion protein is associated with delayed onset of symptoms and an increased occurrence of neurological symptoms, particularly tremors. Larger studies are needed, however, before the effects of this PRNP gene variation on Wilson disease can be established. ### Learn more about the genes associated with Wilson disease * ATP7B * PRNP ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Wilson disease	c0019202	5,203	medlineplus	https://medlineplus.gov/genetics/condition/wilson-disease/	2021-01-27T08:25:10	{"gard": ["7893"], "mesh": ["D006527"], "omim": ["277900"], "synonyms": []}
A rare photodermatosis characterized by the development of pruritic or painful vesicles in a photodistributed pattern in response to sunlight exposure. The lesions heal with permanent varioliform scarring. Ocular involvement, deformities of ears and nose, or contractures of the fingers may occasionally be observed. Systemic signs and symptoms are absent. The condition typically occurs in childhood and regresses spontaneously in adolescence or young adulthood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hydroa vacciniforme	c0020241	5,204	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=330058	2021-01-23T17:23:46	{"gard": ["9654"], "mesh": ["D006837"], "umls": ["C0020241"], "icd-10": ["L56.4"]}
A number sign (#) is used with this entry because congenital disorder of glycosylation type IIa (CDG IIa, CDG2A) is caused by homozygous or compound heterozygous mutation in the gene encoding GlcNAc-T II (MGAT2; 602616) on chromosome 14q21. Description Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002). ### Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II Multiple forms of CDG type II have been identified; see CDG2B (606056) through CDG2Q (617395). Clinical Features Ramaekers et al. (1991) reported an Iranian child with a form of CDG different from CDG1A, and Jaeken et al. (1993) investigated a Belgian boy, aged 9 years, with remarkably similar findings. In contrast to classic CDG1A, both patients had more severe psychomotor retardation, no peripheral neuropathy, and normal cerebellum on MRI. Biochemical differences from classic CDG were the absence of proteinuria, no increase in serum glutamic-pyruvic transaminase activity, normal serum albumin level, deficiency of clotting factors IX and XII, normal activity in serum of arylsulfatase A, and decreased activity of beta-glucuronidase. Both children also had increased serum carbohydrate-deficient transferrin. Cormier-Daire et al. (2000) described a child with CDG IIa who had severe mental retardation, chronic feeding problems with severe diarrhea, growth retardation, distinctive dysmorphic features including a beaked nose, long philtrum, thin vermilion border of the upper lip, large ears, gum hypertrophy, and thoracic deformity. This child also had an abnormal ERG with both cones and rods affected. De Cock and Jaeken (2009) reported a boy with CDG2A who died at age 18 years. Multiple dysmorphic features were noted at birth. He had thin lips, gum hypertrophy, large and posteriorly rotated ears, hook nose, large mouth, retrognathia, short neck, and distal limb anomalies. He also showed severe developmental delay. He later developed gastrointestinal problems, such as gastroesophageal reflux and volvulus, recurrent respiratory infections, and seizures. Kyphoscoliosis was also present. In general, he showed poor growth with muscle atrophy and lack of pubertal development. A coagulopathy developed at age 9 years, which led to the correct diagnosis of CDG2A. Alkuraya (2010) reported a consanguineous Saudi family in which 9 individuals had severe mental retardation associated with a distinct facial appearance. Affected individuals had small head circumference, retrognathia, long eyelashes, thick eyebrows, prominent columella, prominent nasal bridge, thin upper lip, everted lower lip, diastema, and an open mouth due to the combination of retrognathia and an abnormally obtuse lower incisor mandibular plane angle. Other features included mild to moderate bilateral sensorineural hearing loss, early hypotonia and late hypertonia, short terminal phalanges, and poor general growth with postnatal short stature. Microarray studies did not detect chromosomal abnormalities, and the authors postulated that it represented a novel autosomal recessive disorder. Biochemical Features Jaeken et al. (1994) showed that fibroblast extracts from 2 patients with CDG IIa had over 98% reduced activity of UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N-acetylglucosaminyltransferase II (GlcNAc-T II), an enzyme localized to the Golgi apparatus. Charuk et al. (1995) showed that mononuclear cell extracts from a patient with CDG IIa had no detectable activity of GlcNAc-T II and that similar extracts from 12 blood relatives of the patient, including the father, mother, and a brother, had enzyme levels 32 to 67% of normal (average 50.1% +/- 10.7% SD), consistent with autosomal recessive inheritance. The structure of erythrocyte membrane glycoproteins bands 3 and 4.5 were shown to be altered in the CDG patient. Similar to patients with hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS; 224100), erythrocyte membrane glycoproteins in the CDG patient had increased reactivities with concanavalin A, demonstrating the presence of hybrid or oligomannose carbohydrate structures. However, CDG IIa patients had a totally different clinical presentation, and their erythrocytes did not show the serology typical of HEMPAS, suggesting that those 2 disorders are different. Schachter and Jaeken (1999) reviewed both disorders. Patients with CDG Ia have a thrombotic tendency, whereas a patient with CDG IIa, described by Van Geet et al. (2001), had an increased bleeding tendency. Van Geet et al. (2001) observed abnormal glycosylation of platelet glycoproteins in CDG Ia causing enhanced onset of platelet interactions, leading to thrombotic tendency. Reduced GP Ib (231200)-mediated platelet reactivity with vessel wall components in the CDG IIa patient under flow conditions provided a basis for his bleeding tendency. Molecular Genetics In the Iranian and Belgian patients with CDG2A reported by Jaeken et al. (1994), Tan et al. (1996) identified 2 different homozygous mutations in the MGAT2 gene (602616.0001; 602616.0002), respectively. In a patient with CDG IIa, Cormier-Daire et al. (2000) identified compound heterozygosity for 2 point mutations in the MGAT2 gene (602616.0003, 602616.0004). By homozygosity mapping followed by whole-exome sequencing, Alazami et al. (2012) determined that the family reported by Alkuraya (2010) actually had CDG2A caused by a homozygous mutation in the MGAT2 gene (K237N; 602616.0005). The diagnosis was confirmed by isoelectric focusing of serum transferrin, which showed an increase of disialotransferrin and a decrease of longer sialotransferrins. Alazami et al. (2012) emphasized the striking dysmorphic features in this metabolic disorder. Nomenclature CDGs were formerly referred to as 'carbohydrate-deficient glycoprotein syndromes' (Marquardt and Denecke, 2003; Grunewald et al., 2002). Conventionally, untyped and unclassified cases of CDG are labeled CDG-x (see 212067) until they are characterized at the molecular level. Orlean (2000) discussed the revised nomenclature for CDGs proposed by the participants at the First International Workshop on CDGs in Leuven, Belgium, in November 1999. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive \- Postnatal growth retardation HEAD & NECK Head \- Macrocephaly \- Microcephaly \- Brachycephaly Face \- Retrognathia \- Malar underdevelopment \- Obtuse lower incisor mandibular plane angle Ears \- Large dysplastic ears \- Posteriorly rotated ears \- Hearing loss, sensorineural Eyes \- Downslanting palpebral fissures \- Long eyelashes \- Thick eyebrows Nose \- Prominent nasal bridge \- Low hanging columella \- Hook nose Mouth \- Large mouth \- Open mouth \- Thin lips \- Thin upper vermilion \- Everted lower lip \- Gum hypertrophy \- Protruding tongue Teeth \- Large teeth \- Diastema Neck \- Short neck CARDIOVASCULAR Heart \- Ventricular septal defect CHEST External Features \- Pectus excavatum SKELETAL \- Osteopenia Spine \- Thoracolumbar kyphoscoliosis Pelvis \- Coxa valga Limbs \- Gracile long bones Hands \- Proximally placed thumbs \- Short terminal phalanges Feet \- Pes planus \- Irregular position of the toes SKIN, NAILS, & HAIR Skin \- Midfrontal capillary hemangioma Hair \- Hirsutism (in some patients) \- Sparse hair (in some patients) \- Long eyelashes \- Thick eyebrows NEUROLOGIC Central Nervous System \- Mental retardation, severe \- Early hypotonia \- Later hypertonia \- Seizures \- Unsteady gait Behavioral Psychiatric Manifestations \- Self-mutilation \- Aggression \- Stereotypic behaviors (hand-washing movements, head-banging) HEMATOLOGY \- Decreased coagulation factors IX, XI, XII \- Decreased antithrombin III \- Decreased protein S \- Decreased protein C LABORATORY ABNORMALITIES \- Abnormal isoelectric focusing of serum transferrin (type 2 pattern) \- GlcNAc-transferase II deficiency in fibroblast and mononuclear cells MISCELLANEOUS \- Four individual patients and 1 Saudi family have been reported (as of February 2012) MOLECULAR BASIS \- Caused by mutation in the mannosyl (alpha-1,6-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase gene (MGAT2, 602616.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIa	c2931008	5,205	omim	https://www.omim.org/entry/212066	2019-09-22T16:30:07	{"doid": ["0070253"], "mesh": ["C535752"], "omim": ["212066"], "orphanet": ["79329"], "synonyms": ["Alternative titles", "CDG IIa", "ALKURAYA SYNDROME", "MENTAL RETARDATION, GROWTH RETARDATION, PROMINENT COLUMELLA, AND OPEN MOUTH", "CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE II, FORMERLY"], "genereviews": ["NBK1332"]}
A number sign (#) is used with this entry because Werner syndrome is caused by homozygous or compound heterozygous mutation in the RECQL2 gene (604611), which encodes a homolog of the E. coli RecQ DNA helicase, on chromosome 8p12. See also Hutchinson-Gilford progeria syndrome (HGPS; 176670), a more severe progeroid syndrome with earlier onset caused by mutation in the LMNA gene (150330). Clinical Features The features of Werner syndrome are scleroderma-like skin changes, especially in the extremities, cataract, subcutaneous calcification, premature arteriosclerosis, diabetes mellitus, and a wizened and prematurely aged facies. A particularly instructive pedigree was reported by McKusick (1963). The habitus is characteristic, with short stature, slender limbs, and stocky trunk. The nose is beaked. Epstein et al. (1966) studied a Japanese patient living in Seattle. Goto et al. (1981) studied 42 Japanese families containing 80 affected persons. Autosomal recessive inheritance was confirmed. Malignancy was frequent in the patients and in the families generally. HLA was not linked. The frequency of Werner syndrome in Japan was estimated to be about 3 per million persons. The origin of the grandparents of the cases would be of interest. Khraishi et al. (1992) described a 47-year-old woman who had been misdiagnosed as having progressive systemic sclerosis with metastatic calcification for 12 years and then developed a painful, distal femoral, osteoblastic cortical juxtaarticular lesion with exuberant soft tissue calcification. This lesion proved to be an osteosarcoma requiring amputation. Ruprecht (1989) reported that in 10 of 18 eyes from 9 patients with Werner syndrome, cataract surgery was complicated by wound dehiscence and its consequences. Additionally, corneal endothelial decompensation occurred in 8 eyes. In view of the reduced growth potential of fibroblasts, he suggested small surgical incisions and other modifications of the usual procedures of cataract surgery, including no local or systemic use of cortisone. Martin (1997) gave a thoughtful review of the question of whether the Werner mutation is a bona fide reflection of mechanisms of 'normal aging.' Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders. Goto et al. (1996) found in the literature 124 case reports of neoplasia and Werner syndrome from Japan and 34 case reports from outside Japan, from 1939 to 1995. They found a greater diversity of neoplasia in WRN than was previously known. In Japanese, there were 127 cancers, 14 benign meningiomas, and 5 myeloid disorders, as compared with 30 cancers, 7 benign meningiomas, and 2 myeloid disorders, in non-Japanese. The ratio of epithelial to nonepithelial cancers was about 1:1 for Japanese and for non-Japanese, instead of the usual 10:1. Both series had excesses of soft tissue sarcoma (STS), osteosarcoma, myeloid disorders, and benign meningioma. In addition, the Japanese had an excess of thyroid cancer and melanoma, including 5 intranasal and 13 foot. STS, osteosarcoma, melanoma, and thyroid carcinoma accounted for 57% of all cancer in WRN as compared with an expected 2%, based on the Osaka population between 25 and 64 years of age. Multiple tumors were reported in 19 Japanese and 5 non-Japanese. In Japan, 9 first-degree relatives had WRN and cancer, 6 of whom were concordant as to site and/or cell type. Other Features ### Chromosomal Instability in Werner Syndrome 'Variegated translocation mosaicism' was the designation proposed by W. W. Nichols (Hoehn et al., 1975) for a phenomenon he and others observed in cells from patients with Werner syndrome: skin fibroblast cell lines were usually composed of one or several clones, each marked by a distinctive, apparently balanced translocation. Salk (1982) found that somatic cells from Werner syndrome patients reveal a propensity to develop chromosomal aberrations, including translocations, inversions, and deletions. In fibroblast cell lines and lymphoblastoid cell lines made from circulating B lymphocytes in 2 brothers born of first-cousin parents, Schonberg et al. (1984) demonstrated variegated translocation mosaicism as well as the abbreviated life span characteristic of cell lines from these patients. In studies with clastogens, Gebhart et al. (1988) concluded that Werner syndrome cells demonstrate some biochemical differences that distinguishing them from those of other classic chromosome instability syndromes. Fukuchi et al. (1989) demonstrated increased frequency of chromosomal deletions in cell lines from patients with WRN. Scappaticci et al. (1990) found multiple numerical and structural chromosomal abnormalities in cultured lymphocytes of 4 patients with Werner syndrome; several of the changes were clonal. Fukuchi et al. (1990) found an 8-fold higher average frequency of 6-thioguanine-resistant lymphocytes in Werner syndrome patients compared to normal controls, suggesting there were increased spontaneous chromosome rearrangements and deletions in WRN cells consistent with a human genomic instability or 'mutator' syndrome. Monnat et al. (1992) determined the junction region sequences of deletions in the HPRT gene (308000) from thioguanine-resistant Werner syndrome fibroblasts. Given the potential for homologous recombination between copies of repeated DNA sequences that constitute approximately a third of the human HPRT gene, they were surprised to discover that all the deletions were generated by nonhomologous recombination of donor DNA duplexes that share little nucleotide sequence identity. No difference in structure or complexity was observed between deletions isolated from Werner syndrome fibroblasts or from myeloid leukemia cells. This suggested to Monnat et al. (1992) that the Werner syndrome deletion mutator uses deletion mutagenesis pathways that are similar or identical to those used in other human somatic cells. Ogburn et al. (1997) found that immortalized B lymphocytes from individuals with Werner syndrome were hypersensitive to 4-nitro-quinoline-1-oxide (4NQO), supporting earlier work on T lymphocytes. They also showed that B cell lines from clinically normal heterozygous carriers, with approximately 50% residual helicase activity, exhibited intermediate sensitivities to this genotoxic agent. Since the prevalence of carriers is as high as 1 in 150 to 1 in 200, Ogburn et al. (1997) suggested that a deleterious phenotype associated with a carrier state could have potential public health concern. Moser et al. (2000) used the glycophorin A (GPA) somatic cell mutation assay (Jensen and Bigbee, 1996) to analyze genetic instability in vivo in WRN patients and heterozygotes. GPA variant frequencies were determined for 11 patients and 10 heterozygous family members who collectively carried 10 different WRN mutations. An increase in variant frequency was strongly age-dependent in WRN patients. Allele loss variants were also significantly elevated in heterozygous family members, thus providing the first evidence for in vivo genetic instability in heterozygous carriers in an autosomal recessive genetic instability syndrome. Prince et al. (1999) showed that Werner syndrome fibroblast cell lines are unusually sensitive to the DNA-damaging agent 4NQO, although not to gamma radiation or to hydrogen peroxide. The fusion of 4NQO-sensitive WRN and 4NQO-resistant control fibroblast cell lines generated proliferating cell hybrids that expressed WRN protein and were 4NQO-resistant. These results established the recessive nature of 4NQO sensitivity in WRN cell lines and provided a cellular assay for WRN protein function. Crabbe et al. (2007) demonstrated that replication-associated telomere loss was responsible for chromosome fusions found in Werner syndrome fibroblasts. Using metaphase analysis, the authors showed that telomere elongation by telomerase (TERT; 187270) significantly reduced the appearance of new chromosomal aberrations in cells lacking the WRN helicase, similar to complementation of Werner syndrome cells with the WRN helicase. Crabbe et al. (2007) proposed a mechanism in which lack of WRN helicase activity results in dramatic telomere loss from individual sister chromatids, causing a DNA damage and repair response that leads to chromosome fusion-breakage cycles and genomic instability. The findings suggested that genome instability in Werner syndrome cells, which may lead to cancer, depends directly on telomere dysfunction. Pathogenesis Bauer et al. (1986) found that fibroblasts from a patient with Werner syndrome had a markedly attenuated mitogenic response to platelet-derived growth factor (PDGF; see 190040) and fibroblast growth factor (FGF; see 131220) despite normal cellular growth factor binding and receptors. The findings suggested that a defect in growth factor-mediated pathways may contribute to the WRN phenotype. The finite replicative life span of human cells in vitro, the Hayflick phenomenon (Hayflick, 1965), is due to the stochastic loss of replicative ability in a continuously increasing fraction of newborn cells at every generation. Normal human fibroblasts achieve approximately 60 population doublings in culture, while Werner syndrome cells usually achieve only about 20 population doublings. There are 2 alternative kinetic explanations for the decreased life span of Werner syndrome cells. First, the initial fraction of cycling cells in a fresh explant may be approximately the same as in an explant derived from a normal subject, but the rate of loss of reproductive ability may be much higher in Werner syndrome cells. Second, when freshly explanted, the Werner syndrome cells may contain a much smaller fraction of cycling cells, which lose their reproductive ability at a normal rate. Of course, a combination of the 2 mechanisms is possible. To distinguish between the 2 main hypotheses, Faragher et al. (1993) studied cells from an obligate heterozygote, determining the fraction of cells in S phase throughout the life span of cultures. They found that the cells in these cultures usually exited, apparently irreversibly, from the cell cycle at a faster rate than did normal cells, although for the most part they started off with good replicative ability. They proposed that the Werner syndrome gene is a 'counting' gene controlling the number of times that human cells are able to divide before terminal differentiation. Thweatt and Goldstein (1993) arrived at a similar hypothesis. They pointed out that several overexpressed gene sequences isolated from a Werner syndrome fibroblast cDNA library possessed the capacity to inhibit DNA synthesis and disrupt many normal biochemical processes. Because a similar constellation of genes is overexpressed in senescent normal fibroblasts, the findings suggested a common molecular genetic pathway for replicative senescence in the 2 types of cells. Thweatt and Goldstein (1993) proposed that the primary defect in WRN is a mutation in a gene for a trans-acting repressor protein that reduces its binding affinity for shared regulatory regions of several genes, including those that encode inhibitors of DNA synthesis. The mutant WRN repressor gene triggers a sequence of premature expression of inhibitors of DNA synthesis and other genes, with resulting inhibition of DNA synthesis and early cellular senescence, events that occur much later in normal cells. Matsumoto et al. (1997) presented evidence that the helicase that is defective in Werner syndrome is missing the nuclear localization signal (NLS) and that this leads to impaired nuclear import as a major contributing factor in the molecular pathology of the disorder. The finding helped to explain the enigma that most Werner syndrome patients have similar clinical phenotypes no matter how different their mutations. The role the Werner syndrome helicase plays in the nucleus in preventing premature aging remained to be clarified. Wyllie et al. (2000) showed that forced expression of telomerase (187270) in Werner syndrome fibroblasts conferred extended cellular life span and probable immortality. Telomerase activity and telomere extension was is sufficient to prevent premature senescence of Werner syndrome fibroblast cultures. The findings suggested that one consequence of the Werner syndrome defect is an acceleration of normal telomere-driven replicative senescence, and suggested a route to therapeutic intervention in this human progeroid syndrome. Krejci et al. (2003) clarified the role of Srs2 in recombination modulation by purifying its encoded product and examining its interactions with the RAD51 recombinase (179617). Srs2 has a robust ATPase activity that is dependent on single-stranded DNA and binds RAD51, but the addition of a catalytic quantity of Srs2 to RAD51-mediated recombination reactions causes severe inhibition of these reactions. Krejci et al. (2003) showed that Srs2 acts by dislodging RAD51 from single-stranded DNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the RAD51 presynaptic filament efficiently. Krejci et al. (2003) suggested that their findings have implications for the basis of Bloom (210900) and Werner syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated aging. Baird et al. (2004) showed that the mean rate of telomere shortening in WRN bulk cultures ranged between that of normal fibroblasts (99 bp/population doubling) and 4 times that of normal (355 bp/population doubling). Telomere erosion rates in clones of WRN cells were much reduced compared with bulk cultures, as were the variances of the telomere length distributions. The overall lack of length heterogeneity and the normal erosion rates of the clonal populations were consistent with simple end-replication losses as the major contributor to telomere erosion in WRN cells. The authors proposed that telomere dynamics at the single-cell level in WRN fibroblasts are not significantly different from those in normal fibroblasts, and suggested that the accelerated replicative decline seen in WRN fibroblasts may not result from accelerated telomere erosion. Clinical Management Because insulin resistance in Werner syndrome may be due to defective signaling distal to the insulin receptor (147670), Izumino et al. (1997) analyzed the metabolic effects of troglitazone, an antidiabetic drug that sensitizes insulin action, in 5 patients with Werner syndrome. Each patient was treated with 400 mg/day of troglitazone for 4 weeks and underwent a 75-g oral glucose tolerance test (OGTT) and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, expressed as the glucose disappearance rate, improved significantly (1.36 +/- 0.16 to 1.94 +/- 0.30%/min; P less than 0.005). The authors found that troglitazone ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal analysis, in Werner syndrome patients. Mapping In a study of 21 Japanese families originating in 16 different prefectures, Goto et al. (1992) did linkage studies demonstrating close linkage of WRN to a group of markers on chromosome 8. At least 3 of the 4 following major signs were required for the diagnosis: characteristic habitus and stature, premature senescence, scleroderma-like skin changes, and endocrine abnormalities. The first suggestion of linkage was increased homozygosity for ankyrin (ANK1; 612641) and D8S87. The ANK1 locus is located at 8p11.2. The Werner syndrome showed a maximum lod score of 2.89 at theta = 0.058 for linkage with ANK1. A multipoint lod score of 9.92 was obtained for the linkage of Werner syndrome with 3 markers. No linkage was found with lipoprotein lipase (238600), and other evidence suggested that this locus lies closer to 8pter than does the Werner syndrome locus. A likely location for the WRN gene appeared to be 8p12-p11. Schellenberg et al. (1992) confirmed the assignment by homozygosity mapping, i.e., linkage analysis using affected individuals from first- or second-cousin marriages. A peak lod score of 5.58 at a recombination fraction of 0.03 was obtained with D8S87. By linkage studies, Thomas et al. (1993) determined that the heregulin locus (142445) is distal to WRN and that ANK1 and PLAT (173370) are in that order on the centromeric side of WRN. Nakura et al. (1994) studied 27 Werner syndrome kindreds of various ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of definite Werner syndrome and affected subjects in the remaining 3 pedigrees were given the diagnosis of probable Werner syndrome. With 2-point linkage analysis using 13 short tandem repeat polymorphic sites on 8p, Nakura et al. (1994) found that the locus yielding a maximum lod score at the smallest recombination fraction was D8S339. Lod scores in excess of 3.0 were obtained with this marker for both Japanese and Caucasian families. Multipoint analysis of the markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. Combined with the analysis of homozygosity in subjects from inbred pedigrees, the data indicated that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339. Yu et al. (1994) used linkage disequilibrium in an attempt to narrow down the location of the WRN gene. They found that D8S339 and 2 polymorphisms at the glutathione reductase locus (138300) showed strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, they showed that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as 8 or 9 independent WRN mutations in these 2 populations. Ye et al. (1995) used homozygosity mapping with markers derived from an 8p22-p12 microdissection library to type members of Japanese families with WRN. One marker, MS8-134 (D8S1055), showed a lod score of over 20 at theta = 0.00. Molecular Genetics Yu et al. (1996) identified 4 mutations in the WRN gene in patients with Werner syndrome. Two of the mutations (604611.0003 and 604611.0004) were splice-junction mutations with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations (604611.0004), which resulted in a frameshift and a predicted truncated protein, was found in the homozygous state in 60% of Japanese Werner syndrome patients examined. The other 2 mutations were nonsense mutations (604611.0001 and 604611.0002). The identification of a mutated putative helicase as the gene product of the WRN gene suggested to Yu et al. (1996) that defective DNA metabolism is involved in a complex process of aging in Werner syndrome patients. Oshima et al. (1996) reported 9 new WRN mutations in 10 Werner syndrome patients, including 4 Japanese patients and 6 Caucasian patients. These mutations were located at different sites across the coding region. Oshima et al. (1996) noted that all of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature terminations. They noted that the WRN protein is partially homologous to RecQ helicases and that it contains 7 helicase motifs, 2 of which have been found in all ATP-binding proteins. Oshima et al. (1996) briefly reviewed the functions of helicases and reported that DNA helicases have been implicated in a number of molecular processes, including unwinding of DNA during replication, DNA repair, and accurate chromosomal segregation. Goto et al. (1997) studied the helicase gene mutations previously described by Yu et al. (1996) in 89 Japanese Werner syndrome patients. Thirty-five (39.3%) were homozygous for mutation 4 (604611.0004); 1 (1.1%) was homozygous for mutation 1 (604611.0001); 6 (6.7%) were positive for both mutations 1 and 4; 1 was homozygous for a new mutation, which they designated mutation 5 (604611.0005); 13 (14.6%) had a single copy of mutation 4; 3 (3.4%) had a single copy of mutation 1; and the remaining 30 (33.8%) were negative for all 5 mutations. Of the 178 chromosomes in the 89 patients, 89 (50%) carried mutation 4, 11 (6.2%) carried mutation 1, and 2 (1.1%) carried mutation 5. In 76 chromosomes (42.7%), no mutation was identified. Yu et al. (1997) screened Werner syndrome subjects for mutations and identified 5 new ones. Four of these new mutations either partially disrupted the helicase domain region or resulted in predicted protein products lacking the entire helicase region. Their results confirmed that mutations in the WRN gene are responsible for Werner syndrome. In addition, the location of the mutations indicated that the presence or absence of the helicase domain does not influence the Werner syndrome phenotype, suggesting that this syndrome is the result of complete loss of function of the WRN gene product. Moser et al. (1999) reviewed the spectrum of WRN mutations in Werner syndrome, the organization and potential functions of the WRN protein, and the possible mechanisms linking the loss of WRN function with the clinical and cellular phenotypes of Werner syndrome. Monnat (1999) cited results from his own laboratory and from that of the AGENE Research Institute indicating that 80% of the WRN mutations in Japanese Werner syndrome patients led to a lack of detectable mutant protein. Thus many and perhaps all Werner syndrome-associated WRN mutations are likely to be functionally equivalent null alleles. These results contradict the suggestion of Ishikawa et al. (1999) that a different spectrum of mutations in the WRN gene in Japanese may confer a higher risk of thyroid carcinoma of the papillary or follicular type. However, the consistent absence of WRN protein in the cells of patients with Werner syndrome could both favor and partially explain the development of thyroid carcinoma with follicular and anaplastic, as opposed to the more papillary, histology. Using cDNA microanalysis, Kyng et al. (2003) found that fibroblasts from 4 patients with Werner syndrome and fibroblasts from 5 older control individuals (average age 90 years) showed transcription alteration of 435 (6.3%) of 6,192 genes examined compared to cells from young adult controls. Of the 435 genes, 91% of the 249 genes with known function had similar transcription changes in both Werner syndrome patients and normal old age controls. The major functional categories of the similarly transcribed genes of known function included DNA/RNA metabolism, cell growth, and stress response. Kyng et al. (2003) concluded that Werner syndrome may be a good model for normal aging and that both processes are linked to altered transcription. History Thomas et al. (1993) excluded the FGFR1 gene (136350) as the site of the mutation in Werner syndrome. In blood samples from Werner syndrome patients, Sadakane et al. (1994) identified large insertions or deletions in the DNA polymerase beta gene (POLB; 174760), which maps to 8p12-p11. A 107-bp insertion was found in 2 independent Werner syndrome patients and in the carrier mother of 1 of the patients, but not in an unaffected sister or in a healthy population. The authors suggested that mutations in the POLB gene may underlie the disorder. However, Chang et al. (1994) presented several lines of evidence suggesting that POLB is not the Werner syndrome gene. Activity gels showed normal enzyme activity and electrophoretic mobility. Nucleotide sequence analysis of the entire coding region failed to demonstrate mutations, although mistakes in the published sequence for POLB were discovered. Single-strand conformation polymorphism (SSCP) and heteroduplex analyses failed to reveal evidence of mutations in the promoter region. A newly discerned polymorphism failed to reveal homozygosity by descent in a consanguineous patient. Fluorescence in situ hybridization placed the POLB gene centromeric to D8S135 at 8p11.2, beyond the region of peak lod scores for Werner syndrome. Animal Model Lombard et al. (2000) generated mice bearing a mutation that eliminated expression of the C terminus of the helicase domain of the WRN protein. Mutant mice were born at the expected mendelian frequency and did not show any overt histologic signs of accelerated senescence. The mice were capable of living beyond 2 years of age. Cells from these animals did not show elevated susceptibility to 2 genotoxins. However, mutant fibroblasts aged approximately 1 passage earlier than controls. Importantly, mice that were doubly homozygous for WRN and p53 (191170) deficiencies showed an increased mortality rate relative to animals that were heterozygous for WRN deficiency and homozygous for p53 null. Lombard et al. (2000) considered possible models for the synergy between p53 and WRN mutations for the determination of life span. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Stocky trunk HEAD & NECK Face \- Prematurely aged face Eyes \- Cataracts \- Retinal degeneration Nose \- Beaked nose CARDIOVASCULAR Heart \- Premature arteriosclerosis SKELETAL \- Osteoporosis Limbs \- Slender limbs SKIN, NAILS, & HAIR Skin \- Scleroderma-like skin, especially of face and distal extremities \- Subcutaneous calcification \- Ulceration Hair \- Thin, sparse, gray \- Premature balding ENDOCRINE FEATURES \- Diabetes mellitus \- Hypogonadism NEOPLASIA \- Malignancy in approximately 10% \- Osteosarcoma and meningioma especially LABORATORY ABNORMALITIES \- Variegated translocation mosaicism in cultured fibroblasts \- Poor mitogenic response to growth factors MOLECULAR BASIS \- Caused by mutation in the RecQ protein-like 2 gene (RECQL2, 604611.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	WERNER SYNDROME	c0043119	5,206	omim	https://www.omim.org/entry/277700	2019-09-22T16:21:11	{"doid": ["5688"], "mesh": ["D014898"], "omim": ["277700"], "orphanet": ["902"], "genereviews": ["NBK1514"]}
## Summary ### Clinical characteristics. DYRK1A-related intellectual disability syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate to severe range of intellectual disability; however, a few individuals with mild intellectual disability have been reported. About half of affected individuals develop epilepsy including atonic attacks, absences, and generalized myoclonic seizures. About half of affected individuals develop scoliosis, kyphosis, and/or pectus excavatum. About one third have short stature. Rarely, endocrine problems and dental, ophthalmologic, and/or cardiac anomalies are reported. ### Diagnosis/testing. The diagnosis of DYRK1A-related intellectual disability syndrome is established in a proband by identification of a heterozygous pathogenic variant in DYRK1A. ### Management. Treatment of manifestations: Educational programs to address the specific needs identified; speech therapy directed at improving communication skills; occupational therapy for feeding problems; physical therapy for hypertonic musculature and gait disturbances. Routine treatment of epilepsy under the care of a neurologist. Standard treatment for sleep disturbances, and other medical issues (e.g., orthopedic, endocrine, dental, cardiac, and ophthalmologic involvement). Surveillance: Monitoring and guidance as needed for educational and behavior problems, complications of hypertonic musculature (e.g., scoliosis, gait disturbances). Regular lifelong attention to nutritional status, dental hygiene, heart (if a congenital anomaly is present), eyes, and vision. ### Genetic counseling. DYRK1A-related intellectual disability syndrome is inherited in an autosomal dominant manner. To date all affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo DYRK1A pathogenic variant. When the DYRK1A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs appears to be very low but is presumed to be greater than that of the general population because of the possibility of germline mosaicism. Prenatal testing for pregnancies presumed to be at increased risk for DYRK1A-related intellectual disability syndrome is possible. ## Diagnosis No formal clinical criteria exist for DYRK1A-related intellectual disability syndrome. ### Suggestive Findings DYRK1A-related intellectual disability syndrome should be suspected in individuals with the following: * Intellectual disability and/or autism spectrum disorders AND * Microcephaly (often present at birth or early infancy) AND * Two or more of the following features * Typical facial gestalt: * During infancy and childhood facial features include prominent ears, deeply set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. * In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016]. * Neonatal feeding problems that may persist * Seizures * Hypertonia * Abnormal gait * Foot anomalies: mild cutaneous syndactyly of toes 2, 3, 4; hallux valgus; and short fifth toe ### Establishing the Diagnosis The diagnosis of DYRK1A-related intellectual disability syndrome is established in a proband by identification of a heterozygous pathogenic variant in DYRK1A (see Table 1). Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of DYRK1A is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. Note: Two individuals with a de novo apparently balanced translocation with a breakpoint within DYRK1A have been reported [Møller et al 2008]. * A multigene panel that includes DYRK1A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes DYRK1A) fails to confirm a diagnosis in an individual with features of DYRK1A-related intellectual disability syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in DYRK1A-Related Intellectual Disability Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method DYRK1ASequence analysis 331/33 4 Gene-targeted deletion/duplication analysis 52/33 6, 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Courcet et al [2012], O'Roak et al [2012], Redin et al [2014], Bronicki et al [2015], Deciphering Developmental Disorders Study Group [2015], Ji et al [2015], Ruaud et al [2015], van Bon et al [2016] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. These two intragenic deletions were reported by [van Bon et al 2011, Courcet et al 2012]. 7\. Individuals reported to have larger deletions that include more genes in the 21q22 region have phenotypic features that overlap those of the DYRK1A-related intellectual disability syndrome described in this GeneReview [Oegema et al 2010, Valetto et al 2012]. ## Clinical Characteristics ### Clinical Description DYRK1A-related intellectual disability syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies [van Bon et al 2016]. Intellectual disability. The majority of affected individuals function in the moderate to severe range of intellectual disability; however, a few individuals with mild intellectual disability have been reported. Several individuals show speech impairment with a lack of speech or the use of one to two word utterances only. In general, expressive language is more severely affected than receptive language. Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. Motor development is often impaired by gait disturbances and hypertonia. Behavioral phenotype. Autism spectrum disorders, stereotypies, anxious behavior, and sleep disturbances (difficulty falling asleep and awakening at night) have been observed [van Bon et al 2016]. Microcephaly, intrauterine growth restriction, and/or oligohydramnios may be noted prenatally. Low birth weight (<-2 SD) and microcephaly (<-2 SD) are frequently observed [Courcet et al 2012, Deciphering Developmental Disorders Study Group 2015, Ruaud et al 2015, van Bon et al 2016]. Facial gestalt. During infancy and childhood facial features include prominent ears, deeply set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016]. Feeding problems due to gastrointestinal reflux and difficulties with suck and swallowing occur in the majority of infants. Feeding problems may persist during childhood and adulthood, warranting tube feeding in some affected individuals [van Bon et al 2016]. Seizures. Febrile seizures during infancy are common. About 50% of affected individuals develop epilepsy including atonic attacks, absences, and generalized myoclonic seizures [Courcet et al 2012, Bronicki et al 2015, Ji et al 2015, van Bon et al 2016]. Hypertonia. Generalized hypertonia may already be noted during the first months of life. Gait disturbances. The majority are described as having a broad-based/ataxic gait [Ji et al 2015, van Bon et al 2016]. A stiff gait (possibly related to generalized hypertonia) has also been reported [Ji et al 2015]. Foot anomalies. A combination of mild cutaneous syndactyly of toes 2-4, hallux valgus, and a short fifth toe has been noted in several individuals [van Bon et al 2016]. Other In about half of affected individuals scoliosis, kyphosis, and/or pectus excavatum has been reported. Short stature (<-2 SD) is present in about one third of individuals. Onset may occur prior to birth or later in childhood [Bronicki et al 2015, Ji et al 2015, van Bon et al 2016]. Although no major structural brain anomalies have been reported, brain imaging may reveal enlarged ventricles, myelination delay, brain atrophy, and/or hypoplasia of the corpus callosum. Endocrine problems (hypothyroidism, premature thelarche, and low growth hormone levels) have been reported in a few individuals [Ji et al 2015]. Dental anomalies, including widely spaced teeth, extreme calculus (hardened dental plaque), and supernumerary teeth have also been reported. In a small number of individuals the following congenital defects have been observed: * Heart: aortic valve insufficiency, pulmonary valve abnormality, aortic stenosis and ventricular septal defect * Eye: astigmatism, hypermetropia, early cataract, iris coloboma and retinal detachment Other anomalies (each reported in 1 individual only) include [van Bon et al 2011, Courcet et al 2012, Redin et al 2014, Deciphering Developmental Disorders Study Group 2015, Ji et al 2015, Ruaud et al 2015, van Bon et al 2016]: * Cleft of the soft palate * Breast aplasia * Micropenis * Sacral dimple * Inguinal hernia * Polydactyly * Tibial osteochondrosis * Hearing loss ### Genotype-Phenotype Correlations To date the number of published cases is insufficient to determine whether there is a true genotype-phenotype correlation based on the type of DYRK1A truncation. ### Penetrance Penetrance is likely to be 100% in individuals with a de novo pathogenic variant. Haploinsufficiency of DYRK1A has not been observed in control populations. Expressivity is similar in males and females [van Bon et al 2016]. ### Prevalence In the following three studies, DYRK1A-related intellectual disability syndrome accounted for 0.1%-0.5% of individuals with intellectual disability and/or autism. * In 1,133 children with developmental disorders, six individuals with a DYRK1A pathogenic variant were identified [Deciphering Developmental Disorders Study Group 2015]. * In 7,162 individuals with developmental delay and/or autism spectrum disorder, eight individuals with a DYRK1A pathogenic variant were identified [O'Roak et al 2012, van Bon et al 2016]. * In 105 individuals with intellectual disability and at least two of the following – microcephaly, ataxic gait, and seizures – one individual with a DYRK1A pathogenic variant was identified [Courcet et al 2012]. ## Differential Diagnosis Developmental delay, neonatal feeding problems, and microcephaly, the most frequent findings in the DYRK1A-related intellectual disability syndrome, have an extensive differential diagnosis. Diagnoses that may be considered in individuals with findings suggestive of DYRK1A-related intellectual disability syndrome include: * Primary autosomal recessive microcephalies, a heterogeneous set of disorders. Onset of microcephaly before birth and short stature are common. In DYRK1A-related intellectual disability syndrome, microcephaly often develops before birth or in the first months after birth and intrauterine growth restriction is variable. The occurrence of additional findings should distinguish this syndrome from other disorders in which primary microcephaly occurs. (See ASPM Primary Microcephaly.) * Angelman syndrome. Microcephaly, seizures, and absence of speech are common in Angelman syndrome; however, the microcephaly in DYRK1A-related intellectual disability syndrome appears more severe than in Angelman syndrome [Courcet et al 2012]. In addition, in DYRK1A-related intellectual disability syndrome the EEG does not have a specific pattern like that observed in Angelman syndrome [Courcet et al 2012], and the facial gestalt and behavior differ. * MECP2 related disorders. Overlapping features may include speech impairment, epilepsy, microcephaly, growth retardation, stereotypic behavior, and feeding difficulties. Developmental regression is observed in classic Rett syndrome, but not in DYRK1A-related intellectual disability syndrome. * Mowat-Wilson syndrome (MWS). Similar to individuals with DYRK1A-related intellectual disability syndrome, individuals with MWS may present with moderate to severe intellectual disability, severe speech impairment, growth retardation with microcephaly, and seizures. MWS is more likely to be associated with a variety of malformations including Hirschsprung disease and genitourinary anomalies, which are not typically observed in DYRK1A-related intellectual disability syndrome. * Pitt-Hopkins syndrome. Features observed in both disorders include a similar level of intellectual disability, lack of speech, and seizures. Microcephaly may develop postnatally in Pitt-Hopkins syndrome. Episodic hyperventilation and/or breath-holding are not features of DYRK1A-related intellectual disability syndrome. * MBD5 haploinsufficiency syndrome may result in intellectual disability with severe language impairment, autism spectrum disorder, and seizures. Microcephaly is mainly noted in individuals with MBD5 haploinsufficiency due to larger 2q23.1 deletions including nearby genes. See Mental retardation, autosomal dominant – OMIM Phenotypic Series to view genes associated with this phenotype in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of the disease and needs in an individual diagnosed with DYRK1A-related intellectual disability syndrome, the following evaluations are recommended: * Multidisciplinary developmental evaluation including speech/language evaluation focused on nonverbal language ability and related educational and teaching strategies * Sleep history and sleep evaluation if necessary * Feeding assessment in infants and young children to detect gastroesophageal reflux or suck/swallowing problems * Neurologic evaluation including brain imaging studies and EEG in individuals with microcephaly and/or seizures * Musculoskeletal examination for signs of hypertonia and spine curvature anomalies; orthopedic referral if needed * Physical therapy evaluation regarding interventions needed to achieve optimal ambulation * The following baseline evaluations: * Endocrine * Dental * Cardiac (for possible heart anomalies including valve, aorta and septal defects) * Ophthalmology * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Treatment includes the following: * Ongoing routine medical care by a pediatrician or other primary care physician * Educational programs to address the specific needs identified; speech therapy directed at improving communication skills; introduction of sign language and augmentative communication aids such as picture cards, communication boards and/or computer touch screens as early as possible * Therapeutic management of sleep disturbances if necessary * Early intervention with occupational therapy for feeding problems; consideration of tube feeding for severe persisting feeding problems * Epilepsy treatment in accordance with standard practice under care of a neurologist * Early intervention with physical therapy for hypertonic musculature and gait disturbances. A wheeled walker may be useful for children with serious gait disturbances. * Standard treatment for orthopedic, endocrine, dental, cardiac, ophthalmologic, and other medical issues ### Surveillance The following are appropriate: * Monitoring and guidance as needed for educational and behavior problems * Regular lifelong dietary evaluation to assure optimal nutritional status * Monitoring for complications of hypertonic musculature such as scoliosis and the development of a stiff gait * Regular lifelong evaluations of the following: * Teeth: frequency determined by a dentist, based on the dental condition * Heart: based on the type of congenital anomaly. If no congenital cardiac anomaly is present, ongoing cardiac surveillance is not needed. * Eyes ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DYRK1A-Related Intellectual Disability Syndrome	None	5,207	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK333438/	2021-01-18T21:31:17	{"synonyms": []}
KCNQ2-related epileptic encephalopathy is a severe form of neonatal epilepsy that usually manifests in newborns during the first week of life with seizures (that affect alternatively both sides of the body), often accompanied by clonic jerking or more complex motor behavior, as well as signs of encephalopathy such as diffuse hypotonia, limb spasticity, lack of visual fixation and tracking and mild to moderate intellectual deficiency. The severity can range from controlled to intractable seizures and mild/moderate to severe intellectual disability. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	KCNQ2-related epileptic encephalopathy	c3150986	5,208	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=439218	2021-01-23T18:34:41	{"omim": ["613720"], "icd-10": ["G40.4"], "synonyms": ["KCNQ2-NEE", "KCNQ2-related neonatal epileptic encephalopathy"]}
Pyruvate dehydrogenase E1-beta deficiency is an extremely rare form of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by severe lactic acidosis, developmental delay and hypotonia. ## Epidemiology Prevalence is unknown. About 8 cases have been reported to date. ## Clinical description Patients presented with lactic acidosis and hypotonia at birth and were often from consanguineous families. There are no specific clinical features that distinguish this condition from pyruvate dehydrogenase E1-alpha deficiency. ## Etiology The disorder is caused by mutations in the gene coding for the E1-beta subunit of the PDH complex (PDHB; 3p21.1-p14.2). ## Genetic counseling The pattern of inheritance is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pyruvate dehydrogenase E1-beta deficiency	c3279841	5,209	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=255138	2021-01-23T17:20:04	{"mesh": ["C566729"], "omim": ["614111"], "umls": ["C3279841"], "icd-10": ["E74.4"], "synonyms": ["PDHBD", "Pyruvate dehydrogenase complex E1 component subunit beta deficiency"]}
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-70 (EIEE70) is caused by heterozygous mutation in the PHACTR1 gene (608723) on chromosome 6p24. For a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Clinical Features De Ligt et al. (2012) reported a 28-year-old woman with EIEE70. She had her first seizures at 3 weeks of age and thereafter showed severely delayed psychomotor development. She learned to sit and could speak a few words, but later lost these skills. Epilepsy could be relatively controlled with medication. As an adult, she had low normal height, small head circumference (-2.5 SD), spastic tetraparesis with joint contractures, and scoliosis. Hamada et al. (2018) reported 2 unrelated Japanese children, aged 4 and 5 years, with EIEE70. They presented with seizures in the first months of life and also showed global developmental delay. EEG showed hypsarrhythmia in both. One patient was more severely affected, with poor seizure response to medication and no head control. Brain imaging showed cortical atrophy and delayed myelination. He also had cryptorchidism. The other patient had favorable seizure response to ACTH and normal brain imaging; he walked at 18 months and had a few words at 24 months. He was diagnosed with autism spectrum disorder. This patient had mild dysmorphic facial features. Molecular Genetics In a 28-year-old woman (trio 90) with EIEE70, de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the PHACTR1 gene (R521C; 608723.0001). The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. In 2 unrelated patients with EIEE70, Hamada et al. (2018) identified de novo heterozygous missense mutations in the PHACTR1 gene (L500P, 608723.0002 and N479I, 608723.0003). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that these mutations interrupted actin binding, whereas R521C interrupted PP1 (see 176875) binding. The mutations were unable to rescue the neuronal migration defects in Phactr1-null mice (see ANIMAL MODEL), suggesting that they are pathogenic. In addition, expression of the mutations in mice induced migration defects and caused abnormal cortical architecture in a dominant-negative manner. Animal Model Hamada et al. (2018) found that knockdown of the Phactr1 gene in embryonic mouse brain resulted in neuronal migration defects and abnormal cortical architecture. INHERITANCE \- Autosomal dominant GROWTH Height \- Low normal height HEAD & NECK Head \- Small head circumference Face \- Dysmorphic facial features, mild (in some patients) Ears \- Low-set ears Eyes \- Hypertelorism \- Short eyebrows Mouth \- Small mouth GENITOURINARY External Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint contractures (1 patient) Spine \- Scoliosis (1 patient) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Global developmental delay \- Poor head control \- Delayed or absent walking \- Impaired intellectual development \- Poor or absent speech \- Seizures, refractory \- Hypsarrhythmia seen on EEG \- Spastic tetraparesis (1 patient) \- Abnormal brain imaging (in some patients) \- Enlarged ventricles \- Cortical atrophy \- Decreased white matter \- Delayed myelination Behavioral Psychiatric Manifestations \- Autistic features MISCELLANEOUS \- Onset in first months of life \- De novo mutation \- Variable severity \- Three unrelated patients have been reported (last curated January 2019) MOLECULAR BASIS \- Caused by mutation in the phosphatase and actin regulator 1 gene (PHACTR1, 608723.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 70	c0037769	5,210	omim	https://www.omim.org/entry/618298	2019-09-22T15:42:43	{"mesh": ["D013036"], "omim": ["618298"], "orphanet": ["3451"]}
Frontal fibrosing alopecia (FFA) is a form of lichen planopilaris that is characterized primarily by slowly progressive hair loss (alopecia) and scarring on the scalp near the forehead. In some cases, the eyebrows, eye lashes and/or other parts of the body may be involved, as well. Although it has been suggested that FFA may be due to hormonal changes or an autoimmune response, the exact cause of this condition is not yet known. There is currently no cure for FFA; however, treatment with certain types of medications may stop or slow hair loss in some cases. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Frontal fibrosing alopecia	c1274700	5,211	gard	https://rarediseases.info.nih.gov/diseases/10886/frontal-fibrosing-alopecia	2021-01-18T18:00:25	{"orphanet": ["254492"], "synonyms": ["FFA"]}
A number sign (#) is used with this entry because of evidence that nephronophthisis-20 (NPHP20) is caused by homozygous or compound heterozygous mutation in the MAPKBP1 gene (616786) on chromosome 15q15. Description Nephronophthisis-20 is an autosomal recessive tubulointerstitial nephritis characterized by progressive renal fibrosis resulting in end-stage renal failure. The age at onset is relatively late compared to other forms of NPHP, and patients develop end-stage renal disease in the second or third decades. Unlike most other forms of NPHP, NPHP20 does not have features of a ciliopathy and patients do not appear to have extrarenal manifestations (summary by Macia et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Macia et al. (2017) reported 8 patients from 5 unrelated families with NPHP20. The families were of various ethnic origins, including Norwegian, Turkish, Portuguese, and Italian: 4 of the families were consanguineous. The severity was variable: 5 patients from 3 families developed end-stage renal disease between 12 and 25 years of age, including 4 who underwent renal transplant, whereas 3 patients from the other 2 families did not have end-stage renal disease in their twenties. Renal biopsies and ultrasounds showed classic features of NPHP, including atrophic tubules with thickening of the basement membranes, massive interstitial fibrosis, interstitial infiltrates, and cysts. None of the patients had extrarenal manifestations or evidence of a ciliopathy, such as situs inversus or polydactyly. Some had variable additional features, including scoliosis, short stature, or facial dysmorphism, but it was unclear whether these were part of the NPHP20 phenotype. One patient had retinitis pigmentosa (RP43; 613810) associated with a known pathogenic RP mutation in the PDE6A gene (V685M; 180071.0004). Inheritance The transmission pattern of NPHP20 in the families reported by Macia et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 8 patients from 5 unrelated families with NPHP20, Macia et al. (2017) identified compound heterozygous or homozygous mutations in the MAPKBP1 gene (616786.0001-616786.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients were ascertained from a cohort of 141 NPHP families who underwent whole-exome sequencing. In vitro studies in various ciliated cells showed that MAPKBP1 did not associate with the cilia or centrosomes/basal bodies, and patient cells showed normal ciliary numbers, formation, and length. MAPKBP1 immunostaining at mitotic spindle poles was severely decreased in cells derived from 3 probands compared to controls. Transfection of the mutations into HeLa cells showed that all except the R544Q variant (616786.0004) impaired recruitment of MAPKBP1 to the spindle pole. Most of the variants, except R544Q, had decreased interaction with WDR62 (613583) and JNK2 (602896), although overall JNK signaling did not show significant changes from normal. All mutant fibroblasts, a kidney sample from 1 patient, and Mapkbp1-null murine cells showed evidence of an increased DNA damage response, with increased levels of nuclear gamma-phosphorylated H2AFX (601772) compared to controls. Animal Model Macia et al. (2017) found that Mapkbp1-null mice and zebrafish did not show any classic ciliopathy-associated phenotypes such as situs inversus, polydactyly (in the mouse), curved body axis (in the fish), or renal cysts. Only 1 of 8 mutant zebrafish showed dilated renal tubules associated with fibrosis. INHERITANCE \- Autosomal recessive GENITOURINARY Kidneys \- Nephronophthisis \- Renal failure \- End-stage renal disease \- Atrophic renal tubules \- Thickening of the basement membrane \- Interstitial fibrosis \- Interstitial infiltrates \- Renal cysts MISCELLANEOUS \- Onset in first decade \- Progressive disorder \- Variable severity \- Onset of end-stage renal disease occurs in second or third decade \- Patients do not have extra-renal manifestations MOLECULAR BASIS \- Caused by mutation in the mitogen-activated protein kinase-binding protein 1 gene (MAPKBP1, 616786.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEPHRONOPHTHISIS 20	c0687120	5,212	omim	https://www.omim.org/entry/617271	2019-09-22T15:46:21	{"doid": ["0111127"], "omim": ["617271"], "orphanet": ["655", "93589"]}
Autosomal dominant tubulointerstitial kidney disease due to MUC1 mutations (ADTKD-MUC1) is an inherited disorder that causes a gradual loss of kidney function. This may lead to the need for dialysis or kidney transplant usually between the ages of 30 and 70. This condition is not associated with any symptoms outside of the kidney. ADTKD-MUC1 is caused by a mistake (mutation) in the MUC1 gene that leads to production of an abnormal mucin 1 protein, which deposits in the kidney and leads to slow loss of kidney function ADTKD-MUC1 is inherited in families in an autosomal dominant pattern. It is diagnosed based on laboratory testing, family history and genetic testing. Kidney failure may be treated with dialysis and kidney transplant. ADTKD-MUC1 is very rare. Some patients may do well for a long time without any symptoms and may not require kidney transplant or dialysis until later in life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Autosomal dominant tubulointerstitial kidney disease due to MUC1 mutations	c1868139	5,213	gard	https://rarediseases.info.nih.gov/diseases/7002/autosomal-dominant-tubulointerstitial-kidney-disease-due-to-muc1-mutations	2021-01-18T18:01:56	{"mesh": ["C536137"], "omim": ["174000"], "umls": ["C1868139"], "orphanet": ["88949"], "synonyms": ["MCKD1", "Medullary cystic kidney disease type 1", "MUC1-related autosomal dominant medullary cystic kidney disease", "MUCI-related ADTKD", "MUC1-related autosomal dominant tubulointerstitial kidney disease", "Medullary cystic kidney disease 1 (former)", "Mucin-1 kidney disease", "ADTKD due to MUC1 mutations", "ADTKD-MUC1", "Autosomal dominant tubulointerstitial kidney disease, MUC1-associated"]}
Goodman et al. (1975) described 2 families in which offspring of unaffected consanguineous parents had a particularly severe form of cleidocranial dysplasia. Spinal anomalies were present and the affected persons were dwarfed. HEENT \- Brachycephaly Growth \- Dwarfism Inheritance \- Severe autosomal recessive form, usually dominant Skel \- Aplasia of clavicles \- Spinal anomalies ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CLEIDOCRANIAL DYSPLASIA, RECESSIVE FORM	c0008928	5,214	omim	https://www.omim.org/entry/216330	2019-09-22T16:29:31	{"doid": ["13994"], "mesh": ["D002973"], "omim": ["216330"], "orphanet": ["1452"]}
Adipomastia Other namesLipomastia, fatty breasts A male with probable comorbid gynecomastia and pseudogynecomastia. SpecialtyPlastic surgery Adipomastia, also known colloquially as fatty breasts,[1] is a condition defined as an excess of skin and adipose tissue in the breasts without true breast glandular tissue.[2][3] It is commonly present in men with obesity, and is particularly apparent in men who have undergone massive weight loss.[4][5] A related/synonymous term is pseudogynecomastia.[6] The condition is different and should be distinguished from gynecomastia ("women's breasts"), which involves true glandular breast development in a male.[6] The two conditions can usually be distinguished easily by palpation to check for the presence of glandular tissue.[5][7] Another difference between the conditions is that breast pain/tenderness does not occur in pseudogynecomastia.[4] Sometimes, gynecomastia and pseudogynecomastia are present together; this is related to the fact that fat tissue expresses aromatase, the enzyme responsible for the synthesis of estrogen, and estrogen is produced to a disproportionate extent in men with excessive amounts of fat, resulting in simultaneous glandular enlargement.[4][8] ## References[edit] 1. ^ Clinical Assistant Professor Brown University Providence Rhode Island Attending Physician Hallette Center for Diabetes Providence Rhode Island Marc J Laufgraben; Marc J. Laufgraben; Geetha Gopalakrishnan (3 June 2013). Tarascon Adult Endocrinology Pocketbook. Jones & Bartlett Publishers. pp. 205–. ISBN 978-1-4496-4857-2. 2. ^ Mark Dennis; William Talbot Bowen; Lucy Cho (31 August 2016). Mechanisms of Clinical Signs - EPub3. Elsevier Health Sciences. pp. 599–. ISBN 978-0-7295-8561-3. 3. ^ William T. O'Donohue; Lorraine T. Benuto; Lauren Woodward Tolle (8 July 2014). Handbook of Adolescent Health Psychology. Springer Science & Business Media. pp. 246–. ISBN 978-1-4614-6633-8. 4. ^ a b c Z. Hochberg (1 January 2007). Practical Algorithms in Pediatric Endocrinology. Karger Medical and Scientific Publishers. pp. 21–. ISBN 978-3-8055-8220-9. 5. ^ a b Seth Thaller; Mimis Cohen (28 February 2013). Cosmetic Surgery After Massive Weight Loss. JP Medical Ltd. pp. 133–. ISBN 978-1-907816-28-4. 6. ^ a b Nihal Thomas (30 April 2016). Clinical Atlas in Endocrinology & Diabetes: A Case-Based Compendium. JP Medical Ltd. pp. 387–. ISBN 978-93-5152-857-9. 7. ^ Eberhard Nieschlag; Hermann Behre (29 June 2013). Andrology: Male Reproductive Health and Dysfunction. Springer Science & Business Media. pp. 232–. ISBN 978-3-662-04491-9. 8. ^ Michael Steven Kappy; David B. Allen (M.D.); Mitchell E. Geffner (2005). Principles and Practice of Pediatric Endocrinology. Charles C Thomas Publisher. pp. 261–. ISBN 978-0-398-07554-5. ## External links[edit] Classification D * v * t * e Breast disease Inflammation * Mastitis * Nonpuerperal mastitis * Subareolar abscess * Granulomatous mastitis Physiological changes and conditions * Benign mammary dysplasia * Duct ectasia of breast * Chronic cystic mastitis * Mammoplasia * Gynecomastia * Adipomastia (lipomastia, pseudogynecomastia) * Breast hypertrophy * Breast atrophy * Micromastia * Amastia * Anisomastia * Breast engorgement Nipple * Nipple discharge * Galactorrhea * Inverted nipple * Cracked nipples * Nipple pigmentation Masses * Galactocele * Breast cyst * Breast hematoma * Breast lump * Pseudoangiomatous stromal hyperplasia Other * Pain * Tension * Ptosis * Fat necrosis * Amazia This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Adipomastia	c4049281	5,215	wikipedia	https://en.wikipedia.org/wiki/Adipomastia	2021-01-18T18:40:17	{"umls": ["C4049281"], "wikidata": ["Q1827380"]}
Genetic disorder characterized by high cholesterol levels Familial hypercholesterolemia Other namesFamilial hypercholesterolaemia Xanthelasma palpebrarum, yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with FH. SpecialtyEndocrinology Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease.The most common mutations diminish the number of functional LDL receptors in the liver.[citation needed] Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH (such as dietary modification and statin tablets). Nevertheless, treatment (including higher statin doses) is usually effective. FH is classified as a type 2 familial dyslipidemia.[1] There are five types of familial dyslipidemia (not including subtypes), and each are classified from both the altered lipid profile and by the genetic abnormality. For example, high LDL (often due to LDL receptor defect) is type 2. Others include defects in chylomicron metabolism, triglyceride metabolism, and metabolism of other cholesterol-containing particles, such as VLDL and IDL. About 1 in 100 to 200 people have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare.[2] People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million people.[3] Heterozygous FH is normally treated with statins, bile acid sequestrants, or other lipid-lowering agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.[3] ## Contents * 1 Signs and symptoms * 1.1 Physical signs * 1.2 Cardiovascular disease * 2 Diagnosis * 2.1 Lipid measurements * 2.2 Mutation analysis * 2.3 Differential diagnosis * 3 Genetics * 3.1 LDL receptor * 3.2 Apolipoprotein B * 3.3 PCSK9 * 3.4 LDLRAP1 * 4 Pathophysiology * 5 Screening * 6 Treatment * 6.1 Heterozygous FH * 6.2 Homozygous FH * 6.3 Children * 7 Epidemiology * 8 History * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] ### Physical signs[edit] High cholesterol levels normally do not cause any symptoms. Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as xanthelasma palpebrarum), the outer margin of the iris (known as arcus senilis corneae), and in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon (known as a tendon xanthoma).[3][4] ### Cardiovascular disease[edit] Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest pain or tightness on exertion) or heart attacks. Less commonly, arteries of the brain are affected; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such as gangrene).[5] Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history of cardiovascular disease.[3][6] ## Diagnosis[edit] Criteria for diagnosis of probable heterozygous FH (98% specificity)[7] 1st degree relative general population age cholesterol mg/dL mmol/L mg/dL mmol/L < 18 total > 220 > 5.7 > 270 > 7.0 LDL-C > 155 > 4.0 > 200 > 5.2 20–29 total > 240 > 6.2 > 290 > 7.5 LDL-C > 170 > 4.4 > 220 > 5.7 30–39 total > 270 > 7.0 > 340 > 8.8 LDL-C > 190 > 5.0 > 240 > 6.2 ≥ 40 total > 290 > 7.5 > 360 > 9.3 LDL-C > 205 > 5.3 > 260 > 6.7 First-degree relatives are parents, offspring, brothers, and sisters Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments.[8] Physical examination findings can help a physician make the diagnosis of FH. Tendon xanthomas are seen in 20-40% of individuals with FH and are pathognomonic for the condition.[8] A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, but are non-specific findings.[8] ### Lipid measurements[edit] Cholesterol levels may be determined as part of health screening for health insurance or occupational health, when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular disease develop, or a family member has been found to have FH. A pattern compatible with hyperlipoproteinemia type IIa on the Fredrickson classification is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of high-density lipoprotein (HDL), and normal level of triglycerides. Total cholesterol levels of 350–550 mg/dL are typical of heterozygous FH while total cholesterol levels of 650–1000 mg/dL are typical of homozygous FH.[8] The LDL is typically above the 75th percentile, that is, 75% of the healthy population would have a lower LDL level.[3] Cholesterol levels can be drastically higher in people with FH who are also obese.[5] ### Mutation analysis[edit] On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and ApoB mutations can be performed. Mutations are detected in between 50 and 80% of cases; those without a mutation often have higher triglyceride levels and may in fact have other causes for their high cholesterol, such as combined hyperlipidemia due to metabolic syndrome.[9] ### Differential diagnosis[edit] FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis. Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities.[10] ## Genetics[edit] The most common genetic defects in FH are LDLR mutations (prevalence 1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in 2500) and LDLRAP1. The related disease sitosterolemia, which has many similarities with FH and also features cholesterol accumulation in tissues, is due to ABCG5 and ABCG8 mutations.[3] ### LDL receptor[edit] LDLR pathway Schematic representation of the LDL receptor protein. The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3).[8] It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR activity of less than 2%, while heterozygotes have defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known.[3] There are five major classes of FH due to LDLR mutations:[11] * Class I: LDLR is not synthesized at all. * Class II: LDLR is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface. * Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R. * Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis (pathway step 2). * Class V: LDLR is not recycled back to the cell surface (pathway step 5). ### Apolipoprotein B[edit] Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is between 21.08 and 21.12 Mb long. FH is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia.[3][12] ### PCSK9[edit] Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report.[3][13] The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells.[14] ### LDLRAP1[edit] Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973.[15] In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. People with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.[3] ## Pathophysiology[edit] Cholesterol is synthesized in the HMG-CoA reductase pathway. Main articles: LDL receptor and atherosclerosis LDL cholesterol normally circulates in the body for 2.5 days, and subsequently the apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion.[8] This process results in the removal of LDL from the circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway.[16] In FH, LDL receptor function is reduced or absent,[8] and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins.[5] In mutations of ApoB, reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known how the mutation causes LDL receptor dysfunction in mutations of PCSK9 and ARH.[3] Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.[3] Some studies of FH cohorts suggest that additional risk factors are generally at play when a person develops atherosclerosis.[17][18] In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the prothrombin gene (G20210A) increases the risk of cardiovascular events in people with FH.[19] Several studies found that a high level of lipoprotein(a) was an additional risk factor for ischemic heart disease.[20][21] The risk was also found to be higher in people with a specific genotype of the angiotensin-converting enzyme (ACE).[22] ## Screening[edit] Screening among family members of people with known FH is cost-effective.[23] Other strategies such as universal screening at the age of 16 were suggested in 2001.[24][25] The latter approach may however be less cost-effective in the short term.[26] Screening at an age lower than 16 was thought likely to lead to an unacceptably high rate of false positives.[5] A 2007 meta-analysis found that "the proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously."[27] "The use of total cholesterol alone may best discriminate between people with and without FH between the ages of 1 to 9 years."[28][27] Screening of toddlers has been suggested, and results of a trial on 10,000 one-year-olds were published in 2016. Work was needed to find whether screening was cost-effective, and acceptable to families.[29][30] ## Treatment[edit] ### Heterozygous FH[edit] FH is usually treated with statins.[8] Statins act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase) in the liver. In response, the liver produces more LDL receptors, which remove circulating LDL from the blood. Statins effectively lower cholesterol and LDL levels, although sometimes add-on therapy with other drugs is required, such as bile acid sequestrants (cholestyramine or colestipol), nicotinic acid preparations or fibrates.[3] Control of other risk factors for cardiovascular disease is required, as risk remains somewhat elevated even when cholesterol levels are controlled. Professional guidelines recommend that the decision to treat a person with FH with statins should not be based on the usual risk prediction tools (such as those derived from the Framingham Heart Study), as they are likely to underestimate the risk of cardiovascular disease; unlike the rest of the population, FH have had high levels of cholesterol since birth, probably increasing their relative risk.[31] Prior to the introduction of the statins, clofibrate (an older fibrate that often caused gallstones), probucol (especially in large xanthomas) and thyroxine were used to reduce LDL cholesterol levels. More controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown.[32] There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH. Rather, evidence of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, a 1999 observational study of a large British registry showed that mortality in people with FH had started to improve in the early 1990s when statins were introduced.[33] A cohort study suggested that treatment of FH with statins leads to a 48% reduction in death from coronary heart disease to a point where people are no more likely to die of coronary heart disease than the general population. However, if the person already had coronary heart disease the reduction was 25%. The results emphasize the importance of early identification of FH and treatment with statins.[34] Alirocumab and evolocumab, both monoclonal antibodies against PCSK9, are specifically indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, who require additional lowering of LDL cholesterol.[35] ### Homozygous FH[edit] Homozygous FH is harder to treat. The LDL(low Density Lipoprotein) receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels.[36] If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis.[3] Very severe cases may be considered for a liver transplant; this provides a liver with normally functional LDL receptors, and leads to rapid improvement of the cholesterol levels, but at the risk of complications from any solid organ transplant (such as rejection, infections, or side-effects of the medication required to suppress rejection).[37][38] Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allow blood with nutrients from the intestine to bypass the liver.[39][40][41] Lomitapide, an inhibitor of the microsomal triglyceride transfer protein,[42] was approved by the US FDA in December 2012 as an orphan drug for the treatment of homozygous familial hypercholesterolemia.[43] In January 2013, The US FDA also approved mipomersen, which inhibits the action of the gene apolipoprotein B, for the treatment of homozygous familial hypercholesterolemia.[44][45] Gene therapy is a possible future alternative.[46] ### Children[edit] Given that FH is present from birth and atherosclerotic changes may begin early in life,[47] it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many physicians prefer to use bile acid sequestrants and fenofibrate as these are licensed in children.[48] Nevertheless, statins seem safe and effective,[49][50] and in older children may be used as in adults.[5][48] An expert panel in 2006 advised on early combination therapy with LDL apheresis, statins, and cholesterol absorption inhibitors in children with homozygous FH at the highest risk.[51] ## Epidemiology[edit] The global prevalence of FH is approximately 10 million people.[8] In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms.[3] Homozygous FH occurs in about 1:1,000,000.[3][5] LDLR mutations are more common in certain populations, presumably because of a genetic phenomenon known as the founder effect—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The Afrikaner, French Canadians, Lebanese Christians, and Finns have high rates of specific mutations that make FH particularly common in these groups. APOB mutations are more common in Central Europe.[3] ## History[edit] The Norwegian physician Dr Carl Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938.[52] In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas. Initially, they found increased activity of HMG-CoA reductase, but studies showed that this did not explain the very abnormal cholesterol levels in people with FH.[53] The focus shifted to the binding of LDL to its receptor, and effects of impaired binding on metabolism; this proved to be the underlying mechanism for FH.[54] Subsequently, numerous mutations in the protein were directly identified by sequencing.[11] They later won the 1985 Nobel Prize in Medicine for their discovery of the LDL receptor and its impact on lipoprotein metabolism.[55] ## See also[edit] * Primary hyperlipoproteinemia * Familial hypertriglyceridemia * Lipoprotein lipase deficiency * Familial apoprotein CII deficiency * Akira Endo, dicoverer of the first statin ## References[edit] 1. ^ Pejic RN (2014). "Familial Hypercholesterolemia". 14 (4). Ochsner Journal. PMID 25598733. Retrieved 27 Sep 2020. 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Retrieved 2008-02-28. ## External links[edit] * MedicinePlus: Familial Hypercholesterolemia Classification D * ICD-10: E78.0 * ICD-10-CM: E78.01 * ICD-9-CM: 272.0 * OMIM: 143890 * MeSH: D006938 * DiseasesDB: 4707 External resources * MedlinePlus: 000392 * eMedicine: med/1072 * v * t * e Inborn error of lipid metabolism: dyslipidemia Hyperlipidemia * Hypercholesterolemia/Hypertriglyceridemia * Lipoprotein lipase deficiency/Type Ia * Familial apoprotein CII deficiency/Type Ib * Familial hypercholesterolemia/Type IIa * Combined hyperlipidemia/Type IIb * Familial dysbetalipoproteinemia/Type III * Familial hypertriglyceridemia/Type IV * Xanthoma/Xanthomatosis Hypolipoproteinemia Hypoalphalipoproteinemia/HDL * Lecithin cholesterol acyltransferase deficiency * Tangier disease Hypobetalipoproteinemia/LDL * Abetalipoproteinemia * Apolipoprotein B deficiency * Chylomicron retention disease Lipodystrophy * Barraquer–Simons syndrome Other * Lipomatosis * Adiposis dolorosa * Lipoid proteinosis * APOA1 familial renal amyloidosis * v * t * e Cell surface receptor deficiencies G protein-coupled receptor (including hormone) Class A * TSHR (Congenital hypothyroidism 1) * LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty) * FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis) * GnRHR (Gonadotropin-releasing hormone insensitivity) * EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2) * AVPR2 (Nephrogenic diabetes insipidus 1) * PTGER2 (Aspirin-induced asthma) Class B * PTH1R (Jansen's metaphyseal chondrodysplasia) Class C * CASR (Familial hypocalciuric hypercalcemia) Class F * FZD4 (Familial exudative vitreoretinopathy 1) Enzyme-linked receptor (including growth factor) RTK * ROR2 (Robinow syndrome) * FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) * FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome) * FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) * INSR (Donohue syndrome * Rabson–Mendenhall syndrome) * NTRK1 (Congenital insensitivity to pain with anhidrosis) * KIT (KIT Piebaldism, Gastrointestinal stromal tumor) STPK * AMHR2 (Persistent Müllerian duct syndrome II) * TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) * TGFBR1/TGFBR2 (Loeys–Dietz syndrome) GC * GUCY2D (Leber's congenital amaurosis 1) JAK-STAT * Type I cytokine receptor: GH (Laron syndrome) * CSF2RA (Surfactant metabolism dysfunction 4) * MPL (Congenital amegakaryocytic thrombocytopenia) TNF receptor * TNFRSF1A (TNF receptor associated periodic syndrome) * TNFRSF13B (Selective immunoglobulin A deficiency 2) * TNFRSF5 (Hyper-IgM syndrome type 3) * TNFRSF13C (CVID4) * TNFRSF13B (CVID2) * TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A) Lipid receptor * LRP: LRP2 (Donnai–Barrow syndrome) * LRP4 (Cenani–Lenz syndactylism) * LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1) * LDLR (LDLR Familial hypercholesterolemia) Other/ungrouped * Immunoglobulin superfamily: AGM3, 6 * Integrin: LAD1 * Glanzmann's thrombasthenia * Junctional epidermolysis bullosa with pyloric atresia EDAR (EDAR hypohidrotic ectodermal dysplasia) * PTCH1 (Nevoid basal-cell carcinoma syndrome) * BMPR1A (BMPR1A juvenile polyposis syndrome) * IL2RG (X-linked severe combined immunodeficiency) See also cell surface receptors [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Familial hypercholesterolemia	c0020445	5,216	wikipedia	https://en.wikipedia.org/wiki/Familial_hypercholesterolemia	2021-01-18T18:32:23	{"gard": ["10416"], "mesh": ["D006938"], "umls": ["C0549399", "C0020445"], "orphanet": ["406"], "wikidata": ["Q2711291"]}
A number sign (#) is used with this entry because dystonia-24 (DYT24) is caused by heterozygous mutation in the ANO3 gene (610110) on chromosome 11p14. Description Dystonia-24 is an autosomal dominant form of focal dystonia affecting the neck, laryngeal muscles, and muscles of the upper limbs (summary by Charlesworth et al., 2012). Clinical Features Munchau et al. (2000) reported a British family in which 5 individuals had craniocervical dystonia. The mean age at onset was 29 years (range, 19 to 40). Another individual was possibly affected. All patients had jerky cervical dystonia; other variable features included blepharospasm, voice tremor, writing tremor, head tremor, and arm tremor. Four had dystonic arm posturing. Charlesworth et al. (2012) reported 3 additional unrelated patients with dystonia. Most patients had adult-onset of cervical dystonia, often with laryngeal involvement and tremor of the upper limb. One patient had onset in the first decade of life, and another had oromandibular dystonia. Inheritance The transmission pattern of dystonia in the family reported by Munchau et al. (2000) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of a British family with autosomal dominant dystonia-24 reported by Munchau et al. (2000), Charlesworth et al. (2012) identified a heterozygous mutation in the ANO3 gene (R494W; 610110.0001). The mutation, which was identified by linkage analysis combined with exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in several large control exome databases. A different heterozygous mutation (W490C; 610110.0002) was subsequently identified in affected members of another family with autosomal dominant cervical dystonia. High-throughput sequencing of this gene in 188 samples yielded 4 additional putative pathogenic variants (see, e.g., 610110.0003-610110.0004). Patient fibroblasts with the W490C mutation showed a defect in endoplasmic reticulum-related calcium handling. Charlesworth et al. (2012) postulated that mutations in the ANO3 gene may lead to abnormal striatal-neuron excitability, manifest as dystonia. Nomenclature Although Charlesworth et al. (2012) referred to this disorder as dystonia-23 (DYT23), that designation had already been used to refer to a dystonia locus on chromosome 9q34 (614860). Thus, dystonia caused by mutation in the ANO3 gene on chromosome 11p14 is referred to here as DYT24. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Head tremor (in some patients) Face \- Oromandibular dystonia (in some patients) Eyes \- Blepharospasm (in some patients) Teeth \- Cervical dystonia RESPIRATORY Larynx \- Laryngeal tremor SKELETAL Limbs \- Dystonic posturing of the upper limb NEUROLOGIC Central Nervous System \- Dystonia, focal \- Tremor of the upper limb \- Head tremor VOICE \- Voice tremor MISCELLANEOUS \- Average age at onset is 24 years (range 4 to 58 years) \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the anoctamin 3 gene (ANO3, 610110.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DYSTONIA 24	c3554374	5,217	omim	https://www.omim.org/entry/615034	2019-09-22T15:53:18	{"doid": ["0090052"], "omim": ["615034"], "orphanet": ["420485"], "synonyms": ["DYT24", "Dystonia 24"]}
Ollier disease is a skeletal disorder characterized by multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop within the bones. These growths may lead to skeletal deformities, limb discrepancy, and fractures. The enchondromas primarily occur in the limb bones, especially the bones of the hands and feet. They tend to develop near the ends of the bones, where growth occurs. Symptoms often appear in the first decade of life. The underlying cause of Ollier disease is not fully understood. In many people, the condition can be attributed to somatic mutations in the IDH1 or IDH2 gene. The disease is not typically inherited. Treatment is conservative in most cases, although surgery may be indicated in cases where complications (pathological fractures, growth defects, malignant transformation) arise. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Ollier disease	c0014084	5,218	gard	https://rarediseases.info.nih.gov/diseases/7251/ollier-disease	2021-01-18T17:58:36	{"mesh": ["D004687"], "omim": ["166000"], "orphanet": ["296"], "synonyms": ["Dyschondroplasia", "Enchondromatosis", "Multiple cartilaginous enchondroses", "Multiple enchondromatosis"]}
Ischemic hepatitis Other namesIschemic hepatopathy , Shock liver Liver(anatomical section) SymptomsMental confusion[1] CausesHeart failure, Infection[2] Diagnostic methodDoppler ultrasound, Blood test[2] TreatmentResuscitation(acute), Stabilize underlining illness(chronic)[3] Ischemic hepatitis, also known as shock liver, is a condition defined as an acute liver injury caused by insufficient blood flow (and consequently insufficient oxygen delivery) to the liver.[4] The decreased blood flow (perfusion) to the liver is usually due to shock or low blood pressure. However, local causes involving the hepatic artery that supplies oxygen to the liver, such as a blood clot in the hepatic artery, can also cause ischemic hepatitis.[medical citation needed] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Mechanism * 4 Diagnosis * 4.1 Related conditions * 5 Treatment * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] People who develop ischemic hepatitis may have weakness, fatigue, mental confusion, and low urine production (oliguria). A small percentage of affected people may develop hepatic coma. Yellow discoloration of the skin (jaundice) can occur, but is rare and temporary, as is actual loss of function of the liver.[1] ## Cause[edit] Arrhythmia (ventricular fibrillation) Ischemic hepatitis can be caused by a number of reasons (that lead to low blood pressure) including:[2] * Abnormal heart rhythm * Heart failure * Infection * Hypovolemic shock (e.g., due to profuse bleeding) * Blood clots (hepatic artery after surgery) ## Mechanism[edit] The mechanism of ischemic hepatitis depends on the etiopathogenetic origin, be it a cardiomyopathy, cardiac tamponade, trauma, or bleeding.[5] Usually ischemic hepatitis reveals itself after a hypotensive event with increased levels of aminotransferases.[6] Because of this, hypotension is thought to be one of the primary insults leading to ischemic hepatitis.[7] ## Diagnosis[edit] Congestive hepatopathy Blood testing usually shows high levels of the liver transaminase enzymes, AST and ALT, which may exceed 10,000 U/L.[8] It has been found that those who suffer from ischemic hepatitis had significant cardiac disease as well.[9] As a measure of precaution, paracetamol levels and a toxicology screening should be completed to evaluate for possible toxin-mediated injury; it is also imperative to be able to exclude the possibility of acute viral hepatitis.[10] ### Related conditions[edit] Ischemic hepatitis is related to another condition called congestive hepatopathy. Congestive hepatopathy includes a number of liver disorders that occur in right-sided heart failure. The medical term congestive hepatopathy is used, however, the term cardiac cirrhosis is convention. These two entities can coexist in an affected individual.[11] ## Treatment[edit] The treatment of ischemic hepatitis is as follows:[12] * Antibiotic treatment if a bacterial infection causing septic shock is present * Restore and maintain adequate blood pressure * Medication * Control any gastrointestinal bleeding ## See also[edit] * Elevated transaminases ## References[edit] 1. ^ a b Liver: A Complete Book on Hepato-Pancreato-Biliary Diseases. Elsevier India. 2009-01-01. ISBN 9788131216743. 2. ^ a b c "Hepatic ischemia: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-08-24. 3. ^ Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 726. ISBN 9780323529570. Retrieved 2 January 2018. 4. ^ Dancygier, Henryk (2009-11-10). Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases. Springer Science & Business Media. ISBN 9783642045196. 5. ^ Sibal, Anupam; Gopalan, Sarath (2015-04-30). Textbook of Pediatric Gastroenterology, Hepatology and Nutrition. JP Medical Ltd. ISBN 9789351527404. 6. ^ Lang, Florian (2009-03-19). Encyclopedia of Molecular Mechanisms of Disease: With 213 Tables. Springer Science & Business Media. ISBN 9783540671367. 7. ^ Feldman, Mark; Friedman, Lawrence S.; Brandt, Lawrence J. (2010-05-03). Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, Expert Consult Premium Edition - Enhanced Online Features. Elsevier Health Sciences. ISBN 978-1437727678. 8. ^ Raurich JM, Pérez O, Llompart-Pou JA, Ibáñez J, Ayestarán I, Pérez-Bárcena J (July 2009). "Incidence and outcome of ischemic hepatitis complicating septic shock". Hepatol. Res. 39 (7): 700–5. doi:10.1111/j.1872-034X.2009.00501.x. PMID 19473435. 9. ^ Boyer, Thomas D.; Manns, Michael Peter; Sanyal, Arun J.; Zakim, David (2012-01-01). Zakim and Boyer's Hepatology: A Textbook of Liver Disease. Elsevier Health Sciences. ISBN 978-1437708813. 10. ^ Plevris, John; Howden, Colin (2012-04-05). Problem-based Approach to Gastroenterology and Hepatology. John Wiley & Sons. ISBN 9781444346367. 11. ^ "Cardiac Cirrhosis and Congestive Hepatopathy: Background, Pathophysiology, Epidemiology". 2018-06-28. Cite journal requires `\|journal=` (help) 12. ^ Wilson, William C.; Grande, Christopher M.; Hoyt, David B. (2007-02-05). Trauma: Critical Care. CRC Press. ISBN 9781420016840. ## Further reading[edit] * Kirk, Allan D.; Knechtle, Stuart J.; Larsen, Christian P.; Madsen, Joren C.; Pearson, Thomas C.; Webber, Steven A. (2014-07-21). Textbook of Organ Transplantation Set. John Wiley & Sons. ISBN 9781118889626. * Irwin, Richard S.; Rippe, James M. (2012-03-28). Manual of Intensive Care Medicine. Lippincott Williams & Wilkins. ISBN 9781451149074. ## External links[edit] Classification D * ICD-10: K72.0 External resources * MedlinePlus: 000214 Scholia has a topic profile for Ischemic hepatitis. * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical 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View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Ischemic hepatitis	c0473117	5,219	wikipedia	https://en.wikipedia.org/wiki/Ischemic_hepatitis	2021-01-18T18:32:55	{"umls": ["C0473117"], "icd-10": ["K72.0"], "wikidata": ["Q6079228"]}
A number sign (#) is used with this entry because of evidence that severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-3 (FGFR3; 134934) on chromosome 4p16. Clinical Features Tavormina et al. (1999) reported 4 unrelated individuals with a distinctive syndrome comprising severe achondroplasia with developmental delay and acanthosis nigricans, which they referred to as SADDAN dysplasia. Two of the patients had previously been reported in an abstract (Francomano et al., 1996). The severity approached that observed in thanatophoric dysplasia type I (TD1; 187600). Differences included the development of extensive areas of acanthosis nigricans beginning in early childhood in 3 of 4 patients, severe neurologic impairments, and survival past infancy without prolonged life-support measures. Bellus et al. (1999) described in detail the clinical and radiographic features of these patients. Zankl et al. (2008) reported a patient with the SADDAN phenotype. He had severe micromelia, frontal bossing, large anterior fontanel, depressed nasal bridge, reverse tibial bowing, small thorax, and hypotonia. Acanthosis nigricans was not present. He died at age 21 days due to respiratory failure. Zankl et al. (2008) noted that about half of patients reported with the K650M mutation died before 21 days of age, whereas others have shown longer survival. The authors also noted that acanthosis nigricans has been reported in patients with other skeletal dysplasias due to FGFR3 mutations, and thus should be considered a long-term complication rather than a specific feature of SADDAN. In addition, mental retardation only becomes apparent in long-term survivors and thus cannot be used as a diagnostic criterion for SADDAN in the neonatal period. Molecular Genetics In 4 unrelated patients with SADDAN dysplasia, Tavormina et al. (1999) identified a heterozygous mutation in the FGFR3 gene (K650M; 134934.0015), resulting in a dramatic increase in constitutive receptor kinase activity. In a patient with SADDAN dysplasia, Zankl et al. (2008) identified heterozygosity for the K650M mutation in the FGFR3 gene. Animal Model Iwata et al. (2001) introduced the murine equivalent (K644M) of the human SADDAN point mutation (K650M; 134934.0015) into the mouse Fgfr3 gene. Heterozygous mutant mice showed a phenotype similar to human SADDAN, e.g., the majority of the SADDAN mice survived the perinatal period. The long bone abnormalities in SADDAN mice were milder than the TDII model. In addition, overgrowth of the cartilaginous tissues was observed in the rib cartilage, trachea, and nasal septum. Unlike the TDII model, FGF ligands at low concentrations differentially activated Map kinase in primary chondrocyte cultures from wildtype and SADDAN mice. INHERITANCE \- Autosomal dominant GROWTH Height \- Dwarfism \- Short stature, severe disproportionate HEAD & NECK Head \- Megalencephaly \- Large anterior fontanel Face \- Midface hypoplasia \- Frontal bossing Ears \- Hearing loss, mild-to-moderate \- Otitis media Eyes \- Exotropia (in some patients) \- High myopia (in some patients) Nose \- Depressed nasal bridge CARDIOVASCULAR Heart \- Congestive heart failure (in some patients) Vascular \- Pulmonary hypertension (in some patients) RESPIRATORY \- Respiratory compromise at birth \- Sleep apnea CHEST External Features \- Small chest with flaring costal margins ABDOMEN Gastrointestinal \- Gastroesophageal reflux (in some patients) SKELETAL Skull \- Overgrowth of mandible in adults \- Pneumatization of the sinuses Spine \- Platyspondyly \- Kyphosis \- Lumbar lordosis \- Cervical spinal stenosis Pelvis \- Posterior rotation of hips Limbs \- Rhizomelia \- Mesomelia \- Anterior bowing of femora \- Posterior bowing of tibiae SKIN, NAILS, & HAIR Skin \- Redundant skin folds on upper and lower limbs \- Acanthosis nigricans NEUROLOGIC Central Nervous System \- Seizures \- Hydrocephalus \- Central apnea \- Developmental delay \- Limited language acquisition \- Mental retardation, moderate to profound \- Thin corpus callosum MISCELLANEOUS \- Clinical overlap with thanatophoric dysplasia I ( 187600 ) and severe achondroplasia ( 100800 ) MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor receptor-3 gene (FGFR3, 134934.0015 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ACHONDROPLASIA, SEVERE, WITH DEVELOPMENTAL DELAY AND ACANTHOSIS NIGRICANS	c2674173	5,220	omim	https://www.omim.org/entry/616482	2019-09-22T15:48:47	{"doid": ["0111158"], "mesh": ["D000130"], "omim": ["616482"], "orphanet": ["85165"], "synonyms": ["Alternative titles", "SADDAN DYSPLASIA"]}
Radium jaw or radium necrosis is a historic occupational disease brought on by the ingestion and subsequent absorption of radium into the bones of radium dial painters.[1][2] It also affected those consuming radium-laden patent medicines. The symptoms are necrosis of the mandible (lower jawbone) and the maxilla (upper jaw), constant bleeding of the gums, and (usually) after some time, severe distortion due to bone tumors and porosity of the lower jaw. The condition is similar to phossy jaw, an osteoporotic and osteonecrotic illness of matchgirls, brought on by phosphorus ingestion and absorption. The first written reference to the disease was by a dentist, Dr. Theodor Blum, in 1924, who described an unusual mandibular osteomyelitis in a dial painter, naming it "radium jaw".[3] The disease was determined by pathologist Dr. H.S. Martland in 1924 to be symptomatic of radium paint ingestion, after many female workers from various radium paint companies reported similar dental and mandibular pain. Symptoms were present in the mouth due to use of the lips and tongue to keep the radium-paint paintbrushes properly shaped. The disease was the main reason for litigation against the United States Radium Corporation by the Radium Girls. Another prominent example of this condition was the death of American golfer and industrialist Eben Byers in 1932, after taking large doses of Radithor, a radioactive patent medicine containing radium, over several years. His illness garnered much publicity, and brought the problem of radioactive quack medicines into the public eye. The Wall Street Journal ran a story (in 1989 or after) titled "The Radium Water Worked Fine until His Jaw Came Off".[4] ## See also[edit] * Acute radiation syndrome (not involved in radium jaw) * Radium Dial Company * Radium dials ## References[edit] 1. ^ Grady, Denise (October 6, 1998), "A Glow in the Dark, and a Lesson in Scientific Peril", New York Times, retrieved 2019-06-13 2. ^ Orci, Taylor (March 7, 2013), "How We Realized Putting Radium in Everything Was Not the Answer", The Atlantic, retrieved 2019-06-13 3. ^ Blum, Theodor (1924). "Osteomyelitis of the Mandible and Maxilla". The Journal of the American Dental Association. 11 (9): 802–805. doi:10.14219/jada.archive.1924.0111. ISSN 1048-6364. 4. ^ http://www.case.edu/affil/MeMA/MCA/11-20/1991-Nov.pdf Medical Collectors Association, Newsletter No. 20, page 18 ## External links[edit] * Radium in Humans: A Review of U.S. Studies [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Radium jaw	None	5,221	wikipedia	https://en.wikipedia.org/wiki/Radium_jaw	2021-01-18T19:08:22	{"wikidata": ["Q7281381"]}
Psychogenic pain Other namesPsychalgia[1] SpecialtyPsychiatry Psychogenic pain is physical pain that is caused, increased, or prolonged by mental, emotional, or behavioral factors.[2][3][4] Headache, back pain, or stomach pain are some of the most common types of psychogenic pain.[2] It may occur, rarely, in persons with a mental disorder, but more commonly it accompanies or is induced by social rejection, broken heart, grief, lovesickness, or other such emotional events. Sufferers are often stigmatized, because both medical professionals and the general public tend to think that pain from psychological source is not "real". The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (emphasis added). In the note accompanying that definition, the following can be found about pain that happens for psychological reasons:[5] > Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is usually no way to distinguish their experience from that due to tissue damage if we take the subjective report. If they regard their experience as pain and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. Medicine refers also to psychogenic pain or psychalgia as a form of chronic pain under the name of persistent somatoform pain disorder[6] or functional pain syndrome.[7] Causes may be linked to stress, unexpressed emotional conflicts, psychosocial problems, or various mental disorders. Some specialists believe that psychogenic chronic pain exists as a protective distraction to keep dangerous repressed emotions such as anger or rage unconscious.[8] It remains controversial, however, that chronic pain might arise purely from emotional causes.[9] ## See also[edit] * Pain disorder * Psychogenic disease * Psychological trauma * Psychoneuroimmunology * Psychosomatic medicine * Tension myositis syndrome ## References[edit] 1. ^ Psychalgia - Physical pain that is possibly of psychological origin. American Heritage Medical Dictionary. But see also psychalgia in the sense of psychological pain. 2. ^ a b "Psychogenic & Psychological Pain&". Cleveland Clinic. 3. ^ "Psychogenic pain". Biology-Online Dictionary. 4. ^ Merskey and Spear defined psychogenic pain as "... pain which is independent of peripheral stimulation or of damage to the nervous system and due to emotional factors, or else pain in which any peripheral change (e.f. muscle tension) is a consequence of emotional factors." Merskey, H., Spear F.G. (1967). Pain, psychological and psychiatric aspects. London. Bailliere, Tindall & Cassell. ISBN 0-7020-0006-X 5. ^ IASP Pain Terminology 6. ^ "ICD-10 Version:2010". 7. ^ http://www.iasp-pain.org/AM/Template.cfm?Section=IASP_Press_Books2&Template=/CM/HTMLDisplay.cfm&ContentID=10116 Archived 2011-08-22 at the Wayback Machine 8. ^ Sarno, John E., MD, et al., The Divided Mind: The Epidemic of Mindbody Disorders 2006 (ISBN 0-06-085178-3) 9. ^ Stephen Tyrer, Psychosomatic pain, The British Journal of Psychiatry (2006) 188: 91-93 ## External links[edit] Classification D * ICD-10: F45.4 * ICD-9-CM: 307.8 External resources * MedlinePlus: 000922 * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Psychogenic pain	c0152174	5,222	wikipedia	https://en.wikipedia.org/wiki/Psychogenic_pain	2021-01-18T18:41:40	{"icd-9": ["307.8"], "icd-10": ["F45.4"], "wikidata": ["Q695954"]}
A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-16 (LCA16) is caused by homozygous mutation in the KCNJ13 gene (603208) on chromosome 2q37. For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000). Clinical Features Sergouniotis et al. (2011) studied a consanguineous Middle Eastern family in which 2 brothers had nystagmus at birth and were diagnosed with Leber congenital amaurosis shortly thereafter. Poor night vision and difficulty reading print from an early age was reported for both patients; gradual progression of visual problems affecting central and peripheral vision was also noted. Both patients had bilateral cataract surgery in their third decade. Funduscopy revealed significant pigment in the retinal pigment epithelium (RPE), in a configuration unlike that of typical retinitis pigmentosa (see 268000). There was no other family history of retinal disease. Sergouniotis et al. (2011) also studied a 33-year-old man of European descent who was noted to have strabismus, nystagmus, and poor vision before 1 year of age and was diagnosed with LCA at age 2 years. Only mild progression was reported, with night vision having most noticeably deteriorated. He was moderately myopic and underwent bilateral cataract surgery in his early twenties. Examination showed bilateral nystagmus and severe field loss with relative preservation of the inferior field. Funduscopy revealed areas of nummular pigment in the RPE, especially over the posterior pole. In vivo cross-sectional imaging by spectral domain optical coherence tomography (SD-OCT) revealed loss of outer retinal structures, thinning of the hyperreflective band corresponding to RPE/Bruch membrane, and a coarse lamination pattern. Noting the distorted retinal microanatomy in an area of the fundus in which cell death was not evident, Sergouniotis et al. (2011) suggested that this might represent disturbance of the early development of the neurosensory retina. Khan et al. (2015) reported 2 unrelated Saudi Arabian probands with vitreoretinal dystrophy and early-onset cataract. Both patients exhibited fine pendular nystagmus, and their retinas had an unusual dystrophic appearance, with fibrosis over the disc into the posterior vitreous, deep clumped pigmentation in the posterior pole, and relative sparing of the periphery. Electroretinography (ERG) in both revealed severe cone-rod dysfunction, with no recordable cone function and only minimally delayed and depressed scotopic readings recordable. The first proband was a 12-year-old girl who had poor vision and nystagmus noted soon after birth, with worse vision at night. Examination showed photophobia, with a best-corrected visual acuity of hand motion in the right eye, in which she had a total white cataract, and 20/100 in the left eye, where there were posterior lenticular changes. At cataract surgery, the anterior capsule was unusually thick and inelastic. The proband had a younger sister with a diagnosis of nonsyndromic congenital retinal dystrophy; examination was difficult due to uncooperativeness, but showed sunken globes with oculodigital sign, photophobia, nystagmus, and small angle esotropia, as well as attenuated vessels and disc pallor. Their first-cousin parents and 2 brothers were unaffected. The second proband was a 33-year-old man from a consanguineous Saudi Arabian family in which he and 3 of his 10 sibs had early childhood-onset retinal dystrophy. The proband, who presented because of recent decreased vision, had a best-corrected visual acuity of 20/400 in both eyes. Visually significant central anterior and posterior cataracts were present bilaterally; visually insignificant bilateral posterior lens opacities had been noted at age 20 years. Khan et al. (2015) stated that the fundus appearance of the 2 probands was remarkably similar to that of the 2 brothers reported by Sergouniotis et al. (2011), and noted that the 2 brothers also developed early adult-onset cataract. Pattnaik et al. (2015) studied a 10-year-old boy of Jordanian descent who presented with a history of night vision difficulties from the age of 2 years and poor central vision at school age. At age 8 years, his best-corrected visual acuity was 20/200 in the right eye and 20/400 in the left eye. Fundus examination revealed RPE mottling in the macula of both eyes, as well as arteriolar attenuation. Examination at age 10 showed that visual acuity had deteriorated to 20/400 on the right and 'count fingers' on the left. Retinal examination confirmed arteriolar abnormalities, pigmentation of the retina in the macular region, and bilateral RPE abnormalities. On OCT, the retina appeared intact; however, SD-OCT revealed degeneration of the outer retina, with only 1 high-contrast band visualized. There were clearly visible areas of hypertrophy in the choroidal structure, and small sub-RPE focal deposits were also present. Mapping In a consanguineous Middle Eastern family with Leber congenital amaurosis, Sergouniotis et al. (2011) performed genomewide homozygosity mapping and identified 4 chromosomal segments, of which the largest was a 45-cM interval between SNPs rs10192834 and rs10199178 on chromosome 2q. Molecular Genetics In a consanguineous Middle Eastern family with Leber congenital amaurosis mapping to chromosome 2q, Sergouniotis et al. (2011) performed targeted exome sequencing of a 38-Mb target region of chromosome 2q and identified homozygosity for a nonsense mutation in the KCNJ13 gene (603208.0002) that segregated with disease in the family. The authors then analyzed the KCNJ13 gene in 132 additional unrelated patients with recessive LCA or childhood-onset retinal dystrophy who were negative for mutation in known LCA genes as well as 201 patients diagnosed with autosomal recessive adult-onset rod/cone dystrophy, and in a 33-year-old man of European descent with a phenotype 'remarkably similar' to that of the Middle Eastern family, they identified homozygosity for a missense mutation in KCNJ13 (603208.0003). In a 12-year-old Saudi Arabian girl with vitreoretinal dystrophy and early-onset cataract, Khan et al. (2015) analyzed 87 early-onset retinal dystrophy-associated genes and identified homozygosity for a missense mutation in the KCNJ13 gene (I120T; 603208.0004). The mutation segregated with disease in the family. Sequencing of KCNJ13 in a 33-year-old Saudi Arabian man with similar ocular findings revealed homozygosity for the same I120T mutation. Because both probands had recordable ERGs, at age 12 and 33 years, respectively, Khan et al. (2015) suggested that 'early-onset vitreoretinal degeneration with early-onset cataract' would be a more appropriate designation than Leber congenital amaurosis. In a 10-year-old boy of Jordanian descent with Leber congenital amaurosis, Pattnaik et al. (2015) analyzed a panel of LCA-associated genes and identified homozygosity for a nonsense mutation in the KCNJ13 gene (W53X; 603208.0005). His unaffected parents were heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus \- Strabismus (in some patients) \- Photophobia \- Poor visual acuity \- Poor night vision \- Loss of visual fields \- Retinal pigmentation \- Attenuated retinal vessels \- Disc pallor \- Fibrosis over disc into posterior vitreous (in some patients) \- Cataract \- Severe cone-rod dysfunction seen on ERG \- No recordable cone function \- Minimally delayed and depressed scotopic responses MOLECULAR BASIS \- Caused by mutation in the potassium inwardly-rectifying channel, subfamily J, member 13 gene (KCNJ13, 603208.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	LEBER CONGENITAL AMAUROSIS 16	c0339527	5,223	omim	https://www.omim.org/entry/614186	2019-09-22T15:56:13	{"doid": ["0110118"], "mesh": ["D057130"], "omim": ["614186"], "orphanet": ["65"], "genereviews": ["NBK531510"]}
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255). Mapping To identify genetic loci associated with adult height, Axenovich et al. (2009) analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young, genetically isolated Dutch population where genetic heterogeneity was expected to be low. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted 3 genomewide significant and additionally at least 4 suggestive loci involved in height. Significant peaks were located at the chromosomal regions 16q24 (STQTL22, 613547; lod = 3.94), 1p32 (STQTL23, 613548; lod = 3.35), and 2p16 (STQTL24; lod = 3.29). The SNP rs1520446 located within the NRXN1 gene (600565) represents the linkage peak on chromosome 2p16. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	STATURE QUANTITATIVE TRAIT LOCUS 24	c3150795	5,224	omim	https://www.omim.org/entry/613549	2019-09-22T15:58:18	{"omim": ["613549"]}
Esthiomene Esthiomene Esthiomene is a medical term referring to elephantiasis of the female genitals.[1][2] In the past the term has also referred to elephantiasis of the male genitalia.[3] Esthiomene is generally the visible result of lymphogranuloma venereum, lymphatic infection by Chlamydia trachomatis. This sexually transmitted infection produces inflammation of the lymphatic channels in the female genitalia, followed by abscesses, fistulae, ulcerations, and fibrosis of the tissues. The tissues swell, sometimes severely, and the genitalia may grow to a massive size.[1] Esthiomene can also be the result of tuberculosis when the infection takes hold in the genitalia,[4] or of cancer or filariasis, infection with parasitic roundworms.[2] The condition is painful and sometimes disabling. People with the condition can experience mental distress from the pain and physical deformation of their genitalia.[1] Masses can become so large they make walking difficult.[2] Treatment of the condition includes treatment of bacterial chlamydial infections with antibiotics such as doxycycline,[1] or treatment of other infections present. Remaining tissue deformity can be treated with surgery such as labiaplasty to reduce the size of hypertrophied labia minora. Goals of surgery include pain relief, restoration of sexual function, and cosmetic improvement.[1] ## References[edit] 1. ^ a b c d e Pai A, Umadevi V, Narayanasamy S. (2012). Esthiomene: An unusual presentation of elephantiasis. International Journal of Case Reports and Images. 3(9):57–59. 2. ^ a b c Nayak, S., et al. (2008). Cerebriform elephantiasis of the vulva following tuberculous lymphadenitis. Indian J Dermatol Venereol Leprol 74:188 3. ^ Eller, J. J. (1952). Esthiomene (elephantiasis of penis and scrotum) due to lymphogranuloma venereum. AMA Arch Derm Syphilol. 65(2):247. 4. ^ Naik, R. P., et al. (1987). Esthiomene resulting from cutaneous tuberculosis of external genitalia. Genitourin Med. 63(2): 133–134. This women's health related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Esthiomene	c0014903	5,225	wikipedia	https://en.wikipedia.org/wiki/Esthiomene	2021-01-18T18:46:07	{"umls": ["C0014903"], "wikidata": ["Q5401338"]}
## Summary ### Clinical characteristics. Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery. ### Diagnosis/testing. The diagnosis of pseudoachondroplasia can be made on the basis of clinical findings and radiographic features. Identification of a heterozygous pathogenic variant in COMP on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. ### Management. Treatment of manifestations: Analgesics for joint pain; osteotomy for lower-limb malalignment; C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; rarely, surgery for scoliosis; attention to and social support for psychosocial issues related to short stature for affected individuals and their families. Prevention of secondary complications: Encourage physical activities that do not cause excessive wear and/or damage to the joints. Surveillance: Regular examinations for evidence of symptomatic lower limb malalignment, kyphoscoliosis, symptomatic joint hypermobility, degenerative joint disease, and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia. Agents/circumstances to avoid: In those with odontoid hypoplasia, extreme neck flexion and extension should be avoided. ### Genetic counseling. Pseudoachondroplasia is inherited in an autosomal dominant manner. Some individuals diagnosed with pseudoachondroplasia have an affected parent; the proportion of pseudoachondroplasia resulting from a de novo pathogenic variant is unknown. Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the pathogenic variant and having pseudoachondroplasia. Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with pseudoachondroplasia may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. Prenatal testing for pregnancies at increased risk for pseudoachondroplasia is possible if the pathogenic variant in the family is known. ## Diagnosis ### Suggestive Findings Pseudoachondroplasia should be suspected in individuals with the following clinical findings and radiographic features. Clinical findings * Normal length at birth * Normal facies * Waddling gait, recognized at the onset of walking * Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature * Moderate brachydactyly * Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles * Mild myopathy reported for some individuals * Restricted extension at the elbows and hips * Valgus, varus, or windswept deformity of the lower limbs * Mild scoliosis * Lumbar lordosis (~50% of affected individuals) * Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals Radiographic features * Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent) * Small capital femoral epiphyses, short femoral necks, and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals * Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones * Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (Figure 1). #### Figure 1. Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia ### Establishing the Diagnosis The diagnosis of pseudoachondroplasia is established in a proband with the above clinical and radiographic features. The diagnosis is ideally confirmed on radiographs obtained in prepubertal individuals. At a minimum, AP views of the hips, knees, hands, and wrists and a lateral view of the spine are required (see Figure 1). Identification of a heterozygous pathogenic variant in COMP by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive. Molecular genetic testing approaches can include a single-gene testing or use of multigene panel: * Single-gene testing. Sequence analysis of COMP detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes COMP and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.(2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Thus, a panel should be chosen that is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in Pseudoachondroplasia View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method COMPSequence analysis 3>99% 4 Gene-targeted deletion/duplication analysis 5Very rare 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Jackson et al [2012] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Mabuchi et al [2003] ## Clinical Characteristics ### Clinical Description Pseudoachondroplasia is characterized by disproportionate short-limb short stature. Intrafamilial and interfamilial variability are observed. Natural history is well documented [Wynne-Davies et al 1986, McKeand et al 1996]. Growth. Affected individuals are generally of normal length at birth. Typically, the growth rate falls below the standard growth curve by approximately age two years. Growth curves for pseudoachondroplasia have been developed [Horton et al 1982]. Mean adult height is 116 cm for females and 120 cm for males [McKeand et al 1996]. Facies. Head size and shape are normal, without dysmorphic features. Gait. Often the presenting feature is a waddling gait, recognized at the onset of walking. Extremities. Pseudoachondroplasia is a short-limb form of dwarfism. Extension at the elbows may be limited, and the elbows and knees may appear large. Scoliosis/lordosis can be observed in childhood and may persist into adulthood. Osteoarthritis of the upper extremities and the spine may occur in early adult life. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery. Odontoid hypoplasia is not a common finding but does sometimes occur. Cervical spine instability can result, but C1-C2 fixation is not generally necessary. ### Genotype-Phenotype Correlations A systematic analysis of the relationship between genotype and phenotype has been performed on 300 reported COMP pathogenic variants resulting in pseudoachondroplasia and/or autosomal dominant multiple epiphyseal dysplasia (MED) [Briggs et al 2014]. The following are correlations from this study. (For repeat and domain structure, see Molecular Genetics, Normal gene product.) * Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the pseudoachondroplasia phenotype. * Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T34 and T35) showed significant association with the MED compared to the pseudoachondroplasia phenotype. * Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T36, T37, and T38) were significantly associated with the pseudoachondroplasia phenotype. * The majority of pathogenic in-frame deletions, insertions, or indels lead to pseudoachondroplasia (n=74; 82%), whereas a smaller proportion cause MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both pseudoachondroplasia and MED [Briggs et al 2014]. Correlations from prior studies: * Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [Mabuchi et al 2003]. * Individuals heterozygous for the common p.Asp473del (often referred to as p.Asp469del) pathogenic variant, present in approximately 30% of affected individuals, have a consistent, typical form of the disorder and are severely short [Mabuchi et al 2003]. In contrast, the insertion of an adjacent Asp (GAC) codon (p.Asp473del [p.Asp469dup]) results in mild MED [Délot et al 1999, Zankl et al 2007, Jackson et al 2012]. * Most type III calcium-binding repeats have both an N- and C-type motif (see Molecular Genetics, Normal gene product). Specific missense variants that result in pseudoachondroplasia (as opposed to MED) affect residues in the C-type motif, whereas missense variants in the N-type motif generally result in MED [Jackson et al 2012]. In-frame deletions are found equally between the N-type and C-type motifs [Jackson et al 2012] and can cause both pseudoachondroplasia and MED. ### Penetrance Penetrance is 100%. ### Nomenclature In the past, four subtypes of pseudoachondroplasia, including dominant and recessive forms, were recognized under the term pseudoachondroplasia. The current classification recognizes a single, dominantly inherited phenotype. Pseudoachondroplasia was referred to as pseudoachondroplastic dysplasia in the old literature. ### Prevalence No firm data on the prevalence of pseudoachondroplasia are available; it is estimated at 1:30,000 (see Genetics Home Reference). ## Differential Diagnosis Multiple epiphyseal dysplasias * Autosomal dominant multiple epiphyseal dysplasia presents early in childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue during long walking. Waddling gait may be present but is less consistent than in pseudoachondroplasia. Adult height is either in the lower range of normal or mildly shortened but in general greater than in pseudoachondroplasia. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints. Arthritis typically develops at an older age and is less severe than in pseudoachondroplasia. The diagnosis of autosomal dominant MED is based on the clinical and radiographic presentation in the proband and other family members. In the initial stage of the disorder, often before the onset of clinical symptoms, radiographs show delayed ossification of the epiphyses of the long tubular bones. With the appearance of the epiphyses, the ossification centers are small with irregular contours, usually most pronounced in the hips and/or knees. The tubular bones may be mildly shortened. The spine is by definition normal, although Schmorl bodies and irregular vertebral end plates may be observed. A pathogenic variant in one of five genes causes autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 10%-20% of all samples analyzed from individuals with clinically confirmed MED, a pathogenic variant cannot be identified in any of these five genes [Zankl et al 2007, Jackson et al 2012]. Jackson et al [2012] reported pathogenic missense variants in COL2A1 in two individuals with suspected MED for whom there were limited clinical data and radiographic images on which to base an unambiguous diagnosis [Jackson et al 2012]. Both pathogenic variants were in exon 50 and resulted in a glycine substitution (Gly1179Arg and Gly1176Val). A recurrent missense variant (Gly1170Ser) in this exon has also been consistently associated with dominant Legg-Calvé-Perthes disease (LCPD) [Liu et al 2005] while other COL2A1 pathogenic variants, such as p.Gly393Ser [Kannu et al 2011] and p.Gly717Ser [Miyamoto et al 2007], have also been associated with LCPD and avascular necrosis of the femoral head. * Autosomal recessive multiple epiphyseal dysplasia (rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have some abnormal finding at birth (e.g., clubfoot, clinodactyly, or rarely, cystic ear swelling) not seen in pseudoachondroplasia. Onset of articular pain is variable but usually occurs in late childhood – typically later in onset and of lower severity than in pseudoachondroplasia. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild or absent. Autosomal recessive MED is diagnosed on clinical and radiographic findings and is caused by biallelic pathogenic variants in SLC26A2 or CANT1 (OMIM 617719). Other forms of spondyloepimetaphyseal dysplasia (SEMD). Many different skeletal dysplasias have abnormalities of the spine, metaphyses, and epiphyses apparent on x-ray. For example, Spranger et al [2005] described a severe form of SEMD with some radiographic similarity to pseudoachondroplasia but without a COMP pathogenic variant. Generally, a complete genetic skeletal survey can distinguish these phenotypes from pseudoachondroplasia. Another resource to help diagnose skeletal dysplasias using radiographic images, dREAMS, is available online (registration or subscription required). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with pseudoachondroplasia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Height measurement and plotting of growth on a disorder-specific growth chart * Evaluation by history and physical examination for skeletal manifestations, ligamentous laxity, and arthritis * "Genetic" skeletal survey including: AP views of the hips, knees, and hands, as well as lateral views of the knees and spine * Evaluation of the cervical vertebrae because of the potentially serious clinical complications associated with cervical spine instability [Shetty et al 2007], which can be assessed by flexion/extension radiographs or cervical spine MRI examination, especially in persons with neurologic symptoms suggestive of cord compression * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations ### Table 2. Treatment of Manifestations in Individuals with Pseudoachondroplasia View in own window ManifestationTreatmentConsiderations/Other Joint painAnalgesicsNo systematic studies have evaluated effectiveness of various forms of pain control in pseudoachondroplasia. Lower limb malalignmentOsteotomy * Common during childhood * Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected individuals) 1 Neurologic symptoms & radiographic evidence of cervical spine instability or cord compressionC1-C2 fixation ScoliosisSurgerySurgical treatment of scoliosis is rarely needed but may be effective in severe presentations. Short statureExtended limb lengthening * Very few examples of extended limb lengthening reported for pseudoachondroplasia * Outcome of procedure in pseudoachondroplasia not known Psychosocial issues related to short stature, incl stigmatization & discrimination * Awareness * Referral to resources * Awareness is important in caring for the individual. * Social support organizations incl the Little People of America & similar organizations in other countries (see Resources) may be of great benefit in providing information to affected individuals & families. 1\. Hunter [1999], Li et al [2007] ### Prevention of Secondary Complications The articular cartilage of individuals with pseudoachondroplasia is likely to be severely disrupted; therefore, directing the individual toward physical activities that do not accelerate joint degeneration will be beneficial. ### Surveillance Affected individuals should be examined regularly for the following by a clinical geneticist and/or orthopedist familiar with the phenotype: * Symptomatic lower limb malalignment * Evidence of kyphoscoliosis * Symptoms related to joint hypermobility * Evidence of degenerative joint disease manifesting as joint pain or by radiographs * Neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia ### Agents/Circumstances to Avoid In the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management For females with pseudoachondroplasia, delivery by cesarean section is often necessary because of the small size of the pelvis. Cesarean delivery should be considered on a case-by-case basis. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. ### Other Growth hormone treatment is ineffective in pseudoachondroplasia [Kanazawa et al 2003]. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pseudoachondroplasia	c0410538	5,226	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1487/	2021-01-18T21:01:24	{"mesh": ["C535819"], "synonyms": ["PSACH"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-66 (RP66) is caused by homozygous mutation in the RBP3 gene (180290) on chromosome 10q11. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa (RP), see 268000. Clinical Features Den Hollander et al. (2009) studied a consanguineous Italian family in which 3 brothers and a sister had retinitis pigmentosa; 2 of the brothers underwent detailed clinical evaluation, which demonstrated a wide range of severity in this family. The 42-year-old brother reported loss of central vision and onset of night blindness at 32 years of age, whereas his older brother had loss of central vision at age 60 with no night deficiency even at 67 years of age. The older brother had visual acuities of 20/60 and 20/80 and normal color vision, whereas the younger had acuities of 20/200 bilaterally, with a tritan axis of confusion on the Farnsworth-D-15 panel. The authors noted that the older brother had increased macular thickness due to cystoid macular edema and the younger brother had reduced central retinal thickness on optical coherence tomography as possible explanations for their decreased acuities. Visual fields showed marked constriction with central scotoma in both patients, although the visual fields were more severely diminished in the younger brother. Both patients showed clumped bone spicule pigment around the periphery and attenuated retinal vessels; the younger patient had waxy pallor of the optic disc, whereas the older brother had normal color, with a large area of atrophy temporal to each disc. Both brothers had posterior subcapsular cataracts. Electroretinograms (ERGs) in both patients showed profound loss of rod and cone function, with ERG amplitudes so reduced that they could be detected only by computer averaging and narrow band-pass filtering. The cone amplitudes in the younger brother were smaller at age 46 than those in his older brother at age 67; both had delayed cone implicit times that were consistent with progressive disease. Multiple follow-up examinations in the younger brother revealed much slower rates of field and ERG loss than average reported rates for untreated RP. The other 2 sibs were reported to have funduscopy findings compatible with RP and very reduced ERG responses that were virtually nondetectable without computer averaging. Both parents, who died later in life, and 1 brother were unaffected. Mapping In a consanguineous Italian family in which 4 sibs had retinitis pigmentosa, den Hollander et al. (2009) performed homozygosity mapping with SNP microarrays that revealed only 1 homozygous shared region, a 40-Mb region on chromosome 10 spanning 3,780 SNPs that segregated completely with disease in the family. Recombination events narrowed the critical interval to 9 Mb between SNPs rs2460551 and rs7898315. Molecular Genetics In a consanguineous Italian family with retinitis pigmentosa mapping to chromosome 10, den Hollander et al. (2009) analyzed 3 candidate genes and identified a missense mutation in the RBP3 gene (D1080N; 180290.0001) that segregated with disease and was not found in 116 Italian controls or 94 controls of mixed North American ancestry. Analysis of RBP3 in 395 additional unrelated patients with recessive or sporadic RP and in 680 patients with other forms of hereditary retinal degeneration revealed no mutations. Using D-HPLC and direct sequencing, Ksantini et al. (2010) screened the RBP3 gene in 134 patients with autosomal recessive or sporadic RP and 82 patients with other retinal dystrophies, but did not find any pathogenic mutations. The authors concluded that mutations in RPB3 occur rarely in inherited retinal dystrophies. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Decreased visual acuity \- Night blindness \- Visual field constriction \- Central scotoma \- Bone-spicule pigment clumping \- Attenuated retinal vessels \- Optic disc pallor (in some patients) \- Tritan color vision deficits (in some patients) \- Severe loss of rod and cone function on electroretinography \- Cone implicit times consistent with progressive disease \- Posterior subcapsular cataracts MISCELLANEOUS \- Wide range of severity between affected members of the same family MOLECULAR BASIS \- Caused by mutation in the retinol-binding protein-3 gene (RBP3, 180920.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	RETINITIS PIGMENTOSA 66	c0035334	5,227	omim	https://www.omim.org/entry/615233	2019-09-22T15:52:58	{"doid": ["0110393"], "mesh": ["D012174"], "omim": ["615233"], "orphanet": ["791"]}
Placental infarction Micrograph of a placental infarct. H&E stain. SpecialtyObstetrics A placental infarction results from the interruption of blood supply to a part of the placenta, causing its cells to die. Small placental infarcts, especially at the edge of the placental disc, are considered to be normal at term. Large placental infarcts are associated with vascular abnormalities, e.g. hypertrophic decidual vasculopathy, as seen in hypertension.[1] Very large infarcts lead to placental insufficiency and may result in fetal death. ## Contents * 1 Relation to maternal floor infarct * 2 See also * 3 References * 4 External links ## Relation to maternal floor infarct[edit] Maternal floor infarcts are not considered to be true placental infarcts, as they result from deposition of fibrin around the chorionic villi, i.e. perivillous fibrin deposition. ## See also[edit] * Placental disease ## References[edit] 1. ^ Marcorelles, P. (Mar 2010). "[Placenta and preeclampsia: relationships between anatomical lesions and clinical symptoms]". Ann Fr Anesth Reanim. 29 (3): e25-9. doi:10.1016/j.annfar.2010.02.013. PMID 20338716. ## External links[edit] Classification D * Gross pathology of a placental infarct (utah.edu) * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Placental infarction	c0554393	5,228	wikipedia	https://en.wikipedia.org/wiki/Placental_infarction	2021-01-18T18:30:30	{"wikidata": ["Q7200298"]}
Baritosis is an extremely rare, benign form of pneumoconiosis that causes little or no overgrowth, hardening, and/or scarring of the tissue in the lung (fibrosis). Pneumoconiosis is caused by accumulation of inhaled particles and involves a reaction of tissue in the lung. In the case of baritosis, the inhaled particles are made up of barium sulfate and is well described in workers who crush and grind compounds containing barium, a mineral found in paints, paper, ceramics, glass, rubber, electronic components, and in drilling muds in oil and gas exploration. Baritosis is typically characterized by a mixture of very fine punctate and annular (ring-like) lesions and some slightly larger nodular lesions in the lung. The condition generally appears 1 to 2 years after exposure, does not affect the function of the lung, and appears to go away without treatment after exposure stops. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Baritosis	c0340177	5,229	gard	https://rarediseases.info.nih.gov/diseases/8371/baritosis	2021-01-18T18:01:52	{"mesh": ["C537080"], "umls": ["C0340177"], "synonyms": ["Inhalation of barytes", "Deposition of barium in the lungs"]}
Mosaic Trisomy 4 is a rare autosomal anomaly, due to the presence of an extra copy of chromosome 4 in a fraction of all cells, with a variable phenotype characterized by intrauterine growth retardation, low birth weight/length/OFC, mild intellectual deficit, congenital heart defects, hypertrophic cardiomyopathy, dysmorphic features (asymmetry of the face, eyebrow anomalies, low-set, posteriorally rotated, dysplastic ears, micro-/retrognathia), characteristic thumb abnormalities (aplasia, hypoplasia) and skin abnormalities (hypo/hyperpigmentation). Delayed puberty may be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Mosaic trisomy 4	c4272018	5,230	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96059	2021-01-23T17:17:43	{"icd-10": ["Q92.1"], "synonyms": ["Mosaic trisomy chromosome 4", "Trisomy 4 mosaicism"]}
Accumulation of excess fluid in the pleural cavity Pleural effusion Diagram of fluid buildup in the pleura SpecialtyPulmonology A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid are secreted by the parietal pleural capillaries at a rate of 0.01 millilitre per kilogram weight per hour, and is cleared by lymphatic absorption leaving behind only 5–15 millilitres of fluid, which helps maintaining a functional vacuum between the parietal and visceral pleurae. Excess fluid within the pleural space can impair inspiration by upsetting the functional vacuum and hydrostatically increasing the resistance against lung expansion, resulting in a fully or partially collapsed lung. Various kinds of fluid can accumulate in the pleural space, such as serous fluid (hydrothorax), blood (hemothorax), pus (pyothorax, more commonly known as pleural empyema), chyle (chylothorax), or very rarely urine (urinothorax). When unspecified, the term "pleural effusion" normally refers to hydrothorax. A pleural effusion can also be compounded by a pneumothorax (accumulation of air in the pleural space), leading to a hydropneumothorax. ## Contents * 1 Types * 2 Causes * 2.1 Transudative * 2.2 Exudative * 2.3 Other/ungrouped * 3 Pathophysiology * 4 Diagnosis * 4.1 Imaging * 4.2 Thoracentesis * 4.3 Light's criteria * 5 Treatment * 6 See also * 7 References * 8 External links ## Types[edit] Various methods can be used to classify pleural fluid.[citation needed] By the origin of the fluid: * Serous fluid (hydrothorax) * Blood (haemothorax) * Chyle (chylothorax) * Pus (pyothorax or empyema) * Urine (urinothorax) By pathophysiology: * Transudative pleural effusion * Exudative pleural effusion By the underlying cause (see next section). ## Causes[edit] Pleural effusion ### Transudative[edit] The most common causes of transudative pleural effusion in the United States are heart failure and cirrhosis. Nephrotic syndrome, leading to the loss of large amounts of albumin in urine and resultant low albumin levels in the blood and reduced colloid osmotic pressure, is another less common cause of pleural effusion. Pulmonary emboli were once thought to cause transudative effusions, but have been recently shown to be exudative.[1] The mechanism for the exudative pleural effusion in pulmonary thromboembolism is probably related to increased permeability of the capillaries in the lung, which results from the release of cytokines or inflammatory mediators (e.g. vascular endothelial growth factor) from the platelet-rich blood clots. The excessive interstitial lung fluid traverses the visceral pleura and accumulates in the pleural space.[citation needed] Conditions associated with transudative pleural effusions include:[2] * Congestive heart failure * Liver cirrhosis * Severe hypoalbuminemia * Nephrotic syndrome * Acute atelectasis * Myxedema * Peritoneal dialysis * Meigs's syndrome * Obstructive uropathy * End-stage kidney disease ### Exudative[edit] Pleural effusion Anteroposterior Chest X-ray of a pleural effusion. The A arrow shows fluid layering in the right pleural cavity. The B arrow shows the normal width of the lung in the cavity When a pleural effusion has been determined to be exudative, additional evaluation is needed to determine its cause, and amylase, glucose, pH and cell counts should be measured. * Red blood cell counts are elevated in cases of bloody effusions (for example after heart surgery or hemothorax from incomplete evacuation of blood). * Amylase levels are elevated in cases of esophageal rupture, pancreatic pleural effusion, or cancer. * Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis. * pH is low in empyema (<7.2) and may be low in cancer. * If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative, and cancer is still suspected, either a thoracoscopy, or needle biopsy[3] of the pleura may be performed. * Gram staining and culture should also be done. * If tuberculosis is possible, examination for Mycobacterium tuberculosis (either a Ziehl–Neelsen or Kinyoun stain, and mycobacterial cultures) should be done. A polymerase chain reaction for tuberculous DNA may be done, or adenosine deaminase or interferon gamma levels may also be checked. The most common causes of exudative pleural effusions are bacterial pneumonia, cancer (with lung cancer, breast cancer, and lymphoma causing approximately 75% of all malignant pleural effusions), viral infection, and pulmonary embolism. Another common cause is after heart surgery, when incompletely drained blood can lead to an inflammatory response that causes exudative pleural fluid. Conditions associated with exudative pleural effusions:[2] * Parapneumonic effusion due to pneumonia * Malignancy (either lung cancer or metastases to the pleura from elsewhere) * Infection (empyema due to bacterial pneumonia) * Trauma * Pulmonary infarction * Pulmonary embolism * Autoimmune disorders * Pancreatitis * Ruptured esophagus (Boerhaave's syndrome) * Rheumatoid pleurisy * Drug-induced lupus ### Other/ungrouped[edit] Other causes of pleural effusion include tuberculosis (though stains of pleural fluid are only rarely positive for acid-fast bacilli, this is the most common cause of pleural effusions in some developing countries), autoimmune disease such as systemic lupus erythematosus, bleeding (often due to chest trauma), chylothorax (most commonly caused by trauma), and accidental infusion of fluids.[citation needed] Less common causes include esophageal rupture or pancreatic disease, intra-abdominal abscesses, rheumatoid arthritis, asbestos pleural effusion, mesothelioma, Meigs's syndrome (ascites and pleural effusion due to a benign ovarian tumor), and ovarian hyperstimulation syndrome.[citation needed] Pleural effusions may also occur through medical or surgical interventions, including the use of medications (pleural fluid is usually eosinophilic), coronary artery bypass surgery, abdominal surgery, endoscopic variceal sclerotherapy, radiation therapy, liver or lung transplantation, insertion of ventricular shunt as a treatment method of hydrocephalus,[4][5] and intra- or extravascular insertion of central lines.[citation needed] ## Pathophysiology[edit] Pleural fluid is secreted by the parietal layer of the pleura and reabsorbed by the lymphatics in the most dependent parts of the parietal pleura, primarily the diaphragmatic and mediastinal regions. Exudative pleural effusions occur when the pleura is damaged, e.g., by trauma, infection or malignancy, and transudative pleural effusions develop when there is either excessive production of pleural fluid or the resorption capacity is reduced.[citation needed] ## Diagnosis[edit] A large left sided pleural effusion as seen on an upright chest X-ray A pleural effusion is usually diagnosed on the basis of medical history and physical exam, and confirmed by a chest X-ray. Once accumulated fluid is more than 300 mL, there are usually detectable clinical signs, such as decreased movement of the chest on the affected side, dullness to percussion over the fluid, diminished breath sounds on the affected side, decreased vocal resonance and fremitus (though this is an inconsistent and unreliable sign), and pleural friction rub. Above the effusion, where the lung is compressed, there may be bronchial breathing sounds and egophony. A large effusion there may cause tracheal deviation away from the effusion. A systematic review (2009) published as part of the Rational Clinical Examination Series in the Journal of the American Medical Association showed that dullness to conventional percussion was most accurate for diagnosing pleural effusion (summary positive likelihood ratio, 8.7; 95% confidence interval, 2.2–33.8), while the absence of reduced tactile vocal fremitus made pleural effusion less likely (negative likelihood ratio, 0.21; 95% confidence interval, 0.12–0.37).[6] ### Imaging[edit] A pleural effusion appears as an area of whiteness on a standard posteroanterior chest X-ray.[7] Normally, the space between the visceral pleura and the parietal pleura cannot be seen. A pleural effusion infiltrates the space between these layers. Because the pleural effusion has a density similar to water, it can be seen on radiographs. Since the effusion has greater density than the rest of the lung, it gravitates towards the lower portions of the pleural cavity. The pleural effusion behaves according to basic fluid dynamics, conforming to the shape of pleural space, which is determined by the lung and chest wall. If the pleural space contains both air and fluid, then an air-fluid level that is horizontal will be present, instead of conforming to the lung space.[8] Chest radiographs in the lateral decubitus position (with the patient lying on the side of the pleural effusion) are more sensitive and can detect as little as 50 mL of fluid. At least 300 mL of fluid must be present before upright chest X-rays can detect a pleural effusion (e.g., blunted costophrenic angles).[citation needed] Chest computed tomography is more accurate for diagnosis and may be obtained to better characterize the presence, size, and characteristics of a pleural effusion. Lung ultrasound, nearly as accurate as CT and more accurate than chest X-ray, is increasingly being used at the point of care to diagnose pleural effusions, with the advantage that it is a safe, dynamic, and repeatable imaging modality.[9] To increase diagnostic accuracy of detection of pleural effusion sonographically, markers such as boomerang and VIP signs can be utilized.[10] * Massive left-sided pleural effusion (whiteness) in a patient presenting with lung cancer. * CT scan of the chest showing a left-sided pleural effusion. The fluid usually settles at the lowest space due to gravity; in this case, at the back because the patient is supine. * Play media The lung expanding within an area of pleural effusion as seen by ultrasound * Micrograph of a pleural fluid cytopathology specimen showing malignant mesothelioma, one cause of a pleural effusion. * A pleural effusion as seen on lateral upright chest x ray * Play media Pleural effusion as seen behind the heart.[11] * Massive pleural effusion, later proven to be hemothorax in a South Indian male. ### Thoracentesis[edit] Once a pleural effusion is diagnosed, its cause must be determined. Pleural fluid is drawn out of the pleural space in a process called thoracentesis, and it should be done in almost all patients who have pleural fluid that is at least 10 mm in thickness on CT, ultrasonography, or lateral decubitus X-ray and that is new or of uncertain etiology. In general, the only patients who do not require thoracentesis are those who have heart failure with symmetric pleural effusions and no chest pain or fever; in these patients, diuresis can be tried, and thoracentesis is avoided unless effusions persist for more than 3 days.[12] In a thoracentesis, a needle is inserted through the back of the chest wall in the sixth, seventh, or eighth intercostal space on the midaxillary line, into the pleural space. The use of ultrasound to guide the procedure is now standard of care as it increases accuracy and decreases complications.[13][14] After removal, the fluid may then be evaluated for: 1. Chemical composition including protein, lactate dehydrogenase (LDH), albumin, amylase, pH, and glucose 2. Gram stain and culture to identify possible bacterial infections 3. White and red blood cell counts and differential white blood cell counts 4. Cytopathology to identify cancer cells, but may also identify some infective organisms 5. Other tests as suggested by the clinical situation – lipids, fungal culture, viral culture, tuberculosis cultures, lupus cell prep, specific immunoglobulins ### Light's criteria[edit] Transudate vs. exudate * view * talk * edit Transudate Exudate Main causes ↑ hydrostatic pressure, ↓ colloid osmotic pressure Inflammation-Increased vascular permeability Appearance Clear[15] Cloudy[15] Specific gravity < 1.012 > 1.020 Protein content < 2.5 g/dL > 2.9 g/dL[16] fluid protein/ serum protein < 0.5 > 0.5[17] SAAG = Serum [albumin] - Effusion [albumin] > 1.2 g/dL < 1.2 g/dL[18] fluid LDH upper limit for serum < 0.6 or < 2⁄3 > 0.6[16] or > 2⁄3[17] Cholesterol content < 45 mg/dL > 45 Radiodensity on CT scan 2 to 15 HU[19] 4 to 33 HU[19] Instruments for needle biopsy of the pleura.[20] Definitions of the terms "transudate" and "exudate" are the source of much confusion. Briefly, transudate is produced through pressure filtration without capillary injury while exudate is "inflammatory fluid" leaking between cells.[citation needed] Transudative pleural effusions are defined as effusions that are caused by systemic factors that alter the pleural equilibrium, or Starling forces. The components of the Starling forces – hydrostatic pressure, permeability, and oncotic pressure (effective pressure due to the composition of the pleural fluid and blood) – are altered in many diseases, e.g., left ventricular failure, kidney failure, liver failure, and cirrhosis. Exudative pleural effusions, by contrast, are caused by alterations in local factors that influence the formation and absorption of pleural fluid (e.g., bacterial pneumonia, cancer, pulmonary embolism, and viral infection).[21] An accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on a comparison of the chemistries in the pleural fluid to those in the blood, using Light's criteria. According to Light's criteria (Light, et al. 1972), a pleural effusion is likely exudative if at least one of the following exists:[22] 1. The ratio of pleural fluid protein to serum protein is greater than 0.5 2. The ratio of pleural fluid LDH and serum LDH is greater than 0.6 3. Pleural fluid LDH is greater than 0.6 [16] or 2⁄3[22] times the normal upper limit for serum. Different laboratories have different values for the upper limit of serum LDH, but examples include 200[23] and 300[23] IU/l.[24] The sensitivity and specificity of Light's criteria for detection of exudates have been measured in many studies and are usually reported to be around 98% and 80%, respectively.[25][26] This means that although Light's criteria are relatively accurate, twenty percent of patients that are identified by Light's criteria as having exudative pleural effusions actually have transudative pleural effusions. Therefore, if a patient identified by Light's criteria as having an exudative pleural effusion appears clinically to have a condition that usually produces transudative effusions, additional testing is needed. In such cases, albumin levels in blood and pleural fluid are measured. If the difference between the albumin level in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), this suggests that the patient has a transudative pleural effusion.[18] However, pleural fluid testing is not perfect, and the final decision about whether a fluid is a transudate or an exudate is based not on chemical analysis of the fluid, but on accurate diagnosis of the disease that produces the fluid.[citation needed] The traditional definitions of transudate as a pleural effusion due to systemic factors and an exudate as a pleural effusion due to local factors have been used since 1940 or earlier (Light et al., 1972). Previous to Light's landmark study, which was based on work by Chandrasekhar, investigators unsuccessfully attempted to use other criteria, such as specific gravity, pH, and protein content of the fluid, to differentiate between transudates and exudates. Light's criteria are highly statistically sensitive for exudates (although not very statistically specific). More recent studies have examined other characteristics of pleural fluid that may help to determine whether the process producing the effusion is local (exudate) or systemic (transudate). The table above illustrates some of the results of these more recent studies. However, it should be borne in mind that Light's criteria are still the most widely used criteria.[citation needed] The Rational Clinical Examination Series review found that bilateral effusions, symmetric and asymmetric, are the most common distribution in heart failure (60% of effusions in heart failure will be bilateral). When there is asymmetry in heart failure-associated pleural effusions (either unilateral or one side larger than the other), the right side is usually more involved than the left.[6] The instruments pictured are accurately shaped, however most hospitals now use safer disposable trocars. Because these are single use, they are always sharp and have a much smaller risk of cross patient contamination.[citation needed] ## Treatment[edit] Treatment depends on the underlying cause of the pleural effusion. Therapeutic aspiration may be sufficient; larger effusions may require insertion of an intercostal drain (either pigtail or surgical). When managing these chest tubes, it is important to make sure the chest tubes do not become occluded or clogged. A clogged chest tube in the setting of continued production of fluid will result in residual fluid left behind when the chest tube is removed. This fluid can lead to complications such as hypoxia due to lung collapse from the fluid, or fibrothorax if scarring occurs. Repeated effusions may require chemical (talc, bleomycin, tetracycline/doxycycline), or surgical pleurodesis, in which the two pleural surfaces are scarred to each other so that no fluid can accumulate between them. This is a surgical procedure that involves inserting a chest tube, then either mechanically abrading the pleura or inserting the chemicals to induce a scar. This requires the chest tube to stay in until the fluid drainage stops. This can take days to weeks and can require prolonged hospitalizations. If the chest tube becomes clogged, fluid will be left behind and the pleurodesis will fail.[citation needed] Pleurodesis fails in as many as 30% of cases. An alternative is to place a PleurX Pleural Catheter or Aspira Drainage Catheter. This is a 15Fr chest tube with a one-way valve. Each day the patient or care givers connect it to a simple vacuum tube and remove from 600 to 1000 mL of fluid, and can be repeated daily. When not in use, the tube is capped. This allows patients to be outside the hospital. For patients with malignant pleural effusions, it allows them to continue chemotherapy, if indicated. Generally, the tube is in for about 30 days and then it is removed when the space undergoes a spontaneous pleurodesis. ## See also[edit] * Pleural disease * Empyema * Heart failure * Pulmonary embolism * Subpulmonic effusion * Thoracentesis ## References[edit] 1. ^ Porcel JM, Light RW (2008). "Pleural effusions due to pulmonary embolism". Current Opinion in Pulmonary Medicine. 14 (4): 337–42. doi:10.1097/MCP.0b013e3282fcea3c. PMID 18520269. S2CID 44337698. 2. ^ a b Galagan et al. Color Atlas of Body Fluids. CAP Press, Northfield, 2006 3. ^ de Menezes Lyra R (July 1997). "A modified outer cannula can help thoracentesis after pleural biopsy" (PDF). Chest. 112 (1): 296. doi:10.1378/chest.112.1.296. PMID 9228404.[permanent dead link] 4. ^ Gupta, A. K.; Berry, M. (April 1994). "Ventriculo-peritoneal shunt presenting with recurrent pleural effusion: Report of a new complication". Pediatric Radiology. 24 (2): 147. doi:10.1007/bf02020178. ISSN 0301-0449. PMID 8078722. S2CID 28016135. 5. ^ Raicevic Mirjana, Nikolovski Srdjan, Golubovic Emilija. Pleural Effusion as a Ventriculo-Peritoneal Shunt Complication in Children (Meeting Abstract). Acta Med Acad. 2019;48(S1):26. 6. ^ a b Wong CL, Holroyd-Leduc J, Straus SE (Jan 2009). "Does this patient have a pleural effusion?". JAMA. 301 (3): 309–17. doi:10.1001/jama.2008.937. PMID 19155458. 7. ^ Corne; et al. (2002). Chest X-Ray Made Easy. Churchill Livingstone. ISBN 0-443-07008-3. 8. ^ Squire, Lucy Frank; Novelline, Robert A. (2004). Squire's fundamentals of radiology. Cambridge: Harvard University Press. pp. 132–3. ISBN 0-674-01279-8. 9. ^ Volpicelli, Giovanni; Elbarbary, Mahmoud; Blaivas, Michael; Lichtenstein, Daniel A.; Mathis, Gebhard; Kirkpatrick, Andrew W.; Melniker, Lawrence; Gargani, Luna; Noble, Vicki E. (2012-04-01). "International evidence-based recommendations for point-of-care lung ultrasound". Intensive Care Medicine. 38 (4): 577–591. doi:10.1007/s00134-012-2513-4. ISSN 1432-1238. PMID 22392031. 10. ^ Lau, James Siu Ki; Yuen, Chi Kit; Mok, Ka Leung; Yan, Wing Wa; Kan, Pui Gay (2017-11-15). "Visualization of the inferoposterior thoracic wall (VIP) and boomerang signs-novel sonographic signs of right pleural effusion". The American Journal of Emergency Medicine. 36 (7): 1134–1138. doi:10.1016/j.ajem.2017.11.023. ISSN 1532-8171. PMID 29162443. S2CID 41876899. 11. ^ "UOTW #23 - Ultrasound of the Week". Ultrasound of the Week. 22 October 2014. Retrieved 27 May 2017. 12. ^ Light, Richard W. "Pleural Effusion". Merck Manual for Health Care Professionals. Merck Sharp & Dohme Corp. Retrieved 21 August 2013. 13. ^ Feller-Kopman, David (2007-07-01). "Therapeutic thoracentesis: the role of ultrasound and pleural manometry". Current Opinion in Pulmonary Medicine. 13 (4): 312–318. doi:10.1097/MCP.0b013e3281214492. ISSN 1070-5287. PMID 17534178. S2CID 21367134. 14. ^ Gordon, Craig E.; Feller-Kopman, David; Balk, Ethan M.; Smetana, Gerald W. (2010-02-22). "Pneumothorax following thoracentesis: a systematic review and meta-analysis". Archives of Internal Medicine. 170 (4): 332–339. doi:10.1001/archinternmed.2009.548. ISSN 1538-3679. PMID 20177035. 15. ^ a b The University of Utah • Spencer S. Eccles Health Sciences Library > WebPath images > "Inflammation". 16. ^ a b c Heffner J, Brown L, Barbieri C (1997). "Diagnostic value of tests that discriminate between exudative and transudative pleural effusions. Primary Study Investigators". Chest. 111 (4): 970–80. doi:10.1378/chest.111.4.970. PMID 9106577. 17. ^ a b Light R, Macgregor M, Luchsinger P, Ball W (1972). "Pleural effusions: the diagnostic separation of transudates and exudates". Ann Intern Med. 77 (4): 507–13. doi:10.7326/0003-4819-77-4-507. PMID 4642731. 18. ^ a b Roth BJ, O'Meara TF, Gragun WH (1990). "The serum-effusion albumin gradient in the evaluation of pleural effusions". Chest. 98 (3): 546–9. doi:10.1378/chest.98.3.546. PMID 2152757. 19. ^ a b Cullu, Nesat; Kalemci, Serdar; Karakas, Omer; Eser, Irfan; Yalcin, Funda; Boyaci, Fatma Nurefsan; Karakas, Ekrem (2013). "Efficacy of CT in diagnosis of transudates and exudates in patients with pleural effusion". Diagnostic and Interventional Radiology. 20: 116–20. doi:10.5152/dir.2013.13066. ISSN 1305-3825. PMC 4463296. PMID 24100060. 20. ^ de Menezes Lyra R (1997). "A modified outer cannula can help thoracentesis after pleural biopsy". Chest. 112 (1): 296. doi:10.1378/chest.112.1.296. PMID 9228404. 21. ^ Light, Richard W. "Ch. 257: Disorders of the Pleura and Mediastinum". In Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (17th ed.). 22. ^ a b Light RW, Macgregor MI, Luchsinger PC, Ball WC (1972). "Pleural effusions: the diagnostic separation of transudates and exudates". Ann Intern Med. 77 (4): 507–13. doi:10.7326/0003-4819-77-4-507. PMID 4642731. S2CID 31947040. 23. ^ a b Joseph J, Badrinath P, Basran GS, Sahn SA (November 2001). "Is the pleural fluid transudate or exudate? A revisit of the diagnostic criteria". Thorax. 56 (11): 867–70. doi:10.1136/thorax.56.11.867. PMC 1745948. PMID 11641512. 24. ^ Joseph J, Badrinath P, Basran GS, Sahn SA (2002). "Is albumin gradient or fluid to serum albumin ratio better than the pleural fluid lactate dehydroginase in the diagnostic of separation of pleural effusion?". BMC Pulmonary Medicine. 2: 1. doi:10.1186/1471-2466-2-1. PMC 101409. PMID 11914151. 25. ^ Romero S, Martinez A, Hernandez L, Fernandez C, Espasa A, Candela A, Martin C (2000). "Light's criteria revisited: consistency and comparison with new proposed alternative criteria for separating pleural transudates from exudates". Respiration; International Review of Thoracic Diseases. 67 (1): 18–23. doi:10.1159/000029457. PMID 10705257. S2CID 45667293. 26. ^ Porcel JM, Peña JM, Vicente de Vera C, Esquerda A (Feb 18, 2006). "[Reappraisal of the standard method (Light's criteria) for identifying pleural exudates]". Medicina Clinica. 126 (6): 211–3. doi:10.1157/13084870. PMID 16510093. ## External links[edit] Classification D * ICD-10: J90-J91 * ICD-9-CM: 511.9 * MeSH: D010996 * SNOMED CT: 60046008 External resources * MedlinePlus: 000086 * MedlinePlus Encyclopedia: Pleural Effusion * Pleural Effusion Images from MedPix * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pleural effusion	c0032227	5,231	wikipedia	https://en.wikipedia.org/wiki/Pleural_effusion	2021-01-18T18:55:21	{"mesh": ["D010996"], "umls": ["C0032227"], "icd-9": ["511.9"], "icd-10": ["J90", "J91"], "wikidata": ["Q1334541"]}
A number sign (#) is used with this entry because of evidence that mutation at more than one locus can be involved in different families or even in the same case. Breast-ovarian cancer-1 (BROVCA1; 604370) can be caused by mutation in the BRCA1 gene (113705) on chromosome 17q, BROVCA2 (600185) by mutation in the BRCA2 gene (612555) on chromosome 13q12, BROVCA3 (613399) by mutation in the RAD51C gene (602774) on chromosome 17q22, and BROVCA4 (614291) by mutation in the RAD51D gene (602954) on chromosome 17q11. Mutation in the androgen receptor gene (AR; 313700) on the X chromosome has been found in cases of male breast cancer (see 313700.0016). Mutation in the RAD51 gene (179617) has been found in patients with familial breast cancer (179617.0001). Breast cancer susceptibility alleles have been reported in the CHEK2 gene (see 604373.0001 and 604373.0012) and in the BARD1 gene (see 601593.0001). Furthermore, the PPM1D gene (605100) on 17q is commonly amplified in breast cancer and appears to lead to cell transformation by abrogating p53 (191170) tumor suppressor activity (Bulavin et al., 2002). Somatic mutations in the following genes have been identified in breast cancer: SLC22A18 (602631) on 11p15, TP53 (191170) on 17p13, RB1CC1 (606837) on 8q11, PIK3CA (171834) on 3q26, and AKT1 (164730) on 14q32. An allele of the CASP8 gene (601763.0003) has been associated with reduced risk of breast cancer. An allele of the TGFB1 gene (190180.0007) has been associated with an increased risk of invasive breast cancer. An allele of the NQO1 gene (125860.0001) has been associated with breast cancer prognosis, including survival after chemotherapy and after metastasis. Variation in the HMMR gene (600936) has also been shown to modify susceptibility. Mutations in genes responsible for various forms of Fanconi anemia (see, e.g., 227650) have been identified as susceptibility factors for breast cancer. These include BRCA2, PALB2 (610355), BRIP1 (605882), and RAD51C (602774). Breast cancer is a feature of several cancer syndromes, including Li-Fraumeni syndrome (151623) due to germline mutations in p53; Cowden syndrome (158350) due to mutations in the PTEN gene (601728); and Peutz-Jeghers syndrome (175200) due to mutations in the STK11 gene (602216). There also appears to be an increased risk of breast and ovarian cancer in ataxia-telangiectasia (208900), and there is some evidence that heterozygotes for some mutations in the ataxia-telangiectasia mutated gene (ATM; e.g., 607585.0032) have an increased risk of breast cancer. Germline and somatic mutations in the CDH1 gene (192090) have been found in lobular breast cancer and hereditary diffuse gastric cancer (LBC/HDGC; see 137215), which may represent a cancer predisposition syndrome. Some genomic regions have been found to be amplified in breast cancer, including 8q24, 20q13, 11q12, and 8p12-p11 (Yang et al., 2006). The NCOA3 (601937) and ZNF217 (602967) genes, located on 20q, undergo amplification in breast cancer; when overexpressed, these genes confer cellular phenotypes consistent with a role in tumor formation (Anzick et al., 1997; Collins et al., 1998). Description Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Clinical Features Cady (1970) described a family in which 3 sisters had bilateral breast cancer. Together with reports in the literature, this suggested to him the existence of families with a particular tendency to early-onset, bilateral breast cancer. The genetic basis might, of course, be multifactorial. Anderson (1974) concluded that the sisters of women with breast cancer whose mothers also had breast cancer have a risk 47 to 51 times that in control women; a revised estimate was 39 times (Anderson, 1976). The disease in these women usually developed before menopause, was often bilateral, and seemed to be associated with ovarian function. About 30% of daughters with early-onset, bilateral breast cancer inherited the susceptibility. The risk of breast cancer to women with affected relatives is higher when the diagnosis is made at an early age and when the disease is bilateral. Ottman et al. (1983) provided tables that give the cumulative risk of breast cancer to mothers and sisters at various ages. The highest risk group is sisters of premenstrual probands with bilateral disease. Among the sisters of women with breast cancer, Anderson and Badzioch (1985) found the highest lifetime risks when the proband had bilateral disease, an affected mother (25 +/- 7.2%), or an affected sister (28 +/- 11%). The risks were reduced to 18 +/- 3.3% and 14 +/- 2.6%, respectively, with unilateral disease. An early example of familial breast cancer was provided by Broca (1866). According to the pedigree drawn by Lynch (1976), 10 women in 4 generations of the family of Broca's wife died of breast cancer. Eisinger et al. (1998) called attention to an even earlier report of hereditary breast cancer by Le Dran (1757), who related the experience of a colleague in Avignon who had diagnosed a 19-year-old nun with cancer of the right breast. The patient refused a mastectomy not only because of the pain of surgery, but also because of a belief that the operation would be futile. Her grandmother and a grandmaternal uncle died with breast cancer, and she was convinced that this malady was hereditary and that 'her blood was corrupted by a cancerous ferment natural to her family.' Two families with an extraordinary incidence of male breast cancer and father-to-son transmission of same was reported by Everson et al. (1976). They found a suggestion of elevated urinary estrogen in 3 of the affected males. Teasdale et al. (1976) described breast cancer in 2 brothers and in a daughter of 1 brother. Kozak et al. (1986) reported breast cancer in 2 related males, an uncle and nephew. In this family and in several reported families with male breast cancer, Kozak et al. (1986) found women in the same family with breast cancer. Soft tissue sarcomas are associated with breast cancer in Li-Fraumeni syndrome. Mulvihill (1982) used the term cancer family syndrome of Lynch (120435) for the association of colon and endometrial carcinoma and other neoplasms including breast cancer. Seltzer et al. (1990) concluded that dermatoglyphics can help in the identification of women either with or at risk for breast cancer. They found that the presence of 6 or more whorls is associated in a statistically significant manner with breast cancer. Marger et al. (1975) presented the cases of 2 brothers with breast cancer and reviewed the courses of 28 other previously unreported male patients. In one of the brothers, breast cancer was preceded by prostate cancer and estrogen administration, raising the possibility that the breast cancer was a metastatic deposit. The possibility of prostatic metastases was raised in 2 other patients. Demeter et al. (1990) reported breast cancer in a 64-year-old man who had had bilateral gynecomastia since childhood. His maternal grandfather had been found to have adenocarcinoma of the breast at the age of 65. His maternal grandmother had radical mastectomy for breast cancer at the age of 66 and 2 years later underwent radiation therapy for rib metastases. The proband's sister developed breast cancer at the age of 31 years and despite aggressive therapy died 1 year later with extensive metastases. Hauser et al. (1992) reported a family in which 2 females and 2 males in 2 generations had breast cancer. Two females in the family had prophylactic bilateral mastectomy at a young age. One male developed a left breast mass and axillary node at age 59 and died of metastatic disease at age 62. His paternal uncle presented at age 57 years with bleeding from his right breast. Biopsy suggested Paget disease of the breast and he underwent mastectomy. He subsequently died at age 75 years of prostatic carcinoma. He had a daughter who developed breast cancer at age 27 years and died at age 30 with disseminated disease, and a son who developed infiltrating grade 4 adenocarcinoma of the breast at age 54. Other Features Chang et al. (1987) showed that the noncancerous skin fibroblasts of members of a family with Li-Fraumeni syndrome (which show resistance to the killing effect of ionizing radiation) have a 3- to 8-fold elevation in expression of the MYC oncogene (190080) and an apparent activation of the RAF1 gene (164760). Normal fetal and adult skin fibroblasts show distinctive migratory behavior when plated on 3-dimensional collagen gels. Haggie et al. (1987) found that skin fibroblasts from 13 of 15 patients with hereditary breast cancer showed fetal-like behavior compared with only 1 of 12 age-matched healthy controls. In addition, 10 of 15 first-degree relatives of patients with hereditary breast cancer showed a fetal-like fibroblast phenotype, compared with none of 7 surgical controls. Using x-ray diffraction studies with synchrotron radiation, James et al. (1999) found that hair from breast cancer patients had a different intermolecular structure than hair from healthy subjects. All 23 patients with breast cancer, including 8 without BRCA1 mutations, had altered hair structure. Of 5 women without breast cancer but carrying BRCA1 mutations, 3 had fully different structure and 2 had partial changes in hair structure. The authors proposed hair analysis to screen for breast cancer, but suggested additional study of the sensitivity and specificity of the test. Briki et al. (1999) repeated the studies of James et al. (1999), using scalp hair from 10 supposedly healthy people, 7 females and 3 males, and 10 breast cancer patients, all female. They irradiated a bundle of hair in a glass capillary with a 0.5-mm monochromatic x-ray beam. The diffraction patterns from healthy subjects displayed an intense ring at 4.48 +/- 0.05 nm. Eight of the 10 breast cancer patients had the same ring. These results were exactly the opposite of those observed by James et al. (1999). However, the study by Briki et al. (1999) used scalp hair rather than pubic hair. Breast cancer metastasis occurs in a distinct pattern involving the regional lymph nodes, bone marrow, lung, and liver, but rarely other organs. By real-time quantitative PCR, immunohistochemistry, and flow cytometric analysis, Muller et al. (2001) found that CXCR4 is highly expressed in primary and metastatic human breast cancer cells but is undetectable in normal mammary tissue, whereas CCR7 (600242) is highly expressed in normal tissue and is upregulated in breast cancer cells. Quantitative PCR analysis also detected peak expression levels of the CXCR4 ligand, CXCL12 (SDF1; 600835) in lymph nodes, lung, liver, and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant in lymph nodes, the organs to which primary breast cancer cells preferentially migrate. Analysis of malignant melanomas determined that in addition to CXCR4 and CCR7, these tumors also had high levels of CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific chemokine involved in the homing of memory T cells into the skin. Flow cytometric analysis and confocal laser microscopy demonstrated that either CXCL12 or CCL21 induces high levels of F-actin polymerization and pseudopod formation in breast cancer cells. These chemokines, as well as lung and liver extracts, also induce directional migration of breast cancer cells in vitro, which can be blocked by antibodies to CXCR4 or CCL21. Histologic and quantitative PCR analyses showed that metastasis of intravenously or orthotopically injected breast cancer cells could be significantly decreased in SCID mice by treatment with anti-CXCR4 antibodies. Muller et al. (2001) proposed that the nonrandom expression of chemokine receptors in breast cancer and malignant melanoma, and probably in other tumor types, indicates that small molecule antagonists of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to interfere with tumor progression and metastasis in tumor patients. Liotta (2001) reviewed the theories explaining the bias of metastases toward certain organs and addressed questions raised by the work of Muller et al. (2001). Certain breast tumors are characterized by a high prediction uncertainty ('low-confidence') based on ESR1 (133430) expression status. Kun et al. (2003) analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ESR-subtype discrimination. Patients with 'low-confidence' ESR-positive tumors exhibited a significantly worse overall survival (p = 0.03) and shorter time to distant metastasis (p = 0.004) compared with their 'high-confidence' ESR-positive counterparts, indicating that the 'high' and 'low-confidence' binary distinction is clinically meaningful. Elevated expression of ERBB2 (164870) was significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ESR1, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2-positive samples are not known to be estrogen responsive. Kun et al. (2003) proposed that a significant portion of the effect of ERBB2 on ESR-positive breast tumors may involve ESR-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype. Kristiansen et al. (2002) reported an association between skewed X inactivation and breast cancer in young patients. Kristiansen et al. (2005) described the results of X inactivation analysis of 272 patients with familial breast cancer, 35 with BRCA1/BRCA2 germline mutations, and 292 with sporadic breast cancer. X inactivation pattern was determined by PCR analysis of the highly polymorphic CAG repeat in the androgen receptor gene (AR; 213700). Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation, defined as 90% or more of cells preferentially expressing one X chromosome. There was also a strong tendency for middle-aged patients with sporadic breast cancer to be more skewed than middle-aged controls. No association was found, however, between skewed X inactivation and breast cancer for BRCA1/BRCA2 patients. Kristiansen et al. (2005) interpreted the results as indicating that skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X-linked genes. The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. Podsypanina et al. (2008) reported that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes Myc (190080) and Kras bearing the gly12 to asp mutation (190070.0005), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogenic induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors. Hurtado et al. (2008) showed that estrogen-estrogen receptor (ESR; see 133430) and tamoxifen-ESR complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. Hurtado et al. (2008) implicated the paired box-2 gene product (PAX2; 167409) in a previously unrecognized role, as a crucial mediator of ERS repression of ERBB2 by the anticancer drug tamoxifen. Hurtado et al. (2008) showed that PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ESR-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ESR-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer. Using microarray analysis, Miller et al. (2008) found increased expression of MIRN221 (300568) and MIRN222 (300569) in human breast cancer cells that were resistant to tamoxifen compared to parental cancer cells that were sensitive to tamoxifen. MIRNR221 and MIRNR222 expression was also increased about 2-fold in ERBB2-positive breast cancer cells that are known to be resistant to tamoxifen. Increased expression of the microRNAs was associated with decreased expression of the cell cycle inhibitor CDKN1B (600778). Ectopic expression of MIRN221 or MIRN222 rendered sensitive breast cancer cells resistant, and, conversely, overexpression of CDKN1B enhanced cell death when exposed to tamoxifen. Li et al. (2010) found a significant association between amplification of a region on chromosome 8q22 and de novo chemoresistance to anthracyclines and metastatic recurrence in human breast cancer. Within this region, overexpression of both the YWHAZ (601288) and LAPTM4B (613296) genes was found to correlate with the observations. Knockdown of either of these genes using siRNA resulting in sensitivity of tumor cells to anthracyclines. Extensive in vitro studies confirmed the effect. Further studies indicated that LAPTM4B resulted in sequestration of anthracycline and delayed entry into the nucleus, whereas YWHAZ likely protected cells from apoptosis. The findings were specific to anthracyclines. Inheritance Petrakis (1977) listed the evidence for a genetic role in breast cancer as follows: (1) family history of breast cancer, especially bilateral breast cancer; (2) marked differences in rates between certain racial groups (lower in Orientals); (3) lack of major change in incidence over many years despite dramatic decline in other cancers; (4) concordance in monozygotic twins; and (5) concordance of laterality in closely related persons. Lynch et al. (1984) found evidence consistent with a hereditary breast cancer syndrome in 5% of 225 consecutively ascertained patients with verified breast cancer. From a maximum-likelihood mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and the lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. They concluded that inherited susceptibility affected only 4% of the families in the sample; multiple cases of this relatively common disease occurred in other families by chance. They pictured an extended pedigree with 14 cases of breast cancer, 3 of them in men. The Danish twin registry (Holm et al., 1980) had 5 out of 45 MZ twins and 4 out of 77 DZ twins concordant for breast cancer; heritability was calculated at 0.3-0.4. From complex segregation analysis of 200 Danish breast cancer pedigrees, Williams and Anderson (1984) concluded that the distribution of cases was compatible with transmission of an autosomal dominant gene. Newman et al. (1988) used complex segregation analysis to investigate patterns of breast cancer occurrence in 1,579 nuclear families. They concluded that an autosomal dominant model with a highly penetrant susceptibility allele fully explains disease clustering. Iselius et al. (1992) reanalyzed the Danish breast cancer data collected by Jacobsen (1946), using morbid risks that incorporate mortality due to breast cancer. They interpreted the results to favor a dominant gene for familial breast cancer. No evidence of heterogeneity was found. Cases with bilateral breast cancer and males with breast cancer all belonged to families favoring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer was significant in this study. Houlston et al. (1992) showed that the risk of breast cancer increased progressively in inverse relationship to the age of the index patient. First-degree relatives of patients with bilateral breast cancer had a 6.43-fold increase in risk. Houlston et al. (1992) estimated that the genetic contribution to overall lifetime liability to breast cancer in relatives declined with increasing age of onset of breast cancer in the index case from 37% at 20 years to 8% by 45 years. In Iceland, Tulinius et al. (1992) likewise found that early onset and bilaterality of breast cancer increased the risk to relatives. In an analysis of a prospective cohort study, Sellers et al. (1992) found that the increase in the risk of breast cancer associated with a high waist-to-hip ratio (the circumference of the waist divided by that of the hips), low parity, or greater age at first pregnancy was more pronounced among women with a family history of breast cancer. They concluded that there are etiologic differences between familial breast cancer and the sporadic form. Tumors are believed to emerge only when immune surveillance fails. To ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer, Chaudhuri et al. (2000) performed molecular typing of HLA alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB111 alleles were also significantly overrepresented (P less than 0.0001) in controls (16.3%) as compared with patients with early-onset breast cancer (3.5%). Ritchie et al. (2001) introduced multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, thereby improving the identification of polymorphism combinations associated with disease risk. Using simulated case-control data, they demonstrated that MDR has reasonable power to identify interactions among 2 or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control dataset, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among 4 polymorphisms from 3 different estrogen metabolism genes: COMT (116790), CYP1A1 (108330), and CYP1B1 (601771). To study possible genetic components in breast cancer in addition to BRCA1 and BRCA2, Cui et al. (2001) conducted single-locus and 2-locus segregation analyses, with and without a polygenic background, using 3-generation families ascertained through 858 Australian women with breast cancer diagnosed at age less than 40 years. Extensive testing for deleterious mutations in BRCA1 and BRCA2 had identified 34 carriers. Their analysis suggested that, after other possible unmeasured familial factors are considered and the known BRCA1 and BRCA2 mutation carriers are excluded, there is a residual dominantly inherited risk of female breast cancer. The study also suggested that there is a substantial recessively inherited risk of early-onset breast cancer. Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30% of the age-adjusted variation in the percentage of dense tissue. Boyd et al. (2002) undertook 2 studies of twins to determine the proportion of the residual variation in percentage of density measured by mammography that can be explained by the unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variance attributable to additive genetic factors) accounted for 60% of the variation in density in Australian twins, 67% in North American twins, and 63% in all twins studied. The authors concluded that mammographic density may be associated with an increased risk of breast cancer. Hamilton and Mack (2003) used a novel design of a twin study by investigating twin pairs concordant or discordant for breast cancer. On the basis of the very high relative and cumulative risk to a woman who is genomically identical to a woman with cancer, disease in monozygotic twins who were both affected was considered largely to represent hereditary cancer, whereas disease in only 1 twin of a pair was believed to represent sporadic, or less heritable, disease. Cases among disease-discordant dizygotic pairs represent the same mixture of heritable and sporadic cases as those seen in ordinary case-control studies. The analysis reported by Hamilton and Mack (2003) was based on a previously described population (Peto and Mack, 2000) and included all twins in affected pairs who completed a risk factor questionnaire. To determine whether risk factors differed according to genetic susceptibility, they stratified pairs on the basis of zygosity, concordance or discordance of disease, the presence of bilateral or unilateral disease, and the presence or absence of a family history of breast cancer. Hamilton and Mack (2003) found that within disease-discordant monozygotic twins, the twin with an earlier onset of puberty did not have an increased risk of breast cancer. Within disease-concordant monozygotic pairs, the twin with earlier puberty was much more likely to receive the diagnosis first. In contrast, a later first pregnancy, lower parity, and later menopause within the pair was associated with an increased risk of breast cancer when 1 twin was affected but did not predict an earlier diagnosis when both were affected. The absence of linkage to hormonal milestones later in life suggested that most cases of hereditary breast cancer are not related to cumulative hormone exposure and that they may instead result from an unusual sensitivity to pubertal hormones. Associations between breast cancer and early menarche and those with reproductive milestones in adulthood may reflect different genotypes. Hamilton and Mack (2003) did not genotype the twins for mutations in BRCA1 or BRCA2. They suspected that few of the monozygotic concordant twins carried mutations in these genes. Contrariwise they suspected that the twins had potent combinations of common genetic variants that, individually, would be less influential. Thus, genotyping might reveal polymorphisms important in many other women. Diagnosis Van't Veer et al. (2002) used DNA microarray analysis on primary breast tumors of 117 young patients and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases in patients without tumor cells in local lymph nodes at diagnosis. In addition, they established a signature that identified tumors of BRCA1 carriers. Van't Veer et al. (2002) concluded that their gene expression profile (which consists of 70 genes) could outperform all currently used clinical parameters in predicting disease outcome, and provide a strategy to select patients who would benefit from adjuvant therapy. Pharoah et al. (2002) examined the polygenic basis of susceptibility to breast cancer. Availability of the human genome sequence makes possible the identification of individuals as susceptible to breast cancer by their genotype profile. They examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data were compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. The results suggested that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. Although germline mutations in the BRCA1 and BRCA2 genes account for most cases of familial breast and ovarian cancer, a large proportion of cases segregating familial breast cancer alone (i.e., without ovarian cancer) are not caused by mutations in either of these genes. Hedenfalk et al. (2003) noted that identification of additional breast cancer predisposition genes had been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/BRCA2 families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Hedenfalk et al. (2003) showed that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrated that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis. Clinical Management Hartmann et al. (1999) identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Their analyses suggested a reduction in the incidence of breast cancer of at least 90%. Schroth et al. (2009) performed a retrospective analysis of German and US cohorts of women with tamoxifen-treated hormone receptor-positive breast cancer to determine whether CYP2D6 (124030) variation is associated with clinical outcome. The median follow-up of the 1,325 patients was 6.3 years. At 9 years of follow-up, the recurrence rates for breast cancer were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Schroth et al. (2009) concluded that there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes in tamoxifen-treated breast cancer. Weigelt et al. (2011) tested the pharmacologic effects of the rapamycin analog everolimus, an allosteric MTORC1 (see FRAP1, 601231) inhibitor, and PP242, an active-site MTORC1/MTORC2 inhibitor, on a panel of 31 breast cancer cells. Cancer cells with activating PIK3CA (171834) mutations were selectively sensitive to both inhibitors, whereas those with loss-of-function PTEN (601728) mutations were resistant to treatment. In addition, a subset of cancer cells with HER2 (164870) amplification showed increased sensitivity to PP242, but not to everolimus, regardless of PIK3CA/PTEN mutation status. Both drugs exerted their effects by inducing G1 cell cycle arrest. PP42 caused reduced downstream signal transduction of the mTOR pathway as evidenced by a decrease in AKT (164730) phosphorylation. The overall results indicated that PTEN and PIK3CA have distinct functional effects on the mTOR pathway. Weigelt et al. (2011) suggested that PIK3CA mutations in breast cancer may be a predictive marker to guide the selection of patients who would benefit from mTOR inhibitor therapy. Mapping ### Associations Pending Confirmation Goldstein et al. (1989) found a suggestion of linkage to acid phosphatase (ACP1; 171500) on chromosome 2p25 (maximum lod score = 1.01 at theta = 0.001). Narod and Amos (1990) analyzed the effects of phenocopies and genetic heterogeneity on the demonstration of linkage between a putative cancer susceptibility gene and polymorphic DNA markers. De Jong et al. (2003) genotyped 956 breast cancer patients and 1,271 family-based controls at SNPs in TNFA (191160) and TNFB (153440), as well as at 24 microsatellite markers over the HLA region on chromosome 6p. There was a significant difference in mean haplotype sharing between patients and controls for 4 consecutive markers (D6S2671, TNFA, D6S2672, and MICA, 600169), the highest being at D6S2671 (p = 0.017). A single haplotype was more frequent and longer in moderate-risk patients than in controls. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls (odds ratio = 7.14), while heterozygotes were at a lower risk (odds ratio = 1.41), suggesting a recessive effect. No association was observed between the 2 SNPs in TNFA and TNFB and breast cancer risk. The authors concluded that there may be a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk. Easton et al. (2007) conducted a 2-stage genomewide association study of 4,398 familial breast cancer cases, followed by a third stage in which 30 SNPs were tested for confirmation in 22,848 cases from 22 studies. The study identified 5 novel independent loci associated with breast cancer, each at a significance level of p less than 10(-7). Four plausible genes were involved with the identified SNPs: rs2981582 in FGFR2 (176943) on chromosome 10q26; rs889312 in MAP3K1 (600982) on chromosome 5; rs3817198 in LSP1 (153432) on chromosome 11p15.5; and rs12443621, rs8051542, and rs3803662 in the TNRC9 (TOX3; 611416)/LOC643714 gene on chromosome 16q. Another SNP, rs13281615, on chromosome 8q was not located in any known gene. Easton et al. (2007) found that all of these susceptibility alleles are very common in the U.K. population and thus likely show a small increased disease risk individually. However, in combination, the SNPs may become clinically significant. In a genomewide association study of over 2,100 Icelandic patients with breast cancer, Stacey et al. (2007) identified 2 SNPs, rs13387042 and rs3803662, located on chromosomes 2q35 and 16q12, respectively, that were significantly associated with disease. The findings were replicated in 5 sample sets totaling 2,350 European and European American breast cancer patients. The overall risk was confined to estrogen receptor (see ESR1, 133430)-positive tumors. The A allele of rs13387042 had an odds ratio of 1.44 (combined p = 1.3 x 10(-13)), and the T allele of rs3803663 had an odds ratio of 1.64 (combined p = 5.9 x 10(-19)) Hunter et al. (2007) identified a SNP (rs1219648) in intron 2 of the FGFR2 gene that was significantly (p = 1.0 x 10(-10)) associated with sporadic postmenopausal breast cancer in a 2-stage genomewide association study of 1,145 and 1,776 affected individuals of European ancestry, respectively. The pooled odds ratios were 1.20 for heterozygotes and 1.64 for homozygotes. Among 5,028 patients with breast cancer and 32,090 controls of European ancestry, Stacey et al. (2008) found that 2 SNPs on chromosome 5p12, rs4415084 and rs10941679, were associated with increased risk for estrogen receptor-positive breast cancer. The T allele of rs4415084 yielded an OR of 1.16 (P = 6.4 x 10(-10) after Bonferroni correction), and an OR of 1.14 (P = 7.5 x 10(-5)) in the replication sample. The G allele of rs10941679 yielded an OR of 1.19 (P = 2.9 x 10(-11)). The results were not significant for estrogen receptor-negative cases, suggesting that estrogen receptor-positive and estrogen receptor-negative tumors have different genetic components to their risks. Antoniou et al. (2009) evaluated the association of SNPs rs3817198 at LSP1, rs13387042 at 2q35, and rs13281615 at 8q24 with breast cancer risk in 9,442 BRCA1 (113705) and 5,665 BRCA2 (600185) mutation carriers from 33 study centers. The minor allele (C) of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers (P trend = 2.8 x 10(-4)). The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1, P = 0.0047; BRCA2, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appeared to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations varied by mutation type depending on whether the mutated protein was predicted to be stable. In a SNP-based genomewide scan of 41 Spanish families with non-BRCA1/BRCA2 breast cancer, with an average of 4 female breast cancer cases per family and with no blood relatives affected with ovarian or male breast cancer, Rosa-Rosa et al. (2009) found linkage to 3 regions of interest on chromosomes 3q25 (HLOD score of 3.01), 6q24 (HLOD score of 2.26), and 21q22 (HLOD score of 3.55). A subset of 13 families with bilateral breast cancer presented an HLOD of 3.13 in the 3q25 region. By a genomewide linkage analysis of 55 high-risk Dutch breast cancer families without mutations in the BRCA1 or BRCA2 genes and replication studies in an additional 30 families, Oldenburg et al. (2008) found linkage to a region on chromosome 9q21-q22 (nonparametric multipoint lod score of 3.96 at D9S167). However, a parametric HLOD of 0.56 was also found, indicating that most families did not show linkage to this region. No pathogenic changes were found in 5 genes within the candidate region. Zheng et al. (2009) performed a genomewide association study of 1,505 Chinese women with breast cancer and 1,522 controls, followed by replication studies in a second set of 1,554 cases and 1,576 controls and a third set of 3,472 cases and 900 controls. SNP rs2046210 at chromosome 6q25.1, located upstream of the ESR1 gene, showed strong and consistent association with breast cancer across all 3 sets. Adjusted odds ratios were 1.36 and 1.59, respectively, for genotypes A/G and A/A, compared to G/G (p value for trend was 2.0 x 10(-15)) in the pooled analysis. These results implicated chromosome 6q25.1 as a susceptibility locus for breast cancer. Thomas et al. (2009) conducted a 3-stage genomewide association study of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility initiative. In stage 1, 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls were genotyped. In stage 2, 24,909 top SNPs in 4,547 cases and 4,434 controls were analyzed. In stage 3, 21 loci in 4,078 cases and 5,223 controls were investigated. Two new loci achieved genomewide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1 (602948), a gene in the homologous recombination DNA repair pathway. Thomas et al. (2009) also confirmed associations with loci on chromosome 2q35, 5p12, 5q11.2, 8q24, 10q26, and 16q12.1. Ahmed et al. (2009) tested over 800 promising associations detected by Easton et al. (2007) in a further 2 stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. Ahmed et al. (2009) found strong evidence for additional susceptibility loci on 3p (rs4973768; per-allele odds ratio = 1.11, 95% confidence interval = 1.08-1.13; p = 4.1 x 10(-23)) and 17q (rs6504950; per allele odds ratio = 0.95, 95% confidence interval = 0.92-0.97, P = 1.4 x 10(-8)). Ahmed et al. (2009) postulated that the potential causative genes include SLC4A7 (603353) and NEK10 on 3p and COX11 (603648) on 17q. Broeks et al. (2011) provided evidence that low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes, as defined by 5 tumor cell markers (ER, PR, HER2 (164870), KRT5 (148040)/KRT6A (148041), EGFR (131550)), and other pathologic and clinical features. The study included 31 case-control or cohort studies in the Breast Cancer Association Consortium (BCAC), mostly involving European women, and analyzed 10 known susceptibility loci previously identified through genomewide association studies (GWAS) (rs2981582 on 10q26, rs3803662 on 16q12, rs889312 on 5q11, rs13281615 on 8q24, rs3817198 on 11p15, rs13387042 on 2q35, rs4973768 on 3p24, and rs6504950 on 17q23), as well as 2 putative SNPs in candidate genes rs1045485/rs17468277 in CASP8 (601763) and rs1982073 in TGFB1 (190180). The association between breast cancer and these SNPs was confirmed. Six (10q26, 16q12, 8q24, 2q35, 3p24, 17q23) of the 8 loci showed stronger associations with ER+ than ER- tumors. Analysis by PR status generally showed a similar pattern, but the CASP8 and TGFB1 SNPs were more strongly related to PR- tumors. Seven loci (10q26, 16q12, 5q11, 8q24, 2q35, 3p24, and 17q23) were more significantly associated with ER+, PR+, HER2- tumors than with ER+, PR+, HER2+ tumors. Five loci were less significantly associated with triple-negative (ER-, PR-, HER2-) tumors: 16q12, 5q11, 11p15, 2q35, and TGFB1. Of these, the loci at 16q12, 2q35, and TGFB1 were also associated with KRT5/6A+ and EGFR+ tumors. Broeks et al. (2011) suggested that tumor stratification may help in the identification and characterization of novel risk factors for breast cancer subtypes. Alanee et al. (2012) studied the frequency of the HOXB13 (604607) missense mutation G84E (rs138213197) in 1,170 patients with familial breast cancer (including 293 patients of Ashkenazi Jewish ancestry) and wildtype BRCA1 and BRCA2; 1,053 patients with sporadic breast cancer (who were not tested for BRCA1 and 2); 1,052 patients with colon cancer; and 1,650 healthy controls. Among 877 patients, 6 women with BRCA1/2-wildtype familial breast cancer who were not of Ashkenazi Jewish ancestry were carriers of the rs138213197 variant (0.7%); this rate was 7 times as high as the prevalence of the mutation among controls (0.1%) (odds ratio, 5.7; 95% confidence interval, 1.0 to 40.7; exact P = 0.02). The mutation carriers were mainly white women who were 38 to 77 years of age at diagnosis, and 4 patients who had estrogen-receptor-positive tumors. Alanee et al. (2012) observed 3 heterozygous carriers among the patients with sporadic breast cancer (0.3%), 1 heterozygous carrier among patients with colon cancer, and no carriers of the mutation among the 293 patients with breast cancer who were of Ashkenazi Jewish ancestry. Alanee et al. (2012) stated that these findings were consistent with a moderate effect size (a risk that was approximately 6 times as high as the risk among individuals without the mutation), which is greater than the risk associated with individuals with CHEK2 (604373) mutations or common variants from genomewide association studies, but less than the risk conferred by BRACA1/2 mutations. The G84E mutation had been identified in a study of prostate cancer susceptibility (see HPC9, 610997). Orr et al. (2012) conducted a genomewide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B (RAD51L1; 602948) at 14q24.1 was significantly associated with male breast cancer risk (rs1314913, p = 3.02 x 10(-13); OR = 1.57, 95% CI 1.39-1.77). Orr et al. (2012) also refined association at 16q12.1 to rs3803662 within TOX3 (611416) (p = 3.87 x 10(-15); OR = 1.50; 95% CI 1.35-1.66). French et al. (2013) performed an analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies and identified 3 independent association signals for estrogen receptor-positive breast cancers at chromosome 11q13. The strongest signal mapped to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 (600246) transcription and luciferase activity in reporter assays, and may be associated with low cyclin D1 (CCND1; 168461) protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Another risk association signal, rs75915166, creates a GATA3 (131320)-binding site within a silencer element. Chromatin conformation studies demonstrated that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. Meyer et al. (2013) conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. Meyer et al. (2013) identified 3 statistically independent risk signals within the 10q26 FGFR2 (176943) locus. Within risk signals 1 and 3, genetic analysis identified 5 and 2 variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and EMSA to study protein-DNA binding, Meyer et al. (2013) identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 (602294) preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit estrogen receptor-alpha (133430) to this site in an allele-specific manner, whereas E2F1 (189971) preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5-phosphorylated RNA polymerase II (see 180660), suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region Meyer et al. (2013) concluded that a role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen receptor-positive disease. ### Putative 'Breast Cancer 3' (BRCA3) Locus Breast Cancer Linkage Consortium data on 237 breast-ovarian cancer families showed that 52% were linked to BRCA1 (113705) and 32% to BRCA2 (600185). Later studies indicated that the proportion of breast cancer families attributable to these 2 genes may be smaller than initially thought. In Finnish breast cancer families with 3 or more affected cases, a mutation in the BRCA1 gene was seen in only 10% and in the BRCA2 gene in only 11% of the families (Vehmanen et al., 1997). In southern Sweden, the corresponding percentages were 23% and 11% (Hakansson et al., 1997). These studies suggested that in the Nordic populations a significant proportion of familial breast cancer is not explained by the 2 major susceptibility genes. Kainu et al. (2000) adopted a strategy similar to that used in the identification of the locus for the Peutz-Jeghers cancer syndrome (175200), based on the Knudson 2-hit model of development: detection of somatic deletions in the wildtype gene by comparative genomic hybridization (CGH) followed by targeted linkage analysis. They performed CGH analyses of 61 tumor tissues from 37 non-BRCA1/BRCA2 breast cancer families, designated by them BRCAX. Distinction of early genetic events was facilitated by the application of 2 complementary mathematical tree models for analysis of the CGH data. In addition, they searched for deletions that were shared in tumor tissues from multiple affected cases in the same family. The studies predicted that loss of 13q was one of the earliest genetic events in hereditary cancer. In a Swedish family with 5 breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germline haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric 2-point lod score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint lod score under heterogeneity was 3.46. The BRCA2 locus was estimated to be located at a recombination fraction of 0.25 from the new locus. Thompson et al. (2002) evaluated the contribution of the BRCA3 locus on 13q21 to breast cancer susceptibility in 128 high-risk breast cancer families of western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. (2000), was zero (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result. The proportion of linked families reported by Kainu et al. (2000) (0.65) was excluded with a high degree of confidence in the 'new' dataset. Thompson et al. (2002) concluded that if a susceptibility gene does exist at 13q21, it can account for only a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer. ### Exclusion Mapping King et al. (1980) presented evidence suggestive of linkage of breast cancer to the glutamate-pyruvate transaminase gene (GPT; 138200) on chromosome 8q24. Analysis of 6 families with the disorder yielded a lod score of 1.84; all 11 families yielded a score of 1.43. However, in Mormon breast cancer pedigrees McLellan et al. (1984) excluded linkage to GPT (cumulative lod score of -3.86). Goldstein et al. (1989) excluded linkage between breast cancer and the genes ABO, GC, GPT, MNS, and PGM1. In 12 high-risk families with breast cancer, Hall et al. (1990) excluded linkage to the HRAS gene (190020) on 11p (lod score of -19.9). By linkage studies, Bowcock et al. (1990) excluded the RB1 gene (614041) on 13q14 and 13q in general as the site of the primary lesion in breast cancer. Abnormality there was sought because of observation of LOH of alleles on 13q in some ductal breast tumors and because 2 breast cancer lines had been found to have an alteration in the retinoblastoma gene. Cytogenetics In breast cancer tissue, Pathak and Goodacre (1986) found somatic reciprocal translocations involving 1q21 and chromosomes 3, 5, 10, 11. Chen et al. (1989) demonstrated loss of heterozygosity (LOH) in the region 1q23-q32. The most frequently occurring constitutional reciprocal translocation in man is t(11;22)(q23;q11), which has been described in more than 100 unrelated families (Iselius et al., 1983). Lindblom et al. (1994) observed a patient with this translocation and breast cancer, prompting a study of the relationship between the 2 conditions. Among 8 families with a total of 22 balanced carriers, 1 case of breast cancer was found in each of 5 families. In another family, an unknown malignancy was reported in 1 member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P less than 0.001). In the 7 families studied, the breakpoints showed the same localization with the markers used. The information suggested the involvement of a gene on 11q and/or 22q in the pathogenesis of breast cancer. Molecular Genetics ### Somatic Changes A previously reported loss of alleles at the HRAS locus, located at 11p14, in about 20% of breast cancer tumors was confirmed by Mackay et al. (1988). Comparing tumor and blood leukocyte DNA from a consecutive series of patients with primary breast cancer, Mackay et al. (1988) found that 61% of the tumors had allele loss demonstrated with a probe located at 17p13.3. Coles et al. (1990) mapped regions of LOH on chromosome 17 by comparing DNA of paired tumor and blood leukocyte samples. They confirmed a high frequency of LOH on 17p, where 2 distinct regions of LOH were identified in bands p13.3 and p13.1. The latter probably involves the structural gene TP53 (191170). The frequency of LOH was higher, however, at 17p13.3, and there was no correlation between allele loss at the 2 sites. Since LOH at 17p13.3 was associated with overexpression of p53 mRNA, Coles et al. (1990) suggested the existence of a gene some 20 megabases telomeric of TP53 that regulates its expression; see 113721. They concluded that lesions of this regulatory gene are involved in the majority of breast cancers. Devilee et al. (1991) reported LOH data. Davidoff et al. (1991) found that in 11 (22%) of 49 primary invasive human breast cancers, widespread overexpression of p53 was indicated by immunohistochemical staining. The p53 gene was directly sequenced in 7 of the tumors with elevated levels of protein, and in each case a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 exhibited coding sequences from both a mutant and a wildtype allele. Six tumors that were deleted at or near the p53 locus but did not express high levels of the protein were sequenced and all retained a wildtype p53 allele. This was interpreted as indicating that overexpression of the p53 protein, not allelic loss, was associated with mutation of the p53 gene. The ARHGEF5 (600888) oncogene belongs to the DBL family of guanine nucleotide exchange factors (GEFs) for RHO GTPases. Debily et al. (2004) identified 5 novel ARHGEF5 alternative transcripts specifically expressed in breast tumors, which were predicted to generate modified or truncated proteins. Histologic features suggested that ARHGEF5 may activate RAC1 (602048), CDC42 (116952), or ARHG (179505) rather than ARHA (165390). The authors hypothesized that activation of the ARHGEF5 oncogene, possibly by variant isoforms, may play a role in proliferative breast disease. By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Sjoblom et al. (2006) determined the sequence of well-annotated human protein-coding genes in 2 common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of about 90 mutant genes, but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, Sjoblom et al. (2006) identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these were not known to be genetically altered in tumors and were predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. Sjoblom et al. (2006) concluded that their data defined the genetic landscape of 2 human cancer types, provided new targets for diagnostic and therapeutic intervention, and opened fertile avenues for basic research in tumor biology. Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007) commented on the article by Sjoblom et al. (2006), citing statistical problems that, if addressed, would result in the identification of far fewer genes with significantly elevated mutation rates. Parmigiani et al. (2007) responded that the conclusions of the above authors were inaccurate because they were based on analyses that did not fully take into account the experimental design and other critical features of the Sjoblom et al. (2006) study. By array CGH, Yang et al. (2006) analyzed the copy number and expression level of genes in the 8p12-p11 amplicon in 22 human breast cancer specimens and 7 breast cancer cell lines. Of the 21 potential genes identified, PCR analysis and functional analysis indicated that 3 genes, LSM1 (607281), BAG4 (603884), and C8ORF4 (607702), are breast cancer oncogenes that could work in combination to influence a transformed phenotype in human mammary epithelial cells. To catalog the genetic changes that occur during tumorigenesis, Wood et al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, Wood et al. (2007) concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. Wood et al. (2007) described statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. The gene mountains were comprised of well-known cancer genes such as APC (611731), KRAS (190070), and TP53 (191170). Furthermore, Wood et al. (2007) observed that most tumors accumulated approximately 80 mutations, and that the majority of these were harmless. Fewer than 15 mutations are likely to be responsible for driving the initiation progression or maintenance of the tumor. Srivastava et al. (2008) found an alteration of the H2AFX (601772) gene copy number in 25 (37%) of 65 breast cancer tissues derived from patients with sporadic forms of the disorder. Gene deletion accounted for 19 (29%) of total cases and gene amplification for 6 (9%). Patients with estrogen and progesterone receptor (PGR; 607311)-positive tumors had more significantly altered copy numbers of H2AFX compared to those with ER/PR-negative tumors. None of the tissues contained H2AFX sequence alterations. Sotiriou and Pusztai (2009) reviewed gene expression signatures in breast cancer. Stephens et al. (2009) used a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. Curtis et al. (2012) presented an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumors, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single-nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in approximately 40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, Curtis et al. (2012) identified putative cancer genes, including deletions in PPP2R2A (604941), MTAP (156540), and MAP2K4 (601335). Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, estrogen-receptor-positive 11q13/14 cis-acting subgroup and a favorable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Curtis et al. (2012) concluded that their results provided a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome. To correlate the variable clinical features of estrogen-receptor-positive breast cancer with somatic alterations, Ellis et al. (2012) studied pretreatment tumor biopsies accrued from patients in 2 studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including 5 genes (RUNX1, 151385; CBFB, 121360; MYH9, 160775; MLL3, 606833; and SF3B1, 605590) previously linked to hematopoietic disorders. Mutant MAP3K1 (600982) was associated with luminal A status, low-grade histology, and low proliferation rates, whereas mutant TP53 (191170) was associated with the opposite pattern. Moreover, mutant GATA3 (131320) correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in estrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology, but most recurrent mutations are relatively infrequent. Ellis et al. (2012) suggested that prospective clinical trials based on these findings will require comprehensive genome sequencing. Primary triple-negative breast cancers (TNBCs), a tumor type defined by lack of estrogen receptor (133430), progesterone receptor (607311), and ERBB2 (611223) gene amplification, represent approximately 16% of all breast cancers. Shah et al. (2012) showed in 104 TNBC cases that at the time of diagnosis these cancers exhibited a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing revealed that only approximately 36% of mutations are expressed. Using deep resequencing measurements of allelic abundance for 2,414 somatic mutations, Shah et al. (2012) determined in an epithelial tumor subtype the relative abundance of clonal frequencies among cases representative of the population. They showed that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than nonbasal TNBC. Although p53, PIK3CA (171834), and PTEN (601728) somatic mutations seem to be clonally dominant compared to other genes, in some tumors their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape, and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumor progression. Shah et al. (2012) concluded that their results showed that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumor clonal genotypes. Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1 (164730), GATA3, and MAP3K1, Banerji et al. (2012) discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, they identified a recurrent MAGI3-AKT3 (611223) fusion enriched in TNBC, lacking estrogen and progesterone receptors, and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor. The Cancer Genome Atlas Network (2012) analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing, and reverse-phase protein arrays. They demonstrated the existence of 4 main breast cancer classes (luminal A, luminal B, HER2 (164870)-enriched, and basal-like) when combining data from 5 platforms, each of which showed significant molecular heterogeneity. Somatic mutations in only 3 genes (TP53, PIK3CA, and GATA3) occurred at greater than 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1 with the luminal A subtype. The Cancer Genome Atlas Network (2012) identified 2 novel protein expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR (131550)/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumors with high-grade serous ovarian tumors showed many molecular commonalities, indicating a related etiology and similar therapeutic opportunities. The biologic finding of the 4 main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raised the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer. Employing a new methodology that combines cistromics, epigenomics, and genotype imputation, Cowper-Sal-lari et al. (2012) annotated the noncoding regions of the genome in breast cancer cells and systematically identified the functional nature of SNPs associated with breast cancer risk. Their results showed that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 (602294) and ESR1 (133430) and the epigenome of histone H3 lysine-4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP in the TOX3 gene (611416) within the 16q12.1 risk locus. Rheinbay et al. (2017) performed deep sequencing in 360 primary breast cancers and developed computational methods to identify significantly mutated promoters. Clear signals were found in the promoters of 3 genes. FOXA1 (602294), a driver of hormone-receptor positive breast cancer, harbored a mutational hotspot in its promoter leading to overexpression through increased E2F (189971) binding. RMRP (157660) and NEAT1 (612769), 2 noncoding RNA genes, carried mutations that affected protein binding to their promoters and altered expression levels. Rheinbay et al. (2017) concluded that promoter regions harbor recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. ### Mutation in the BARD1 Gene on Chromosome 2q34-q35 In 7 of 126 (5.6%) index cases from Finnish families with breast and/or ovarian cancer, Karppinen et al. (2004) identified a cys557-to-ser substitution in the BARD1 gene (C557S; 601593.0001) at elevated frequency compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele. ### Mutation in the CYP17A1 Gene on Chromosome 10q24.3 In 3 sisters with early-onset breast cancer (diagnosed at ages 34, 38, and 42 years, respectively) who did not have mutations in BRCA1 or BRCA2, Hopper et al. (2005) identified a germline R239X mutation in the CYP17A1 gene (609300.0006). A sister who was cancer-free at age 58 did not have the R239X mutation; the mutation was not found in 788 controls. Hopper et al. (2005) suggested that there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly inherited breast cancer risk. Although Haiman et al. (2003) presented initial evidence that haplotypes in the CYP19A1 (107910) gene, which encodes the enzyme aromatase, were associated with increased risk for breast cancer, Haiman et al. (2007) did not find an association between haplotypes or SNPs in the CYP19A1 gene among 5,356 patients with invasive breast cancer and 7,129 controls composed primarily of white women of European descent. Haiman et al. (2007) found that common haplotypes spanning the coding and proximal 5-prime region of the CYP19A1 gene were significantly associated with a 10 to 20% increase in endogenous estrogen levels in postmenopausal women, but not with breast cancer. ### Mutation in the PALB2 Gene on Chromosome 16p12 Mutations in the PALB2 gene (610355), which encodes a BRCA2-interacting protein, cause Fanconi anemia of complementation group N (FANCN; 610832). To investigate whether monoallelic PALB2 mutations confer susceptibility to breast cancer, Rahman et al. (2007) sequenced the PALB2 gene in individuals with breast cancer from familial breast cancer pedigrees in which mutations in BRCA1 or BRCA2 had not been found, and in 1,084 controls. They identified monoallelic truncating PALB2 mutations in 10 of 923 individuals with familial breast cancer and in none of the controls (p = 0.0004), and showed that such mutations confer a 2.3-fold higher risk of breast cancer. The results established PALB2 as a breast cancer susceptibility gene and further demonstrated the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition. Foulkes et al. (2007) identified a single protein-truncating mutation (Q775X; 610355.0012) in the PALB2 gene in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and was not present in any of 6,440 newborn controls (p = 0.003). By screening the PALB2 gene, Tischkowitz et al. (2012) identified 5 pathogenic truncating mutations in 0.9% of 559 patients with contralateral breast cancer compared to no PALB2 mutations among 565 women with unilateral breast cancer, who were used as controls (p = 0.04). Among the mutation carriers, the median ages of the first and second breast cancers were 46 and 55 years, respectively, and all probands had at least 1 first-degree relative with breast cancer, yielding a relative risk of 5.3 for carriers of a pathogenic PALB2 mutation. The frequency of rare missense mutations was similar in both groups, suggesting that rare PALB2 missense mutations do not strongly influence breast cancer risk. Teo et al. (2013) identified 2 nonsense mutations, 2 frameshift mutations, 10 missense variants, 8 synonymous variants, and 4 variants in intronic regions of the PALB2 gene among 747 women from Australia and New Zealand who were negative for BRCA1 and BRCA2 mutations. Of the 4 PALB2 null mutations, only 1 had not been previously reported. Most of the patients had high-grade invasive ductal carcinomas. Teo et al. (2013) concluded that approximately 1.5% (95% confidence interval, 0.6 to 2.4) of Australasian multiplex breast cancer families segregate null mutations in PALB2, most commonly W1038X (610355.0013). Antoniou et al. (2014) analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The risk of breast cancer for female PALB2 mutation carriers compared to the general population was 8 to 9 times as high among those younger than 40 years of age, 6 to 8 times as high among those 40 to 60 years of age, and 5 times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval, 9 to 20) by 50 years of age and 35% (95% confidence interval, 26 to 46) by 70 years of age. Breast cancer risk was also significantly influenced by birth cohort (p less than 0.001) and by other familial factors (p = 0.04). The absolute breast cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% confidence interval, 25 to 44) for those with no family history of breast cancer to 58% (95% confidence interval, 50 to 66) for those with 2 or more first-degree relatives with breast cancer at 50 years of age. Antoniou et al. (2014) calculated that PALB2 loss-of-function mutations account for approximately 2.4% of familial aggregation of breast cancer. Antoniou et al. (2014) concluded that their data suggested that the breast cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. Lee and Ang (2014) responded to the paper by Antoniou et al. (2014). They screened for PALB2, BRCA1, and BRCA2 mutations using targeted capture methods and next-generation sequencing in 100 Asian patients enrolled from a risk-assessment clinic in Singapore. Protein-truncating mutations were detected in 3 (4%) of 78 patients who did not carry BRCA1 or BRCA2 mutations, and the mutations were validated by Sanger sequencing. In addition, deleterious PALB2 mutations were detected in a male patient with breast cancer and in a patient with ovarian cancer, underscoring the need to screen for PALB2 mutations in persons in whom BRCA2 mutations are suspected. ### Association with the NQO2 Gene on Chromosome 6p25 In a hospital-based study of 893 Chinese breast cancer patients and 711 Chinese cancer-free controls, Yu et al. (2009) genotyped 11 polymorphisms of the NQO2 (160998) gene, which encodes NRH:quinone oxidoreductase-2 and has enzymatic activity on estrogen-derived quinones and is able to stabilize p53 (TP53; 191170). The authors identified significant association between the incidence of breast cancer and a 29-bp insertion/deletion polymorphism (29-bp I/D; p = 0.0027; OR, 0.76) and the rs2071002 SNP (+237A-C; p = 0.0031; OR, 0.80), both of which are within the NQO2 promoter region. The findings were replicated in a second Chinese population of 403 familial/early-onset breast cancer patients and 1,039 controls. Decreased risk was associated with the D allele of 29 bp-I/D and the +237C allele of rs2071002. The susceptibility variants within NQO2 were notably associated with breast carcinomas with wildtype p53. The 29-bp insertion allele introduced a transcriptional repressor Sp3 binding sites, and the authors demonstrated that the 237A allele of rs2071002 abolished a transcriptional activator Sp1 binding site. Real-time PCR assay showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Yu et al. (2009) suggested that NQO2 is a susceptibility gene for breast carcinogenesis. Pathogenesis Tavazoie et al. (2008) searched for general regulators of cancer metastasis and found a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. They demonstrated that restoring the expression of these microRNAs in malignant cells suppressed lung and bone metastasis in human cancer cells in vivo. Of these microRNAs, miR126 (611767) restoration reduced overall tumor growth and proliferation, whereas miR335 (611768) inhibited metastatic cell invasion. miR335 regulates a set of genes whose collective expression in a large cohort of human tumors was associated with risk of distal metastasis. miR335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 (184430) and extracellular matrix component tenascin C (187380). Expression of miR126 and miR335 is lost in the majority of primary breast tumors from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. Tavazoie et al. (2008) concluded that miR335 and miR126 are metastasis suppressor microRNAs in human breast cancer. Yang et al. (2009) found that overexpression of LCN2 (600181) in clones of human MFC-7 breast cancer cells induced expression of mesenchymal markers on these cells, including vimentin (VIM; 193060) and fibronectin (FN1; 135600), and downregulated the epithelial cell marker E-cadherin (CDH1; 192090), consistent with an epithelial to mesenchymal transition. Cell motility and invasiveness were also increased. The cancer cell clones with increased LCN2 expression also showed decreased ESR1 expression and increased SLUG (SNAI2; 602150) expression. Inhibition of LCN2 in aggressive breast cancer cells (MDA-MB-231) reduced migration and suppressed the mesenchymal phenotype. Studies in mice showed that breast cancer cells with high LCN2 expression resulted in increased local invasion and lymph node metastases compared to those with low LCN2 expression. In humans, increased urinary LCN2 levels correlated with invasive breast cancer. Overexpression of the hepatic growth factor (HGF; 142409) protein has been observed in breast cancer tissue, but not in normal breast epithelium, of some patients. Ma et al. (2009) identified a cis-acting DNA element located 750 bp upstream from the transcription start site of the human HGF promoter that acts as a transcriptional repressor. The promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which the authors termed 'deoxyadenosine tract element' (DATE). A scan of human breast cancer cells overexpressing HGF identified somatic truncating mutations within the DATE region of the HGF gene that modulated chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter. Truncating DATE variants with 25 or fewer deoxyadenosines were found in breast cancer tumors of 51% of African Americans and 15% of individuals of mixed European descent. Notably, breast cancer patients with the truncated DATE variant were substantially younger than those with a wildtype genotype. Stephens et al. (2009) used a pair-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. They found that there were more rearrangements in some breast cancers than had been previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicated that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicated that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provided a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. Schramek et al. (2010) demonstrated that in vivo administration of medroxyprogesterone acetate (MPA), used in women for hormone replacement therapy and contraceptives, triggers massive induction of the key osteoclast differentiation factor RANKL (602642) in mammary gland epithelial cells. Genetic inactivation of the RANKL receptor RANK (603499) in mammary gland epithelial cells prevented MPA-induced epithelial proliferation, impaired expansion of CD49f(hi) stem cell-enriched population, and sensitized these cells to DNA damage-induced cell death. Deletion of RANK from the mammary epithelium resulted in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. Schramek et al. (2010) concluded that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer. Gonzalez-Suarez et al. (2010) showed that RANK and RANKL are expressed within normal, premalignant, and neoplastic mammary epithelium, and, using complementary gain-of-function and loss-of-function approaches, defined a direct contribution of this pathway in mammary tumorigenesis. Accelerated preneoplasias and increased mammary tumor formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacologic inhibition of RANKL attenuated mammary tumor development not only in hormone- and carcinogen-treated MMTV-RANK and wildtype mice, but also in the MMTV-neu transgenic spontaneous tumor model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in preneoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 (168461) levels. Gonzalez-Suarez et al. (2010) concluded that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. Tan et al. (2011) examined whether RANKL (602642), RANK (603499), and IKK-alpha (600664) are involved in mammary/breast cancer metastasis. RANK signaling in mammary carcinoma cells that overexpress the protooncogene Erbb2 (also known as Neu; 164870), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(186940)+CD25(147730)+ T cells, whose major prometastatic function was RANKL production. Most RANKL-producing T cells expressed FOXP3 (300292), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (see 102540)-positive stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK-positive human breast cancer cells. Tan et al. (2011) concluded that their results were consistent with the adverse impact of tumor-infiltrating CD4+ or FOXP3+ T cells on human breast cancer prognosis and suggested that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumors to prevent recurrent metastatic disease. Possemato et al. (2011) developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, they screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH; 606879) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of estrogen receptor-negative breast cancers. PHGDH catalyzes the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, caused a strong decrease in cell proliferation and a reduction in serine synthesis. Possemato et al. (2011) found that PHGDH suppression does not affect intracellular serine levels, but causes a drop in levels of alpha-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. Possemato et al. (2011) concluded that certain breast cancers are dependent on increased serine pathway flux caused by PHGDH overexpression. Ross-Innes et al. (2012) mapped genomewide estrogen receptor (ER; 133430)-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases, and found that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumors from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumors revealed gene signatures that predict clinical outcome in ER-positive disease exclusively. Ross-Innes et al. (2012) found that the differential ER binding program observed in tumors from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1 (602294)-mediated reprogramming of ER binding on a rapid time scale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histologic coexpression of ER and FOXA1 in metastatic samples. By establishing transcription factor mapping in primary tumor material, Ross-Innes et al. (2012) showed that there is plasticity in ER binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes. Montagner et al. (2012) showed that SHARP1 (BHLHE41; 606200) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is upregulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1-alpha (HIF1A; 603348) and HIF2A (603349). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviors in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of the VHL tumor suppressor (608537), hypoxia, and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. Burns et al. (2013) showed that the DNA cytosine deaminase APOBEC3B (607110) is a probable source of somatic C-to-T mutations in breast cancer. APOBEC3B mRNA is upregulated in most primary breast tumors and breast cancer cell lines. Tumors that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53 (191170). Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments showed that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression caused cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX (601772) accumulation, and C-to-T mutations. Burns et al. (2013) concluded that their data suggested a model in which APOBEC3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explained how some tumors evolve rapidly and manifest heterogeneity. Hypercholesterolemia is a risk factor for estrogen receptor (ER; 133430)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Nelson et al. (2013) showed that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (see LXRA, 602423) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 (606530) and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, Nelson et al. (2013) concluded that lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer. Toy et al. (2013) conducted a comprehensive genetic analysis of 2 independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 (133430) affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding tyr537 to ser, tyr537 to asn, and asp538 to gly alterations. Molecular dynamics simulations suggested that the structures of the tyr537 to ser and asp538 to gly mutants involve hydrogen bonding of the mutant amino acids with asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drove ER-dependent transcription and proliferation in the absence of hormone and reduced the efficacy of ER antagonists. Robinson et al. (2013) enrolled 11 patients with ER-positive metastatic breast cancer in a prospective clinical sequencing program for advanced cancers. Whole-exome and transcriptome analysis identified 6 cases that harbored mutations of ESR1 affecting its LBD, all of whom had been treated with antiestrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified 4 endometrial cancers with similar mutations of ESR1. The 5 LBD-localized ESR1 mutations identified, encoding leu536 to gln, tyr537 to ser, tyr537 to cys, tyr537 to asn, and asp538 to gly, were shown to result in constitutive activity and continued responsiveness to antiestrogen therapies in vitro. In an analysis of whole-genome sequencing of 560 breast cancers, Nik-Zainal et al. (2016) identified 93 protein-coding cancer genes that carried probable driver mutations. Mertins et al. (2016) described quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 (602907) and SKP1 (601434) to elevated expression of epidermal growth factor receptor (EGFR; 600492), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12 (615514), PAK1 (602590), PTK2 (600758), RIPK2 (603455), and TLK2 (608439). Mertins et al. (2016) demonstrated that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets. Spinelli et al. (2017) found that human breast cancer cells primarily assimilate ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH; 138130); secondary reactions enable other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. Spinelli et al. (2017) concluded that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass. Using a kinomewide RNA interference-based screening method, Dasgupta et al. (2018) identified the metabolic enzyme PFKFB4 (605320) as a robust stimulator of SRC3 (601937), which coregulates the estrogen receptor (ESR1; 133430). PFKFB4 phosphorylates SRC3 at serine-857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient ser857-to-ala (S857A) mutant SRC3 abolished the SRC3-mediated transcriptional output. PFKFB4-driven SRC3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase (TKT; 606781). Dasgupta et al. (2018) identified adenosine monophosphate deaminase-1 (AMPD1; 102770) and xanthine dehydrogenase (XDH; 607633), which are involved in purine metabolism, as SRC3 targets that may or may not be directly involved in purine synthesis. Phosphorylation of SRC3 at ser857 increases its interaction with the transcription factor ATF4 (604064) by stabilizing the recruitment of SRC3 and ATF4 to target gene promoters. Ablation of SRC3 or PFKFB4 suppressed breast tumor growth in mice and prevented metastasis to the lung from an orthotopic setting, as did S857A-mutant SRC3. Dasgupta et al. (2018) found that PFKFB4 and phosphorylated SRC3 levels are increased and correlate in estrogen receptor-positive tumors, and in patients with the basal subtype, PFKFB4 and SRC3 drive a common protein signature that correlates with poor survival. Dasgupta et al. (2018) concluded that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC3 to promote aggressive metastatic tumors. Animal Model Parallels may exist with breast cancer in mice, which has long been studied from the viewpoint of genetic-viral etiology and pathogenesis. This story begins with Bittner's 'milk agent,' originally discovered by Bittner (1936); using reciprocal matings between high tumor and low tumor strains, the Jackson Laboratory staff showed in 1933 that the tumor incidence in F1 females was a function of the strain of the mother. Virologists demonstrated that the mouse mammary tumor virus (MMTV, also called MuMTV) is indeed transmitted through the milk and is an RNA virus seen in its mature form as the B particle. This was the first virus universally accepted in this country as a cancer-causing virus. Some mouse strains have been shown to carry a potent MMTV transmitted in milk and also in the egg and sperm (see review by Heston and Parks, 1977). Strains of mice purged of the MMTV by foster-nursing the young on a clean strain still show a low incidence of breast cancer developing at a late age. By introducing the cancer-enhancing gene A(vy), the incidence could be raised to 90%; however, the agent was not transmitted through the milk but by both eggs and sperm. In one strain developed by Muhlbock (1965), Bentvelzen (1972) demonstrated that the high incidence of mammary tumors was caused by an MMTV transmitted in milk, eggs, and sperm. Particles resembling B-type retroviruses have been identified in human milk (Moore et al., 1971); MMTV-related RNA has been found in some breast cancers (Axel et al., 1972) and a breast cancer cell line that releases retrovirus-like particles has been established (McGrath et al., 1974). Callahan et al. (1982) and Westley and May (1984) demonstrated sequences in normal human DNA that appear to be homologous to endogenous retroviral sequences. By transfection of NIH 3T3 mouse cells, Lane et al. (1981) demonstrated a transforming gene in a human mammary tumor cell line (MCF-7). See 164820 for information on the human homolog of the putative mammary tumor oncogene. History Familial breast cancer shares several features with hereditary tumors that satisfy the conditions predicted by the 2-hit hypothesis of Knudson (1971); tumors are frequently bilateral and multifocal. They tend to occur in premenopausal women, while the overall incidence of breast cancer shows a peak at postmenopausal age; and male relatives in high-risk families are more often affected than are males in the general population. Lundberg et al. (1987) tested their hypothesis that the pathogenesis of breast cancer in males and young females involves a chromosomal rearrangement that serves to unmask a recessive cancer gene. Lundberg et al. (1987) studied 10 cases of ductal breast cancer: 8 premenopausal females and 2 males. In 3 females and 1 male, somatic loss of constitutional heterozygosity was observed at loci on chromosome 13 in primary tumor tissue. In 2 cases, specific loss of heterozygosity at 3 distinct genetic loci along the length of chromosome 13 was observed. In a third case, concurrent loss of alleles at loci on chromosomes 2, 13, 14, and 20 was detected, whereas a fourth case showed loss of heterozygosity for chromosomes 5 and 13. In each instance, the data were consistent with loss of one of the homologous chromosomes by mitotic nondisjunction. The relative specificity of the events was suggested by the fact that analysis of loci on several other chromosomes showed retention of constitutional heterozygosity. On the other hand, analyses of other breast cancers, including comedocarcinoma, medullary carcinoma, and juvenile secretory carcinoma, showed no loss of alleles at loci on chromosome 13. Lundberg et al. (1987) interpreted these data as suggesting that in a substantial proportion of cases, the pathogenesis of ductal breast cancer involves the unmasking of a recessive locus on chromosome 13 and involvement of the same locus in heritable forms of this disease. Lundberg et al. (1987) raised the possibility of using molecular cytogenetics as an adjunct to histopathology in the diagnosis of breast tumors. The article by Zhao et al. (2008) describing expression of MIRN221 and MIRN222 in ESR1-negative breast cancer cells and tumors was retracted. INHERITANCE \- Autosomal dominant \- Somatic mutation NEOPLASIA \- Breast carcinoma MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the breast cancer type 1 gene (BRCA1, 113705.0001 ) \- Caused by mutation in the breast cancer type 2 gene (BRCA2, 600185.0001 ) \- Caused by mutation in the solute carrier family 22, member 1-like gene (SLC22A1L, 602631.0001 ) \- Caused by mutation in the tumor protein p53 gene (TP53, 191170.0023 ) \- Caused by mutation in the BRCA1-associated C-terminal helicase 1 gene (BRIP1, 605882.0001 ) \- Caused by mutation in the homolog of the S. cerevisiae RAD51A gene (RAD51A, 179617.0001 ) \- Susceptibility conferred by mutation in the homolog of the S. pombe checkpoint kinase 2 gene (CHEK2, 604373.0007 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	BREAST CANCER	c0346153	5,232	omim	https://www.omim.org/entry/114480	2019-09-22T16:43:50	{"doid": ["1612"], "mesh": ["C562840"], "omim": ["114480"], "icd-10": ["C50-C50", "C50"], "orphanet": ["227535"], "synonyms": ["Alternative titles", "BREAST CANCER, FAMILIAL"], "genereviews": ["NBK1247"]}
A number sign (#) is used with this entry because of evidence that isolated colobomatous microphthalmia-7 (MCOPCB7) is caused by heterozygous mutation in the ABCB6 gene (605452) on chromosome 2q35. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Mapping In members of a 3-generation Chinese family with autosomal dominant iris and chorioretinal coloboma who were negative for mutation in known coloboma-associated genes, Wang et al. (2012) performed genomewide linkage analysis and found linkage to chromosome 2q35. This family was originally reported by Dong et al. (2009). Molecular Genetics In a 3-generation Chinese family with autosomal dominant iris and chorioretinal coloboma mapping to chromosome 2q35 and known to be negative for mutation in known coloboma-associated genes, Wang et al. (2012) sequenced the exons of 76 candidate genes and identified a heterozygous missense mutation in the ABCB6 gene (L811V; 605452.0006) that segregated with disease in the family and was not found in DNA samples from 600 ethnically matched controls. Subsequent analysis of ABCB6 in 116 sporadic Indian coloboma patients, 63 of whom had microphthalmia and coloboma, 21 isolated coloboma, and 32 aniridia, who were all negative for mutation in 9 known coloboma genes, revealed heterozygosity for a different missense mutation (A57T; 605452.0007) in 3 unrelated patients with microphthalmia and coloboma; the mutation was not found in DNA samples from 200 ethnically matched controls. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Coloboma, iris \- Coloboma, chorioretinal \- Microphthalmia (in some patients) MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily B, member 6 gene (ABCB6, 605452.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MICROPHTHALMIA, ISOLATED, WITH COLOBOMA 7	c2931501	5,233	omim	https://www.omim.org/entry/614497	2019-09-22T15:55:00	{"mesh": ["C537463"], "omim": ["614497"], "orphanet": ["98938"]}
Trichomegaly-retina pigmentary degeneration-dwarfism syndrome, also known as Oliver-McFarlane syndrome, is an extremely rare genetic disorder characterized by hair abnormalities, severe chorioretinal atrophy, hypopituitarism, short stature, and intellectual disability. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome	c1848745	5,234	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3363	2021-01-23T18:13:03	{"gard": ["5266"], "mesh": ["C536554"], "omim": ["275400"], "umls": ["C1848745"], "synonyms": ["Long eyelashes-intellectual disability syndrome", "Oliver-McFarlane syndrome"]}
A number sign (#) is used with this entry because of evidence that spermatogenic failure-23 (SPGF23) is caused by homozygous mutation in the TEX14 gene (605792) on chromosome 17q23. For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). Clinical Features Gershoni et al. (2017) studied 2 infertile brothers from a consanguineous Iraqi Jewish family who had nonobstructive azoospermia. Testicular histology showed spermatogonia in all tubules, with only a few spermatocytes in some tubules. Fakhro et al. (2018) reported 2 infertile Jordanian brothers who exhibited nonobstructive azoospermia, with no sperm in their semen. Testicular biopsy showed maturation arrest. Molecular Genetics In 2 infertile brothers with nonobstructive azoospermia from a consanguineous Iraqi Jewish family (family B), Gershoni et al. (2017) performed whole-genome sequencing and identified homozygosity for a 10-bp deletion in the TEX14 gene (605792.0001) that was not found in controls. Mutation status of unaffected family members was not reported. In 8 Middle Eastern families in which at least 2 brothers had nonobstructive azoospermia (NOA), Fakhro et al. (2018) analyzed whole-exome sequencing data and identified 2 Jordanian brothers who were homozygous for a missense mutation in the TEX14 gene (R85L; 605792.0002). Their unaffected consanguineous parents were heterozygous for the mutation, and a fertile brother did not carry the mutation. Exome sequencing in 75 unrelated men with NOA revealed 2 additional men who were homozygous for TEX14 variants: a Nepalese man with Sertoli cell-only histology carried a frameshift variant, and a Tunisian man with Sertoli cell-only histology carried a splice site variant. Neither of those variants was found in 74 ethnically matched fertile men. INHERITANCE \- Autosomal recessive GENITOURINARY Internal Genitalia (Male) \- Infertility \- Azoospermia, nonobstructive \- Maturation arrest seen on testicular biopsy \- No metaphase spermatocytes detected MOLECULAR BASIS \- Caused by mutation in the testis-expressed gene 14 gene (TEX14, 605792.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	SPERMATOGENIC FAILURE 23	c4540185	5,235	omim	https://www.omim.org/entry/617707	2019-09-22T15:45:02	{"omim": ["617707"]}
A number sign (#) is used with this entry because autosomal recessive cutis laxa type IIA (ARCL2A) is caused by homozygous or compound heterozygous mutations in the ATP6V0A2 gene (611716), which encodes the alpha-2 subunit of the V-type H+ ATPase, on chromosome 12q24. The occurrence of mutations in the same gene in wrinkly skin syndrome (WSS; 278250) indicates that autosomal recessive cutis laxa type IIA and some cases of WSS represent variable manifestations of the same genetic defect. Description Autosomal recessive cutis laxa type II represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type II), and ARCL2B, those without a metabolic disorder (summary by Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100). ### Genetic Heterogeneity of Cutis Laxa Type II ARCL2A is caused by mutation in the ATP6V0A2 gene. ARCL2B (612940) is caused by mutation in the PYCR1 gene (179035). ARCL2C (617402) is caused by mutation in the ATP6V1E1 gene (108746). ARCL2D (617403) is caused by mutation in the ATP6V1A gene (607027). Clinical Features Fittke (1942) described a 10.5-month-old female whose skin from birth had been in loose, redundant folds. The face was spared, however. On stretching, the skin returned only slowly to its original position. The skeletal system showed widely persistent fontanels, slight oxycephaly, and dislocation of one hip. The parents were not known to be related but lived in an area of Europe where most persons were related in some degree. The mother, aged 25 years, had long suffered from 'weak knee joints.' An 8-year-old cousin of the proband showed the same skin changes, as well as pigeon breast, static scoliosis, and flat feet. The fontanels had not closed until the third year. The case of Debre et al. (1937) may be identical. Theopold and Wildhack (1951) restudied Fittke's family and demonstrated consanguinity of the parents of the affected cousin. Reisner et al. (1971) described 2 sisters with congenital cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. The parents were first cousins. The authors suggested that the severe form may occur only or mainly in females because it is lethal to the male fetus. They also suggested that this disorder is unusually frequent in Saudi Arabia. Sakati et al. (1983) reported 6 cases, bringing the reported total to 13, all female, and raised the question of X-linked dominant lethal in the hemizygous male. However, Philip (1978) observed a case in a male infant. Fitzsimmons et al. (1985) and Goldblatt et al. (1988) also reported males with this special cutis laxa syndrome. Allanson et al. (1986) reported an affected girl with first-cousin parents of Saudi Arabian extraction. Ogur et al. (1990) reported the cases of Turkish brother and sister. Van Maldergem et al. (1989) pictured a 23-month-old patient born to Turkish first-cousin parents. Facial features included a bossing of the forehead, reversed-V eyebrows, and downward slant of palpebral fissures. The patient also had enormous bilateral inguinal hernias. Imaizumi et al. (1994) described a nineteenth case; the ratio of males to females was 5 to 14. Their patient, a 5-year-old boy, had pre- and postnatal growth retardation, delayed motor development, cutis laxa, delayed closure of large fontanels, congenital hip dislocation, and characteristic facies. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, Morava et al. (2005) performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome. They described 5 patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay, and neurologic findings. Three of these 5 children had an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans, and 2 of these patients had bilateral pachygyria on brain MRI. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were identified in the FBLN5 gene (604580). Morava et al. (2005) concluded that these patients had a unique combined glycosylation defect with a distinct clinical phenotype and that a combined defect of glycosylation may be a causative factor in autosomal recessive congenital cutis laxa. Morava et al. (2008) described 10 patients with cutis laxa and congenital disorder of glycosylation, including 3 patients reported by Morava et al. (2005). Clinical features included transient feeding problems in infancy, late closure of the fontanelles, and variable central nervous system involvement including hypotonia, developmental delay, mental retardation, seizures, microcephaly, pachygyria, and myopia. All patients had dysmorphic facial features with downslanting palpebral fissures, midface hypoplasia, anteverted nares, short nose and small mouth. Other features included congenital hip dislocation and joint hyperlaxity. Skin biopsy showed decreased amounts of elastin and abnormal elastin structure. Biochemical analysis showed a combined defect of N- and O-glycosylation. All patients had mutations in the ATP6V0A2 gene (Kornak et al., 2008). Van Maldergem et al. (2008) reported 11 patients from 9 families with the Debre type of cutis laxa, which was confirmed by genetic analysis of the ATP6V0A2 in all patients except 1. All had dysmorphic craniofacial features, most commonly including large anterior fontanel, prominent supraorbital ridges and nasal root, downslanting palpebral fissures, and coarse hair. Four patients had microcephaly. The skin showed generalized overfolding and wrinkling, but no hyperelasticity, and skin biopsies showed a sparse elastin network. Connective tissue problems were common, and included inguinal hernia, hip dislocation, and high myopia. There tended to be improvement of cutis laxa throughout childhood. All had mental retardation that varied in severity, and 5 patients developed refractory seizures. Transferrin isoelectric focusing showed CDG type II. Brain imaging was performed in 9 patients, 8 of whom showed a cobblestone-like malformation predominantly in the posterior frontal, perisylvian, and parietal regions. It resembled polymicrogyria, but the cortical ribbon appeared smooth in some areas and irregular in others. These cortical malformations were reminiscent of those observed in the alpha-dystroglycanopathies, such as Walker-Warburg syndrome (see, e.g., MDDGA1, 236670). Two patients had a Dandy-Walker malformation. Morava et al. (2009) reviewed the spectrum of clinical features of the various autosomal recessive syndromes associated with cutis laxa, including ARCL1 (219100), ARCL2, de Barsy syndrome (219150), X-linked cutis laxa (304150), WSS, geroderma osteodysplasticum (GO; 231070), and Costello syndrome (218040). ### Relationship to Wrinkly Skin Syndrome Zlotogora (1999) pointed out that the 2 sisters reported by Reisner et al. (1971) as one of the first examples of the syndrome of cutis laxa with growth and developmental delay were reported later, along with their newborn brother, as examples of WSS. Conformation that these 2 syndromes represent variable presentations of one disorder may be provided by the report of Ogur et al. (1990) on 2 affected Turkish sibs. The boy was severely affected with the classic form of cutis laxa and developmental delay, while his sister showed improvement with the years and at the age of 6.5 years presented with a relatively mild disease, including cutaneous manifestations similar to those found in the wrinkly skin syndrome. Another source of confusion is that some of the children reported with recessive infantile cutis laxa with growth and developmental delay were, in fact, affected with Costello syndrome (see later). Since the wrinkly skin syndrome is not a true form of cutis laxa (Azuri et al., 1999), Zlotogora (1999) suggested use of the designation 'wrinkly skin syndrome' for all of the patients who were reported as affected with either one or the other of these 2 syndromes. Pathogenesis Congenital disorders of glycosylation (CDG) form a growing class of hereditary disorders caused by defective glycosylation at the level of the endoplasmic reticulum or the Golgi apparatus (Freeze, 2006). An association of a cutis laxa phenotype with CDG has been described (Morava et al., 2005), and wrinkly skin has been observed in an individual with a defect in the conserved oligomeric Golgi (COG) complex (Wu et al., 2004). On the basis of these observations, Kornak et al. (2008) investigated glycosylation of serum proteins isolated from individuals with autosomal recessive cutis laxa type II and found that they showed a CDG type II pattern, which corresponds to a defect of N-glycosylation at the level of processing in the Golgi apparatus. Reduced sialic acid content of the glycans from affected individuals indicated that sialylation, a terminal step of glycan synthesis, was particularly impaired. A strict correlation between phenotype and degree of glycan abnormality was not seen. Mapping In 15 consanguineous families with a cutis laxa or wrinkly skin syndrome phenotype, Kornak et al. (2008) performed homozygosity mapping, microsatellite marker analysis, and haplotype analysis and identified a 5.7-Mb region of homozygosity on chromosome 12q24 between markers D12S395 and D12S304 containing the ATP6V0A2 gene. Molecular Genetics In 12 families with diagnoses of either autosomal recessive cutis laxa type II or wrinkly skin syndrome, Kornak et al. (2008) identified 10 different loss-of-function mutations in the ATP6V0A2 gene. The mutations resulted in abnormal glycosylation of serum proteins (CDG II) and caused an impairment of Golgi trafficking in fibroblasts from affected individuals. The results indicated that the alpha-2 subunit of the proton pump has an important role in the Golgi function. Leao-Teles et al. (2010) stated that 1 of the patients studied by Kornak et al. (2008) and found to have a mutation in the ATP6V0A2 gene (patient 'CoFe') displayed the full clinical picture of the De Barsy syndrome (see 219150), including cutis laxa, facial dysmorphism, dwarfism, psychomotor retardation, dystonia, congenital hip dysplasia, and corneal dystrophy requiring repeated corneal transplantation. Leao-Teles et al. (2010) suggested that a subgroup of patients with de Barsy syndrome belongs to the spectrum of ATP6V0A2-associated CDG, and recommended that mutations in the ATP6V0A2 gene be sought in patients diagnosed with de Barsy syndrome. Morava et al. (2010) noted that none of their cohort of 6 patients with de Barsy syndrome had N-linked or O-linked glycosylation abnormalities nor mutations in ATP6V0A2; they stated that further description and photographs of patient CoFe would be helpful, since corneal abnormalities with a movement disorder would widen the range of symptoms evoking glycosylation studies in patients with cutis laxa. In 13 patients with ARCL2, Fischer et al. (2012) identified 17 ATP6V0A2 mutations: 1 mutation of the start codon, 3 missense mutations, 3 nonsense mutations, 3 splice site mutations, 3 in-frame deletions, and 4 frameshift mutations; 14 of the mutations were novel. All mutations but 1 were found in homozygous or compound heterozygous state. A heterozygous mutation was detected at the genomic as well as the cDNA level in a 40-year-old patient (patient 2), but a pronounced nonsense-mediated decay of the ATP6V0A2 mRNA in fibroblasts corroborated an ATP6V0A2-related ARCL2. Fischer et al. (2012) suggested that the second mutation most probably resided in noncoding regions not included in the mutation screening. This patient, who was described as the oldest affected individual reported to that time, showed a strikingly progressive phenotype leading to kyphoscoliosis, facial coarsening, mild to moderate mental retardation, and seizures without progression. Heterogeneity ### Exclusion Studies In 3 unrelated patients with autosomal recessive cutis laxa type II, Scherrer et al. (2008) excluded mutations in the FBLN4 (604633), FBLN5 (604580), and LOX (153455) genes. The ATP6V0A2 gene was not studied in these patients. History Under the title 'congenital cutis laxa with retardation of growth and development,' Patton et al. (1987) reported 7 patients. Autosomal recessive inheritance was supported by the inclusion of 2 brother-sister pairs. In 1 of these, the parents were second cousins from the Middle East. The authors were impressed with the occurrence of widespread dental caries. Later, Patton and Baraitser (1993) reviewed 5 of the cases and concluded that the appropriate diagnosis was Costello syndrome (218040). Davies and Hughes (1994) reviewed case 7 from the paper and, on both history and clinical examination, made 'an unequivocal diagnosis of Costello syndrome.' INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation (IUGR) \- Failure to thrive HEAD & NECK Head \- Microcephaly Face \- Midface hypoplasia \- Long philtrum \- Flat face Ears \- Low-set ears Eyes \- Downslanting palpebral fissures \- Strabismus \- Myopia Nose \- Short nose \- Anteverted nares Mouth \- Small mouth \- High-arched palate Teeth \- Dental caries ABDOMEN Gastrointestinal \- Feeding problems in infancy SKELETAL \- Joint hyperextensibility Skull \- Large anterior fontanel \- Delayed closure of the fontanel Pelvis \- Congenital hip dislocation SKIN, NAILS, & HAIR Skin \- Cutis laxa \- Loose redundant skin \- Excessive skin folds Skin Histology \- Abnormal, broken, shortened elastic fibers \- Decreased amount of elastin Hair \- Sparse, brittle hair \- Coarse hair MUSCLE, SOFT TISSUES \- Hypotonia \- Lipodystrophy \- Abnormal distribution of subcutaneous fat NEUROLOGIC Central Nervous System \- Delayed motor development \- Mental retardation \- Seizures \- Hypotonia \- Partial pachygyria \- Cobblestone lissencephaly, posterior frontal and parietal regions \- Board and poorly defined gyri \- Polymicrogyria \- Dandy-Walker malformation LABORATORY ABNORMALITIES \- Abnormal isoelectric focusing of serum transferrin \- Defect in N- and O-glycosylation MISCELLANEOUS \- Skin abnormalities tend to decrease with age MOLECULAR BASIS \- Caused by mutation in the ATPase, H+ transporting, lysosomal, V0 subunit A2 gene (ATP6V0A2, 611716.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIA	c0268355	5,236	omim	https://www.omim.org/entry/219200	2019-09-22T16:29:09	{"doid": ["0070134"], "mesh": ["C562632"], "omim": ["219200"], "orphanet": ["357058", "357074"], "synonyms": ["Alternative titles", "ARCL2", "CUTIS LAXA WITH CONGENITAL DISORDER OF GLYCOSYLATION", "CUTIS LAXA WITH GROWTH AND DEVELOPMENTAL DELAY", "CUTIS LAXA, DEBRE TYPE", "CUTIS LAXA WITH BONE DYSTROPHY", "CUTIS LAXA WITH JOINT LAXITY AND RETARDED DEVELOPMENT"], "genereviews": ["NBK5200"]}
## Summary ### Clinical characteristics. COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: * Classic non-deforming OI with blue sclerae (previously OI type I) * Perinatally lethal OI (previously OI type II) * Progressively deforming OI (previously OI type III) * Common variable OI with normal sclerae (previously OI type IV) ### Diagnosis/testing. The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing. ### Management. Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in medical management of OI, clinical genetics, orthopedics, rehabilitation medicine, pediatric dentistry, otology/otolaryngology, and mental health. Parents / other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs depending on OI severity; orthotics to stabilize lax joints; physical activity; physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, prevent head and spine deformity, and improve muscle strengthening; mobility devices as needed; and pain management. Fractures are treated with: as short a period of immobility as is practical; small and lightweight casts; physical therapy as soon as casts are removed; and intramedullary rodding when indicated to provide anatomic positioning of limbs. Progressive scoliosis in severe OI may not respond well to conservative or surgical management. Bisphosphonates continue to be used most extensively in severely affected children with OI. Surgical treatment for basilar impression should be done in a center experienced in the necessary procedures. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as when caused by other conditions. Mental health support through psychiatry/psychology and appropriate social worker intervention can improve quality of life. Prevention of secondary complications: During general anesthesia, proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures. Surveillance: Orthopedic evaluation with ancillary therapy services (physical and rehabilitation medicine) as indicated every three months until age one year, every six months from ages one to three years, and then annually or with any new fractures. Physical therapy evaluation in infancy for those with motor delays and as needed to improve mobility and function. CT and/or MRI examination with views across the base of the skull to evaluate for basilar impression if concerning signs or symptoms are present. Cervical spine flexion and extension radiographs in children able to cooperate with the examination or before participating in sporting activities in more mildly affected individuals. Twice-yearly dental visits beginning in early childhood or even infancy for those with (or at risk for) DI. Hearing evaluation at three- to five-year intervals from age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions. Agents/circumstances to be avoided: Contact sports should be avoided. ### Genetic counseling. COL1A1/2-OI is inherited in an autosomal dominant manner. The proportion of affected individuals who represent simplex cases (i.e., a single occurrence of the disorder in a family) varies by the severity of disease. Approximately 60% of probands with mild OI represent simplex cases. Virtually 100% of probands with progressively deforming or perinatally lethal OI represent simplex cases and have a de novo pathogenic variant or a pathogenic variant inherited from a parent with somatic and/or germline mosaicism. Parental somatic and/or germline mosaicism is present in up to 16% of families. Each child of an individual with a dominantly inherited form of COL1A1/2-OI has a 50% chance of inheriting the causative variant and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 causative variant has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur. ## Diagnosis An algorithm for the diagnosis of osteogenesis imperfecta (OI) has been published [Basel & Steiner 2009]. See Figure 1. #### Figure 1. Recommended testing algorithm for evaluation of osteogenesis imperfecta Adapted from Basel & Steiner [2009] ### Suggestive Findings COL1A1/2 osteogenesis imperfecta (OI) should be suspected in individuals with the following clinical, radiographic, and laboratory features. Clinical features (Table 1) * Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known disorders of bone * Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity * Blue/gray scleral hue * Dentinogenesis imperfecta (DI) * Progressive, postpubertal hearing loss * Ligamentous laxity and other signs of connective tissue abnormality * Family history of OI, usually consistent with autosomal dominant inheritance ### Table 1. Clinical Features of COL1A1/2 Osteogenesis Imperfecta by Type View in own window TypeMOISeverityFracturesBone DeformityStatureDIScleraeHearing Loss Classic non-deforming OI w/blue scleraeADMildFew to 100UncommonNormal or slightly short for familyRareBluePresent in ~50% Perinatally lethal OIADPerinatal lethalMultiple fracture of ribs, minimal calvarial mineralization, platyspondyly, marked compression of long bonesSevereSeverely short+Dark blue— Progressively deforming OIADSevereThin ribs, platyspondyly, thin gracile bones w/many fractures, "popcorn" epiphyses commonModerate to severeVery short+BlueFrequent Common variable OI w/normal scleraeADModerate to mildMultipleMild to moderateVariably short+/–Normal to graySome AD = autosomal dominant; DI = dentinogenesis imperfecta; MOI = mode of inheritance Radiographic features of OI change with age. The major findings include the following (Table 2): * Fractures of varying ages and stages of healing, often of the long bones but may also rarely involve ribs and skull. Metaphyseal fractures can be seen in a very small number of children with OI. Rib fractures are much more common in NAT than in OI. * "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in adults * Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrangement in a mosaic pattern" [Cremin et al 1982]. Wormian bones are suggestive of but not pathognomonic for OI. * Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum * Low bone mass or osteoporosis detected by dual energy x-ray absorptiometry (DEXA). Bone density can be normal, especially in individuals with OI type I, as DEXA measures mineral content rather than collagen [Deodhar & Woolf 1994, Paterson & Mole 1994, Cepollaro et al 1999, Lund et al 1999]. Note: (1) A major determinant of bone density may be the individual's ability to ambulate. (2) Bone density standards for children under age two years have been determined after sampling very small populations (often <10 persons); thus, reliability is an issue. (3) Bone density standards for children are based on height; corrections for short stature of severely affected individuals need to be made. (4) Bone density is not typically measured in children before age four years because of their inability to lie still, though this may be accomplished with patience in sleeping infants. (5) The purpose of measuring bone density in individuals known to have OI is to allow for monitoring of the individual's bone density over time, and not for comparison with unaffected individuals. ### Table 2. Radiographic Findings of COL1A1/2 Osteogenesis Imperfecta by Type View in own window TypeSeveritySkullBackExtremitiesOther Classic non-deforming OI w/blue scleraeMildWormian bonesCodfish vertebrae (adults)Thin corticesOsteopenia Perinatally lethal OIPerinatal lethalUndermineralization; plaques of calcificationPlatyspondylySeverely deformed; broad, crumpled, bent femursSmall beaded ribs (pathognomonic) Progressively deforming OISevereWormian bonesCodfish vertebrae; kyphoscoliosisFlared metaphyses ("popcorn"-like appearance in childhood), bowing, thin corticesThin ribs, severe osteoporosis Common variable OI w/normal scleraeIntermediate± wormian bonesCodfish vertebraeThin corticesProtrusio acetabuli in a subset Laboratory features * Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, alkaline phosphatase may be elevated acutely in response to fracture and rare instances of abnormally low alkaline phosphatase levels have been noted anecdotally in severe OI. * Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy reflects the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI [Wenstrup et al 1990; PH Byers, personal communication]. Biochemical analysis is essentially no longer used clinically with the advances in molecular diagnostics. #### Establishing the Diagnosis The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing (see Table 3). An approach to the molecular diagnosis of OI has been published (see Figure 2) [van Dijk et al 2012], but such approaches are in flux as technology is changing rapidly. #### Figure 2. Preferred diagnostic flow in OI The approach to diagnosis is designed to maximize the likelihood that causative variants will be identified in all affected individuals or assign those without causative variants to research pools. This flow assumes that (more...) Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of COL1A1/2-OI, molecular genetic testing approaches can include concurrent gene testing or use of a multigene panel: * Concurrent gene testing. Sequence analysis of COL1A1 and COL1A2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes COL1A1, COL1A2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 3). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by bone fragility and/or skeletal dysplasia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible and becoming more widely available. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 3. Molecular Genetic Testing Used in COL1A1/2 Osteogenesis Imperfecta View in own window Gene 1, 2Proportion of OI Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 COL1A1~5%-70% 6>95% 71%-2% 8 COL1A2~5%-30 6>95% 71%-2% 8 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. PH Byers, personal communication 7\. Sequence analysis of COL1A1 and COL1A2 cDNA to detect pathogenic variants in the coding sequence and sequence analysis of COL1A1 and COL1A2 genomic DNA to detect pathogenic variants that alter either sequence or stability of mRNA identify close to 100% of pathogenic variants in these two genes. 8\. van Dijk et al [2010] and data derived from Human Gene Mutation Database [Stenson et al 2017] ## Clinical Characteristics ### Clinical Description The severity of COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) ranges from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal life span. COL1A1/2-OI is classified into four more common types based on clinical presentation, radiographic features, family history, and natural history [Sillence et al 1979]. An update of the Sillence classification has been proposed and has gained some acceptance [Emery & Rimoin 2012]. Although this classification of COL1A1/2-OI into types is helpful in providing information about prognosis and management of a given individual, the features of different types of COL1A1/2-OI overlap and it is not always easy to categorize the extent of the clinical disorder. It is helpful to remember that the severity of clinical and radiographic features lies on a continuum and that the "types" are defined using characteristics that appear to form clinical "nodes." Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same causative variant. Nonetheless, it is reasonable to continue to think of COL1A1/2-OI in terms of these types in order to provide information about the expected natural history of the disorder. Classic non-deforming OI with blue sclerae (previously OI type I) is characterized by blue sclerae and normal stature. A small proportion of infants with OI type I have femoral bowing at birth. The first fractures may occur at birth or with diapering. More often, the first fractures occur when the infant begins to walk and, more importantly, to fall. Fractures generally occur at a rate of a few to several per year and then decrease in frequency after puberty. Fracture frequency often increases again in adulthood, especially in postmenopausal women and men beyond the fifth decade [Paterson et al 1984]. Affected individuals may have anywhere from a few fractures to more than 100, but the fractures usually heal normally with no resulting deformity. Most affected individuals have normal or near normal stature but are often shorter than other members of their families and shorter than predicted based on parental heights. Joint hypermobility predisposes to a number of minor comorbidities. The primary clinical concern is early-onset degenerative joint disease due to malalignment of articular surfaces. In their classification of OI, Sillence et al [1979] designated a subset of classic non-deforming OI with dentinogenesis imperfecta (DI) (OI type IB). In individuals with DI, morbidity results not from dental decay but rather from premature wearing down of the teeth. DI can be a significant cosmetic concern. Dental eruption in classic non-deforming OI can sometimes occur early. Progressive hearing loss occurs in about 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss but often with an additional sensorineural hearing loss component in time. Perinatally lethal OI (previously OI type II). Abnormalities characteristic of perinatally lethal OI are evident at birth. Weight and length are small for gestational age. The sclerae are dark blue and connective tissue is extremely fragile. The skull is large for the body size and soft to palpation. Callus formation on the ribs may be palpable. Extremities are short and bowed. Hips are usually flexed and abducted in a "frog-leg" position. Although some fetuses with perinatally lethal OI die in utero or are spontaneously aborted, more typically infants die in the immediate perinatal period. More than 60% of affected infants die on the first day; 80% die within the first week; survival beyond one year is exceedingly rare and usually involves intensive support such as continuous assisted ventilation [Byers et al 1988]. Death usually results from pulmonary insufficiency related to the small thorax, rib fractures, or flail chest because of unstable ribs. Those who survive the first few days of life may not be able to ingest sufficient calories because of respiratory distress. Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [Horton et al 1980]. Cortical bone is hypercellular with large osteocytes. Trabeculae contain woven bone with large immature osteoblasts [Cole et al 1992, Cole & Dalgleish 1995]. Progressively deforming OI (previously OI type III). The diagnosis of progressively deforming OI is readily apparent at birth. Fractures in the newborn period, simply with handling of the infant, are common. In some affected infants, the number and severity of rib fractures lead to death from pulmonary failure in the first few weeks or months of life. Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheelchair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of obvious fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement. Growth is extremely delayed and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter. Intellect is normal unless there have been intracerebral hemorrhages (extremely rare). Faqeih et al [2009] published a report identifying increased risk for intracranial hemorrhage (ICH) in a "small number" of individuals who were identified to have pathogenic variants affecting exon 49 of COL1A2, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen alpha-2(I) chain. They concluded that this pathogenic variant appeared to increase the risk for abnormal limb development and intracranial bleeding. Budsamongkol et al [2019] reported a young boy with marked joint hypermobility, significant DI, brachydactyly, and a COL1A2 pathogenic variant found to be associated with ICH by Faqeih et al [2009]. The boy had not experienced an ICH, but as some of the original affected individuals only presented with ICH in their teenage years, this does not eliminate the risk in this young individual. Even within progressively deforming OI, considerable heterogeneity is observed at the clinical level. Some individuals have normal-appearing teeth and facies while others have DI, a large head, and enlarged ventricles that reflect the soft calvarium. Relative macrocephaly and barrel chest deformity are observed. Usually sclerae are blue in infancy but lighten with age. Hearing loss generally begins in the teenage years. As molecular testing of this subgroup further differentiates those with COL1A1/2-OI from the autosomal recessive forms, the clinical profile of this heterogeneous group will become more refined. Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal CSF flow [Charnas & Marini 1993, Sillence 1994, Hayes et al 1999]. Symptoms of basilar impression become apparent with neck flexion. Findings include posterior skull pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm. When swimming, affected individuals may perceive that water temperature differs below and above the umbilicus. Lhermitte's sign (tingling on neck flexion) can be demonstrated at any stage. Basilar impression can cause headache with coughing, trigeminal neuralgia, loss of function of the extremities, or paresthesias. At its most severe involvement, sleep apnea and death can occur. Common variable OI with normal sclerae (previously OI type IV) is characterized by mild short stature, DI, adult-onset hearing loss, and normal-to-gray sclerae. This is the most variable form of OI, ranging in severity from moderately severe to so mild that it may be difficult to make the diagnosis. Stature is variable and may vary markedly within the family. DI is common but may be mild. Sclerae are typically light blue or gray at birth but quickly lighten to near normal. Hearing loss occurs in some and basilar impression can occur. #### Other Considerations Facial features. Infants and children with OI are often described as having a triangular face. The skull is relatively large compared to body size. Other skeletal problems. Individuals with OI may also have scoliosis, early-onset arthritis, non-inflammatory arthralgia, and myofascial pain. Skin. Easy bruising is a frequent observation in individuals with OI. This is believed to be caused by microvascular fragility and poor microstructural support of the connective tissues. Hearing loss. Mixed conductive and sensorineural hearing loss afflicts the majority of adults with OI. Childhood-onset hearing loss affects approximately 7% of affected children between ages five and nine years; progressive postpubertal hearing loss is more typical. The initial conductive hearing loss results from fractures of the bones of the middle ear with contracture and scarring of the incus. With age, sensorineural hearing loss compounds the preexisting conductive element. Fixation of the stapes is not unlike otosclerosis and surgical techniques such as stapedotomy used to treat otosclerosis have shown similar success in treating hearing loss in OI [van der Rijt & Cremers 2003, Kuurila et al 2004, Doi et al 2007]. Bisphosphonate therapy has not been shown to influence hearing loss. Gastrointestinal. Although complaints of constipation are common in adults with OI who are mobile in wheelchairs, it is not clear if this is a complication of OI itself or of the mode of transport. Bowel obstruction can occur as a result of protrusio acetabuli [Lee et al 1995] but appears to be uncommon. Cardiovascular. Emerging data support an increased risk for cardiac and vascular disease in OI. Ashournia et al [2015] performed a systematic review of the literature in 2015 documenting a broad array of cardiovascular phenotypes with higher prevalence in individuals with a clinical diagnosis of OI including arterial and aortic dissection. Balasubramanian et al [2019] reported three additional individuals with COL1A1/2-OI and aortic aneurysms. There is still no consensus on cardiovascular surveillance, although some centers have initiated screening echocardiograms every three to five years to monitor for this risk. Development. Cognition is expected to be normal but gross motor development may be hindered by joint hypermobility and progressive deformity due to recurrent fractures. Functional limitations. Individuals with OI may experience other functional limitations, although these will be highly dependent on the specific physical manifestations of OI. Life expectancy. The severely affected neonates with perinatally lethal OI typically do not survive, with a significant proportion of infants dying within the first 48 hours. Aggressive life support can prolong survival but ultimately the most severe forms remain perinatally lethal. Life expectancy for classic non-deforming OI and common variable OI is normal. Progressively deforming OI is highly variable and life expectancy may be shortened by the presence of severe kyphoscoliosis with attendant restrictive pulmonary disease resulting in cardiac insufficiency. ### Phenotype Correlations by Gene Most commonly OI results from pathogenic heterozygous variants in either of the genes encoding the alpha helical chains of type 1 collagen that form the collagen triple helical molecule. Quantitative impacts on type 1 collagen tend to result in a milder phenotype when compared to qualitative changes due to a dominant-negative effect. Loss-of-function variants generally are associated with classic non-deforming OI with blue sclerae (previously OI type I). In general, a clear genotype-phenotype correlation does not exist. General rules for genotype-phenotype correlations in COL1A1/2-OI have been published [Ben Amor et al 2011], but there are exceptions to these rules (e.g., glycine to serine substitutions may lead to a more severe phenotype in COL1A1 than a similar change in COL1A2). The extent of variation and the clinical presentation is represented in Maioli et al [2019] (see Figure 2). ### Genotype-Phenotype Correlations It is important to keep the exceptions in mind when providing genetic counseling, particularly in the prenatal setting. Genotyping can be helpful in distinguishing classic non-deforming OI from all other types of OI. Classic non-deforming OI almost always results from a pathogenic variant in one COL1A1 or COL1A2 allele that introduces premature termination codons and decreases the stability of mRNA (nonsense-mediated decay of the message resulting in a quantitative reduction of the collagen fibril). These causative variants may occur by codon changes, by frame shifts, and by splicing that results in use of cryptic splice sites and premature termination. The type I collagen molecule contains two pro α1(I) chains and a single α2(I) chain. If the number of available pro α1(I) chains decreases, the amount of the trimer manufactured is diminished because no more than one pro α2(I) chain can be accommodated per molecule. Perinatally lethal OI, progressively deforming OI, and common variable OI all result from pathogenic variants that alter the structure of either pro α1(I) or pro α2(I) chains. This causes a dominant-negative effect whereby the abnormal protein is integrated into the triple helix and collagen fibril, which in turn undergoes continual remodeling, thus resulting in significantly compromised structural integrity of the bone matrix (a qualitative impact on the protein product). The most common pathogenic variants result in substitution of another amino acid for glycine in the triple helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon. Glycine is the least bulky amino acid, and other substituting amino acids do not fit well into the collagen triple helix. * Substitutions in the pro α1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain. * For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized. * Much more variability occurs with pathogenic variants that affect glycine residues in the pro α2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship. The other common disease-causing variants affect splice sites. Variants that lead to exon skipping in the pro α1(I) chain beyond exon 14 and in the pro α2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility. A relatively small number of pathogenic variants that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association and pathogenic variants have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of pathogenic variants that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain. Somatic mosaicism for dominant pathogenic variants has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI. The phenotype of the individual with somatic mosaicism can range from no identifiable characteristics of OI to one of the mild forms. The current estimate for the incidence of somatic/gonadal mosaicism is up to 16% of families. * Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells. * Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic. ### Penetrance The penetrance in individuals heterozygous for a COL1A1 or COL1A2 pathogenic variant is 100%, although expression may vary considerably, even in the same family. ### Nomenclature Current (and previously used) nomenclature: * Classic non-deforming OI with blue sclerae (previously, osteogenesis imperfecta type I) * Perinatally lethal OI (osteogenesis imperfecta type II) * Progressively deforming OI (osteogenesis type III) * Common variable OI with normal sclerae (osteogenesis imperfecta type IV) The classification scheme of "OI congenita" and "OI tarda" was discarded because fractures at birth can be noted in mild OI and infants with severe OI may not have fractures at birth. In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility. ### Prevalence Considering all types, OI has a prevalence of approximately 6-7:100,000. COL1A1/2-OI comprises the largest proportion of OI, representing about 90% of all causes of OI. ## Differential Diagnosis ### Distinguishing COL1A1/2 Osteogenesis Imperfecta (COL1A1/2-OI) from Other Types of OI The primary differential diagnoses for individuals with features of COL1A1/2-OI are non-collagen-associated forms of OI. There are both dominant and recessive types, which can be phenotypically indistinct from COL1A1/2-OI. In a small subset of individuals, specific causative variants have not yet been identified. Table 5 summarizes the molecular basis of these subtypes of OI, the mode of inheritance, the corresponding clinical OI type, and distinguishing clinical and radiographic features. ### Table 5. Other Types of Osteogenesis Imperfecta in the Differential Diagnosis of COL1A1/2 Osteogenesis Imperfecta View in own window Functional GroupGeneMOIOMIM-Defined Genetic OI Type 1Clinical OI Type 2Distinguishing from COL1A1/2-OI Collagen type I processingBMP1AROI type XIII (OMIM 614856)OI-IIIUmbilical hernia; hypertelorism; no DI or HL CRTAPAROI type VII (OMIM 610682)OI-II, III, or IVNormal birth length; proptosis; no DI; pulmonary vasculature malformations; rhizomelia FKBP10ARBruck syndrome 1 / OI type XI (OMIM 259450 & 610968)OI-III or IVBrachycephaly; no easy bruising; no DI or HL; white sclera; inguinal hernia; joint contractures; pterygia P3H1 (LEPRE1)AROI type VIII (OMIM 610915)OI-II or IIINo DI; white sclerae; proptosis; long phalanges PLOD2ARBruck syndrome 2 (OMIM 609220)OI-IIINo DI or HL; white sclerae; inguinal hernia; joint contractures; pterygia PPIBAROI type IX (OMIM 259440)OI-II, III, or IVNo DI or HL; white sclerae SEC24DARCole-Carpenter syndrome 2 (OMIM 616294)OI-IIITurricephaly; proptosis; hypertelorism; dysplastic ears; no HL; white sclerae; hydrocephalus; high-pitched voice SERPINH1AROI type X (OMIM 613848)OI-IIIMacrocephaly; proptosis; renal calculi SPARCAROI type XVII (OMIM 616507)OI-IVNo DI or HL; white sclerae; risk for intracranial hemorrhage TMEM38BAROI type XIV (OMIM 615066)OI-IIINo DI or HL; white sclerae Other osteoblast genesCREB3L1AROI type XVI (OMIM 616229)OI-IIITooth agenesis IFITM5ADOI w/calcification in interosseous membranes, OI type V (OMIM 610967)Short stature & fracturesSclerae generally white; DI rare; hypertrophic callus formation; calcification of interosseous membrane between ulna & radius that leads to inability to fully supinate & pronate forearm; no HL MBTPS2XLOI type XIX (OMIM 301014)OI-III or IVNo HL; sclerae generally white; rhizomelia; epiphyseal "popcorn" calcification MESD 3AROI type XX (OMIM 618644)OI-III-IVFacial dysmorphisms incl arched eyebrows & tented shape of lips; long fingers w/5th finger camptodactyly; oligodontia SERPINF1AROI type VI (OMIM 613982)OI-III or IVNo DI or HL SP7AROI type XII (OMIM 613849)OI-III or IVNo DI; white sclerae TENT5A (FAM46A)AROI type XVIII (OMIM 617952)OI-III or IVNo DI or HL; umbilical hernia WNT1AROI type XV (OMIM 615220)OI-III or IVStructural brain malformations; rhizomelia AD = autosomal dominant; AR = autosomal recessive; DI = dentinogenesis imperfecta; HL = hearing loss; MOI = mode of inheritance; XL = X-linked 1\. See OMIM: Clinical Synopsis Table. 2\. Bonafe et al [2015], Robinson & Rauch [2019] 3\. Moosa et al [2019] ### Distinguishing OI from Other Disorders and Non-Accidental Trauma The differential diagnosis of OI depends largely on the age at which the individual is assessed [Plotkin 2004]. Clinical features that help to differentiate COL1A1/2-OI from other conditions include characteristic triangular facies, blue sclerae, joint hypermobility, dental abnormalities, and, in adults, hearing loss. #### In Utero Assessment Early prenatal ultrasound examination or radiographic findings may lead to a consideration of hypophosphatasia, thanatophoric dysplasia, campomelic dysplasia, and achondrogenesis as well as perinatally lethal OI. In some cases, either biochemical or molecular testing can be a useful adjunct. ### Table 6. Genes of Interest in the Differential Diagnosis of COL1A1/2 Osteogenesis Imperfecta – In Utero Assessment View in own window GeneDifferential Diagnosis Disorder 1MOIPrenatal Ultrasound & Radiographic Findings in Differential Diagnosis Disorder Overlapping w/COL1A1/2-OINot observed in COL1A1/2-OI ALPLPerinatal hypophosphatasiaARBlue sclerae; abnormal teeth; fracturesRickets; GI: poor feeding, emesis; craniosynostosis; vertebral clefts; low alkaline phosphatase; high calcium in serum & urine; bone spurs FGFR3Thanatophoric dysplasiaADIn severe OI: fetal hydrops & respiratory distressSevere micromelia; cloverleaf skull; small iliac bones, narrow sacroiliac notch SLC26A2Achondrogenesis type 1BARThin short ribs in severe OIAbsent mineralization; severe micromelia SOX9Campomelic dysplasiaADRespiratory distress in severe OI; short limbs & small chestCurved femurs w/skin dimpling; absent/hypoplastic scapula; macrocephaly; large anterior fontanelle; male sex reversal (46XY, female); undermineralized thoracic vertebral pedicles; congenital heart defect AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance 1\. See OMIM: Clinical Synopsis Table. #### Infancy and Childhood Assessment Non-accidental trauma (NAT; child abuse). COL1A1/2-OI needs to be distinguished from child physical abuse / non-accidental trauma. The prevalence of physical abuse is much greater than the prevalence of COL1A1/2-OI, and on rare occasion, it can occur in a child with COL1A1/2-OI. Patient history, family history, physical examination, radiographic imaging, and the clinical course all contribute to distinguishing COL1A1/2-OI from child abuse. The overlap in clinical features includes multiple or recurrent fractures, fractures that do not match the history of trauma, and the finding of fractures of varying ages and at different stages of healing [Carty 1988, Ablin et al 1990, Steiner et al 1996, Ablin & Sane 1997, Marlowe et al 2002]. The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of COL1A1/2-OI. Metaphyseal and rib fractures, thought to be virtually pathognomonic for child abuse, can rarely occur in COL1A1/2-OI. The presence or absence of blue sclerae is unreliable in distinguishing COL1A1/2-OI from child abuse because blue sclerae are often found in unaffected normal infants until about age 18 months; children with OI type IV may not have blue sclerae. Family history is often unrevealing; families suspected of possible child abuse often provide an unverified family history of frequent fractures; conversely, the family history of individuals with COL1A1/2-OI often does not reveal any other affected individuals because of a de novo pathogenic variant in the proband or the presence of a mild phenotype in relatives. Laboratory testing (typically molecular genetic testing of COL1A1 and COL1A2) usually is not needed to differentiate COL1A1/2-OI from NAT, and in some cases, the time required to perform such testing can delay proper disposition of child abuse cases [Steiner et al 1996]. Marlowe and colleagues suggest: "Given the inability to identify all children with OI by clinical examination in situations of suspected non-accidental injury, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI" [Marlowe et al 2002]. Laboratory testing in such cases is no substitute for proper clinical evaluation that includes history, family history, physical examination, and radiographic evaluation. Other genetic disorders. See Table 7. ### Table 7. Other Genetic Disorders of Interest in the Differential Diagnosis of COL1A1/2 Osteogenesis Imperfecta View in own window GeneDifferential Diagnosis Disorder 1MOIClinical Features of the Differential Diagnosis Disorder Overlapping w/COL1A1/2-OINot observed in COL1A1/2-OI ANO5Gnathodiaphyseal dysplasia (OMIM 166260)ADOsteopenia & bone fragilityEnlarged jaw; osteomyelitis DSPPDentinogenesis imperfecta (OMIM 125490)ADDIPrimary teeth more impacted than secondary teeth GORABGerodermia osteodysplastica (OMIM 231070)AROsteopenia & bone fragilityMicrocephaly; premature aged facial appearance; camptodactyly; intellectual disability LRP5Osteoporosis pseudoglioma syndrome (OMIM 259770)AROsteopenia & bone fragilityMicrocephaly; pseudoglioma; cataracts; blindness; congenital heart defect NOTCH2Hadju-Cheney syndrome (OMIM 102500)ADOsteopenia & bone fragilityCoarse facial appearance; early tooth loss; congenital heart defect; male hypospadias/cryptorchidism; renal cysts P4HBCole-Carpenter syndrome 1 (OMIM 112240)ADEnamel hypoplasia; osteopenia & fracturesMidface hypoplasia; frontal bossing; proptosis; pseudoclubbing; acroosteolysis AD = autosomal dominant; MOI = mode of inheritance 1\. See OMIM: Clinical Synopsis Table. Idiopathic juvenile osteoporosis (OMIM 259750) typically presents in pre-adolescents with fractures and osteoporosis. The fracture susceptibility and osteoporosis usually resolve spontaneously with puberty. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI), the evaluations summarized in Table 8 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 8. Recommended Evaluations Following Initial Diagnosis in Individuals with COL1A1/2 Osteogenesis Imperfecta View in own window System/ConcernEvaluationComment MusculoskeletalPhysical examinationTo assess deformities & presence of joint laxity * Referral to PT & OT * Surgical intervention as needed through experienced orthopedic management As indicated by clinical presentation NeurologicCT &/or MRI examination w/views across base of skull to evaluate for basilar impressionIf concerning signs or symptoms are present 1 Cervical spine flexion & extension radiographsIn children able to cooperate w/examination or before participating in sporting activities in more mildly affected individuals DentalDental examination * When teeth erupt in those w/DI or at risk for DI * By age 2-3 yrs for all children w/OI AudiologicFormal hearing assessmentIn all individuals at diagnosis OtherConsultation w/clinical geneticist &/or genetic counselor DI = dentinogenesis imperfecta; OT = occupational therapist; PT = physical therapist 1\. There is no universal agreement on when screening for basilar impression should be performed. A positive "Lhermitte's sign" (tingling in fingers with neck flexion) should prompt neurosurgical referral. Surgery is typically undertaken before persistent/permanent neurologic features are present. ### Treatment of Manifestations Management focuses on supportive therapy to minimize fractures and maximize function, minimize disability, foster independence, and maintain overall health [Marini & Gerber 1997]. Ideally, COL1A1/2-OI is managed by a multidisciplinary team including specialists in the medical management of COL1A1/2-OI, clinical genetics, orthopedics, rehabilitation medicine, pediatric dentistry, otology/otolaryngology, and mental health. Supportive therapy is individualized depending on the severity, degree of impairment, and age of the affected individual. Considerable support from medical personnel is generally required by parents caring for infants with perinatally lethal COL1A1/2-OI. Physical medicine treatment * Parents and other caregivers should be instructed in safe handling techniques. These are mostly commonsense practices in order to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid any situation where increased pressure is placed on a single point on any long bone; when assisting an affected child in standing up, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Older children should not ride on amusement park rides. Caregivers should avoid re-creating the circumstances of a fracture, as it is likely to happen again. * The use of bracing to try to stabilize progressively deforming limbs depends in part on the subtype of COL1A1/2-OI. Progressively deforming OI has proven to be progressive despite external or internal bracing. The use of internal rods or braces to support and stabilize deforming limbs is more successful in the milder subtypes of COL1A1/2-OI and is guided by the expertise of the managing orthopedist. * Orthotics to support ankle instability are used in toddlers with delayed walking secondary to joint hypermobility and in other affected individuals who suffer recurrent subluxations of their ankle joints. * Physical activity serves a number of purposes. It provides gravitational stressors required for bone growth and remodeling. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Physical activity can be self directed or coordinated through the services of a physical therapist. Each affected individual's needs are unique and thus both physical and occupational therapy should be initiated for increased stability of bone, improved mobility, prevention of contractures, prevention of head and spinal deformity, and improved aerobic fitness and muscle strengthening. * Mobility devices, such as scooters and chairs for children and modified automobiles for adults, should be considered. * Some individuals with COL1A1/2-OI experience chronic daily pain associated with both fractures and nonspecific myofascial pain associated with the generalized connective tissue disorder. Pain management plays an important role in the management of COL1A1/2-OI. Some affected individuals do well with minimal analgesics, but many benefit from a multidisciplinary pain management service. Analgesics can be used to control pain from fractures. Orthopedic treatment. Fractures are treated as they would be in unaffected children and adults with attention to the following: * The period of immobility in children with COL1A1/2-OI should be shortened as much as is practical. * Casts should be small and lightweight. * Physical therapy should begin as soon as the cast is removed to promote mobility and enhance muscle strength and bone mass. * At this time, intramedullary rodding remains a mainstay of orthopedic care to provide anatomic positioning of limbs to permit more normal function. Progressive spinal deformities are particularly difficult to treat because of the poor quality of bone in severely affected children. Progressive scoliosis in severe COL1A1/2-OI may not respond well to conservative management and response to surgical intervention may be limited. Pharmacologic treatment. Bisphosphonates, analogs of pyrophosphate that decrease bone resorption, are being evaluated in both uncontrolled and controlled trials to assess the extent to which they can increase bone mass and bone strength and improve function in children with COL1A1/2-OI. These studies are still ongoing. Bisphosphonates have been used most extensively in severely affected children; they may be useful in adults as well [Adami et al 2003]. The role of treatment with bisphosphonates in changing the natural history of COL1A1/2-OI is incompletely understood. The Cochrane Collaboration is an international network that assembles reviews on various management strategies based on randomized controlled clinical trials within its database in order to improve the practice of evidence-based medicine. As of the Cochrane Collaboration's most recent update of the OI review, bisphosphonate therapy did not appear to reduce fracture incidence but it did affect bone density and adult height [Dwan et al 2014] (full text). In a more recent publication Bains et al [2019] collated data from the Osteogenesis Imperfecta Foundation's linked clinical research centers on 466 patients with all forms of OI who had been treated with bisphosphonates. The review of the data primarily focused on classic non-deforming OI with blue sclerae (type I). Primary findings indicated increased lumbar vertebral body density, and statistical regression analysis indicated reduced probability of fracture and scoliosis in individuals treated with bisphosphonates compared with those untreated. Pamidronate use is invasive and typically requires intravenous infusions every three months, four hours a day, for three days. Pamidronate has been used to treat newborn infants with severe OI; complications include transient asymptomatic hypocalcemia [Plotkin et al 2000] and symptomatic hypocalcemia [Chien et al 2002]. The long-term consequences of lowering bone turnover in children with COL1A1/2-OI are unknown but may include delayed bone union after fracture or osteotomy. A randomized controlled clinical trial using the oral bisphosphonate alendronate found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal BMD (bone mineral content measured by DEXA divided by bone area in square centimeters) but was not associated with improved fracture outcomes [Ward et al 2011]. In a second study with a different oral bisphosphonate, Bishop and colleagues found that oral risedronate increased areal BMD and reduced first and recurrent clinical fractures in children with OI [Bishop et al 2010]. Zoledronic acid, a bisphosphonate with a longer half-life, greater potency, and more convenient dosing, has been studied in children with OI. Lv et al [2018] compared the efficacy of an annual infusion of zoledronic acid to weekly oral alendronate and concluded that these treatment approaches had similar increases in vertebral BMD and were well tolerated. Basilar impression. It is important to screen for this finding so that timely surgical intervention can be planned. A positive "Lhermitte's sign" (tingling in fingers with neck flexion) should prompt neurosurgical referral. Surgery is typically undertaken before persistent/permanent neurologic features are present. If surgery is undertaken, it should be done in a center experienced in the procedures used. Dental treatment. The goals are the maintenance of both primary and permanent dentition, functional bite or occlusion, optimal gingival health, and overall appearance. Pediatric dentists are the most knowledgeable about dentinogenesis imperfecta (DI) in children. Some consensus exists that early dental restorative coverage of the primary molars and (if possible) aesthetic coverage of the upper anterior teeth is optimal. Plastic polymers are sometimes used to coat teeth. As anxiety can be an issue with children, pre-medication for anxiolysis (e.g., nitrous oxide analgesia or midazolam) can be used for treatment in a clinic setting. If warranted, orthodontic treatment can be initiated, but care must be taken in the use of orthodontic appliances because of the brittleness of the teeth. Dental restorations in adults may best be done by a general dentist knowledgeable about OI or a specialist in prosthetic dentistry. Hearing loss. Surgical repair of the middle-ear bones and creation of a prosthetic incus can improve unaided hearing. Later hearing loss appears to have a significant sensorineural component that does not respond to middle ear surgery. Cochlear implantation has been used in a small number of individuals; outcome data are limited. Mental health support through psychiatry/psychology and appropriate social worker intervention can improve quality of life. Management of lethal OI. It is appropriate to offer parents the option of allowing the infant to expire without attempting heroic interventions such as assisted ventilation. Other therapies. Early trials of anabolic steroids, sodium fluoride, testosterone, vitamins C and D, flavinoids, and calcitonin showed minimal or no improvement in bone formation, or too small a sample size was utilized for meaningful conclusions [reviewed in Byers & Steiner 1992]. ### Prevention of Secondary Complications Special attention should be paid to anesthesia concerns including proper positioning on the operating room table, for which egg crate foam is recommended to avoid fractures. ### Surveillance ### Table 9. Recommended Surveillance for Individuals with COL1A1/2 Osteogenesis Imperfecta View in own window System/ConcernEvaluationFrequency MusculoskeletalOrthopedic evaluationEvery 3 mos until age 1 yr, every 6 mos from 1 to 3 yrs, then annually or w/any new fractures Physical & rehabilitation medicineAnnually or more frequently if necessary for more severe clinical forms Physical therapyIn infancy for individuals w/motor delays & as needed to improve mobility & function NeurologicCT &/or MRI examination w/views across base of skull to evaluate for basilar impressionIf concerning signs or symptoms are present 1 Cervical spine flexion & extension radiographsIn children able to cooperate w/examination or before participating in sporting activities in more mildly affected individuals DentalDental examinations2x/yr for those w/DI or at risk for DI AudiologicHearing evaluationEvery 3-5 yrs from age 5 yrs until HL is identified, then as indicated based on nature & degree of HL & associated interventions DI = dentinogenesis imperfecta; HL = hearing loss 1\. There is no universal agreement on when screening for basilar impression should be performed. ### Agents/Circumstances to Avoid Contact sports should be avoided. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from cervical spine examination and dental and hearing evaluations. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Fertility is normal in OI. Pregnancy in women with OI, especially those with progressively deforming OI, can be complicated because of a small pelvis, which may necessitate delivery by cesarean section. For most women who have mild non-deforming OI, pregnancy is uncomplicated. Joint laxity may increase, as it does with unaffected women, and reduce mobility in small, moderately affected women. Bleeding is not more common than usual and complications of vaginal tearing during delivery are not common. Women with OI who are very small require pre-term cesarean section because of respiratory compromise. It is uncertain whether postpartum pelvic relaxation is more common. The mode of delivery of infants with OI has been examined to determine if the frequency of complications is higher with vaginal or cesarean section delivery. No difference in the frequency of complications was found. A higher-than-expected frequency of non-vertex presentations has been noted [Cubert et al 2001]. The role of pregnancy in later fractures, loss of bone mineralization, progression of hearing loss, or any other physical consideration has not been examined in detail. Women with OI who have significant skeletal deformity and short stature should be followed during pregnancy at a high-risk prenatal care center. Cesarean section and vaginal delivery of an infant with OI have about the same rate of complications for each type of OI. Delivery of an infant with OI by cesarean section is more frequent than in the general population because a non-vertex presentation cannot be corrected by external manipulation. ### Therapies Under Investigation RANK ligand antibodies, which inhibit osteoclast maturation, have been studied as a therapeutic option in children and results have shown an increase in vertebral body BMD, normalization of vertebral shape, and a reduction in vertebral compression fractures while on therapy. Ongoing studies are determining long-term efficacy and tolerance [Hoyer-Kuhn et al 2014, Hoyer-Kuhn et al 2016, Boyce 2017]. Human growth hormone has been evaluated as an adjunctive therapy in conjunction with bisphosphonates in a randomized controlled study. In this study, growth hormone therapy was reported to correlate with improved linear growth and increased BMD [Antoniazzi et al 2010]. An additional study presented similar results in 26 children with moderate to severe OI when growth hormone was used in isolation [Marini et al 2003]. Teriparatide, a PTH analog, has been used to treat osteoporosis and is being explored as an adjunctive therapy in OI [Orwoll et al 2014]. The risk for osteosarcoma in those treated with teriparatide has limited its widespread use in children with more severe forms of OI. An ongoing registry monitoring the risk in adults treated with teriparatide has not documented an instance of osteosarcoma in the eight years since it was established but longer observation is needed to identify the actual risk of osteosarcoma [Gilsenan et al 2018]. Bone marrow transplantation (BMT) to introduce normal mesenchymal stem cells that have the capacity to differentiate into normal osteoblasts as well as transplanted mesenchymal stromal cells, which produce factors that stimulate endogenous bone growth in individuals with OI, has been evaluated in a pilot clinical trial. Preliminary data suggested a positive impact on growth [Otsuru et al 2012, www.clinicaltrials.gov]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	COL1A1/2 Osteogenesis Imperfecta	c0029434	5,237	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1295/	2021-01-18T21:37:33	{"mesh": ["D010013"], "synonyms": ["Brittle Bone Disease", "OI"]}
feeling of unease and insecurity experienced in learning or using a foreign language [1]Foreign language anxiety, also known as xenoglossophobia, is the feeling of unease, worry, nervousness and apprehension experienced in learning or using a second or foreign language. The feelings may stem from any second language context whether it is associated with the productive skills of speaking and writing or the receptive skills of reading and listening.[2] Research has shown that foreign language anxiety is a significant problem in language classrooms throughout the world especially in terms of its strong relationship to the skill of speaking in a foreign or second language.[1] Foreign language anxiety is a form of what psychologists describe as a specific anxiety reaction.[1] Some individuals are more predisposed to anxiety than others and may feel anxious in a wide variety of situations. Foreign language anxiety, however, is situation-specific and so it can also affect individuals who are not characteristically anxious in other situations.[3] The main causes of foreign language anxiety are communication-apprehension, test anxiety, and fear of negative evaluation.[4] There is also a psychological component to foreign language anxiety.[5] Foreign language anxiety has a variety of detrimental effects on foreign language performance, but both the student and the teacher can adopt strategies to minimize the anxiety.[6] ## Contents * 1 Causes * 2 Effects * 2.1 Cross-cultural code-switching * 3 Measures * 4 Reduction and management * 5 Issues and area of research * 6 See also * 7 References ## Causes[edit] This article needs attention from an expert in the subject, as much of the article is largely incoherent. Please add a reason or a talk parameter to this template to explain the issue with the article. WikiProject The subject, as much of the article is largely incoherent may be able to help recruit an expert. (July 2017) Although all aspects of using and learning a foreign language can cause anxiety, both listening and speaking are regularly cited as the most anxiety provoking of foreign language activities.[7][8] Foreign language anxiety is usually studied and seen in a language classroom environment, as this is where many students start learning a new language a fear of embarrassment. General theories of anxiety can help explain the root of foreign language anxiety. The following theories of anxiety play a role in describing foreign language anxiety: * Self-efficacy and appraisal: An anxiety reaction first depends on the individual's appraisal of how threatening a situation is. In the case of a perceived threatening situation, the amount of anxiety then depends on the individual's perception of their self-efficacy, or their confidence in their ability to effectively control the situation. Potential negative events that individuals do not believe they are equipped to handle often lead to anxiety. In terms of foreign language learning, appraisals of foreign language situations are seen as threatening with self-deprecating thoughts about an individual's language ability, which decreases their self-efficacy leading to foreign language anxiety:[9] * State, trait, and situational anxiety: Anxiety can be classified into trait anxiety, state anxiety, and the more recent distinction of situation-specific anxiety. Individuals with trait anxiety have chronic, persisting anxiety in all situations, whereas individuals with state anxiety are only anxious in particular situations. When applied to learning a language, this theory results in the additional distinction of situation-specific anxiety, which builds on state anxiety to describe a particular situation that induces anxiety only when specific conditions (e.g. a foreign language) are at play.[9] An example of when foreign language anxiety may occur would be in a classroom. The causes of foreign language anxiety have been broadly separated into three main components: communication apprehension, test anxiety and fear of negative evaluation.[8]Communication apprehension is the anxiety experienced when speaking or listening to other individuals. Test-anxiety is a form of performance anxiety, that is associated with the fear of doing badly or failing altogether. Fear of negative evaluation is the anxiety associated with the learner's perception of how other onlookers (instructors, classmates or others) may negatively view their language ability. These three factors cause an increase of an individual's anxiety levels as well as a decrease in self-efficacy.[9] In addition, specifically in an ESL classroom, students learning a foreign language out of their country are very vulnerable to high levels of anxiety pertaining to language learning. For they perceive more social distance between themselves and the native individuals of the target language, which as a result may cause them to experience a language shock.[9] Sparks and Ganschow[10] draw attention to the fact that anxiety could result in or cause poor language learning. If a student is unable to study before a language examination, the student could experience test anxiety. Context anxiety could be viewed as a result.[11] In contrast, anxiety becomes a cause of poor language learning, leading that student to then be unable to adequately learn the target language.[12] There can be various physical causes of anxiety, such as hormone levels, but the underlying causes of excessive anxiety while learning are fear[13] and a lack of confidence.[citation needed] There is a psychological component to foreign language anxiety as well; language learning is a "profoundly unsettling psychological proposition"[14] as it jeopardizes an individual's self-understanding and perspective.[14] It stems from one's self-perceptions of language ability.[15] Foreign language anxiety is rooted in three psychological challenges: * performance difficulty * threat to one's image * identity conflict Those psychological states thus have task-performance and identity dimensions. People tend to act or speak in a way that would be judged appropriate to the other people native to the foreign culture, but the behavior that individuals are producing grapples with ingrained values and behaviors. Emotions by the psychological challenges has something to do with attempting to switch codes in an interactive encounter.[16] ## Effects[edit] The effects of foreign language anxiety are particularly evident in the foreign language classroom, and anxiety is a strong indicator of academic performance. Anxiety is found to have a detrimental effect on students' confidence, self-esteem and level of participation.[17] Anxious learners suffer detrimental effects during spontaneous speaking activities in performance, affective reactions and their overall attitudes towards learning their target second language.[18] Furthermore, they may lack confidence, be less able to self-edit and identify language errors and more likely to employ avoidance strategies such as skipping class.[19] Anxious students also forget previously learned material, volunteer less and tend to be more passive in classroom activities than their less anxious classmates.[17][20] The effects of foreign language anxiety also extend outside the second language classroom. A high level of foreign language anxiety may also correspond with communication apprehension, causing individuals to be quieter and less willing to communicate.[21] People who exhibit this kind of communication reticence can also sometimes be perceived as less trustworthy, less competent, less socially and physically attractive, tenser, less composed and less dominant than their less reticent counterparts. ### Cross-cultural code-switching[edit] The effects of these negative emotions may also lead to cross-cultural code-switching, in which bilingual people alter a language to their other language[clarification needed] through their interactions with other bilinguals. Unlike linguistic code-switching, cross-cultural code-switching is the socio-linguistic phenomenon of changing culturally-ingrained behaviors in a foreign situation.[22] Although cross-cultural code-switching possibly results from both positive and negative emotions, negative emotions are more common and more likely to affect the way a bilingual person speaks. Negative emotions include embarrassment, performance anxiety, guilt, distress and anxiety in general.[22][23] "Molinsky identifies three psychological states that appraise under the influence of emotions while code-switching. These are: "experienced performance difficulty, face threat and identity conflict—all of which mediate the relationship between personal and contextual variables and the negative and positive emotions an individual experiences while code-switching".[24] There are three types of cross-cultural code-switching:[25] * situational code-switching * conversational code-switching * borrowing This code-switching could be considered as an unconscious behavior because of its negative and usually threatening situations.[clarification needed] In that sense, although code-switching results from foreign language anxiety, it is more often caused by external circumstances than by internal mental change.[clarification needed][25] ## Measures[edit] A number of tools have been developed to investigate the level of foreign language anxiety experienced by language learners. The Foreign Language Classroom Anxiety Scale (FLCAS)[17] is a 33-question, 5-point Likert scale survey, which is widely used in research studies. It investigates participants' communication apprehension, test-anxiety and fear of negative evaluation and focuses on speaking in a classroom context. It has been translated and used in several languages, including Spanish and Chinese. Following the success of the Foreign Language Classroom Anxiety scale, similar instruments have been devised for measuring Foreign Language Reading Anxiety (FLRAS),[26] Foreign Language Listening Anxiety (FLLAS) and Second Language Writing Apprehension (SLWAT).[27] ## Reduction and management[edit] The reduction of foreign language anxiety necessitates the involvement of both the student and the teacher, each of which are able to adopt strategies to mitigate anxiety. [28] Students play an active role in acknowledging and managing their foreign language anxiety. The first step of recognizing and acknowledging the anxiety is needed in order to communicate their needs with their teacher and more effectively reach a strategy for reducing their anxiety. Specifically recognizing what types of foreign language activities induce their anxiety and what their personal language style is also helps as a first step in controlling the anxiety. From there, the student can seek help and support.[28] Recommended personal strategies for reducing foreign language anxiety include joining language clubs, journal writing, positive self-talk, and in general taking advantage of any opportunities to use the language.[28][29] Support groups can also be a useful tool, as well as other forms of collaboration among peers at a similar level of experience with the language.[28] Teachers can also adopt strategies and teaching methods that can help prevent foreign language anxiety to their students. Teaching-based strategies for reducing foreign language anxiety involve fostering a comfortable and relaxed classroom environment in which the teacher is supportive and friendly. Focusing on positive reinforcement and normalizing mistakes rather than focusing on the negative errors can help create an ideal classroom environment. [28][29] For instance, teachers can adopt a "modeling approach" in which, instead of explicitly correcting errors in front of everyone in the class, the teacher repeats the utterance back to the student, but with the errors fixed.[28][29] Specific strategies that teachers can use in the classroom include playing language games, conducting grammar language in the native language instead of the target language, leading group activities, and facilitating discussions of anxiety. This would allow students to document and recognize their own anxiety as well as understand that other students may feel the same way. Offering additional help outside of class can also be helpful.[28] One study recommends teaching songs in the classroom as a specific methodological strategy that can improve academic performance, which in turn decreases the anxiety level of students as they become more comfortable and proficient in the language. The study found that this tool is most beneficial to those with high anxiety.[30] ## Issues and area of research[edit] In the 1990s, the challenge was a clear categorization of grammatical or sociolinguistic constraints on code-switching caused by foreign language anxiety and to determine how bilinguals produce different code-mixed patterns. Previously, most researches focused more upon syntactic aspects on code-switching; in other words, psychological elements were completely ignored.[31] ## See also[edit] * Schizoglossia – linguistic insecurity about one's native language * Linguistic insecurity – lack of confidence about one's way of speaking ## References[edit] 1. ^ a b c Horwitz, Elaine K.; Horwitz, Michael B.; Cope, Joann (1986-06-01). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (2): 125–132. doi:10.1111/j.1540-4781.1986.tb05256.x. ISSN 1540-4781. 2. ^ MacIntyre, P. D.; Gardner, R. C. (1994). "The subtle effects of language anxiety on cognitive processing in the second language". Language Learning. 44 (2): 283–305. doi:10.1111/j.1467-1770.1994.tb01103.x. 3. ^ Horwitz, Elaine K.; Horwitz, Michael B.; Cope, Joann (1986-06-01). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (2): 125–132. doi:10.1111/j.1540-4781.1986.tb05256.x. ISSN 1540-4781. 4. ^ Horwitz, Elaine K.; Horwitz, Michael B.; Cope, Joann (1986-06-01). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (2): 125–132. doi:10.1111/j.1540-4781.1986.tb05256.x. ISSN 1540-4781. 5. ^ Molinsky, Andrew (1 January 2007). "Cross-Cultural Code-Switching: The Psychological Challenges of Adapting Behavior in Foreign Cultural Interactions". The Academy of Management Review. 32 (2): 622–640. doi:10.2307/20159318. JSTOR 20159318. 6. ^ Huang, Jinyan (2012). Overcoming Foreign Language Classroom Anxiety. New York: Nova Science Publishers. pp. 11–12. ISBN 9781613247754. 7. ^ MacIntyre, P. D.; Gardner, R. C. (1994). "The subtle effects of language anxiety on cognitive processing in the second language". Language Learning. 44 (2): 283–305. doi:10.1111/j.1467-1770.1994.tb01103.x. 8. ^ a b Horwirz, E. K.; Horwitz, M. B.; Cope, J. (1986). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (ii): 125–132. doi:10.2307/327317. JSTOR 327317. 9. ^ a b c d Pappamihiel, N. Eleni (1 January 2002). "English as a Second Language Students and English Language Anxiety: Issues in the Mainstream Classroom". Research in the Teaching of English. 36 (3): 327–355. JSTOR 40171530. 10. ^ Sparks, Richard L.; Ganschow, Leonore (1991). "Foreign Language Learning Differences: Affective or Native Language Aptitude Differences?". The Modern Language Journal. 75 (1): 3–16. doi:10.1111/j.1540-4781.1991.tb01076.x. ISSN 0026-7902. 11. ^ Huang, Jinyan (2012). Overcoming Foreign Language Classroom Anxiety. New York: Nova Science Publishers. pp. 11–12. ISBN 9781613247754. 12. ^ Horwitz, Elaine K.; Horwitz, Michael B.; Cope, Joann (1986-06-01). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (2): 125–132. doi:10.1111/j.1540-4781.1986.tb05256.x. ISSN 1540-4781. 13. ^ Shahsavari, Mahmood (2012). "Relationship between anxiety and achievement motivation among male and female students" (PDF). Journal of American Science. 8 (11): 329–332. ISSN 2375-7264. Retrieved 23 January 2017. 14. ^ a b Horwitz, Elaine K.; Horwitz, Michael B.; Cope, Joann (1986-06-01). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (2): 125–132. doi:10.1111/j.1540-4781.1986.tb05256.x. ISSN 1540-4781. 15. ^ Young, Dolly Jesusita (1991). "Creating a Low-Anxiety Classroom Environment: What Does Language Anxiety Research Suggest?". The Modern Language Journal. 75 (4): 426–439. doi:10.1111/j.1540-4781.1991.tb05378.x. JSTOR 329492 – via JSTOR. 16. ^ Molinsky, Andrew (1 January 2007). "Cross-Cultural Code-Switching: The Psychological Challenges of Adapting Behavior in Foreign Cultural Interactions". The Academy of Management Review. 32 (2): 622–640. doi:10.2307/20159318. JSTOR 20159318. 17. ^ a b c Horwirz, E. K.; Horwitz, M. B.; Cope, J. (1986). "Foreign Language Classroom Anxiety". The Modern Language Journal. 70 (ii): 125–132. doi:10.2307/327317. JSTOR 327317. 18. ^ Phillips, E. M. (1992). "The effects of language anxiety on students' oral test performance and attitudes". The Modern Language Journal. 76 (1): 14–26. doi:10.1111/j.1540-4781.1992.tb02573.x. 19. ^ Gregerson, T. (2003). "To err is human: A reminder to teachers of language-anxious students". Foreign Language Annals. 36 (1): 25–32. doi:10.1111/j.1944-9720.2003.tb01929.x. 20. ^ Ely, C. M. (1986). "An analysis of discomfort, risk-taking, sociability, and motivation in the L2 classroom". Language Learning. 36: 1–25. doi:10.1111/j.1467-1770.1986.tb00366.x. 21. ^ Liu, M.; Jackson, J. (2008). "An exploration of Chinese EFL learners' Unwillingness to Communicate and Foreign Language Anxiety". The Modern Language Journal. 92 (i): 71–86. doi:10.1111/j.1540-4781.2008.00687.x. 22. ^ a b Molinsky, Andrew (1 January 2007). "Cross-Cultural Code-Switching: The Psychological Challenges of Adapting Behavior in Foreign Cultural Interactions". The Academy of Management Review. 32 (2): 622–640. doi:10.2307/20159318. JSTOR 20159318. 23. ^ Molinsky, Andrew (2007-01-01). "Cross-Cultural Code-Switching: The Psychological Challenges of Adapting Behavior in Foreign Cultural Interactions". The Academy of Management Review. 32 (2): 622–640. doi:10.2307/20159318. JSTOR 20159318. 24. ^ "Diplom.de - Cross-cultural Code Switching and Application". www.diplom.de (in German). Retrieved 2017-10-26. 25. ^ a b Titone, Renzo (1994-01-01). "Some Italian Investigations of 'Code Switching' in Diglossic Settings: A Summary Report". La Linguistique. 30 (2): 67–73. JSTOR 30249052. 26. ^ Saito, Y.; Horwitz, E. K.; Garza, T. J. (1999). "Foreign Language Reading Anxiety". The Modern Language Journal. 83 (2): 202–218. doi:10.1111/0026-7902.00016. 27. ^ Cheng, Y. S.; Horwitz, E. K.; Shallert, D. L. (1999). "Language anxiety: Differentiating writing and speaking components". Language Learning. 49 (3): 417–446. doi:10.1111/0023-8333.00095. 28. ^ a b c d e f g Huang, Jinyan (2012). Overcoming Foreign Language Classroom Anxiety. New York: Nova Science Publishers. pp. 11–12. ISBN 9781613247754. 29. ^ a b c Young, Dolly Jesusita (1991). "Creating a Low-Anxiety Classroom Environment: What Does Language Anxiety Research Suggest?". The Modern Language Journal. 75 (4): 426–439. doi:10.1111/j.1540-4781.1991.tb05378.x. JSTOR 329492 – via JSTOR. 30. ^ Dolean, Dacian Dorin (October 5, 2015). "The Effects of Teaching Songs during Foreign Language Classes on Students' Foreign Language Anxiety". Language Teaching Research. 20 (5): 638–653. doi:10.1177/1362168815606151. S2CID 151928258 – via SAGE Journals. 31. ^ Myers-Scotton, Carol (1 January 1993). "Common and Uncommon Ground: Social and Structural Factors in Codeswitching". Language in Society. 22 (4): 475–503. doi:10.1017/s0047404500017449. JSTOR 4168471. * Lin, G. H. C. (2009). "An exploration into foreign language writing anxiety from Taiwanese university students' perspectives" (PDF). National Changhua University of Education, Department of English, Taiwan, ROC: 307–318. Cite journal requires `\|journal=` (help) * v * t * e Second-language acquisition General * Outline * Common misconceptions Subfields * Attrition * Classroom research * Education * Phonology * Writing Learners * Multilingualism * Heritage language * Multi-competence Learner language * Contrastive analysis * Contrastive rhetoric * Error (linguistics) * Error analysis * Error treatment * Interlanguage * Silent period Linguistic factors * Language transfer * Linguistic universal * Word lists by frequency Individual variation * Language-learning aptitude * Critical period hypothesis * Motivation * Willingness to communicate * Foreign language anxiety * Metalinguistic awareness Strategies * Language learning strategies * Communication strategies * Code-switching * Good language learner studies SLA hypotheses * Competition model * Comprehensible output * Connectionism * Dynamic Systems Theory * Generative second-language acquisition * Input hypothesis * Interaction hypothesis * Interface hypothesis * Interface position * Noticing hypothesis * Processability theory * Order of acquisition * Skill-based theories In the classroom * Focus on form * Input enhancement Aptitude tests * MLAT * DLAB * PLAB * CANAL-F Notable researchers * Alderson * Arguelles * Bialystok * Carroll * Crossley * Cumming * de Bot * Brown * Bygate * Corder * Cumming * van Dijk * Ellis * Ellis * Ervin-Tripp * Gass * van Geert * Green * Grosjean * Guardado * Harding * Jarvis * Johnson * Kormos * Krashen * Kroll * Larsen-Freeman * Li * Long * Lowie * Mackey * MacWhinney * Manchón * Marian * Matsuda * Matthews * Meisel * Myers-Scotton * Nation * Ortega * Pica * Polio * Pimsleur * Rivers * Schmidt * Schmitt * Silva-Corvalan * Slobin * Storch * Swain * Terrell * Ullman * Vaid * VanPatten * Verspoor * White * Wray * Yip Associations * European Association for the Teaching of Academic Writing * EUROSLA Computational tools * Coh-Metrix * L2 Syntactic Complexity Analyzer Journals * Applied Linguistics * Bilingualism: Language and Cognition * Language Learning * Language Testing * Journal of Second Language Writing * System * TESOL Journal * TESOL Quarterly * The Modern Language Journal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Foreign language anxiety	None	5,238	wikipedia	https://en.wikipedia.org/wiki/Foreign_language_anxiety	2021-01-18T18:30:16	{"wikidata": ["Q5468412"]}
Localized epidermolysis bullosa simplex, formerly known as EBS, Weber-Cockayne, is a basal subtype of epidermolysis bullosa simplex (EBS, see this term). The disease is characterized by blisters occurring mainly on the palms and soles, exacerbated by warm weather. ## Epidemiology Reported prevalence ranges from 1/318,000 for localized EBS in the United States to 1/35,000 for localized EBS and non-Dowling-Meara generalized EBS (combined) in Scotland. About two-thirds of EBS patients have the localized basal form. ## Clinical description Onset is usually in late infancy or early childhood. The usual distribution of blisters in these patients is on the palms and soles, although other skin surfaces may also blister if subjected to significant trauma. Milia and scarring are rare in localized EBS, and dystrophic nails are uncommon. Focal keratoderma of the palms and soles may occur by adulthood in some patients. The only common extracutaneous finding in localized EBS, i.e. localized intraoral erosions or blisters, tends to be asymptomatic, occurs in about one third of patients, and is usually seen only during infancy. ## Etiology Localized EBS is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively. ## Genetic counseling Transmission is autosomal dominant and sporadic cases are frequent. ## Prognosis Although the disease can be disabling, life-expectancy is normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Localized epidermolysis bullosa simplex	c0080333	5,239	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79400	2021-01-23T19:02:36	{"gard": ["2146"], "mesh": ["D016110"], "omim": ["131800"], "umls": ["C0080333"], "icd-10": ["Q81.0"], "synonyms": ["EBS-loc", "Epidermolysis bullosa simplex of palms and soles", "Epidermolysis bullosa simplex, Weber-Cockayne type"]}
Hereditary central diabetes insipidus is a rare genetic subtype of central diabetes insipidus (CDI, see this term) characterized by polyuria and polydipsia due to a deficiency in vasopressin (AVP) synthesis. ## Epidemiology The prevalence is unknown. ## Clinical description Symptoms usually develop between 1 and 6 years of age but onset in the neonatal period or in elderly patients has been described. They include polyuria, polydipsia and nocturia (often manifesting as enuresis in children). Additional symptoms seen in children can include: lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In the autosomal recessive form, symptoms are secondary to reduced biological activity of mutant AVP; heterozygous carriers have subclinical manifestations or are asymptomatic. ## Etiology The origin of the disease is genetic and is usually due to a mutation in the AVP gene located on chromosome 20p13 that encodes a precursor protein consisting of arginine vasopressin and two associated proteins, neurophysin 2 and copeptin. All except a few cases show an autosomal dominant pattern of inheritance. Rarely, an autosomal recessive or X-linked pattern of inheritance is reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hereditary central diabetes insipidus	c0687720	5,240	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=30925	2021-01-23T18:03:01	{"mesh": ["D020790"], "omim": ["125700", "304900"], "icd-10": ["E23.2"], "synonyms": ["Hereditary CDI", "Hereditary neurogenic diabetes insipidus"]}
Granulosa cell tumor of the ovary is a rare type of ovarian cancer that accounts for approximately 2% of all ovarian tumors. This type of tumor is known as a sex cord-stromal tumor and usually occurs in adults. Granulosa cell tumors of the ovary cause higher than normal levels of estrogen in a woman's body. The symptoms of this excess estrogen depend on the woman's menstrual status; the most common symptoms include early puberty for affected young girls, an increase in abdomen size or irregularities of menstrual cycles in premenopausal women, and abnormal uterine bleeding in postmenopausal women. The exact cause of granulosa cell tumors is unknown. Treatment consists of surgery to remove the tumor, and additional treatments may also be used depending on the extent of the tumor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Granulosa cell tumor of the ovary	c1370419	5,241	gard	https://rarediseases.info.nih.gov/diseases/8642/granulosa-cell-tumor-of-the-ovary	2021-01-18T18:00:12	{"mesh": ["C537296"], "umls": ["C1370419"], "synonyms": ["GCT of the ovary", "Granulosa theca cell tumor", "GTCT", "Adult granulosa cell tumor of the ovary", "Granulosa theca cell tumor of the ovary"]}
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 2P (CMT2P) can be caused by homozygous or heterozygous mutation in the LRSAM1 gene (610933) on chromosome 9q33. For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210). Clinical Features Guernsey et al. (2010) identified an extended multiply consanguineous family derived from a rural eastern Canadian isolate with 7 members affected with axonal CMT. Three further individuals were suspected to be affected. The index patient noted gradual onset of weakness around age 20, particularly affecting his distal lower extremities but also present in the hands. He noted episodic muscle cramping of extremity and trunk muscles. At the time of the examination he demonstrated bilateral pes cavus with marked wasting of distal lower extremity muscles and mild wasting of hand intrinsic muscles. Fasciculations were present in upper and lower extremity muscles. There was no gait ataxia. Upper and lower tendon reflexes were absent. He had mild loss of sensation on fingertips and severe loss of sensation in feet and legs, most markedly to vibration but also involving proprioception and pain perception. Other affected family members exhibited sensory and motor dysfunction with pes cavus. Autonomic symptoms were not consistently reported. Weakness and wasting were moderate and predominantly in distal lower extremity muscles. Onset was usually in the early adult years. Weterman et al. (2012) reported a large 3-generation family with autosomal dominant inheritance of an axonal peripheral neuropathy consistent with CMT. Affected individuals presented in the second or third decade of life with progressive distal muscle weakness and mild sensory disturbances in the feet. Electrophysiologic studies in affected individuals revealed a severe axonal neuropathy. Sural nerve biopsy in one affected individual demonstrated severe axonal degeneration. Nicolaou et al. (2013) reported a large 4-generation family from Sardinia with autosomal dominant axonal CMT. The proband developed distal weakness in the left lower limb and foot drop at about 34 years of age. At age 43, he showed moderate foot drop, could not stand on his heels, and had difficulty standing on his toes. There was atrophy in the lower legs and feet, as well as distal sensory loss. The upper limbs were not affected. He reported occasional cramps in the calf muscles and erectile dysfunction. Nerve conduction studies were consistent with an axonal form of CMT. Other affected family members had a similar phenotype, with onset between ages 15 and 50 years of slowly progressive distal weakness, atrophy, and multimodal hypesthesia in the lower limbs, diffusing to the upper limbs in later years. All except 1 patient remained ambulatory. Berciano et al. (1986) described a large family of Spanish descent in which 10 members over 3 generations had a neuronal form of hereditary motor and sensory neuropathy. Peak age at onset was in the second decade. Some members showed slight slowing of conduction velocities, and 3 had normal conduction studies. Nerve biopsy showed regenerating fibers and atrophic axons, with some loss of myelinated fibers. There were several instances of male-to-male transmission. Nelis et al. (2004) presented follow-up studies on the family reported by Berciano et al. (1986). They noted that a total of 14 members of the family were affected. The age at onset ranged from 9 to 76 years (mean, 29 years), although most patients developed symptoms in the second decade. The disease presented with foot deformity and difficulty walking, with very slow progression. Ankle reflexes were absent or hypoactive in all patients, whereas knee reflexes were sometimes preserved. Mild stocking hypesthesia was present. There were normal or mildly decreased motor nerve conduction velocities (NCV) consistent with axonal CMT. Peeters et al. (2016) reported follow-up of the family reported by Berciano et al. (1986). Thirteen affected individuals spanning 3 generations had a mild, very slowly progressive or nonprogressive sensorimotor neuropathy affecting the lower limbs and resulting in difficulty walking. Affected individuals in the last generation, ranging in age from 35 to 47, were asymptomatic, but showed variable features including pes cavus, toe clawing, stocking hypoesthesia, ankle areflexia, and amyotrophy. Electrophysiologic studies showed normal or slightly decreased nerve conduction velocities and variably decreased SNAP and CMAP amplitudes. EMG studies were consistent with chronic denervation. MRI of lower limb muscles showed atrophy and fatty replacement. The findings were consistent with a length-dependent sensorimotor axonopathy affecting lumbosacral motor and sensory neurons. Several individuals previously thought to be affected in previous reports were reexamined and reclassified as being unaffected. Peeters et al. (2016) emphasized that many of the patients had very mild or even clinically asymptomatic disease, making the diagnosis difficult in the absence of electrophysiologic studies. Inheritance The transmission pattern of axonal CMT in the family described by Guernsey et al. (2010) was consistent with autosomal recessive inheritance. The transmission pattern in the family reported by Weterman et al. (2012) was consistent with autosomal dominant inheritance. The transmission pattern of CMT2P in the family reported by Peeters et al. (2016) was consistent with autosomal dominant inheritance with incomplete penetrance. Mapping By genomewide linkage analysis of a Sardinian family with autosomal dominant axonal CMT, Nicolaou et al. (2013) found linkage to chromosome 9q33-q34 (maximum 2-point lod score of 8.06 at D9S63). By linkage analysis in the Spanish CMT family originally reported by Berciano et al. (1986), Nelis et al. (2004) mapped the disease locus, designated CMT2G, to a 13.2-Mb (12.8-cM) region on chromosome 12q12-q13.3. However, later linkage studies by Peeters et al. (2016) reassigned the disease locus to a 23.6-Mb region on 9q31.3-q34.2 between markers D9S2026 and D9S164 (Zmax = 3.186). Molecular Genetics In affected members of a large consanguineous family with CMT2, Guernsey et al. (2010) found homozygosity for a splice site mutation in the LRSAM1 gene (610933.0001). Heterozygous mutation carriers were unaffected. In affected members of a large 3-generation family with autosomal dominant axonal CMT2P, Weterman et al. (2012) identified a heterozygous frameshift mutation in the LRSAM1 gene (610933.0002). The mutation was identified by next-generation sequencing in the region of interest as determined by linkage analysis. Weterman et al. (2012) noted that zebrafish models had disturbed neurodevelopment and affected tail formation and movement. In affected members of a large Sardinian family with autosomal dominant axonal CMT, Nicolaou et al. (2013) identified a heterozygous truncating mutation in the LRSAM1 gene (610933.0003). In affected members of a large Spanish family with autosomal dominant CMT2P, Peeters et al. (2016) identified a heterozygous missense mutation in the LRSAM1 gene (C694Y; 610933.0004). Transcriptome analysis of patient lymphoblasts showed several misregulated transcripts, including increased levels of NEDD4L (606384), another ubiquitin ligase, and TNFRSF21 (605732), a regulator of axonal degeneration, compared to controls. TSG101 (601387) levels were unchanged in patient cells. The family was originally reported by Berciano et al. (1986) and Nelis et al. (2004) as having CMT2G. INHERITANCE \- Autosomal dominant \- Autosomal recessive SKELETAL \- Pes cavus (in some patients) \- Hammertoes (in some patients) \- Foot deformities MUSCLE, SOFT TISSUES \- Distal limb muscle weakness due to peripheral neuropathy (lower limbs are more affected than upper limbs) \- Distal limb muscle atrophy due to peripheral neuropathy (lower limbs are more affected than upper limbs) \- Muscle cramping NEUROLOGIC Peripheral Nervous System \- Loss of ability to run due to lower limb weakness \- Difficulty in heel-to-toe walking \- Foot drop \- Steppage gait \- Fasciculations \- Hyporeflexia \- Areflexia \- Distal sensory loss \- Sensorimotor axonal neuropathy \- Normal or mildly decreased motor nerve conduction velocity (NCV) (greater than 38 m/s) \- Sural nerve biopsy shows axonal degeneration \- Axonal degeneration/regeneration on nerve biopsy \- Decreased number of myelinated fibers may be found MISCELLANEOUS \- Peak age of onset in second decade (range childhood to 76 years) \- Usually begins in feet and legs (peroneal distribution) \- May progress to upper limbs \- Onset usually in adulthood \- Slowly progressive disorder \- Some patients may become wheelchair-bound \- Incomplete penetrance \- Both homozygous and heterozygous mutations in LRSAM1 have been reported MOLECULAR BASIS \- Caused by mutation in the leucine-rich repeat- and sterile alpha motif-containing 1 gene (LRSAM1, 610933.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P	c3280797	5,242	omim	https://www.omim.org/entry/614436	2019-09-22T15:55:16	{"doid": ["0110169"], "omim": ["614436"], "orphanet": ["300319"], "synonyms": ["CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2G, FORMERLY", "Alternative titles", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2P", "CMT2P"]}
Skin disease Sebaceous adenitis and hair loss in a dog Sebaceous adenitis in an uncommon skin disease found in some breeds of dog, and more rarely in cats, rabbits and horses.[1] characterised by an inflammatory response against the dog's sebaceous glands (glands found in the hair follicles in the skin dermis), which can lead to the destruction of the gland. It was first described in veterinary literature in the 1980s.[2] ## Contents * 1 Signs * 2 Cause * 3 Diagnosis * 4 Treatment * 4.1 Topical therapy * 4.2 Immunosuppressant therapy * 4.3 Dietary supplementation * 5 Epidemiology * 6 Etymology * 7 See also * 8 References * 9 Further reading ## Signs[edit] There are two expressions of this condition, one for long or double coated breeds and one for short coated breeds, both with differing presentations.[3] * For long- or double-coated breeds such as Poodles, Akitas and Samoyeds, the condition often presents itself with silvery dandruff which adheres to the coat, hair loss (not to be confused with moulting or "blowing coat"), a dull and brittle coat, and later on skin lesions along the back and ears[3] as well as thickened skin and a musty or rancid odour.[4] * For short-coated breeds such as Vizslas, the condition causes facial swellings, nodular skin lesions, fine dandruff which does not adhere to the coat, and a general "moth-eaten" appearance to the coat.[3] ## Cause[edit] Anatomy of human skin, which shows the location of human and canine sebaceous glands The signs of sebaceous adenitis are caused by an inflammatory disease process which affects the sebaceous glands of the skin.[5] The cause of the inflammatory disease is unknown.[6] Different breeds of dogs may have different underlying causes of the disease.[6] Research is currently underway to find if there is a genetic predisposition for sebaceous adenitis; the exact mode of inheritance remains unknown.[7] In Standard Poodles, sebaceous adenitis is most likely an autosomal recessive inherited disease, with variable expression.[5] ## Diagnosis[edit] In general, sebaceous adenitis is underdiagnosed in dogs.[1] Diagnosis confirmation requires multiple punch biopsies analysed by a dermopathologist who will comment on the condition of the sebaceous glands, revealing granulomatous or pyogranulomatous inflammation surrounding the sebaceous glands or even complete destruction of sebaceous glands.[8] Other conditions with similar presentations include: bacterial folliculitis and demodicosis, dermatophytosis, endocrinopathy, pemphigus foliaceus, zinc responsive dermatosis, vitamin A-responsive dermatosis, ichthyosis, and nutritional deficiencies.[9] As well as, superficial pyoderma, primary idiopathic seborrhea and other endocrine diseases.[8] ## Treatment[edit] There is no cure for this condition.[10] Treatment is generally lifelong[3] and takes the form of bathing and soaking in mineral oils and washing with antibiotic shampoos to try to alleviate symptoms and slow the condition's progression.[11] Antiseptic and antibiotic shampoos (chlorhexidine or benzoyl peroxide) are used to manage further secondary bacterial infection.[9] For some breeds, cyclosporine or corticosteroids and immunosuppressant drugs may be effective,[3] and it is postulated, through some studies, that large doses of vitamin A given orally may result in some improvement.[3] It has been suggested that the more aggressively one applies the topical methods of treatment, the less aggressively one needs to employ the immunosuppressant therapy. The suggestion is that this phenomenon may be due to a cyclic feedback whereby secondary infection, when not aggressively treated with topical therapy, increases and contributes to further sebaceous gland inflammation.[9] ### Topical therapy[edit] This forms a major and critical part in the disease treatment and the shampoo treatment can need to be applied as often as 3 to 4 times per week.[9] An antiseborrheic shampoo removes the scale blocking the follicles. The mineral oil soak, whereby the oil remains on the affected animal for at least 2 hours, is needed to replace epidermal lipids as well as to restore normal epidermal barrier function. The oil is then removed through the process of many baths. This oil treatment needs to be repeated at least once a week for 4 to 7 weeks until new hair growth is observed.[9] Once new hair growth is observed, topical treatment can be decreased to every 2 to 4 weeks. ### Immunosuppressant therapy[edit] Immunosuppressant and anti-inflammatory therapy serves to stop on-going destruction of the sebaceous glands. Like other inflammatory diseases, most animals receive an initial course to stop the inflammation and treatment is tapered off to the lowest dose that keeps the disease in remission.[9] Oral cyclosporine may be used.[9] Corticosteroids (e.g. prednisone) are used only if pruritus is a major clinical feature.[9] ### Dietary supplementation[edit] Commonly used dietary supplements include: * Omega-6 fatty acids (e.g., safflower or sunflower oil) * Omega-3 fatty acids (e.g., fish oils) * Vitamin A.[9] ## Epidemiology[edit] While the condition has been seen in over 60 breeds of dog (including cross breeds),[9][12] certain breeds have been found to be more susceptible than others to sebaceous adenitis: * American Akita and Akita Inu[13][8] * Standard Poodle[13][8] * Vizsla[13][8] * English Springer Spaniel[14] * Chow Chow[15][9] * Samoyed[1][8] * Weimaraner[8] * Havanese[16] Breeds also mentioned in scientific literature as having some susceptibility include: * German Shepherd[15] * Dachshund[1] * Old English Sheepdog[15] * Lhasa Apso[15] * Boxer[15] * Collie[15] * Toy Poodle[15] * Mixed-breeds[3] Sebaceous adenitis has no sex-predisposition.[1] Sebaceous adenitis also occurs in cats,[8] rabbits,[3][17] and horses.[18] ## Etymology[edit] Sebaceous refers to the gland which is affected by the disease. Adenitis is a general term referring to the inflammation of a gland. ## See also[edit] * Dogs portal ## References[edit] 1. ^ a b c d e Craig, Mark (2006). "Clinical refresher: Canine sebaceous adenitis". Companion Animal. 11 (5): 62–8. doi:10.1111/j.2044-3862.2006.tb00066.x. 2. ^ Spaterna, A.; Antognoni, M.T.; Cappuccini, S.; Tesei, B. (2003). "Sebaceous Adenitis in the Dog: Three Cases". Veterinary Research Communications. 27: 441–443. doi:10.1023/B:VERC.0000014199.39879.bb. PMID 14535449. S2CID 30352408. 3. ^ a b c d e f g h Linek, Monika (2008). "Sebaceous adenitis in the dog" (PDF). Veterinary Focus. 18 (1): 12–16. doi:10.1055/s-0034-1381781. Archived from the original (PDF) on 22 March 2012. Retrieved 10 April 2011. 4. ^ "Sebaceous Adenitis". Canine Inherited Disorders Database. 1998. Archived from the original on June 5, 2011. Retrieved 10 April 2011. 5. ^ a b Rosser, EJ, Jr (2014). "Therapy for sebaceous adenitis". In Bonagura, JD; Twedt, DC (eds.). Kirk's current veterinary therapy (15th ed.). St. Louis, Mo.: Elsevier/Saunders. ISBN 9780323227629. 6. ^ a b Paterson, Sue (2009). "Chapter 17: Keratinisation defects". Manual of Skin Diseases of the Dog and Cat (2nd ed.). Chichester: John Wiley & Sons. pp. 277–291. ISBN 9781444309324. 7. ^ Koch, Sandra N. (June 1, 2009 – November 30, 2010). "01346-A: Genetic Basis of Sebaceous Adenitis in Dogs". University of Minnesota. Archived from the original on 2011-10-02. Retrieved 7 April 2011. 8. ^ a b c d e f g h Hall, Jan A. (2005). "Congenital and Hereditary Defects in Skin Disease". Ontario Veterinary College, University of Guelph, Canada: Omnibooks Online. Retrieved 2 June 2011.[permanent dead link] 9. ^ a b c d e f g h i j k Angus, DVM, DACVD, John C. (2009). "How I Treat Sebaceous Adenitis". Animal Dermatology Clinic, Pasadena, CA, USA: Omnibooks Online. p. 1. Retrieved 2 June 2011.CS1 maint: multiple names: authors list (link) 10. ^ "Sebaceous Adenitis". Orthopedic Foundation for Animals. Retrieved 2019-09-27. 11. ^ "Inflammatory Skin Disease in Dogs". Retrieved 10 April 2011. 12. ^ Mr Charlie Walker BVetMed CertVD MRCVS (2010). "Skin: idiopathic/granulomatous sebaceous adenitis". Cambridge CB21 4EN, UK: VetStream. Retrieved 19 July 2011.CS1 maint: location (link) 13. ^ a b c Pfeiffer, Ina (April 1 – June 30, 2006). "577-AT: Sebaceous Adenitis in the Akita". Archived from the original on 2011-10-02. Retrieved 7 April 2011. 14. ^ Hernblad Tevell, E; Bergvall, K; Egenvall, A (2008). "Sebaceous adenitis in Swedish dogs, a retrospective study of 104 cases". Acta Veterinaria Scandinavica. 50: 11. doi:10.1186/1751-0147-50-11. PMC 2412885. PMID 18501018. 15. ^ a b c d e f g Gross, Thelma Lee; Peter J. Ihrke; Emily J. Walder; Verena K. Affolter (2005). Skin diseases of the dog and cat: clinical and histopathologic diagnosis (second ed.). Wiley-Blackwell. pp. 186–8. ISBN 978-0-632-06452-6. 16. ^ Frazer, Megan; Anthea E. Schick; Thomas P. Lewis; Edward Jazic (June 2011). "Sebaceous adenitis in Havanese dogs: a retrospective study of the clinical presentation and incidence". Veterinary Dermatology. 22 (3): 267–274. doi:10.1111/j.1365-3164.2010.00942.x. PMID 21210878. 17. ^ Anna Meredith; Stephen White (2010). "Sebaceous adenitis". Cambridge CB21 4EN, UK: VetStream. Retrieved 19 July 2011.CS1 maint: location (link) 18. ^ Osborne, Christina (2006). "Sebaceous adenitis in a 7-year-old Arabian gelding". The Canadian Veterinary Journal. 47 (6): 583–6. PMC 1461412. PMID 16808233. ## Further reading[edit] * Reichler, Iris M.; Hauser, Beat; Schiller, Irene; Dunstan, Robert W.; Credille, Kelly M.; Binder, Heinrich; Glaus, Toni; Arnold, Susi (2001). "Sebaceous adenitis in the Akita: clinical observations, histopathology and heredity". Veterinary Dermatology. 12 (5): 243–53. doi:10.1046/j.0959-4493.2001.00251.x. PMID 11906649. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Sebaceous adenitis	c3670767	5,243	wikipedia	https://en.wikipedia.org/wiki/Sebaceous_adenitis	2021-01-18T18:30:31	{"wikidata": ["Q1344999"]}
A number sign (#) is used with this entry because of evidence that Weill-Marchesani syndrome-3 (WMS3) is caused by homozygous mutation in the LTBP2 gene (602091) on chromosome 14q24. One such family has been reported. Description Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities (Faivre et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of WMS, see 277600. Clinical Features Haji-Seyed-Javadi et al. (2012) studied a large consanguineous Iranian family in which a brother and sister and their cousin had Weill-Marchesani syndrome, whereas 3 older sibs of the brother and sister displayed some features of WMS without meeting diagnostic criteria for the disorder. The proband was a 17-year-old boy who had ectopia lentis, myopia, elevated intraocular pressure, shallow anterior chamber, microspherophakia, short stature, brachydactyly, joint stiffness, and pulmonary and aortic stenosis. His 19-year-old sister also showed all of these features. In addition, 3 sibs had no eye findings but displayed some of the other features of WMS: a 30-year-old sister had brachydactyly, joint stiffness, and pulmonary and aortic stenosis; a 36-year-old brother had brachydactyly, joint stiffness, and pulmonary stenosis; and a 22-year-old sister had pulmonary and aortic stenosis. Their 37-year-old female cousin displayed all of the eye findings as well as brachydactyly and joint stiffness, but did not have pulmonary or aortic stenosis. Molecular Genetics Haji-Seyed-Javadi et al. (2012) screened the LTBP2 gene for sequence variations in 30 unrelated Iranian probands with ectopia lentis (see 129600), which was isolated in 13 and associated with WMS in 4 and with Marfan syndrome (MFS; 154700) in 13. The proband of a large consanguineous Iranian family with ectopia lentis and WMS was found to be homozygous for a missense mutation (V1177M; 602091.0012), which was also identified in 2 more affected family members, as well as in 3 relatives with WMS-like features. Analysis of FBN1 (134797), ADAMTS10 (608990), and ADAMTS17 (607511) in 2 family members, 1 diagnosed with WMS and 1 with WMS-like features, revealed no disease-causing variations. Whole-genome homozygosity mapping on DNA from 5 affected and 4 unaffected family members confirmed that the only homozygous region segregating with affected status was an interval bordered by SNPs rs8017852 and rs7150688, containing the LTBP2 gene. Haji-Seyed-Javadi et al. (2012) also identified heterozygosity for a nonsense mutation in LTBP2 in a proband with ectopia lentis associated with Marfan syndrome; the proband and his MFS-affected daughter, who did not carry the LTBP2 mutation, were both found to also carry a mutation in the FBN1 gene. However, the proband's mother and brother, who had mitral valve prolapse (MVP) and primary closed angle glaucoma and MVP, myopia, and mild pectus excavatum, respectively, had the LTBP2 mutation but not the FBN1 mutation. Haji-Seyed-Javadi et al. (2012) concluded that the FBN1 mutation was highly likely to be the major cause of the ectopia lentis-Marfan syndrome phenotype in the pedigree, but that LTBP2 also contributed to disease status. No disease-associated mutation was identified in the 13 probands with isolated ectopia lentis; however, the authors thought that it remained a plausible candidate gene and suggested that larger cohorts be screened. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Eyes \- Ectopia lentis \- Myopia \- Increased intraocular pressure \- Shallow anterior chamber \- Microspherophakia CARDIOVASCULAR Heart \- Pulmonary valve stenosis \- Aortic valve stenosis SKELETAL \- Joint stiffness Hands \- Brachydactyly MISCELLANEOUS \- Based on 1 family (last curated September 2012) MOLECULAR BASIS \- Caused by mutation in the latent transforming growth factor-beta-binding protein 2 gene (LTBP2, 602091.0012 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	WEILL-MARCHESANI SYNDROME 3	c0265313	5,244	omim	https://www.omim.org/entry/614819	2019-09-22T15:54:11	{"doid": ["0050475"], "mesh": ["D056846"], "omim": ["614819"], "orphanet": ["3449"], "genereviews": ["NBK1114"]}
Foix–Chavany–Marie syndrome Other namesFacio-pharyngo-glosso-masticatory diplegia Operculum (brain) SpecialtyNeurology Foix-Chavany-Marie Syndrome (FCMS), also known as Bilateral Opercular Syndrome, is a neuropathological disorder characterized by paralysis of the facial, tongue, pharynx, and masticatory muscles of the mouth that aid in chewing.[1] The disorder is primarily caused by thrombotic and embolic strokes, which cause a deficiency of oxygen in the brain. As a result, bilateral lesions may form in the junctions between the frontal lobe and temporal lobe, the parietal lobe and cortical lobe, or the subcortical region of the brain.[2][3] FCMS may also arise from defects existing at birth that may be inherited or nonhereditary. Symptoms of FCMS can be present in a person of any age and it is diagnosed using automatic-voluntary dissociation assessment, psycholinguistic testing, neuropsychological testing, and brain scanning. Treatment for FCMS depends on the onset, as well as on the severity of symptoms, and it involves a multidisciplinary approach. ## Contents * 1 Classification * 1.1 Bilateral * 1.2 Unilateral * 2 Symptoms * 3 Causes * 3.1 Cerebrovascular disease * 3.2 Central nervous system infection * 3.3 Epilepsy * 3.4 Unusual Causes * 4 Mechanism * 4.1 Neuropathology * 5 Diagnosis * 5.1 Criteria * 5.2 Techniques * 5.2.1 Automatic-voluntary dissociation assessment * 5.2.2 Psycholinguistic testing * 5.2.3 Neuropsychological testing * 5.3 Imaging * 5.3.1 Magnetic resonance imaging * 5.3.2 CT Scan * 5.3.3 SPECT * 5.4 Other techniques * 6 Management * 7 See also * 8 References * 9 Further reading * 10 External links ## Classification[edit] Frontal (coronal) section human brain. Lesions occurring in the highlighted regions are characteristic of Foix-Chavany-Marie Syndrome. There are two forms (also referred to as "classifications") of FCMS; bilateral and unilateral. The bilateral form is most common (also referred to as the "classical form") and is caused by the formation of lesions on both sides of the anterior or posterior region of the operculum. In contrast, the unilateral form is rare and is caused by the formation of lesions on one side of the anterior or posterior region of the operculum.[1] Lesions located in the anterior regions of the operculum are associated with motor deficits and anarthria, a total absence of the ability to form speech or language. Lesions located in the posterior regions of the operculum are associated with parietal opercular functions.[2] The two classifications of FCMS were established based on the location of the lesion, stroke, and trauma affecting the brain. Classifying FCMS based solely upon lesions yields five specific subtypes of FCMS currently known to fall into the bilateral and unilateral categories:[1][3] * Bilateral anterior opercular syndrome (lesion in both the anterior or in the frontal operculum) * Opercular-subopercular syndrome (lesions in the opercular cortex on one side and the subopercular lesion in the contralateral side). * Subopercular syndrome (lesions in the subcortical corticobulbar projections only). * Unilateral anterior syndrome involving the frontal operculum. * Posterior syndrome involving the junction between the frontal and the parietal lobe of the operculum. ### Bilateral[edit] The bilateral form of FCMS (also known as facio-labio-pharyngo-glosso-laryngo-brachial paralysis) is consistent with the classic presentation of bilateral corticobulbar involvement. It is characterized by well-preserved automatic and reflex movements. It is caused by lesions in the cortical or subcortical region of the anterior opercular area surrounding the insula forming the gyri of the frontal, temporal, and parietal lobes.[4] ### Unilateral[edit] The unilateral operculum syndrome is a very rare form of FCMS caused by the formation of unilateral lesions. In this form of FCMS, the unaffected hemisphere of the brain compensates for the unilateral lesion. Usually, this occurs when the unaffected region is the individual's dominant hemisphere.[1] ## Symptoms[edit] An individual affected with FCMS develops disabilities associated with voluntary movements using the facial, lingual, pharyngeal, and masticatory muscles. However, the reflexive and autonomic functions of these muscles groups are usually intact. Common symptoms include drooling, an inability to elevate and depress the mandible, difficulty chewing, inability of protruding tongue, swallowing, and loss of speech.[3][1][4] Classification of the disorder is distinguished by the location of the lesions formed, which causes certain symptoms to be present or amplified. FCMS caused by the formation of bilateral lesions causes paralysis of the facial, lingual, pharyngeal, and masticatory muscles. This form of FCMS involves voluntary-autonomic dissociation and an inability to form speech. The formation of bilateral lesions confined to the posterior operculum has a distinct symptom of word deafness, an inability to understand language. FCMS caused by the formation of lesions unilaterally causes muteness of speech and upper motor neuron cranial nerve paresis, muscular weakness. The formation of unilateral lesions confined to the posterior operculum has distinct symptoms that includes sensory loss in the hand and face contralateral to the location of the lesion.[4] ## Causes[edit] Foix-Chavany-Marie Syndrome is primarily caused by multiple strokes and lesions. However, less common causes that can eventually produce lesions to the operculum resulting in the FCMS syndrome include the following; tumors, trauma, encephalitis, neurodegenerative diseases, and vasculitis. Viral infections, such as Herpes and HIV can also cause FCMS. Moreover, any lesion in the cortical or sub-cortical region affecting the corticobulbar pathways will produce FCMS.[1] ### Cerebrovascular disease[edit] Strokes are one of the most common causes of Foix-Chavany-Marie Syndrome. The type of strokes associated with this syndrome include embolic and thrombotic strokes. Strokes affecting the middle cerebral artery and the branches that pass through or near the operculum are characteristic of FCMS.[1] ### Central nervous system infection[edit] Symptoms of infections specifically HIV and Herpes simplex encephalitis can cause FCMS. Numerous lesions can develop with HIV infections, which likely result in the development of FCMS.[1][5] ### Epilepsy[edit] Epilepsy symptoms such as seizures can spread discharges that cause FCMS. This causation results in the only reversible development of FCMS as it is the only cause that allows full recuperation from speech, swallowing, and mastication difficulties when treated.[3] This causation is most commonly seen in children with FCMS.[3] ### Unusual Causes[edit] * Tumors * Multiple Sclerosis * Neurodegenerative diseases * Acute disseminated encephalomyelitis * Moyamoya disease * Vasculitis[6] * Trauma ## Mechanism[edit] FCMS is primarily originates from damages in the posterior region of the inferior frontal gyrus and inferior region of the precentral gyrus.[6] Anatomically, the word operculum is defined as the cortices encompassing the insula, which includes the pre and post-central, inferior-frontal, supramarginal, angular inferior parietal, and superior temporal convolutions.[1] Parts of the brain such as Heschl's gyrus, Brodmann's area, Broca's Area, Wernicke's Area are amongst the most relevant in the operculum. These areas are responsible for auditory functions for language and speech.[7] Operculum of the inferior frontal gyrus. FCMS, sometimes called cortical pseudobulbar palsy, is characterized by lesions affected both sides of the operculum. These lesions typically damage the cranial nerves leading to both motor and sensory deficits. The cranial nerves that are impaired include the following; Cranial Nerve (CN) V (the trigeminal nerve), CN VII (the facial nerve), CN IX (the glossopharyngeal nerve), CN X (the vagus nerve), and CN XII (the hypoglossal nerve). Cerebral malformation, namely unilateral schizencephaly in association with contralateral polymicrogyria symmetrically in the perisylvian area is another known characteristic of FCMS. Moreover, another deformation found with FCMS includes the failure of opercularization caused by the underdevelopment of the anterior part of the opercula found in the fetal brain in the 32nd week.[7] ### Neuropathology[edit] The anatomic basis for the automatic voluntary dissociation is characterized by the following. Neurons that lie adjacently in the operculum project supranuclear fibers to the cranial nuclei for the voluntary movement of facial, pharyngeal, lingual, and masticatory muscles. Emotional movement of these muscles is controlled by alternative pathways that run from the amygdala and lateral hypothalamus to the brainstem via the medial forebrain bundle and dorsal longitudinal fasciculus.[8] The opercular cortex surrounding the insula is separated by two anatomical components: the ascending rami of the lateral sulcus and the posterior rami into three different sections of the operculum.[3] 1. Frontal operculum formed by posterior part of the inferior frontal gyrus. 2. Fronto-parietal opercula formed by the lowermost part of the precentral and postcentral gyrus and the anterior and lowermost part of the inferior parietal lobule. 3. Temporal opercula formed by the superior temporal gyrus.[3] ## Diagnosis[edit] ### Criteria[edit] FCMS shares similar characteristics with the following disorders: catatonia, akinetic mutism, orobuccal apraxia, Broca’s aphasia, pseudobulbar palsy, bulbar palsy secondary to myasthenia gravis, Guillain-Barré syndrome, and brainstem strokes.[1] In determining a diagnosis between with catatonia, akinetic mutism, and FCMS, a person must demonstrate their ability to perform voluntary function of the limbs. Patients with catatonia or akinetic mutism are not able to perform voluntary commands that involve the use of limbs, while patients with FCMS still possess voluntary usage of limbs.[1] If a person can demonstrate ability in voluntary usage of limbs, catatonia and akinetic mutism are most likely ruled out from the diagnosis. In determining a diagnosis between Broca’s aphasia and FCMS, a person must demonstrate their ability in voluntary movement of cranial musculature. People with Broca’s aphasia may not exhibit a complete loss of voluntary movement facial muscles, pharyngeal muscles, laryngeal muscles, brachial muscles, tongue muscles, and muscles of the mouth that aid in chewing. These voluntary functions may still be present, to varying degrees. People with FCMS do not possess this ability. For people with FCMS, voluntary movement of cranial musculature is completely absent.[1] In determining a diagnosis between pseudobulbar palsy, a person must demonstrate whether or not muteness is present, as well as the ability to move the facial, buccal, lingual, and pharyngeal muscles. People with pseudobulbar palsy exhibit, to varying degrees, an ability in these functions, while patients with FCMS do not.[1] ### Techniques[edit] There are three general classes of tests utilized by physicians when determining a diagnosis for FCMS: (1) automatic-voluntary dissociation assessment, (2) psycholinguistic testing, and (3) neuropsychological testing.[9] In addition, brain scanning techniques are utilized to observe whether ischemic abnormalities or lesions are present within the operculum region of the cortices. #### Automatic-voluntary dissociation assessment[edit] FCMS is largely characterized by the paralysis of voluntary movement in facial, lingual, pharyngeal, and masticatory muscles, while automatic, involuntary functions of these four muscle groups remain.[3] Automatic functions are performed by inducing involuntary reflexes, such as palatal, laryngeal, blink, and gag reflexes. Other involuntary functions that are tested include spontaneous smiling, laughter, and yawning.[10] Patients with the disorder are able to these functions under automatic, involuntary reflex. An individual’s ability to perform these functions voluntarily are tested determined through a series of commands by the physician. Typically, individuals with the disorder are not able to perform any of these functions upon command. Dissociation between automatic and voluntary dissociation is indicated by an individuals’ ability to perform the involuntary, automatic functions, and their inability to perform the same actions, voluntary. #### Psycholinguistic testing[edit] Psycholinguistics pertain to the psychological and neurobiological components that allow humans to acquire, utilize, comprehend, and produce language. The tests most commonly used for psycholinguistic testing include the Dutch version of Aachen aphasia test, syntactic comprehension test, and the Token test.[10] Psycholinguistics allow physicians to narrow down and rule out other disorders that may be similar to FCMS when diagnosing a patient. #### Neuropsychological testing[edit] Neuropsychology is the study of neurobiology and psychology. Neuropsychological tests are utilized for the purpose of observing an individuals’ abilities in cognitive functioning, reasoning, and memories.[10] The tests most commonly used for neuropsychological testing include WAIS-III, Stroop test, Bourdon Wiersma test, and the Rey-Osterrieth complex figure test. These tests allow physicians to evaluate the degree to which the bilateral lesions in the operculum have been affected, and allow for the determination of proper treatment. ### Imaging[edit] Scanning techniques include EEG, SPECT, MRI, and CT brain scanning.[1][2] These additional techniques are useful in determining what type of lesion the patient has, and allows physicians to determine more effective ways in treating the patient. (A) CT scan of a patient with middle cerebral artery stroke illustrating hypodensity areas within the temporal and frontal lobes. (B) CT scan displaying an ischemic stroke bordering the fronto-parietal opercular cortex (red arrow) and a left-sided ichemic lesion of the fronto-parietal opercular cortex (blue arrow). #### Magnetic resonance imaging[edit] MRI is one of the best techniques that can detect the lesions in the brain of the FCMS that some of the times are missed by just using a Computer-Tomography Scan. Also, this type of imaging can reveal right frontal lobes contusions encompassing the anterior operculum, the premotor area, and the association area.[10] #### CT Scan[edit] This computer-tomography type of imaging is one of the most used in any clinical environment and although it can detect some of the brain areas affected by a stroke or a trauma it does not provide the same acuity as the magnetic resonance imaging. CT scans can also reveal, in patients with the syndrome, the bilateral cortical infarcts located in the posterior frontal region involving the opercular areas.[3] #### SPECT[edit] The single photon emission computed tomography of the brain can show uptake area in the right frontal lobe and normal uptake are in the left hemisphere.[10] This type of imaging can give a more detailed view of a specific region of the brain. ### Other techniques[edit] An electroencephalography (EEG) is also used in patients with the FCMS and it can reveal focal slowing and epileptic discharges from left fronto-temporal regions.[3] ## Management[edit] Treatment of Foix–Chavany–Marie syndrome depends on the onset of symptoms and involves a multidisciplinary approach. Drugs are used in neurological recovery depending on the etiological classification of FCMS. FCMS caused by epilepsy, specifically resulting in the development of lesions in the bilateral and subcortical regions of the brain can be treated using antiepileptic drugs to reverse abnormal EEG changes and induce complete neurological recovery.[3] In addition, a hemispherectomy can be performed to reverse neurological deficits and control the seizures. This procedure can result in a complete recovery from epileptic seizures.[3] Physical therapy is also used to manage symptoms and improve quality of life. Classical FCMS resulting in the decline of ones ability to speak and swallow can be treated using neuromuscular electrical stimulation and traditional dysphagia therapy. Speech therapy further targeting dysphagia can strengthen oral musculature using modified feeding techniques and postures. Therapeutic feedings include practicing oral and lingual movements using ice chips.[1] In addition, different procedures can be performed by a neurosurgeon to alleviate some symptoms. ## See also[edit] * Pseudobulbar Palsy * Operculum * Corticobulbar Tracts * Wernicke's Aphasia * Broca's Aphasia ## References[edit] 1. ^ a b c d e f g h i j k l m n o Bakar, M; Kirshner, HS; Niaz, F (1998). "The opercular-subopercular syndrome: four cases with review of the literature". Behavioural Neurology. 11 (2): 97–103. doi:10.1155/1998/423645. PMID 11568407.[unreliable source?] 2. ^ a b c Starkstein, SE; Berthier, M; Leiguarda, R (July 1988). "Bilateral opercular syndrome and crossed aphemia due to a right insular lesion: a clinicopahological study". Brain and Language. 34 (2): 253–61. doi:10.1016/0093-934X(88)90137-X. PMID 3401694.[unreliable source?][non-primary source needed] 3. ^ a b c d e f g h i j k l Lekhjung, Thapa; Raju, Paudel; PVS, Rana (2010). "Opercular syndrome: Case reports and review of literature" (PDF). Neurology Asia. 15 (2): 145–152.[unreliable source?] 4. ^ a b c Desai, SD; Patel, D; Bharani, S; Kharod, N (May 2013). "Opercular syndrome: A case report and review". Journal of Pediatric Neurosciences. 8 (2): 123–5. doi:10.4103/1817-1745.117842. PMC 3783719. PMID 24082930. 5. ^ Johanna C. van der Poel, PhD, Charles A. Haenggeli, MD, and Wouterina C.G. Overweg-Plandsoen, PhD (1995). "Operculum Syndrome: Unusual Feature of Herpes Simplex Encephalitis". Pediatric Neurology. 12 (3): 246–249. doi:10.1016/0887-8994(95)00005-z. PMID 7619193.CS1 maint: multiple names: authors list (link) 6. ^ a b Milanlioglu, A; Aydın, MN; Gökgül, A; Hamamcı, M; Erkuzu, MA; Tombul, T (2013). "Ischemic bilateral opercular syndrome". Case Reports in Medicine. 2013: 513572. doi:10.1155/2013/513572. PMC 3588394. PMID 23476665. 7. ^ a b Szabó, N; Hegyi, A; Boda, M; Páncsics, M; Pap, C; Zágonyi, K; Romhányi, E; Túri, S; Sztriha, L (May 2009). "Bilateral operculum syndrome in childhood". Journal of Child Neurology. 24 (5): 544–50. doi:10.1177/0883073808327841. PMID 19196875. 8. ^ Ohtomo, R; Iwata, A; Tsuji, S (January 2014). "Unilateral opercular infarction presenting with Foix-Chavany-Marie Syndrome". Journal of Stroke and Cerebrovascular Diseases. 23 (1): 179–81. doi:10.1016/j.jstrokecerebrovasdis.2012.08.015. PMID 23040957. 9. ^ Theys, Tom; Van Cauter, Sofie; Kho, Kuan H.; Vijverman, Anne-Catherine; Peeters, Ronald R.; Sunaert, Stefan; van Loon, Johannes (2013-02-01). "Neural correlates of recovery from Foix-Chavany-Marie syndrome". Journal of Neurology. 260 (2): 415–420. doi:10.1007/s00415-012-6641-0. ISSN 1432-1459. PMID 22893305. 10. ^ a b c d e Nitta, N; Shiino, A; Sakaue, Y; Nozaki, K (August 2013). "Foix-Chavany-Marie syndrome after unilateral anterior opercular contusion: a case report". Clinical Neurology and Neurosurgery. 115 (8): 1539–41. doi:10.1016/j.clineuro.2012.12.036. PMID 23369402.[non-primary source needed] ## Further reading[edit] * Ole Daniel Enersen. "Foix-Chavany-Marie syndrome". Who Named It?. Retrieved 2006-07-25. ## External links[edit] Classification D * ICD-10: G12.2 * MeSH: C537069 External resources * Orphanet: 2048 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Foix–Chavany–Marie syndrome	c2931412	5,245	wikipedia	https://en.wikipedia.org/wiki/Foix%E2%80%93Chavany%E2%80%93Marie_syndrome	2021-01-18T18:47:57	{"gard": ["2351"], "mesh": ["C537069"], "umls": ["C2931412"], "orphanet": ["2048"], "wikidata": ["Q1435202"]}
A number sign (#) is used with this entry because retinitis pigmentosa-11 (RP11) is caused by heterozygous mutation in the PRPF31 gene (606419) on chromosome 19q13. Description Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment. For a discussion of genetic heterogeneity of RP, see 268000. Clinical Features Moore et al. (1993) described 4 families with autosomal dominant retinitis pigmentosa. Of the 15 patients who were studied from 3 of the families (families 1, 3, and 4), 14 had early onset of night blindness, 10 before age 10 years and 4 before age 20 years, and evidence of severe disease. Patients in all families showed typical fundus features of RP. The majority also had posterior subcapsular lens opacities, macular edema, and/or macular atrophy. Inheritance The transmission pattern of retinitis pigmentosa in the families studied by Moore et al. (1993) was consistent with autosomal dominant inheritance. Mapping In a family (family 4; ADRP5) with retinitis pigmentosa previously reported by Moore et al. (1993), Al-Maghtheh et al. (1994) found linkage of the disorder to chromosome 19q13.4. Three-point analysis of the RP phenotype and markers D19S180 and D19S214 gave a maximum lod score of 4.87. Combining data from these and other markers, Al-Maghtheh et al. (1994) found a lod score of 5.34 in the interval between the 2 markers mentioned, located in the region 19q13.4. Linkage data indicated that this form of retinitis pigmentosa, designated RP11, is separate from the locus for cone-rod dystrophy (120970) mapped to 19q by Evans et al. (1994). Al-Maghtheh et al. (1996) studied families 3 and 4 of Moore et al. (1993) and 2 additional RP families (RP1907 and ADRP2) linked to 19q. They suggested that 19q is a major locus for RP. They were able to refine the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibited incomplete penetrance; some obligate gene carriers remained asymptomatic throughout their lives, whereas symptomatic individuals experienced night blindness and visual field loss in their teens and were generally registered as blind by their thirties. Al-Maghtheh et al. (1996) stated that patients with RP mapping to chromosome 19q were either severely affected or asymptomatic, showing an 'all or nothing' form of incomplete penetrance that the authors called 'bimodal expressivity.' This same entity was apparently identified by Xu et al. (1995) in 4 generations of a Japanese family in which autosomal dominant RP of highly variable expression was segregating. Linkage to D19S180 and other markers on 19q was found. Xu et al. (1995) pointed out that several members of the family reported by Al-Maghtheh et al. (1994) likewise had variable expression; several asymptomatic carriers exhibited functional abnormalities both in electrophysiologic and psychophysical testing. McGee et al. (1997) studied 3 families with reduced penetrance retinitis pigmentosa, including family W reported by Berson et al. (1969). In all 3 families, the disease gene appeared to be linked to 19q13.4, the region containing the RP11 locus, as defined by previously reported linkage studies based on 5 other reduced penetrance families. Meiotic recombinants in 1 of the newly identified RP11 families and in 2 of the previously reported families served to restrict the disease locus to a 6-cM region bounded by markers D19S574 and D19S926. McGee et al. (1997) also compared the disease status of RP11 carriers with the segregation of microsatellite alleles within 19q13.4 from the noncarrier parents in the newly reported and the previously reported families. The results supported the hypothesis that wildtype alleles at the RP11 locus or at a closely linked locus inherited from noncarrier parents are a major factor influencing the penetrance of pathogenic alleles at this locus. 'Isoallele' is the designation used for an allele that modifies the expression of the disease allele in trans. Another example is provided by the variable severity of elliptocytosis due to mutation in alpha-spectrin of the erythrocyte (182860) depending on the state of the 'normal allele' (Gratzer, 1994). Modification by an isoallele has also been suggested as the explanation for variability of phenotype and unusual inheritance in erythropoietic protoporphyria (177000). Molecular Genetics Vithana et al. (2001) identified mutations in the PRPF31 gene in families and individuals with RP11. The mutations included missense substitutions, deletions, and insertions (606419.0001-606419.0007). Wang et al. (2003) described a Chinese kindred with high penetrance of retinitis pigmentosa in association with a 12-bp deletion of PRPF31 (606419.0008). Waseem et al. (2007) noted that RP11 only results from coinheritance of a mutated allele and a wildtype low-expressed allele. They suggested that a high prevalence of low-expressing alleles in certain populations may account for the PRPF31 mutations being identified in patients with RP11 with apparent complete penetrance. Waseem et al. (2007) identified 6 PRPF31 mutations, 4 of which were novel, in a cohort of 118 patients with autosomal dominant RP in the U.K., including members of family RP1907 described by Al-Maghtheh et al. (1996). The age of onset and the severity of the disease varied with different mutations, and individuals carrying the same mutation showed a range of phenotypic variation, suggesting the involvement of other modifying genes. In a previously reported family segregating autosomal dominant RP with reduced penetrance (family W in Berson et al., 1969; family 1562 in McGee et al., 1997) in which extensive screening had failed to detect a PRPF31 mutation (McGee et al., 2002; Rivolta et al., 2006), Rio Frio et al. (2009) sequenced the entire PRPF31 genomic region using the Sanger method and ultrahigh-throughput analysis and identified a splice site mutation (606419.0009) that was common to all patients and obligate asymptomatic carriers and was not found in 300 control chromosomes. History Al-Maghtheh et al. (1998) reported a missense change (arg659 to ser) in the PRKCG gene (176980) in 2 families with RP11-linked dominant RP. Only 1 of the 2 families clearly exhibited the hallmark characteristic of RP11, namely asymptomatic, obligate carriers who transmitted the disease to offspring. Al-Maghtheh et al. (1998) failed to discover a mutation in PRKCG in 3 other families with reduced penetrance showing linkage to this region. Dryja et al. (1999) found no mutations in PRKCG in 3 families that showed linkage to 19q, where both RP11 and PRKCG map, and the characteristic reduced penetrance of RP11. Vithana et al. (2001) stated that the PRKCG gene is not involved in RP11. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Retinitis pigmentosa \- Night blindness (onset in teens) \- Blindness (onset in 30s) \- Posterior subcapsular lens opacities (in some patients) \- Macular edema (in some patients) \- Macular atrophy (in some patients) \- Macular degeneration (in some patients) MISCELLANEOUS \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the pre-mRNA processing factor 31 gene (PRPF31, 606419.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	RETINITIS PIGMENTOSA 11	c0035334	5,246	omim	https://www.omim.org/entry/600138	2019-09-22T16:16:33	{"doid": ["0110408"], "mesh": ["D012174"], "omim": ["600138"], "orphanet": ["791"], "genereviews": ["NBK1417"]}
A number sign (#) is used with this entry because of evidence that Pitt-Hopkins syndrome (PTHS) is caused by heterozygous mutation in the TCF4 gene (602272) on chromosome 18q21. Description The Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (Zweier et al., 2007). See also Pitt-Hopkins-like syndrome-1 (610042), caused by mutation in the CNTNAP2 gene (604569) on chromosome 7q35, and Pitt-Hopkins-like syndrome-2 (600565), caused by mutation in the NRXN1 gene (600565) on chromosome 2p16.3. Clinical Features Pitt and Hopkins (1978) described 2 unrelated patients with a sporadic disorder comprising mental retardation, wide mouth, and intermittent overbreathing. The first patient, a male born of unrelated Greek parents, was profoundly retarded with poor muscular development. Head circumference and body measurements were normal. The mouth was wide with thick fleshy lips and a broad palate; the nose was beaked with broad nasal bridge, and the nostrils flared. There was bilateral pes cavus. Mild clubbing of the fingers and toes was present, and he had a left simian crease. An abnormal respiratory cycle was present every day, and showed extreme fluctuations. He overbreathed at up to 120 breaths per minute for 1 to 2 minutes and then had a period of apnea for up to 2 minutes, during the latter part of which he became cyanosed until a new episode of overbreathing terminated the cyanosis. The rhythm was absent at times during wakefulness and regularly during sleep, and increased with emotional stimuli. He died of pneumonia at the age of 20 years. The second patient, a female of unrelated Sicilian parents, was also retarded and had similar facial features. She was dwarfed and microcephalic, with everted feet and clubbing of fingers and toes. She also had an abnormal pattern of breathing with periodicity similar to that of the first patient. Electroencephalograms of both patients showed an excess of slow components. Singh (1993) described a male patient with features similar to those of the patients reported by Pitt and Hopkins (1978), notably, wide mouth, thick lips, prominent nose, clubbing of fingers and toes, pes cavus, mental retardation, abnormal breathing pattern, and a history of epilepsy. Van Balkom et al. (1998) described a similar female patient. Mental retardation and poor motor development were present. Daily episodic hyperbreathing, which caused massive swallowing of air and necessitated changing to clothes of a larger size during the daytime because of abdominal distention, was noted. Height and head circumference were below the 3rd centile. She had coarse hair, heavy eyebrows, a broad nasal bridge, large nose, flared nares, wide mouth with thick, fleshy lips, a broad palate, and an abnormal ear with a dysplastic helix on the right side. At the age of 40 years, all fingers as well as the great toes were clubbed. Peippo et al. (2006) noted that to the time of their report, 4 patients with PTHS had been described. All showed dysmorphism consisting of large beaked nose, cup-shaped ears with broad helices, a wide mouth, cupid's-bow upper lip, wide and shallow palate, and broad or clubbed fingertips. They further defined the Pitt-Hopkins syndrome phenotype with a description of 2 new patients. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing, and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease (see 142623) in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp wave discharges on electroencephalography. MRI in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Amiel et al. (2007) ascertained 4 cases of PTHS. They noted that the abnormal ventilatory pattern characterized by daily bouts of diurnal hyperventilation that is the hallmark of PTHS was not reported in patients younger than 3 years of age. Epilepsy generally occurred later in the course of the disease. Zweier et al. (2007) studied the 2 sporadic cases reported by Peippo et al. (2006) and 29 additional patients with severe mental retardation, breathing anomalies, and PTHS-like facial dysmorphism. These patients included the sib pair described by Orrico et al. (2001) and the patient of Van Balkom et al. (1998). Brockschmidt et al. (2007) reported a girl with PTHS resulting from a 0.5-Mb microdeletion on chromosome 18q21.2. She had severely delayed psychomotor development, only achieving assisted walking at age 5 years. At age 7 years, she had no speech, hypotonia, and truncal ataxia. Dysmorphic features included coarse face with a broad and slightly depressed nasal bridge, wide mouth with a bow-shaped upper lip, short philtrum, dysplastic ears with anteverted earlobes, short neck, and low frontal and nuchal hairlines. Other features included widely spaced nipples, long tapering fingers, simian creases, proximally-inserted thumbs, and flat feet with superimposed toes. She had a happy disposition and began to have hyperventilation attacks at age 7.5 years. Rosenfeld et al. (2009) identified 7 new cases of Pitt-Hopkins syndrome due to deletions of TCF4 and reviewed the 59 previously reported cases in the literature. Among their newly identified patients, all had features consistent with Pitt-Hopkins syndrome, although only 3 had breathing anomalies and none had seizures. Review of the literature indicated that although all reported patients had severe psychomotor retardation, the onset of seizures and hyperventilation episodes were limited to the first decade in most patients. Hyperventilation episodes were more common than seizures and were seen in the oldest patients, and individuals with missense TCF4 mutations were more likely to develop seizures. Marangi et al. (2011) identified haploinsufficiency for the TCF4 gene in 14 of 63 Italian patients referred for suspicion of Pitt-Hopkins syndrome. One patient with the full syndrome had a balanced translocation involving the TCF4 gene. The patients ranged in age between 2 and 12 years, and all had severe intellectual disability with nearly absent language development. Eleven patients had a distinctive facial appearance, with bitemporal narrowing, square forehead, deep-set eyes, upslanted palpebral fissures, broad nasal bridge with pointed tip and flaring nostrils, full cheeks, protruding lower jaw and lip, and cup-shaped ears. Most (86%) had breathing abnormalities. Variable additional features included myopia, constipation, epilepsy, and uncoordinated movements. Marangi et al. (2011) noted the phenotypic overlap with Angelman (105830) and Rett (312750) syndromes, but concluded that the facial gestalt of PTHS combined with additional features can lead to the correct clinical diagnosis. Lehalle et al. (2011) reported 4 unrelated patients with genetically confirmed PTHS who had fetal pads on the fingers and toes. They suggested that the presence of fetal pads can be a useful feature in the diagnosis of Pitt-Hopkins syndrome. ### Clinical Variability Zweier et al. (2007) failed to find a mutation in the TCF4 gene in 2 sibs described by Orrico et al. (2001), or in the patient reported by Van Balkom et al. (1998). Kalscheuer et al. (2008) reported a girl with a de novo heterozygous balanced translocation t(18;20)(q21.1;q11.2) that disrupted the TCF4 gene and CHD6 gene on chromosome 20. She had mild to moderate mental retardation and minor facial anomalies, including a broad, square face, hypertelorism, flat nasal bridge, prominent ears, and a short neck. She also had mild hearing loss. However, she did not have features of the classic Pitt-Hopkins phenotype, such as breathing problems, hyperventilation, or epilepsy. PCR analysis showed that the breakpoints in TCF4 and CHD6 were in intron 3 and intron 1, respectively. Fusion transcripts were produced, with CHD6 exon 1 spliced to TCF4 exon 4. The findings indicated that not all mutations in TCF4 cause the severe PTHS phenotype. Diagnosis Whalen et al. (2012) evaluated the clinical features of 112 patients with PTHS, 79 of whom had previously been reported, to better define the phenotype and allow for a more accurate clinical diagnosis. The most recognizable feature was the facial gestalt, including deep-set eyes, strabismus, myopia, marked nasal root, broad and/or beaked nasal bridge, large mouth, everted lower lip, tented upper lip, and/or prominent Cupid's bow, and ears with thick and overfolded helix. Of the 33 new patients, 63% had a single palmar crease, 65% had long, slender fingers, and 57% had flat feet. Intellectual disability was severe in all cases, and language was always absent or limited to only a few words. All had delayed walking, most had hypotonia (73%), and most had an ataxic or unsteady gait. Hyperventilation was present in over half of the patients, occurring spontaneously or triggered by emotional situations. Most (94%) also had stereotypic movements, particularly of the arms, wrists, and fingers. Most (89%) had a smiling appearance, as well as anxiety (81%). Variable features included constipation (77%) and cryptorchidism (33%). Less common features included microcephaly (7%), seizures (20%), and abnormalities on brain imaging (about 50%). Whalen et al. (2012) suggested and outlined a clinical diagnostic score for PTHS. The TCF4 mutational spectrum included 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Almost all cases occurred de novo; 1 resulted from somatic mosaicism in the mother, and there was 1 pair of monozygotic twins. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. There were no apparent genotype/phenotype correlations. The findings confirmed that TCF4 haploinsufficiency is the molecular mechanism underlying PTHS. Inheritance In all PTHS patients with heterozygous mutation in the TCF4 gene whose parents were available for analysis, the mutation was shown to occur de novo (Amiel et al., 2007; Zweier et al., 2007). Molecular Genetics By array-comparative genomic hybridization in a patient with PTHS, Amiel et al. (2007) demonstrated a 1.8-Mb de novo microdeletion on 18q21.1; by molecular karyotyping with SNP arrays, Zweier et al. (2007) detected a 1.2-Mb deletion on 18q21.2 in another patient with this syndrome. In studies of patients with phenotypic features consistent with Pitt-Hopkins syndrome, both Amiel et al. (2007) and Zweier et al. (2007) demonstrated de novo heterozygous mutations in the TCF4 gene (see 602272.0001-602272.0004), which is located within the region of the deletion. Brockschmidt et al. (2007) identified a de novo 0.5-Mb microdeletion of 18q21.2 encompassing the TCF4 gene in a girl with PTHS. RT-PCR analysis showed that the deletion resulted in functional TCF4 haploinsufficiency. The deletion occurred on the paternal chromosome. Zweier et al. (2008) identified 16 different TCF4 mutations (see, e.g., 602272.0005-602272.0006) in 16 (14%) of 117 patients with a phenotype similar to PTHS. Thirteen of the mutations were frameshift, nonsense, or splice-site mutations, consistent with haploinsufficiency as the disease-causing mechanism. De Pontual et al. (2009) identified 12 different mutations in the TCF4 gene among 13 patients with Pitt-Hopkins syndrome. A clustering of mutations in the basic domain of the E-protein indicated a mutation hotspot. In vitro studies demonstrated that wildtype TCF4 only activated the reporter construct when cotransfected with ASCL1 (100790) and ASCL1/TCF4 mutant heterodimers had decreased transcriptional activity compared to ASCL1/TCF4 wildtype heterodimers, consistent with a loss of TCF4 function. All mutations occurred de novo, except for 1 that was inherited from a mother who had chronic depression and epilepsy from age 20 years and was somatic mosaic for the mutation. In addition to severe mental retardation and characteristic facial features, all patients had low levels of IgM, but none showed features of an immunodeficiency. De Pontual et al. (2009) noted that the patients had been diagnosed over a 12-month period, suggesting that the disorder may be more common than originally thought. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Face \- Coarse face \- Bitemporal narrowing \- Square forehead \- Protruding lower face \- High cheekbones \- Full cheeks \- Short philtrum Ears \- Cup-shaped ears \- Fleshy ears Eyes \- Deep-set eyes \- Strabismus \- Myopia \- Astigmatism \- Upslanting palpebral fissures Nose \- Broad nasal bridge \- Beaked nasal bridge \- Downturned, pointed nasal tip \- Flaring nostrils Mouth \- Wide open mouth \- Cupid's bow upper lip \- Thick, fleshy lips Teeth \- Widely spaced teeth Neck \- Short neck RESPIRATORY \- Abnormal breathing patterns \- Intermittent breathing \- Hyperventilation ABDOMEN Gastrointestinal \- Constipation \- Gastroesophageal reflux GENITOURINARY External Genitalia (Male) \- Small penis Internal Genitalia (Male) \- Cryptorchidism SKELETAL Hands \- Small, slender palms \- Clubbing of the fingers \- Tapered fingers \- Simian crease \- Clinodactyly \- Fetal pads Feet \- Slender feet \- Pes planus \- Pes valgus \- Fetal pads MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Mental retardation, severe \- Poor or absent speech development \- Delayed motor development \- Limited walking abilities \- Unstable, ataxic gait \- Incoordination \- Seizures \- Bulging of the caudate nuclei \- Ventricular asymmetry \- Agenesis or hypoplasia of the corpus callosum \- Atrophy of the frontal and parietal cortex \- Hypotonia Behavioral Psychiatric Manifestations \- Happy personality \- Aggression \- Sterotypical movements MOLECULAR BASIS \- Caused by mutation in the transcription factor-4 gene (TCF4, 602272.0001}) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	PITT-HOPKINS SYNDROME	c1970431	5,247	omim	https://www.omim.org/entry/610954	2019-09-22T16:03:53	{"doid": ["0060488"], "mesh": ["C537403"], "omim": ["610954"], "orphanet": ["2896"], "synonyms": ["Alternative titles", "ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION", "MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION"], "genereviews": ["NBK100240"]}
Human disease (bacterial infection of the skin) Erysipelas Other namesIgnis sacer, holy fire, St. Anthony's fire Erysipelas of the face due to invasive Streptococcus Pronunciation * /ɛrɪˈsɪpələs/ SpecialtyDermatology, Infectious disease Erysipelas, is a relatively common bacterial infection of the superficial layer of the skin (upper dermis), extending to the superficial lymphatic vessels within the skin, characterized by a raised, well-defined, tender, bright red rash, typically on the face or legs, but which can occur anywhere on the skin. It is a form of cellulitis and is potentially serious.[1][2][3] Erysipelas is usually caused by the bacteria Streptococcus pyogenes, also known as group A β-hemolytic streptococci, through a break in the skin such as from scratches or an insect bite. It is more superficial than cellulitis, and is typically more raised and demarcated.[4] The term is from Greek ἐρυσίπελας (erysípelas), meaning "red skin".[5] In animals, erysipelas is a disease caused by infection with the bacterium Erysipelothrix rhusiopathiae. The disease caused in animals is called Diamond Skin Disease, which occurs especially in pigs. Heart valves and skin are affected. Erysipelothrix rhusiopathiae can also infect humans, but in that case the infection is known as erysipeloid.[citation needed] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Differentiating from cellulitis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 6.1 Preventative Measures * 7 Notable cases * 8 History * 9 Citations * 10 External links ## Signs and symptoms[edit] Symptoms often occur suddenly. Affected individuals may develop a fever, shivering, chills, fatigue, headaches, vomiting and be generally unwell within 48 hours of the initial infection.[1][2] The red plaque enlarges rapidly and has a sharply demarcated, raised edge.[4][6] It may appear swollen, feel firm, warm and tender to touch and may have a consistency similar to orange peel.[2] Pain may be extreme.[6] More severe infections can result in vesicles (pox or insect bite-like marks), blisters, and petechiae (small purple or red spots), with possible skin necrosis (death).[6] Lymph nodes may be swollen, and lymphedema may occur. Occasionally, a red streak extending to the lymph node can be seen.[citation needed] The infection may occur on any part of the skin, including the face, arms, fingers, legs and toes; it tends to favour the extremities.[1] The umbilical stump and sites of lymphoedema are also common sites affected.[6] Fat tissue and facial areas, typically around the eyes, ears, and cheeks, are most susceptible to infection.[citation needed] Repeated infection of the extremities can lead to chronic swelling (lymphoedema).[2] * Erysipelas (ear) * Erysipelas (arm) * Erysipelas (leg) * Recurrent erysipelas ## Cause[edit] Streptococcus pyogenes Most cases of erysipelas are due to Streptococcus pyogenes, also known as group A β-hemolytic streptococci, less commonly by group C or G streptococci and rarely due to Staphylococcus aureus. Newborns may contract erysipelas due to Streptococcus agalactiae, also known as group B streptococcus or GBS.[6] The infecting bacteria can enter the skin through minor trauma, human, insect or animal bites, surgical incisions, ulcers, burns and abrasions. There may be underlying eczema, athlete's foot, and it can originate from streptococci bacteria in the subject's own nasal passages or ear.[6] The rash is due to an exotoxin, not the Streptococcus bacteria, and is found in areas where no symptoms are present; e.g., the infection may be in the nasopharynx, but the rash is found usually on the epidermis and superficial lymphatics.[citation needed] ## Diagnosis[edit] Erysipelas is usually diagnosed by the clinician looking at the characteristic well-demarcated rash following a history of injury or recognition of one of the risk factors.[2] Tests, if performed, may show a high white cell count, raised CRP or positive blood culture identifying the organism.[2] Erysipelas must be differentiated from herpes zoster, angioedema, contact dermatitis, erythema chronicum migrans of early Lyme disease, gout, septic arthritis, septic bursitis, vasculitis, allergic reaction to an insect bite, acute drug reaction, deep venous thrombosis and diffuse inflammatory carcinoma of the breast.[citation needed] ### Differentiating from cellulitis[edit] Erysipelas can be distinguished from cellulitis by two particular features;its raised advancing edge and its sharp borders. The redness in cellulitis is not raised and its border is relatively indistinct.[6] Bright redness of erysipelas has been described as a third differentiating feature.[7] Erysipelas does not affect subcutaneous tissue. It does not release pus, only serum or serous fluid. Subcutaneous edema may lead the physician to misdiagnose it as cellulitis.[8][clarification needed] ## Treatment[edit] Depending on the severity, treatment involves either oral or intravenous antibiotics, using penicillins, clindamycin, or erythromycin. While illness symptoms resolve in a day or two, the skin may take weeks to return to normal. The FDA approved 3 antibiotics, oritavancin (Orbactiv), dalbavancin (Dalvance), and tedizolid (Sivextro), for the treatment of acute bacterial skin and skin structure infections. Because of the risk of reinfection, prophylactic antibiotics are sometimes used after resolution of the initial condition.[2] ## Prognosis[edit] The disease prognosis includes: * Spread of infection to other areas of body can occur through the bloodstream (bacteremia), including septic arthritis. Glomerulonephritis can follow an episode of streptococcal erysipelas or other skin infection, but not rheumatic fever. * Recurrence of infection: Erysipelas can recur in 18–30% of cases even after antibiotic treatment. A chronic state of recurrent erysipelas infections can occur with several predisposing factors including alcoholism, diabetes, and tinea pedis (athlete's foot).[9] Another predisposing factor is chronic cutaneous edema, such as can in turn be caused by venous insufficiency or heart failure.[10] * Lymphatic damage * Necrotizing fasciitis, commonly known as "flesh-eating" bacterial infection, is a potentially deadly exacerbation of the infection if it spreads to deeper tissue. ## Epidemiology[edit] There is currently no validated recent data on the worldwide incidence of erysipelas.[11] From 2004-2005, UK hospitals reported 69,576 cases of cellulitis and 516 cases of Erysipelas. [11] One book stated that several studies have placed the prevalence rate between every one in 10,000 people and every 250 in 10,000 people. [12] The development of antibiotics, as well as increased sanitation standards has contributed to the decreased rate of incidence.[13] Erysipelas caused systemic illness in up to 40% of cases reported by UK hospitals and 29% of people had recurrent episodes within three years.[11] Anyone can be infected, although incidence rates are higher in infants and elderly.[13] Several studies also reported a higher incidence rate in females. [13] Four out of five cases occur on the legs, although historically the face was a more frequent site.[3] Risk factors for developing the disease include [12][11][13][14] * Arteriovenous fistula * Chronic skin conditions such as psoriasis, athlete’s foot, and eczema * Excising the saphenous vein * Immune deficiency or compromise, such as * Diabetes * Alcoholism * Obesity * Human immunodeficiency virus (HIV) * In newborns, exposure of the umbilical cord and vaccination site injury * Issues in lymph or blood circulation * Leg ulcers * Lymphatic edema * Lymphatic obstruction * Lymphoedema * Nasopharyngeal infection * Nephrotic syndrome * Pregnancy * Previous episode(s) of erysipelas * Toe web intertrigo * Traumatic wounds * Venous insufficiency or disease ### Preventative Measures[edit] Individuals can take preventative steps to increase the chance they do not catch the disease. Properly cleaning and covering wounds is important for people battling an open wound. Effectively treating athlete's foot or eczema if they were the cause for the initial infection will decrease the chance of the infection occurring again. People with diabetes should pay attention to maintaining good foot hygiene.[12] It is also important to follow up with doctors to make sure the disease has not come back or spread. About one third of people who have had erysipelas will be infected again within three years.[11] Rigorous antibiotics may be needed in the case of recurrent bacterial skin infections.[12] ## Notable cases[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2020) (Learn how and when to remove this template message) Fatal, in order of death * Archibald Douglas, 6th Earl of Angus, (d. 1557), Scottish nobleman active in the reigns of James V and Mary, Queen of Scots * John of the Cross, Spanish saint and priest (d. 1591) * Michiel de Ruyter, Dutch admiral in the Anglo-Dutch wars, contracted from injuries sustained from a cannonball. (d. 1676) * Christina, Queen of Sweden (d. 1689) * Anne, Queen of Great Britain and Ireland (d. 1714) * Norborne Berkeley, baron de Botetourt, Royal Governor of Virginia (d. 1770)[15] * Princess Amelia of the United Kingdom, daughter of George III of the United Kingdom (1783–1810) * Grand Duchess Catherine Pavlovna of Russia, daughter of Tsar Paul I of Russia and wife of King William I of Württemberg (d. 1819) * William Wirt, United States Attorney General and U.S. presidential candidate (d. 1834) * Charles Lamb, English writer and essayist (d. 1834) * Prince Augustus Frederick, Duke of Sussex sixth son and ninth child of King George III (d. 1843) * Barbara Hofland, English children's writer and novelist (d. 1844)[16] * Pope Gregory XVI (d. 1846) * Mary Lyon, American women's education pioneer (d. 1849)[17] * Marie, Dowager Duchess of Saxe-Coburg-Gotha (d. 1860) * John Herbert White, youngest son of James S. and Ellen G. White, co-founders of the Seventh-day Adventist church (d. 1860) * Ralph Bullock, English jockey (d. 1863) * Frederick VII of Denmark, king of Denmark (d. 1863)[18] * John Timon, First Roman Catholic Bishop of Buffalo, NY (d. 1867)[19] * Nehemiah Bushnell, American attorney, railroad president, and politician (d. 1873) * John Stuart Mill, English political philosopher (d. 1873)[20] * Marcus Clarke, Australian journalist, poet, playwright and novelist, who wrote "For the Term of His Natural Life", died age 35 (d. 1881) [21] * John Brown, Scottish personal servant and companion to Queen Victoria (d. 1883)[22] * Mihai Eminescu, Romanian poet, novelist, journalist (d. 1889) * Pat Killen, American heavyweight boxer, died at age 29 while in hiding in Chicago from police after assaulting two men (d. 1891) * Samuel Augustus Ward, American organist, composer, teacher, businessman (d. 1903)[23] * Johann Most, German-American anarchist politician, newspaper editor, and orator. (d. 1906) * James Anthony Bailey, American circus ringmaster (d. 1906)[24] * George Herbert, 5th Earl of Carnarvon (d. 1923), English aristocrat known as the financial backer of the search for and excavation of Tutankhamun's tomb in the Valley of the Kings. His death led to the story of the Curse of Tutankhamun. * Miller Huggins, American baseball player and manager (d. 1929)[25] * Father Solanus Casey, American Capuchin priest declared "blessed" by the Roman Catholic Church (d. 1957)[26] Chronic, recurrent * Richard Wagner, opera composer, was prone to outbreaks of erysipelas throughout his adult life. He suffered notably from attacks throughout the year 1855, when he was 42. Recovered * Lenin suffered an infection in London, and party leadership was exercised by Martov until he recovered.[27][28][29] * Ernest Hemingway developed an infection near his left eye after being hit with an oar. He was treated at the Casa di Cura Morgagni in Padua.[30] Fictional * In D. H. Lawrence's novel Sons and Lovers one of the major characters in the novel, William Morel, dies quickly from the complications of erysipelas in conjunction with pneumonia. * In Anton Chekhov's 1892 short story "Ward No. 6", erysipelas is among the afflictions suffered by the patients committed to a poorly run mental illness facility in a small town in tsarist Russia. * In J. G. Farrell's novel The Siege of Krishnapur the Collector, Mr. Hopkins, is afflicted during the Siege and recovers. * In Mark Twain's Roughing It, mention is made of the disease due to the rarefied atmosphere (Chapter 43). * In Dashiell Hammett's The Thin Man, the name is used for a pun on the word "ear" (Chapter 22). * In Willa Cather's One of Ours, the main character, Claude, contracts the disease in "the queerest" way, after being dragged into wire by mules, and the next day continuing to work in the dust. The disease plays a key role in the novel, persuading him to marry Enid after she cares for him in recovery. (Book II, Chapter IV, p. 138). ## History[edit] It was historically known as St. Anthony's fire.[3] ## Citations[edit] 1. ^ a b c O'Brian, Gail M. (2019). "Section 1. Diseases and Disorders; Erysipelas". In Fred F. Ferri (ed.). Ferri's Clinical Advisor 2019: 5 Books in 1. Philadelphia: Elsevier. p. 523. ISBN 978-0-323-53042-2. 2. ^ a b c d e f g Stanway, Amy; Oakley, Amanda; Gomez, Jannet (2016). "Erysipelas \| DermNet NZ". dermnetnz.org. Retrieved 6 June 2020. 3. ^ a b c Davis, Loretta S. (9 November 2019). "Erysipelas: Background, Pathophysiology and Etiology, Epidemiology". Medscape. 4. ^ a b Wanat, Karolyn A.; Norton, Scott A. "Skin & Soft Tissue Infections - Chapter 11 - 2020 Yellow Book \| Travelers' Health \| CDC". wwwnc.cdc.gov. CDC. Retrieved 6 June 2020. 5. ^ Bhat M, Sriram (2019). SRB's Clinical Methods in Surgery. New Delhi: Jaypee Brothers Medical Publishers. p. 141. ISBN 978-93-5270-545-0. 6. ^ a b c d e f g Wolff, Klaus; Johnson, Richard (2009). "Part III; Diseases due to microbial agents". Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology: Sixth Edition. McGraw Hill Professional. p. 609. ISBN 978-0-07-163342-0. 7. ^ Stevens, Dennis L.; Bryant, Amy E. (2016), Ferretti, Joseph J.; Stevens, Dennis L.; Fischetti, Vincent A. (eds.), "Impetigo, Erysipelas and Cellulitis", Streptococcus pyogenes: Basic Biology to Clinical Manifestations, University of Oklahoma Health Sciences Center, PMID 26866211, retrieved 8 June 2020 8. ^ Spelman, Denis. "Cellulitis and skin abscess: Clinical manifestations and diagnosis". UpToDate. UpToDate. Retrieved 30 July 2019. 9. ^ Jorup-Rönström, Christina; Britton, S. (1987-03-01). "Recurrent erysipelas: Predisposing factors and costs of prophylaxis". Infection. 15 (2): 105–106. doi:10.1007/BF01650206. ISSN 0300-8126. PMID 3110071. S2CID 29789051. 10. ^ Nigar Kirmani; Keith F. Woeltje; Hilary Babcock (2012). The Washington Manual of Infectious Disease Subspecialty Consult. Lippincott Williams & Wilkins. ISBN 9781451113648. Page 194 11. ^ a b c d e Morris, Andrew D (2008-01-02). "Cellulitis and erysipelas". BMJ Clinical Evidence. 2008. ISSN 1752-8526. PMC 2907977. PMID 19450336. 12. ^ a b c d Information, National Center for Biotechnology; Pike, U. S. National Library of Medicine 8600 Rockville; MD, Bethesda; Usa, 20894 (2018-02-22). Erysipelas and cellulitis: Overview. Institute for Quality and Efficiency in Health Care (IQWiG).CS1 maint: numeric names: authors list (link) 13. ^ a b c d Michael, Youstina; Shaukat, Nadia M. (2020), "Erysipelas", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30335280, retrieved 2020-11-13 14. ^ "Erysipelas \| DermNet NZ". dermnetnz.org. Retrieved 2020-11-30. 15. ^ "Berkeley, Norborne, baron de Botetourt (1717–1770)". 16. ^ Dennis Butts, "Hofland, Barbara (bap. 1770, d. 1844)", Oxford Dictionary of National Biography (Oxford, UK: OUP, 2004 Retrieved 20 December 2015, pay-walled. 17. ^ Green, Elizabeth Alden (1979). Mary Lyon and Mount Holyoke. Hanover, New Hampshire: University Press of New England. p. 310. ISBN 978-0-87451-172-7. 18. ^ Møller, Jan (1994). Frederik 7. En kongeskæbne. Copenhagen: Aschehoug Dansk Forlag. p. 235. ISBN 978-87-11-22878-4. 19. ^ Castillo, Dennis (2017-04-14). "Viewpoints: Remembering Buffalo's first Catholic bishop, John Timon, 'a great and good man'". The Buffalo News. Retrieved 2017-04-17. 20. ^ Capaldi, Nicholas (2004). John Stuart Mill: a biography. Cambridge, UK: Cambridge University Press. pp. 356. ISBN 978-0-521-62024-6. 21. ^ Australian Variety Theatre Archive • http://ozvta.com/practitioners-other-a-l/ 22. ^ Ridley, Jane (2013). The Heir Apparent: a life of Edward VII, the Crown Prince. New York, NY: Penguin Random House LLC. p. 287. 23. ^ America the Beautiful by Lynn Sherr 24. ^ Macy, Beth. Truevine. Little, Brown & Co, New York, 2016, page 151. 25. ^ Trachtenberg, Leo (1995). The Wonder Team: The True Story of the Incomparable 1927 New York Yankees. Bowling Green State University Popular Press. p. 151. ISBN 0-87972-677-6. 26. ^ Wollenweber, Brother Leo (2002). "Meet Solanus Casey". St. Anthony Messenger Press, Cincinnati, Ohio, page 107, ISBN 1-56955-281-9, 27. ^ Rice, Christopher (1990). Lenin: Portrait of a Professional Revolutionary. London: Cassell. ISBN 978-0304318148. pp. 77–78. 28. ^ Service, Robert (2000). Lenin: A Biography. London: Macmillan. ISBN 9780333726259. p. 150. 29. ^ Rappaport, Helen (2010). Conspirator: Lenin in Exile. New York: Basic Books. ISBN 978-0-465-01395-1 pp. 85–87. 30. ^ Hemingway, Mary Welsh (1976). How It Was. London: Weidenfeld & Nicolson. ISBN 0-297-77265-1. p. 236. ## External links[edit] Wikimedia Commons has media related to Erysipelas. Classification D * ICD-10: A46.x * ICD-9-CM: 035 * MeSH: D004886 * DiseasesDB: 4428 External resources * MedlinePlus: 000618 * eMedicine: derm/129 * v * t * e * Firmicutes (low-G+C) Infectious diseases * Bacterial diseases: G+ Bacilli Lactobacillales (Cat-) Streptococcus α optochin susceptible * S. pneumoniae * Pneumococcal infection optochin resistant * Viridans streptococci: S. mitis * S. mutans * S. oralis * S. sanguinis * S. sobrinus * S. anginosus group β A * bacitracin susceptible: S. pyogenes * Group A streptococcal infection * Streptococcal pharyngitis * Scarlet fever * Erysipelas * Rheumatic fever B * bacitracin resistant, CAMP test+: S. agalactiae * Group B streptococcal infection ungrouped * Streptococcus iniae * Cutaneous Streptococcus iniae infection γ * D * BEA+: Streptococcus bovis Enterococcus * BEA+: Enterococcus faecalis * Urinary tract infection * Enterococcus faecium Bacillales (Cat+) Staphylococcus Cg+ * S. aureus * Staphylococcal scalded skin syndrome * Toxic shock syndrome * MRSA Cg- * novobiocin susceptible * S. epidermidis * novobiocin resistant * S. saprophyticus Bacillus * Bacillus anthracis * Anthrax * Bacillus cereus * Food poisoning Listeria * Listeria monocytogenes * Listeriosis Clostridia Clostridium (spore-forming) motile: * Clostridium difficile * Pseudomembranous colitis * Clostridium botulinum * Botulism * Clostridium tetani * Tetanus nonmotile: * Clostridium perfringens * Gas gangrene * Clostridial necrotizing enteritis Finegoldia (non-spore forming) * Finegoldia magna Mollicutes Mycoplasmataceae * Ureaplasma urealyticum * Ureaplasma infection * Mycoplasma genitalium * Mycoplasma pneumoniae * Mycoplasma pneumonia Anaeroplasmatales * Erysipelothrix rhusiopathiae * Erysipeloid * v * t * e Bacterial skin disease Gram +ve Firmicutes * Staphylococcus * Staphylococcal scalded skin syndrome * Impetigo * Toxic shock syndrome * Streptococcus * Impetigo * Cutaneous group B streptococcal infection * Streptococcal intertrigo * Cutaneous Streptococcus iniae infection * Erysipelas / Chronic recurrent erysipelas * Scarlet fever * Corynebacterium * Erythrasma * Listeriosis * Clostridium * Gas gangrene * Dermatitis gangrenosa * Mycoplasma * Erysipeloid of Rosenbach Actinobacteria * Mycobacterium-related: Aquarium granuloma * Borderline lepromatous leprosy * Borderline leprosy * Borderline tuberculoid leprosy * Buruli ulcer * Erythema induratum * Histoid leprosy * Lepromatous leprosy * Leprosy * Lichen scrofulosorum * Lupus vulgaris * Miliary tuberculosis * Mycobacterium avium-intracellulare complex infection * Mycobacterium haemophilum infection * Mycobacterium kansasii infection * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Rapid growing mycobacterium infection * Scrofuloderma * Tuberculosis cutis orificialis * Tuberculosis verrucosa cutis * Tuberculous cellulitis * Tuberculous gumma * Tuberculoid leprosy * Cutaneous actinomycosis * Nocardiosis * Cutaneous diphtheria infection * Arcanobacterium haemolyticum infection * Group JK corynebacterium sepsis Gram -ve Proteobacteria * α: Endemic typhus * Epidemic typhus * Scrub typhus * North Asian tick typhus * Queensland tick typhus * Flying squirrel typhus * Trench fever * Bacillary angiomatosis * African tick bite fever * American tick bite fever * Rickettsia aeschlimannii infection * Rickettsialpox * Rocky Mountain spotted fever * Human granulocytotropic anaplasmosis * Human monocytotropic ehrlichiosis * Flea-borne spotted fever * Japanese spotted fever * Mediterranean spotted fever * Flinders Island spotted fever * Verruga peruana * Brill–Zinsser disease * Brucellosis * Cat-scratch disease * Oroya fever * Ehrlichiosis ewingii infection * β: Gonococcemia/Gonorrhea/Primary gonococcal dermatitis * Melioidosis * Cutaneous Pasteurella hemolytica infection * Meningococcemia * Glanders * Chromobacteriosis infection * γ: Pasteurellosis * Tularemia * Vibrio vulnificus * Rhinoscleroma * Haemophilus influenzae cellulitis * Pseudomonal pyoderma / Pseudomonas hot-foot syndrome / Hot tub folliculitis / Ecthyma gangrenosum / Green nail syndrome * Q fever * Salmonellosis * Shigellosis * Plague * Granuloma inguinale * Chancroid * Aeromonas infection * ε: Helicobacter cellulitis Other * Syphilid * Syphilis * Chancre * Yaws * Pinta * Bejel * Chlamydia infection * Leptospirosis * Rat-bite fever * Lyme disease * Lymphogranuloma venereum Unspecified pathogen * Abscess * Periapical abscess * Boil/furuncle * Hospital furunculosis * Carbuncle * Cellulitis * Paronychia / Pyogenic paronychia * Perianal cellulitis * Acute lymphadenitis * Pilonidal cyst * Pyoderma * Folliculitis * Superficial pustular folliculitis * Sycosis vulgaris * Pimple * Ecthyma * Pitted keratolysis * Trichomycosis axillaris * Necrotizing fascitis * Gangrene * Chronic undermining burrowing ulcers * Fournier gangrene * Elephantiasis nostras * Blistering distal dactylitis * Botryomycosis * Malakoplakia * Gram-negative folliculitis * Gram-negative toe web infection * Pyomyositis * Blastomycosis-like pyoderma * Bullous impetigo * Chronic lymphangitis * Recurrent toxin-mediated perineal erythema * Tick-borne lymphadenopathy * Tropical ulcer [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Erysipelas	c0014733	5,248	wikipedia	https://en.wikipedia.org/wiki/Erysipelas	2021-01-18T18:56:40	{"gard": ["6370"], "mesh": ["D004886"], "umls": ["C0014733"], "wikidata": ["Q207092"]}
Guttate psoriasis Back torso lesions, 30-year-old female patient SpecialtyDermatology Guttate psoriasis (also known as eruptive psoriasis) is a type of psoriasis that presents as small (0.5–1.5 cm in diameter) lesions over the upper trunk and proximal extremities; it is found frequently in young adults.[1]:410[2]:194 The term "guttate" is used to describe the drop-like appearance of skin lesions. Guttate psoriasis is classically triggered by a bacterial infection, usually an upper respiratory tract infection.[3]:726 ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Management * 5 Epidemiology * 6 References * 7 External links ## Signs and symptoms[edit] Typically, guttate psoriasis erupts after a throat infection, or strep throat.[4] Initially, when the throat infection has cleared up, the person can feel fine for several weeks before noticing the appearance of red spots. They appear small at first, like a dry red spot which is slightly itchy. When scratched or picked, the top layer of dry skin is removed, leaving dry, red skin beneath with white, dry areas marking where flakes of dry skin stop and start. In the weeks that follow, the spots can grow to as much as an inch in diameter. Some of the larger ones may form a pale area in the center which is slightly yellow. Guttate psoriasis can occur on any part of the body, particularly the legs, arms, torso, eyelids, back, bottom, bikini-line and neck. The number of lesions can range from 5 to over 100.[5] Generally the parts of the body most affected are seen on the arms, legs, back and torso. ## Causes[edit] Genetic and environmental factors can influence the predilection for guttate psoriasis. Human leukocyte antigens, especially those in the HLA-C group are associated with the skin disorder.[6] Beta-hemolytic streptococci infection is the major contributing environmental factor. The typical route of infection is the upper respiratory system. Rarely it is also caused by a skin infection surrounding the anus (perianal streptococcal dermatitis).[7][8] ## Diagnosis[edit] Guttate psoriasis can typically be diagnosed by clinical examination alone.[9] ## Management[edit] The treatments used for plaque psoriasis can also be used for guttate psoriasis. Few studies have specifically focused on guttate psoriasis management, so there are currently no firm guidelines for managing guttate psoriasis differently from plaque psoriasis.[10][11] Immunosuppressive drugs that inhibit T cell activation have been effective in treating severe cases of chronic guttate psoriasis.[12] Due to the role streptococcal infection plays in the development of guttate psoriasis, systemic antibiotics have been considered as a potential treatment option. There is uncertain evidence whether systemic antibiotics or tonsillectomy are effective and safe in treating the disease.[13] The condition often clears up on its own within weeks to months, and only about one third of patients will develop chronic plaques.[14] ## Epidemiology[edit] Guttate psoriasis accounts for approximately 2% of psoriasis cases.[5] ## References[edit] 1. ^ Freedberg IM, Fitzpatrick TB (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ James W, Berger T, Elston D (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Pardasani AG, Feldman SR, Clark AR (February 2000). "Treatment of psoriasis: an algorithm-based approach for primary care physicians". American Family Physician. 61 (3): 725–33, 736. PMID 10695585. Retrieved 30 Mar 2011. 4. ^ Prinz JC (June 2001). "Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis". Clinical and Experimental Dermatology. 26 (4): 326–32. doi:10.1046/j.1365-2230.2001.00831.x. PMID 11422184. 5. ^ a b Langley RG, Krueger GG, Griffiths CE (March 2005). "Psoriasis: epidemiology, clinical features, and quality of life". Annals of the Rheumatic Diseases. 64 Suppl 2 (suppl 2): ii18-23, discussion ii24-5. doi:10.1136/ard.2004.033217. PMC 1766861. PMID 15708928. 6. ^ Mallon E, Bunce M, Savoie H, Rowe A, Newson R, Gotch F, Bunker CB (December 2000). "HLA-C and guttate psoriasis". The British Journal of Dermatology. 143 (6): 1177–82. doi:10.1046/j.1365-2133.2000.03885.x. PMID 11122018. 7. ^ Patrizi A, Costa AM, Fiorillo L, Neri I (June 1994). "Perianal streptococcal dermatitis associated with guttate psoriasis and/or balanoposthitis: a study of five cases". Pediatric Dermatology. 11 (2): 168–71. doi:10.1111/j.1525-1470.1994.tb00574.x. PMID 8041660. 8. ^ Herbst RA, Hoch O, Kapp A, Weiss J (May 2000). "Guttate psoriasis triggered by perianal streptococcal dermatitis in a four-year-old boy". Journal of the American Academy of Dermatology. 42 (5 Pt 2): 885–7. doi:10.1016/s0190-9622(00)90263-9. PMID 10767696. 9. ^ Mehlis S (2019). Duffin KC, Ofori AO (eds.). "Guttate psoriasis". Up-to-date. Wolters Kluwer. 10. ^ Chalmers RJ, O'Sullivan T, Owen CM, Griffiths CE (December 2001). "A systematic review of treatments for guttate psoriasis". The British Journal of Dermatology. 145 (6): 891–4. doi:10.1046/j.1365-2133.2001.04505.x. PMID 11899141. 11. ^ Chalmers RJ, O'Sullivan T, Owen CM, Griffiths CE (2000-01-01). "Interventions for guttate psoriasis". The Cochrane Database of Systematic Reviews (2): CD001213. doi:10.1002/14651858.CD001213. PMID 10796758. (Retracted, see doi:10.1002/14651858.cd001213.pub2. If this is an intentional citation to a retracted paper, please replace `{{Retracted}}` with `{{Retracted\|intentional=yes}}`.) 12. ^ Vence, L; Schmitt, A; Meadows, CE; Gress, T. "Recognizing Guttate Psoriasis and Initiating Appropriate Treatment". West Virginia Medical Journal. 111 (2015): 26–29. 13. ^ Dupire G, Droitcourt C, Hughes C, Le Cleach L (March 2019). Cochrane Skin Group (ed.). "Antistreptococcal interventions for guttate and chronic plaque psoriasis". The Cochrane Database of Systematic Reviews. 3: CD011571. doi:10.1002/14651858.CD011571.pub2. PMC 6400423. PMID 30835819. 14. ^ Martin BA, Chalmers RJ, Telfer NR (June 1996). "How great is the risk of further psoriasis following a single episode of acute guttate psoriasis?". Archives of Dermatology. 132 (6): 717–8. doi:10.1001/archderm.1996.03890300147032. PMID 8651734. ## External links[edit] Classification D * ICD-10: L40.4 (ILDS L40.400) * DiseasesDB: 34089 * v * t * e Papulosquamous disorders Psoriasis Pustular * Generalized pustular psoriasis (Impetigo herpetiformis) * Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid) * Annular pustular psoriasis * Localized pustular psoriasis Other * Guttate psoriasis * Psoriatic arthritis * Psoriatic erythroderma * Drug-induced psoriasis * Inverse psoriasis * Napkin psoriasis * Seborrheic-like psoriasis Parapsoriasis * Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica) * Lymphomatoid papulosis * Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans) * Large plaque parapsoriasis (Retiform parapsoriasis) Other pityriasis * Pityriasis rosea * Pityriasis rubra pilaris * Pityriasis rotunda * Pityriasis amiantacea Other lichenoid Lichen planus * configuration * Annular * Linear * morphology * Hypertrophic * Atrophic * Bullous * Ulcerative * Actinic * Pigmented * site * Mucosal * Nails * Peno-ginival * Vulvovaginal * overlap synromes * with lichen sclerosus * with lupus erythematosis * other: * Hepatitis-associated lichen planus * Lichen planus pemphigoides Other * Lichen nitidus * Lichen striatus * Lichen ruber moniliformis * Gianotti–Crosti syndrome * Erythema dyschromicum perstans * Idiopathic eruptive macular pigmentation * Keratosis lichenoides chronica * Kraurosis vulvae * Lichen sclerosus * Lichenoid dermatitis * Lichenoid reaction of graft-versus-host disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Guttate psoriasis	c0343052	5,249	wikipedia	https://en.wikipedia.org/wiki/Guttate_psoriasis	2021-01-18T18:56:09	{"gard": ["10569"], "umls": ["C0343052"], "icd-10": ["L40.4"], "wikidata": ["Q5621891"]}
## Summary ### Clinical characteristics. Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild. ### Diagnosis/testing. Diagnosis of EDM4/rMED is based on clinical and radiographic findings. SLC26A2 is the only gene in which pathogenic variants are known to cause EDM4/rMED. ### Management. Treatment of manifestations: Physiotherapy for muscular strengthening and maintaining mobility; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs); orthopedic surgery (joint replacement) as indicated; career counseling. Prevention of secondary complications: Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility. Surveillance: Radiographs as indicated. Agents/circumstances to avoid: Sports involving joint overload. ### Genetic counseling. EDM4/rMED is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both pathogenic alleles in the family are known and the carrier status of the parents has been confirmed. Requests for prenatal testing for mild conditions such as EDM4/rMED are not common. ## Diagnosis ### Clinical Diagnosis The diagnosis of recessive multiple epiphyseal dysplasia (EDM4/rMED) is usually established during childhood or early adulthood. The diagnosis is suspected in individuals with the following: Clinical features * Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain. * Deformity of hands, feet, and knees * Scoliosis Radiographic findings. Skeletal radiographs establish the diagnosis in clinically suspected individuals (see Figure 1). Typical findings include the following: #### Figure 1. Double patella Ballhausen et al [2003]; reprinted with permission from the BMJ Publishing Group * Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint) * Mild brachydactyly * Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) observed in approximately 60% of individuals on lateral knee radiographs. This finding appears to be age-related and may disappear in adults (Figure 1). ### Molecular Genetic Testing Gene. SLC26A2 (DTDST) is the only gene in which pathogenic variants are known to cause with EDM4/rMED. Clinical testing. ### Table 1. Molecular Genetic Testing Used in Multiple Epiphyseal Dysplasia, Recessive View in own window Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3 SLC26A2Targeted analysis for pathogenic variantsPanel of selected pathogenic variants 4See footnote 5 Sequence analysis 6Sequence variants>90% 7 Deletion/duplication analysis 8(Multi)exon and whole-gene deletions/duplicationsUnknown; none reported 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants. 3\. % of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of ACG1B 4\. Variant panel may vary by laboratory. 5\. Dependent on variant panel and population tested. The four most common SLC26A2 pathogenic variants (p.Arg279Trp, c.-26+2T>C, p.Arg178Ter, and p.Cys653Ser) account for approximately 70% of disease alleles in all SLC26A2-related dysplasias, but only 10% of disease alleles in ACG1B. 6\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results, click here. 7\. 90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of sulfate transporter-related dysplasias [Rossi & Superti-Furga 2001]. 8\. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. ### Testing Strategy To confirm/establish the diagnosis in a proband. Clinical and radiologic features may strongly suggest the diagnosis of EDM4/rMED in a proband. The presence of a double-layered patella at lateral x-ray of the knee is a very specific, although not highly sensitive, sign of EDM4/rMED [Mäkitie et al 2003]. Targeted analysis for the four most common SLC26A2 pathogenic variants is indicated in probands with clinical and radiologic features very suggestive for EDM4/rMED and/or with a clinical diagnosis of MED and no evidence of autosomal dominant inheritance. This test allows identification of at least one pathogenic allele in nearly 100% of EDM4/rMED cases (80% of individuals with EDM4/rMED carry two of the most common pathogenic variants, and another 16% of cases carry one of the most common pathogenic variants in compound heterozygosity with another pathogenic allele). Sequence analysis of SLC26A2 is indicated in probands with only one heterozygous SLC26A2 pathogenic variant and in probands who tested negative with targeted analysis for pathogenic variants and have very specific signs of EDM4/rMED (double-layered patella and/or classic signs of sulfate transporter-related dysplasia, like clubfoot, cleft palate, and cystic swelling of the ears). Sequence analysis of SLC26A2 may be considered in simplex cases (i.e., a single occurrence in a family) with no specific signs for a distinct autosomal dominant MED type before testing other known MED-related genes, as recessive pathogenic variants in SLC26A2 are found more frequently in simplex cases than dominant pathogenic variants in other MED-related genes [Jakkula et al 2005]. Single-gene testing. One strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is sequence analysis of only SLC26A2. Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is use of a multigene panel (see Differential Diagnosis). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family. ## Clinical Characteristics ### Clinical Description In retrospect, approximately 50% of individuals with recessive multiple epiphyseal dysplasia (EDM4/rMED) have an abnormal finding at birth, such as clubfoot (frequently), clinodactyly, or cleft palate. However, only half of those with findings at birth are suspected of having a skeletal dysplasia. The majority of affected individuals are diagnosed with a skeletal disorder in childhood, but some are not diagnosed until adulthood. Reasons for seeking medical assistance are mainly chronic joint pain (hips, knees, wrists, and fingers), waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis. There is no specific timing of joint involvement or specific location of joint pain at different ages. Adolescents are usually symptomatic in multiple joints and joint pain increases after physical exercise. Brachydactyly is evident after puberty in most cases. Habitus is unremarkable in most affected individuals, except for genu valgum in some. Facies and body proportions are usually normal. Bowing of the extremities is not observed. Functional disability is mild or absent [Ballhausen et al 2003] in childhood and adolescence; joint involvement progresses slightly in young adults, but hip and knee surgery is usually not needed. Stature is usually within the normal range prior to puberty and downward crossing of the growth curve does not occur. In adulthood, stature is only slightly diminished, with the median height shifting from the 50th to the tenth centile; range of adult height is 150-180 cm. Approximately one third of affected adults have stature below 2 SD for age. ### Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in a spectrum that goes from lethal achondrogenesis 1B (ACG1B) to mild EDM4/rMED. * Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B. * Pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996a, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004]. Variant p.Arg279Trp, the most common SLC26A2 pathogenic variant outside Finland (45% of alleles) is a mild pathogenic variant resulting in the EDM4/rMED phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) phenotype when compounded. Variant p.Arg178Ter is the second-most common pathogenic variant (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp pathogenic variant. It has also been found in some cases of more severe rMED and of ACG1B, making it one of two pathogenic variants identified in all four SLC26A2-related dysplasias. Variants p.Cys653Ser and c.-26+2T>C are the third most common pathogenic variants (8% of alleles for each). c.-26+2T>C is sometimes referred to as the "Finnish" pathogenic variant because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous and in rMED when compounded with another mild pathogenic variant (p.Arg279Trp, p.Cys653Ser). Together with p.Arg178Ter, c.-26+2T>C is the only pathogenic variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Dwyer et al 2010; Bonafé, unpublished results]. Pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other pathogenic variants. The same pathogenic variants associated in some individuals with the ACG1B phenotype can be found in individuals with a milder phenotype (AO2 and DTD) if the second allele is a relatively mild pathogenic variant. Indeed, missense variants located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of the null allele [Rossi & Superti-Furga 2001]. ### Nomenclature Multiple epiphyseal dysplasia is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [International Working Group on Constitutional Diseases of Bone 1998]. The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the gene involved: * EDM4/rMED is classified in the "sulfation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders of Bone [Warman et al 2011]. It accounts for about 25% of cases of MED. * The other autosomal dominant subtypes of MED are classified in the "multiple epiphyseal dysplasia and pseudoachondroplasia group" in the revised Nosology. The most frequent form of MED is caused by dominant pathogenic variants in COMP (~50% of cases). The remaining 20%-25% of cases are split between MATN3, COL9A1, COL9A2, and COL9A3. * Some cases of MED are not caused by pathogenic variants in a known gene [Zankl et al 2007, Unger et al 2008] and remain unclassified. ### Prevalence Exact data about the prevalence of MED and its subtypes are not available. Based on the number of cases seen in growth clinics, rheumatology clinics, or genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., achondroplasia, osteogenesis imperfecta), it seems reasonable to estimate an overall prevalence of 1:20,000 [Unger et al 2008]. This prevalence is most probably an underestimation as several simplex cases (i.e., a single occurrence in a family) may remain undiagnosed. EDM4/rMED is indeed one of the most frequent forms, accounting for almost 25% of all cases of MED [Jackson et al 2012]. ## Differential Diagnosis Recessive multiple epiphyseal dysplasia (EDM4/rMED) needs to be distinguished from other multiple epiphyseal dysplasia (MED) types [Unger & Hecht 2001, Ballhausen et al 2003]. Clinical and radiographic differences between the genetically distinct forms of these skeletal dysplasias may allow clinicians to distinguish between them. In contrast to other MED types, prepubertal children with EDM4/rMED usually do not show short stature. Autosomal dominant forms of MED and their associated proteins and genes: * Cartilage oligomeric matrix protein, a glycoprotein of the cartilage extracellular matrix that belongs to the family of extracellular calcium-binding proteins. Pathogenic variants in COMP occur in different autosomal dominant forms of MED (EDM1, OMIM 132400) as well as in the more severe disorder, pseudoachondroplasia. Individuals with MED and COMP pathogenic variants usually have significant involvement at the capital femoral epiphyses and irregular acetabuli [Unger et al 2001]. * Type IX collagen, a structural component of the extracellular matrix, is a heterotrimer composed of three different chains (alpha-1, alpha-2, and alpha-3) encoded by COL9A1, COL9A2, and COL9A3. Pathogenic variants in individuals with MED have been identified in COL9A2 (EDM2) [Muragaki et al 1996, Holden et al 1999], COL9A3 (EDM3) [Paassilta et al 1999], and COL9A1 [Czarny-Ratajczak et al 2001]. These forms of MED appear to have more severe knee involvement but relative sparing of the hip, resulting in a milder course than the MED associated with COMP or SLC26A2 pathogenic variants [Unger et al 2001]. * Matrilin 3 (EDM5), an oligomeric protein in the cartilage extracellular matrix. Different pathogenic missense variants in MATN3 were identified in two unrelated families with autosomal dominant MED [Chapman et al 2001]. While it appears to be the mildest form of MED identified to date; EDM5 is associated with a high degree of intrafamilial variability [Mäkitie et al 2004, Zankl et al 2007, Unger et al 2008]. See Epiphyseal dysplasia, multiple: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with recessive multiple epiphyseal dysplasia (EDM4/rMED), the following evaluations are recommended: * Height measurement * Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral) * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Symptomatic individuals should be seen by a physical therapist and an orthopedist in order to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs [NSAIDs]) and the optimal time for surgery (joint replacement), if indicated. Career counseling is recommended. ### Prevention of Secondary Complications Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility. ### Surveillance Radiographic surveillance by an orthopedist is appropriate. ### Agents/Circumstances to Avoid Sports involving joint overload are to be avoided. ### Evaluation of Relatives at Risk Presymptomatic testing of at-risk relatives is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Women affected by EDM4/rMED may suffer from chronic joint pain which may be increased during pregnancy due to maternal weight gain. Appropriate pain management should be offered and physical therapy should be intensified. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Multiple Epiphyseal Dysplasia, Recessive	c1847593	5,250	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1306/	2021-01-18T21:10:09	{"mesh": ["C535504"], "synonyms": ["EDM4", "rMED"]}
Dravet syndrome (DS) is a genetic epilepsy of childhood characterized by a variety of drug-resistant seizures often induced by fever, presenting in previously healthy children, and which frequently leads to cognitive and motor impairment. ## Epidemiology Worldwide birth prevalence is thought to be <1/40,000. In the UK it is estimated at 1/28,000. ## Clinical description Onset of the first seizure is mainly in the 1st year of life (usually at 5-8 months of age) in previously healthy infants and most often consists of a unilateral or generalized, clonic seizure. Fever often triggers the seizures that include generalized tonic-clonic, alternating unilateral clonic and generalized tonic-clonic seizures. Afebrile complex partial and focal seizures are also reported during the course of the disease. Some seizures may present as febrile status epilepticus (SE), lasting for more than 20 minutes. The frequency of SE in the first year may be high, but generally decreases with time. Complex partial, absence and atonic seizures may also occur. Photosensitivity, high temperatures, intermittent photic stimulation and exercise may also provoke seizures. By age 2, developmental delay is often apparent, followed by cognitive plateauing and impairment. Impaired speech, ataxia, sleeping difficulties and sometimes pyramidal signs may also appear at this stage. Seizures can regress in adulthood but most patients have ongoing seizures that are refractory to medication. Borderline DS describes variants with most but not all manifestations of DS. ## Etiology Around 85% of DS cases are due to a mutation or deletion in the SCN1A gene (2q24.3), encoding a voltage-gated sodium channel essential for the excitability of neurons. Most mutations are de novo but in 5-10% they are familial and often part of the generalized epilepsy with febrile seizures-plus (GEFS+; see this term) spectrum. Mutations in the PCDH19 gene (Xq22.1), also seen in female restricted epilepsy with intellectual deficit (see this term), are thought to account for about 5% of female DS cases. In about 10% of cases the etiology is unknown but other genes are likely implicated. Mutations in GABRG2 (5q34), SCN1B (19q13.12), SCN2A (2q24.3), CHD2 (15q26) and HCN1 (5p12) have been reported in a few patients with DS. ## Diagnostic methods Diagnosis is based on clinical and electroencephalic (EEG) findings. At onset, EEG is usually normal but later spikes or poly spike-waves with a slowing of background activity are noted as well as multifocal discharges. Brain MRI is usually normal. Molecular genetic testing can identify a SCN1A alteration, confirming the diagnosis. ## Differential diagnosis Differential diagnoses include Lennox-Gastaut syndrome and myoclonic-astatic epilepsy (see these terms). ## Genetic counseling In families with a known SCN1A mutation, inheritance is autosomal dominant and genetic counseling is possible, even though the phenotypic range in families can be wide. In cases with de novo mutations, counseling may help with the decision making process for future children. ## Management and treatment The main aim of treatment is to reduce seizure frequency and prevent SE occurrence. Valproate, clobazam, stiripentol and bromide may control the recurrence of febrile seizures early in the disease. Stiripentol may be effective in reducing the frequency of seizures when combined with valproate and clobazam. The ketogenic diet, topiramate and levetiracetam may provide substantial efficacy as adjunctive therapy. Carbamazepine and lamotrigine should be avoided as they may provoke seizures. Midazolam may be used to treat acute seizures. Supportive therapy (i.e. protective head gear) may be recommended in children with prominent atonic seizures. ## Prognosis Moderate to severe cognitive impairment and intractable epilepsy into adulthood is common. Preventing the occurrence of convulsive SE in children may improve the long-term prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Dravet syndrome	c0751122	5,251	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33069	2021-01-23T17:54:03	{"gard": ["10430"], "mesh": ["D004831"], "omim": ["607208", "612164", "615744"], "umls": ["C0751122"], "icd-10": ["G40.4"], "synonyms": ["SMEI", "Severe myoclonic epilepsy of infancy", "Severe myoclonus epilepsy of infancy"]}
Term describing the finding of symmetrical joint swelling seen in patients with congenital syphilis Clutton's joints is a term describing the finding of symmetrical joint swelling seen in patients with congenital syphilis. It most commonly affects the knees, presenting with synovitis and joint effusions (collections of fluid within the joint capsules) lasting up to a year. It has also been reported affecting the ankles, elbows, wrists and fingers. It is usually painless, although pain in the absence of trauma can occur in a few cases. There is usually no disability associated with the joint swelling, and recovery is usually complete. It occurs between 5 and 20 years of age in both sexes.[citation needed] The condition was described in 1886 by Henry Hugh Clutton in The Lancet.[1] ## References[edit] 1. ^ RODIN P (September 1961). "Clutton's Joints: A BRIEF REVIEW OF THE LITERATURE, AND AN UNUSUAL CASE TREATED WITH INTRA-ARTICULAR HYDROCORTISONE". Br J Vener Dis. 37 (3): 204–6. doi:10.1136/sti.37.3.204. PMC 1047420. PMID 14493118. * ICD10 code: M03.1 * v * t * e Symptoms and signs relating to infectious diseases Bacterial disease * syphilis * Hutchinson's teeth * Hutchinson's triad * Westphal's sign * Clutton's joints * Dennie–Marfan syndrome Viral disease * measles * Koplik's spots Parasitic disease * African trypanosomiasis * Winterbottom's sign General * Meningism * Fever * Liebermeister's rule * Faget sign * v * t * e Musculoskeletal examination Leg Hip examination * Galeazzi test * Allis test * Barlow maneuver * Ober's test * Ortolani test * Patrick's test * Thomas test * Trendelenburg's sign Knee examination * Ballottement * Clarke's test * Drawer test * Lachman test * Patellar tap * Pivot-shift test * Valgus stress test * meniscus * Apley grind test * McMurray test * ligament and meniscus * Unhappy triad Foot and ankle * Hubscher's maneuver * Mulder's sign * Simmonds' test * Thompson test * Ankle * Simmonds' test General * Straight leg raise * Lasègue's sign * Gait abnormality * Trendelenburg gait * Unequal leg length Arm Shoulder examination * Apprehension test * Jobe's test * Neer impingement sign * Yergason's test * rotator cuff * Hawkins–Kennedy test * Watson's test Elbow examination * Cozen's test * Elbow extension test Hand and wrist * Durkan's test * Finkelstein's test * Froment's sign * Lunotriquetral shear test * Phalen maneuver * Tinel sign * Watson's test Spine * Gaenslen's test * Low back pain * Waddell's signs * Lower back flexibility * Schober's test * sacroiliitis * Larrey's sign Other * Range of motion * Palpation * Codman triangle This medical sign article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Clutton's joints	c0239075	5,252	wikipedia	https://en.wikipedia.org/wiki/Clutton%27s_joints	2021-01-18T18:49:03	{"icd-10": ["M03.1"], "wikidata": ["Q1103561"]}
Homocystinuria refers to a group of inherited disorders in which the body is unable to process certain building blocks of proteins (amino acids) properly. This leads to increased amounts of homocysteine and other amnio acids in the blood and urine. The most common type of genetic homocystinuria, called CBS deficiency, is caused by the lack of an enzyme known as cystathionine beta-synthase (CBS). Most states in the United States test for homocystinuria due to CBS deficiency at birth by newborn screening. Other types are less common, and are caused by different missing or non-working enzymes. Homocystinuria can affect the eyes, skeleton, central nervous system and the blood clotting system. Mutations in the MTHFR, MTR, MTRR and MMADHC genes can cause homocystinuria. All these forms of homocystinuria are inherited in an autosomal recessive manner. Treatment and long-term outlook varies depending upon the cause of the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Homocystinuria	c0019880	5,253	gard	https://rarediseases.info.nih.gov/diseases/10770/homocystinuria	2021-01-18T17:59:58	{"mesh": ["D006712"], "synonyms": []}
Inclusion body myositis (IBM) is a progressive muscle disorder characterized by muscle inflammation, weakness, and atrophy (wasting). It is a type of inflammatory myopathy. IBM develops in adulthood, usually after age 50. The symptoms and rate of progression vary from person to person. The most common symptoms include progressive weakness of the legs, arms, fingers, and wrists. Some people also have weakness of the facial muscles (especially muscles controlling eye closure), or difficulty swallowing (dysphagia). Muscle cramping and pain are uncommon, but have been reported in some people. Most people with IBM progress to disability over a period of years. In general, the older a person is when IBM begins, the more rapid the progression of the condition. Most people need assistance with basic daily activities within 15 years, and some people will need to use a wheelchair. Lifespan is thought to be normal, but severe complications (e.g. aspiration pneumonia) can lead to loss of life. The underlying cause of IBM is poorly understood and likely involves the interaction of genetic, immune-related, and environmental factors. Some people may have a genetic predisposition to developing IBM, but the condition itself typically is not inherited. There is currently no cure for IBM. The primary goal of management is to optimize muscle strength and function. Management may include exercise, fall prevention, physical therapy, occupational therapy, and speech therapy (for dysphagia). There is limited evidence that a small proportion of patients may benefit from drugs that suppress the immune system (particularly those with underlying autoimmune disorders), but this therapy is otherwise typically not recommended. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Inclusion body myositis	c0238190	5,254	gard	https://rarediseases.info.nih.gov/diseases/3896/inclusion-body-myositis	2021-01-18T17:59:47	{"mesh": ["D018979"], "omim": ["147421"], "orphanet": ["611"], "synonyms": ["IBM", "Inflammatory myopathy", "Sporadic inclusion body myositis"]}
Most people suffer from a form of fear of medical procedures during their life. There are many different aspects of this fear and not everyone has every part. Some of these parts include fear of surgery, fear of dental work, and fear of doctors. These fears are often overlooked, but when a patient has one to the extreme it can be very damaging to their health. Formally, medical fear is defined as "any experience that involves medical personnel or procedures involved in the process of evaluating or modifying health status in traditional health care settings."[1] ## Contents * 1 Classification * 2 Fear of surgery * 2.1 Children * 2.2 Adults * 3 Fear of dental work * 3.1 Children * 3.2 Adults * 4 Fear of doctors and fear of needles * 4.1 Fear of doctors * 4.2 Fear of needles * 5 Notes and references * 5.1 Articles used * 6 Further reading ## Classification[edit] Fear of medical procedures can be classified under a broader category of “blood, injection, and injury phobias”. This is one of five subtypes that classify specific phobias.[2] A specific phobia is defined as a “marked and persistent fear that is excessive or unreasonable, cued by the presence (or anticipation) of a specific object or situation.”[3][4] Often these fears begin to appear in childhood, around the age of five to nine.[2] It is normal to become squeamish at the sight of blood, injury, or gross deformity,[5] but many overcome these fears by the time they reach adulthood. Those who do not are more likely to avoid medical and dental procedures necessary to maintain health, jobs, etc.[2] Research shows that when people encounter something that they have a specific phobia of many of them have a feeling of disgust[6] which makes them not want to come near or experience the object or situation which is disgusting to them. This feeling of disgust, especially in the blood, injection, and injury phobias may be passed down in families.[2] Women have been known to avoid becoming pregnant because it requires blood and medical examinations that they would rather avoid.[7] Also, most phobic people have an increased heart rate upon encountering the thing they fear, but blood, injection, injury phobic people also seem to have an increase of fainting after the initial speeding up of heart rate. Their heart rate will go up and then slow again, leading to nausea, sweating, pallor, and fainting.[7] This fainting can also lead to seizures, making life very difficult for those who have this fear.[8] However, only 4.5% of individuals who have this phobia as a child will have this fear their entire lifetime.[9] For those who do experience this phobia in an extreme manner, specific coping treatments have been found to help them. Biological treatments, such as medications used for other anxiety ailments, are generally found to be inappropriate for fear of medical procedures or other specific phobias. Psychological treatments are the treatment of choice because they are more accurate at addressing the problem. Some of these treatments used especially for fear of medical procedures include exposure-based treatments, eye movement desensitization and reprocessing, and applied tension to react against fainting.[10] ## Fear of surgery[edit] Fear of surgery or other invasive medical procedure is known as tomophobia.[11] Fear of surgery is not a fear experienced often, but is still just as harmful as other phobias that are more common. Since surgery is not a common occurrence, the fear is based on inexperience or something that is out of the ordinary.[citation needed] This fear is one of those categorized under all fears of medical procedures that can be experienced by anyone, all ages, and have little need for actual psychological treatment, unless it is uncharacteristically causing the patient to react in a way that would be harmful to his or her health.[citation needed] ### Children[edit] Fear of surgery is common among young children. Christine Gorman, of Kids and Surgery, states “Surgery is scary enough for adults. But imagine what goes through the mind of a three-year-old when he sees a doctor or nurse all suited up and wearing a surgical mask: “It’s a monster! It’s got big eyes and no mouth! It’s taking me away from Mommy and Daddy.” No wonder half of all children from ages of 2 to 10 show evidence of distress—from bed-wetting to nightmares—for at least two weeks after their operation. Some of them remain traumatized even six months later.”[12] This statement shows that the fear that comes when young children go into surgery can be a serious matter because they are still traumatized by the effects for weeks after the surgery has taken place. Being scared of surgery has led to “eating disorders, sleep disturbances, regression to earlier levels of behavior, depression, and somatizations such as loss of voice after tonsillectomy.” [13] Many children see surgery as a form of punishment[12] and, since they sometimes can’t see what they did “wrong”, the fear is escalated, leaving greater chance for a longer effect on the psychological and emotional feelings of the child. Many ways have been tried to help children overcome this fear, including their parents and doctors simply telling them that the surgery won’t hurt, or sedatives given by the doctor to minimize the feelings of anxiety later.[12] There are certain types of treatments that have been proven to be better methods than others. Some hospitals allow parents to come into the surgery room and stay with the child, calming them until the anesthetic has taken effect. This is noted to keep anxiety down for both the parent and the child.[14] If the child can enter the surgery calmly, there is much less of a chance that they will have many complications after the surgery due to fear.Other ways to treat the fear of surgery for children include having a doctor explain to them what the surgery is going to do and acting out the operation on a doll or stuffed animal.[12] This makes the surgery something less scary and able to be understood in the child’s mind. When the surgery is understood by the child, the fear of the unknown is less of a factor of how scared the child will be, and how much that will impact their reaction to the surgery. ### Adults[edit] Children are not the only ones to express fear of surgery, or have after effects that can affect the mental and physical well being of the person. Adults most fear the pain they expect to receive from the surgery. “The Roche Pain Management Survey polled 500 Americans, 27% of whom had surgery during the previous five years. Of those who had surgery, 77% reported pain afterwards, with four out of five of those saying they experienced moderate to extreme pain. 70%, indicated they experienced pain even after receiving medication; 80% reported they received pain medication on time, although 33% had to ask for it; and 16% had to wait for medication.”[15] Unlike children, adults seem to have less fear of the surgery itself, but rather fear of the effects of surgery. Milano and Kornfeld in 1980 said “Any operation is a destructive invasion of the body and therefore frightens many patients”.[16] Some operations seem to invoke more fear from patients than others. Aged persons who require cataract surgery often fear the procedure, even though success is very likely. The fear of going blind because of the surgery is more apparent in women, who over all fear surgery more than men.[17] The cataract is a disease that attacks the lens, causing it to swell until sight becomes obscured.[16] Operation is recommended when the disease begins to hamper everyday activities.[18] Even though becoming blind was the only option without the surgery, over 25% of the patients were afraid of becoming blind as a result of the surgery: 34% feared the failure of the operation.[19] Ritva Fagerström, concerning the fears of cataract operation said, “These fears are understandable as the condition of the retina was not known in advance,” [20] Two women out of 75, taking part in a study dealing with the fear of cataract operation felt that the experience of the first operation was so bad that they would not agree to have the second eye operated on.[21] If a patient had this fear, understandable, and did not go through with the surgery, the blindness that would follow would keep them from being able to do normal things, easily leading them into situations of depression, or other dangerous situations which would be destructive to their overall health. Ways to overcome this fear are specific to the individual. Often adults seem to become less fearful when given more information about the surgery, those who will be performing it, or the things to expect during recovery; 69% said that they had received much information and half of the patients trusted the ophthalmologist to do his best.[20] Although adults have less fear of surgery than children, the impact of this fear can still be just as great for both. Fear of surgery no matter who has it can be harmful to the patient if not taken care of properly before the surgery. ## Fear of dental work[edit] Main article: Dental fear Fear of surgery is not the only fear based on medical procedures that can be harmful to the health of those who experience it; fear of dental work can also be dangerous if taken to an extreme. Dental fear has been ranked fifth among the most common fears. (DeJongh, Morris, Schoemakers, & Ter Horst, 1995)[22] Those who start with dental fear when they are young and continue with it into adulthood can have total avoidance of all dental work, causing problems for their health.[23] Fear of dental care is often diagnosed using a fear measurement instrument like Corah’s Dental Anxiety Scale or the Modified Dental Anxiety Scale. ### Children[edit] Dental fear in children varies from 3%-21% depending on age and method used to measure dental fear.[23] “A very young child may find the smells of a dental surgery and the sounds of the equipment working very overwhelming” says H.R. Chapman and N. C. Kirby-Turner.[23] Such overwhelming situations can make a child afraid and if the fear is not corrected, it can become harder to get the child to participate in dental procedures. Some forms of treatment for children who do experience dental fear include allowing the family to come into the room with them to allow the child to see that the other members of the family are not scared, allowing the child to have time to explore the room and the equipment used on them, under the supervision of the dentist, to become familiar with the things surrounding them.[23] Other methods include tell-show-do, positive reinforcement, distraction, nonverbal communication or even general anesthesia and conscious sedation.[24] ### Adults[edit] When fear of dental work is not overcome in childhood it is very likely to continue into adulthood, causing a total avoidance of dental visits, which can lead to poor hygiene and lack of proper care for their teeth. Both age and gender have huge differences in how people express and deal with their fear of dental work. Overall women express a fear of dental procedures more than men.[25] Although dental anxiety is shown to be lower in men than in women, men expect more pain from the procedure.[25] This expectance of pain leads many to miss appointments and be unwilling to seek professional help for simple things like toothaches. These simple things can lead to larger problems resulting in decaying teeth and poorly cared for gums. Age also makes a difference in how dental work is dealt with. Dental fear in young adults (ages 18–23) is significantly higher than fear in adults (ages 26–79)[22] showing that over the years, with maturity the fear of dental work decreases. Still many are making appointments and breaking them or not making them at all, leading to a deterioration of their dental condition.[22] Treatment for this medical fear is similar to that of the treatment of adults who suffer from fear of surgery. Explanations of what is going on can help, also dentists speaking to patients with less embarrassing wording (such as calling what they have a phobia or treating them like a child while discussing their problem) to encourage them to express and cope with their dental fear.[25] ## Fear of doctors and fear of needles[edit] Two of the most common fears of medical procedures are the fear of doctors and the fear of needles. These simple fears, when not overcome by patients, either by themselves or with medical help, can cause great problems in the future for their health. ### Fear of doctors[edit] People of all ages deal with fear of doctors (iatrophobia). Children often express fear by trying to hide from doctors when their parents take them in for checkups or by trying to avoid going to the doctor by not telling their parents when they don’t feel well. This fear as a child can be easily treated in much the same way that doctors deal with children in surgery. An explanation or example (like seeing the doctor check an older sibling, or a stuffed animal) can help a child feel more comfortable with what the doctor will do for them. Fear of doctors for adults can be extreme. Avoidance of visiting a doctor can lead to problems with not only short term but also long term health. There is a medical condition called white coat hypertension that deals with the raising of high blood pressure while in the presence of doctors.[26] Such high blood pressure is not good for health considerations, so this fear leads to more complications in health aspects of life for those who deal with it. ### Fear of needles[edit] Main article: Fear of needles The fear of needles (also known as trypanophobia) is sometimes a complex condition that can cause serious health problems that may sometimes result in the death of the patient.[27] Some needle phobics refuse to receive shots that are mandatory, thus leading to greater risk of getting certain diseases, and many avoid treatment for serious medical conditions. Needle phobia is unique in the fact that it is a phobia that is documented to have resulted directly in the deaths of a few patients.[27] In the New England Journal of Medicine, Lountzis and Rahman published an article about a 34-year-old woman who had a growth on her fingers that doctors were unable to completely remove because of her fear of needles.[28] ## Notes and references[edit] 1. ^ Marion E. Broome & Teri Mobley (2003). "The Child Medical Fear Scale". In Carolyn F. Waltz; Colleen Dilorio & Ora L. Strickland (eds.). Measurement of Nursing Outcomes. Springer Publishing Company. p. 197. ISBN 0-8261-1427-X. 2. ^ a b c d Specific Phobias: Clinical Applications of Evidence-Based Psychotherapy pg 5 3. ^ Diagnostic and Statistical Manual for Mental Disorders (DSM-IV; American Psychiatric Association, 1994) 4. ^ Phobic Disorders and Panic in Adults: A guide to Assessment and Treatment pg 79 5. ^ Fears, Phobias, and Rituals: Panic, Anxiety and their Disorders pg 376 6. ^ Phobic Disorders and Panic in Adults: A guide to Assessment and Treatment pg 82 7. ^ a b Fears, Phobias, and Rituals: Panic, Anxiety and their Disorders pg 377 8. ^ Fears, Phobias, and Rituals: Panic, Anxiety and their Disorders pg 378 9. ^ Phobic Disorders and Panic in Adults: A guide to Assessment and Treatment pg 84 10. ^ Phobic Disorders and Panic in Adults: A guide to Assessment and Treatment pg 98-102 11. ^ Schmid, Markus; Wolf, Robert C; Freudenmann, Roland W; Schönfeldt-Lecuona, Carlos (2009-11-18). "Tomophobia, the phobic fear caused by an invasive medical procedure - an emerging anxiety disorder: a case report". Journal of Medical Case Reports. 3: 131. doi:10.1186/1752-1947-3-131. ISSN 1752-1947. PMC 2803803. PMID 20062769. 12. ^ a b c d Kids and Surgery by: Gorman, Christine, Time, 0040781X, 06/07/99, Vol. 153, Issue 22 13. ^ The Children’s Surgical Worries Questionnaire: Reliability and Validity of a New Self-Report Measure, (Fosson, Martin & Haley, 1990; Setterstro:m, 1984) 14. ^ Assuaging Children’s Fear of Surgery, by Linda Saslow The New York Times, January 7, 1990 15. ^ Surgery Patients’ Number-One Fear. USA Today Magazine, 01617389, Feb96, Vol. 124, Issue 2609 16. ^ a b Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339-1346, pg.1339 17. ^ Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339-1346pg.1339 (Paddison, Strain, Strain & Strain, 1989) 18. ^ Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339- 1346, pg. 1340 19. ^ Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339-1346, pg. 1342 20. ^ a b Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339-1349, pg. 1344 21. ^ Fear of Cataract Operation in Aged Persons, Ritva Fagerstro:m Psychological Reports, 1993, 72, 1339-1349, pg. 1345 22. ^ a b c Dental fear: Comparisons Between Younger and Older Adults, M. Michelle Rowe, PhD American Journal of Health Studies: 20(4) 2005 pg. 219-224 23. ^ a b c d Dental Fear in Children- a proposed model, H.R. Chapman and N.C. Kirby-Turner, British Dental Journal, Vol. 187, No.8 October 23, 1999 24. ^ A Controlled Trial of the impact of exposure to positive images of dentistry on anticipatory dental fear in children, C. Fox and J.T. Newton, Community Dentistry and Oral Epidemiology 2006; 34: 455-459 25. ^ a b c Gender differences in reported dental fear and fear of dental pain, Marc W. Heft, Xiaoxian Meng, Margaret M. Bradley and Peter J. Lang Community Dentistry and Oral Epidemiology 2007; 35: 421-428 26. ^ White coat Hypertension: how should it be diagnosed? E O’Brien Journal of Human Hypertension 1999 13, 801-802 27. ^ a b James G. Hamilton (August 1995). "Needle Phobia - A Neglected Diagnosis". Journal of Family Practice. 41 (2): 169–175 REVIEW. PMID 7636457. 28. ^ Lountzis and Rahman 359 (2): 177, July 10, 2008 The New England Journal of Medicine ### Articles used[edit] * Specific Phobias: Clinical Applications of Evidence-Based Psychotherapy * Fears, Phobias, and Rituals: Panic, Anxiety and their Disorders * Phobic Disorders and Panic in Adults: A guide to Assessment and Treatment * Kids and Surgery by: Gorman, Christine, Time, 0040781X, 06/07/99, Vol. 153, Issue 22 * Assuaging Children’s Fear of Surgery, by Linda Saslow The New York Times, January 7, 1990 * The Children’s Surgical Worries Questionnaire: Reliability and Validity of a New Self-Report Measure. * Surgery Patients’ Number-One Fear. USA Today Magazine, 01617389, Feb96, Vol. 124, Issue 2609 * Ritva Fagerstrom "Fear of Cataract Operation in Aged Persons Psychological Reports, 1993; 72, 1339–1346, * H.R. Chapman and N.C. Kirby-Turner "Dental Fear in Children- a proposed model" British Dental Journal, Vol. 187, No.8 October 23, 1999 * Fox C., Newton J.T. (2006). "A Controlled Trial of the impact of exposure to positive images of dentistry on anticipatory dental fear in children". Community Dentistry and Oral Epidemiology. 34: 455–459. doi:10.1111/j.1600-0528.2006.00303.x. * Heft Marc W., Meng Xiaoxian, Bradley Margaret M., Lang Peter J. (2007). "Gender differences in reported dental fear and fear of dental pain". Community Dentistry and Oral Epidemiology. 35: 421–428. doi:10.1111/j.1600-0528.2006.00344.x.CS1 maint: multiple names: authors list (link) * Rowe M. Michelle (2005). "Dental fear: Comparisons Between Younger and Older Adults". American Journal of Health Studies. 20 (4): 219–224. * O'Brien E (1999). "White coat Hypertension: how should it be diagnosed?". Journal of Human Hypertension. 13: 801–802. doi:10.1038/sj.jhh.1000939. * Hamilton James G (1995). "Needle Phobia - A Neglected Diagnosis". Journal of Family Practice. 41 (2): 169–175. PMID 7636457. * Lountzis and Rahman 359 (2): 177, July 10, 2008 The New England Journal of Medicine ## Further reading[edit] * Margaret S. Steward & David S. Steward (2006-02-14). "Children's conceptions of medical procedures". New Directions for Child and Adolescent Development. Wiley Periodicals, Inc. 1981 (14): 67–83. doi:10.1002/cd.23219811406. * Robert G. Reidel (1981). "Behaviour Therapies". In Carl Eisdorfer (ed.). Annual Review of Gerontology and Geriatrics. Springer Publishing Company. pp. 181–182. ISBN 0-8261-3081-X. — reports on two studies of how to reduce the fear, made by Kendall and Shipley [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Fear of medical procedures	None	5,255	wikipedia	https://en.wikipedia.org/wiki/Fear_of_medical_procedures	2021-01-18T18:47:07	{"wikidata": ["Q5439395"]}
Rickets is a condition that causes children to have soft, weak bones. It usually occurs when children do not get enough vitamin D, which helps growing bones absorb important nutrients. Vitamin D comes from sunlight and food. Skin produces vitamin D in response to the sun's rays. Some foods also contain vitamin D, including fortified dairy products and cereals, and some kinds of fish. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Rickets	c0035579	5,256	gard	https://rarediseases.info.nih.gov/diseases/5700/rickets	2021-01-18T17:57:54	{"mesh": ["D012279"], "synonyms": ["Vitamin-D deficiency rickets", "Nutritional rickets", "Hypovitaminosis D", "Vitamin D deficiency disease"]}
A number sign (#) is used with this entry because of evidence that Parkinson disease-1 (PARK1) is caused by heterozygous mutation in the alpha-synuclein gene (SNCA; 163890) on chromosome 4q22. See also dementia with Lewy bodies (127750), an allelic disorder with overlapping clinical features. Description Parkinson disease is the second most common neurogenic disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50. Clinical manifestations include resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia (Polymeropoulos et al., 1996). For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see 168600. Clinical Features Golbe et al. (1990) reported 2 large kindreds originating from Contursi, a village in the Salerno province of Italy, in which 41 individuals in 4 generations had autosomal dominant Parkinson disease. Male-to-male transmission occurred, and penetrance was estimated at 96%; only 1 instance of definite nonpenetrance was recognized. The disorder was characterized by early onset (mean 46.5 years) and rapid progression (average 9.7 years from onset to death). Clinical appearance and response to levodopa were typical for Parkinson disease. Autopsy of 2 patients in 1 of the kindreds showed pathologic changes typical of PD with Lewy bodies. Affected persons who spent most of their lives in Italy survived longer than their affected U.S. relatives. Golbe et al. (1990) postulated a single gene as the main factor in these kindreds and concluded that the findings enhanced the likelihood of a significant genetic component in sporadic PD. In a follow-up study of these kindreds, Golbe et al. (1996) found 60 affected individuals in 5 generations. There was variation in clinical features regarding age of onset, tremor, and levodopa responsiveness, suggesting that a presumably single mutation can produce a heterogeneous PD phenotype, even among sibs. A suggestion of anticipation disappeared after adjustment for age-related ascertainment bias. Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs affected with PD, 3 of whom were examined in detail and were found to carry a mutation in the SNCA gene (163890.0001). The 3 sibs presented in their forties with progressive bradykinesia and rigidity, which was initially dopa-responsive, and cognitive decline. Additional features included central hypoventilation, postural hypotension, bladder incontinence, and myoclonus. Puschmann et al. (2009) reported 2 affected members of a Swedish family with the SNCA A53T mutation (163890.0001). Haplotype analysis indicated a different haplotype than the previously identified Greek founder haplotype, suggesting a de novo event in this Swedish family. The proband had insidious onset of decreased range of motion, stiffness, and hypokinesia between ages 39 and 41 years. About 6 months later, she developed word-finding difficulty and monotone speech. The disorder was progressive, and by age 47, she had developed dementia and severe motor disturbances, including myoclonus. Her father developed motor signs of the disorder at age 32, with speech difficulties at age 33. At age 38, he was moved to a nursing home, and at 40, he was aphonic with dementia and an inability to walk or feed himself independently. Both patients had an initial favorable response to levodopa treatment. Both patients had normal brain MRI and increased CSF protein levels, and SPECT scan of the daughter showed decreased blood flow in the language region. Puschmann et al. (2009) emphasized the early onset, rapid progression, and presence of dementia in this family with PD, and suggested that an underlying cortical encephalopathy contributed to the disease course. ### Clinical Variability Golbe et al. (1993) described a family with very slowly progressive atypical autosomal dominant Parkinson disease that showed, in most affected members, poor response to levodopa and subjective visual difficulty. Four cases in 3 generations had onset of symptoms at age 35, 25, 16, and 16, and 4 suspicious cases had occurred in 3 other generations. There seemed to be a trend toward progressively earlier age of onset. One autopsied case showed a distribution of cell loss and Lewy bodies typical of PD. Golbe et al. (1993) noted several previously described kindreds with clinically atypical autosomal dominant PD, including a report by Inose et al. (1988). Lesage et al. (2013) reported a French family in which 4 individuals had a disorder comprising rapidly progressive Parkinson disease, pyramidal signs, and psychiatric features. Three affected individuals had onset at age 31 to 35 years, whereas the fourth had onset at age 60. The initial symptoms were parkinsonism with moderate response to levodopa and development of levodopa-induced dyskinesia. All also had pyramidal tract involvement, with hyperreflexia and extensor plantar responses; 1 had severe spasticity. Two patients had marked psychiatric manifestations, including hallucinations, delusions, anxiety, and depression, but not dementia. The disorder was rapidly progressive: all became bedridden within 5 to 7 years, and 3 patients died within 5 to 7 years of onset. Neuropathologic examination of 1 patient showed neuronal loss in the substantia nigra and striatum, as well as astrogliosis. There was also neuronal loss in the motor cortex, the anterior horn of the spinal cord, and the corticospinal tracts. Lewy bodies and dystrophic Lewy neurites were present mostly in the brainstem. There were fine, diffuse, neuronal cytoplasmic inclusions in all superficial cortical layers. ### Pathologic Findings In Parkinson disease, the specific pattern of neuronal degeneration is accompanied by eosinophilic intracytoplasmic inclusions known as Lewy bodies in surviving neurons in the substantia nigra, locus ceruleus, nucleus basalis, cranial nerve motor nuclei, central and peripheral divisions of the autonomic nervous system, hypothalamus, and cerebral cortex (Polymeropoulos et al., 1996). Neuropathologic examination of 2 of the 5 sibs with PD reported by Spira et al. (2001) showed depigmentation of the substantia nigra, severe cell loss and gliosis in the brainstem, and multiple alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic changes associated with tissue vacuolization were present, mostly in the medial temporal regions. Seidel et al. (2010) reported neuropathologic findings of a patient with PD due to the SNCA A30P mutation (163890.0002). He had onset at age 54 years, had L-DOPA-related complications, and died in a mute, bedridden state at age 69. Progressive cognitive decline was also reported. Postmortem examination showed depigmentation and neuronal loss in the substantia nigra and neuronal loss in the locus ceruleus and dorsal motor vagal nucleus. There were widespread SNCA-positive Lewy bodies, Lewy neurites, and glial aggregates in the cerebral cortex and many other regions of the brain, including the hippocampus, hypothalamus, brainstem, and cerebellum. Biochemical analysis showed a significant load of insoluble SNCA. The findings were similar to, but more severe, than those observed in idiopathic PD. Inheritance The transmission pattern of PARK1 in the families reported by Golbe et al. (1990) and Lesage et al. (2013) was consistent with autosomal dominant inheritance. Mapping Polymeropoulos et al. (1996) performed a genomewide linkage scan in the large Italian kindred previously reported by Golbe et al. (1990). Linkage to markers in the 4q21-q23 region was found with a maximum lod score of 6.00 at recombination fraction theta = 0.00 for marker D4S2380. In a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan, Satake et al. (2009) found strong association with the SNCA gene (163890) on 4q22.1 (p = 7.35 x 10(-17)), implicated in PARK1. In a genomewide association study in 1,713 individuals of European ancestry with PD and 3,978 controls, followed by replication in 3,361 cases and 4,573 controls, Simon-Sanchez et al. (2009) identified association with the SNCA gene (rs2736990, OR = 1.23, p = 2.24 x 10(-16)). Molecular Genetics In the Italian kindred first reported by Golbe et al. (1990) and in 3 unrelated families of Greek origin with autosomal dominant inheritance of Parkinson disease, Polymeropoulos et al. (1997) identified a heterozygous mutation in the SNCA gene (A53T; 163890.0001), which encodes a presynaptic protein thought to be involved in neuronal plasticity. Duvoisin and Golbe (1995) reviewed the genetics of parkinsonism with Lewy body pathology, which they considered to be 'true' Parkinson disease. In 4 members of a French family with autosomal dominant PD, pyramidal signs, and psychiatric abnormalities, Lesage et al. (2013) identified a heterozygous missense mutation in the SNCA gene (G51D; 163890.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies showed that the mutant protein oligomerized more slowly than wildtype, but that its fibrils conferred significant cellular toxicity. In a Caucasian English woman with onset of pathologically confirmed PD at age 71 and death at age 83, Proukakis et al. (2013) identified a heterozygous missense mutation in the SNCA gene (H50Q; 163890.0007). ### SNCA Gene Duplication Nishioka et al. (2006) identified heterozygosity for duplication of the SNCA gene (163890.0005) in 2 of 113 Japanese probands with autosomal dominant PD. In the first family, 2 patients with the duplication had typical PD, whereas 4 duplication carriers over the age of 43 years were unaffected, yielding a penetrance of 33%. In the second family, 1 affected and 2 asymptomatic members had the duplication. The affected patient from the second family developed dementia 14 years after diagnosis of PD, consistent with Lewy body dementia. Fuchs et al. (2007) reported a Swedish family with parkinsonism due to duplication of the SNCA gene. The proband presented with dysautonomia followed by rapidly progressive parkinsonism. Family history revealed multiple affected members with a similar disorder. Features of dementia, including hallucinations, occurred late in the disease. This family was determined to be a branch of a large family originally reported by Mjones (1949). A Swedish American branch of that family was found by Farrer et al. (2004) to have a triplication of the SNCA gene (163890.0003). Fuchs et al. (2007) found that genotypes within and flanking the duplicated region in the Swedish family were identical to genotypes in the Swedish American family reported by Farrer et al. (2004), suggesting a common founder. Hybridization signals indicated a tandem multiplication of the same genomic interval in the 2 families, a duplication and triplication, respectively. Sequence analysis indicated that the multiplications were mediated by centromeric and telomeric long interspersed nuclear element (LINE L1) motifs. Brueggemann et al. (2008) and Troiano et al. (2008) independently identified duplications of the SNCA gene in 2 patients with sporadic early-onset PD, at ages 36 and 35 years, respectively. The mutation was confirmed to be de novo in the case of Brueggemann et al. (2008). Neither patient had cognitive impairment. The prevalence of the SNCA duplication in sporadic PD was reported to be 0.25 and 1%, respectively. Pathogenesis Lotharius and Brundin (2002) reviewed the literature on SNCA and suggested a possible role for this protein in vesicle recycling via its regulation of phospholipase D2 and its fatty acid-binding properties. They hypothesized that impaired neurotransmitter storage arising from SNCA mutations could lead to cytoplasmic accumulation of dopamine, resulting in breakdown of this labile neurotransmitter in the cytoplasm and promoting oxidative stress and metabolic dysfunction in the substantia nigra. Kazantsev and Kolchinsky (2008) reviewed current concepts on the pathogenesis of PD and noted that the symptoms result from acute shortage of dopamine due to selective loss of dopaminergic neurons in the substantia nigra. The metabolism of dopamine yields toxic derivatives that are normally polymerized to form dark nontoxic neuromelanin, which is deposited in the cells. The lack of pigmentation in PD substantia nigra may reflect an inability to process these toxic metabolites. These findings support a role for reactive oxygen species (ROS) in PD. The presence of SNCA-containing Lewy bodies implicates protein misfolding as a pathogenic event that disrupts normal cellular function. Kam et al. (2018) found that pathologic alpha-synuclein (163890) activates PARP1 (173870), and poly ADP-ribose (PAR) generation accelerates the formation of pathologic alpha-synuclein, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP1 prevented pathologic alpha-synuclein toxicity. In a feed-forward loop, PAR converted pathologic alpha-synuclein to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with Parkinson disease, suggesting that PARP activation plays a role in Parkinson disease pathogenesis. Clinical Management Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking. Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (163890), a key protein involved in Parkinson disease. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons. Animal Model To determine if SNCA lesions lead to neurodegeneration, Giasson et al. (2002) generated transgenic mice expressing the A53T mutation (163890.0001) in CNS neurons. Mice expressing the A53T mutant developed a severe and complex motor impairment leading to paralysis and death. The animals developed age-dependent intracytoplasmic neuronal SNCA inclusions paralleling disease onset, and the inclusions recapitulated features of human counterparts. Using immunoelectron microscopy, Giasson et al. (2002) revealed that the SNCA inclusions in the mutant mice contained fibrils similar to human pathologic inclusions. The authors concluded that A53T leads to the formation of toxic filamentous SNCA neuronal inclusions that cause neurodegeneration. Kuo et al. (2010) developed transgenic mice expressing mutant alpha-synuclein, either A53T (163890.0001) or A30P (163890.0002), from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines showed abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also had abnormal motor behavior, but neither line demonstrated cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions, or neurodegeneration. These animals recapitulated the early gastrointestinal abnormalities seen in human Parkinson disease. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Masked facies ABDOMEN Gastrointestinal \- Dysphagia GENITOURINARY Bladder \- Urinary urgency NEUROLOGIC Central Nervous System \- Parkinsonism \- Bradykinesia \- Rigidity \- Postural instability \- Resting tremor \- Hypokinesia \- Micrographia \- Gait disturbances \- Shuffling gait \- Dystonia \- Dysarthria \- Myoclonus \- Monotonous speech \- Dysautonomia may occur \- Visual hallucinations may occur \- Cognitive decline \- Dementia may occur \- Sleep disturbances \- Neuronal loss and gliosis in the substantia nigra pars compacta \- Loss of dopaminergic neurons \- Intracellular Lewy bodies \- Aggregation of SNCA-immunopositive inclusions Behavioral Psychiatric Manifestations \- Depression MISCELLANEOUS \- Onset mid to late adulthood \- Insidious onset \- Progressive disorder \- Levodopa-responsive MOLECULAR BASIS \- Caused by mutation in the alpha-synuclein gene (SNCA, 163890.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	PARKINSON DISEASE 1, AUTOSOMAL DOMINANT	c1850100	5,257	omim	https://www.omim.org/entry/168601	2019-09-22T16:36:34	{"doid": ["0060367"], "mesh": ["C538104"], "omim": ["168601"], "orphanet": ["411602", "171695"], "synonyms": ["PARKINSON DISEASE 1, AUTOSOMAL DOMINANT LEWY BODY", "Alternative titles", "Autosomal dominant late-onset Parkinson disease", "LOPD"], "genereviews": ["NBK1223"]}
Anxiety/aggression-driven depression (also known as 5-HT related depression) is a proposed subtype of Major depressive disorder first proposed by the Dutch psychiatrist Herman M. van Praag in 1996. Van Praag has continued to write on this topic in subsequent academic articles. ## Onset and symptoms[edit] This proposed subtype is characterized by depression occurring as a consequence of psychic, somatic or external stressors. Praag theorizes that if the individual's stress threshold is insufficient or overly sensitive, a prolonged stress response via the HPA axis can trigger anxiety followed by significant lowering of mood, the mechanisms of which act to reenforce each other, keeping the sufferer in a perpetual state of stress arousal, coupled with dysphoria; and that this occurs as a result of the stress response inhibiting the normal expression of neurotransmitters associated with wellbeing and pleasure.[1] He proposes that sufferers may experience panic attacks, depersonalization and other psychic and somatic symptoms common to both anxiety and depression disorders. According to van Praag, in Anxiety/Aggression-Driven Depression "...dysregulation of anxiety and/or aggression are primordial and mood lowering is a derivative phenomenon."[2] ## Treatment[edit] It is proposed that ameliorating the stress response will allow neurotransmission to return to homeostasis. Anxiolytic medications that act as 5-HT receptor agonists (in particular, 5-HT1A) together with CRH and/or cortisol antagonists (which are implicated in the stress response) are hypothesized to be an appropriate method of achieving this therapeutic response. Psychological interventions can also help to raise the threshold for stress and thereby restore the stress response to normal.[2] ## References[edit] 1. ^ van Praag, HM (2001). "Anxiety/aggression--driven depression. A paradigm of functionalization and verticalization of psychiatric diagnosis". Prog Neuropsychopharmacol Biol Psychiatry. 25 (4): 893–924. PMID 11383984. 2. ^ a b van Praag, HM (1996). "Serotonin-related, anxiety/aggression-driven, stressor-precipitated depression. A psycho-biological hypothesis". European Psychiatry. 11 (2): 57–67. doi:10.1016/0924-9338(96)84782-1. PMID 19698426. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Anxiety/aggression-driven depression	None	5,258	wikipedia	https://en.wikipedia.org/wiki/Anxiety/aggression-driven_depression	2021-01-18T18:38:59	{"wikidata": ["Q4778101"]}
For other uses, see RCC (disambiguation). Renal cell carcinoma Micrograph of the most common type of renal cell carcinoma (clear cell)—on right of the image; non-tumour kidney is on the left of the image. Nephrectomy specimen. H&E stain SpecialtyOncology Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90–95% of cases.[1] RCC occurrence shows a male predomiance over women with a ratio of 1.5:1. RCC most commonly occurs between 6th and 7th decade of life.[2] Initial treatment is most commonly either partial or complete removal of the affected kidney(s).[3] Where the cancer has not metastasised (spread to other organs) or burrowed deeper into the tissues of the kidney, the five-year survival rate is 65–90%,[4] but this is lowered considerably when the cancer has spread. The body is remarkably good at hiding the symptoms and as a result people with RCC often have advanced disease by the time it is discovered.[5] The initial symptoms of RCC often include blood in the urine (occurring in 40% of affected persons at the time they first seek medical attention), flank pain (40%), a mass in the abdomen or flank (25%), weight loss (33%), fever (20%), high blood pressure (20%), night sweats and generally feeling unwell.[1] When RCC metastasises, it most commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones.[6] Immunotherapy and targeted therapy have improved the outlook for metastatic RCC.[7][8] RCC is also associated with a number of paraneoplastic syndromes (PNS) which are conditions caused by either the hormones produced by the tumour or by the body's attack on the tumour and are present in about 20% of those with RCC.[1] These syndromes most commonly affect tissues which have not been invaded by the cancer.[1] The most common PNSs seen in people with RCC are: high blood calcium levels, high red blood cell count, high platelet count and secondary amyloidosis.[6] ## Contents * 1 Signs and symptoms * 2 Risk factors * 2.1 Lifestyle * 2.2 Genetics * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 4.2 Laboratory tests * 4.2.1 Urine analysis * 4.2.2 Complete blood cell count * 4.2.3 Blood chemistry * 4.3 Radiology * 4.3.1 Computed tomography * 4.3.2 Ultrasound * 4.3.3 Magnetic resonance imaging * 4.3.4 Intravenous pyelogram * 4.3.5 Renal angiography * 4.4 Staging * 4.5 Histopathology * 5 Prevention * 6 Management * 6.1 Active surveillance * 6.2 Surgery * 6.3 Percutaneous ablative therapies * 6.4 Targeted drugs * 6.5 Chemotherapy * 6.6 Adjuvant and neoadjuvant therapy * 7 Metastasis * 8 Prognosis * 9 Epidemiology * 10 History * 10.1 Hypernephroma controversy * 11 See also * 12 References * 13 External links ## Signs and symptoms[edit] Historically, medical practitioners expected a person to present with three findings. This classic triad[9] is 1: haematuria, which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hip and ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptoms only occurs in 10–15% of cases, and is usually indicative that the renal cell carcinoma (RCC) is in an advanced stage.[9] Today, RCC is often asymptomatic (meaning few to no symptoms) and is generally detected incidentally when a person is being examined for other ailments.[10] Other signs and symptom may include haematuria;[9] loin pain;[9] abdominal mass;[10] malaise, which is a general feeling of unwellness;[10] weight loss and/or loss of appetite;[11] anaemia resulting from depression of erythropoietin;[9] erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion;[9] varicocele, which is seen in males as an enlargement of the pampiniform plexus of veins draining the testis (more often the left testis)[10] hypertension (high blood pressure) resulting from secretion of renin by the tumour;[12] hypercalcemia, which is elevation of calcium levels in the blood;[13] sleep disturbance or night sweats;[11] recurrent fevers;[11] and chronic fatigue.[14] ## Risk factors[edit] ### Lifestyle[edit] The greatest risk factors for RCC are lifestyle-related; smoking, obesity and hypertension (high blood pressure) have been estimated to account for up to 50% of cases.[15] Occupational exposure to some chemicals such as asbestos, cadmium, lead, chlorinated solvents, petrochemicals and PAH (polycyclic aromatic hydrocarbon) has been examined by multiple studies with inconclusive results.[16][17][18] Another suspected risk factor is the long term use of non-steroidal anti-inflammatory drugs (NSAIDS).[19] Finally, studies have found that women who have had a hysterectomy are at more than double the risk of developing RCC than those who have not.[20] Moderate alcohol consumption, on the other hand, has been shown to have a protective effect.[21] The reason for this remains unclear. ### Genetics[edit] Hereditary factors have a minor impact on individual susceptibility with immediate relatives of people with RCC having a two to fourfold increased risk of developing the condition.[22] Other genetically linked conditions also increase the risk of RCC, including hereditary papillary renal carcinoma, hereditary leiomyomatosis, Birt–Hogg–Dube syndrome, hyperparathyroidism-jaw tumor syndrome, familial papillary thyroid carcinoma, von Hippel–Lindau disease[23] and sickle cell disease.[24] The most significant disease affecting risk however is not genetically linked – patients with acquired cystic disease of the kidney requiring dialysis are 30 times more likely than the general population to develop RCC.[25] ## Pathophysiology[edit] The tumour arises from the cells of the proximal renal tubular epithelium.[1] It is considered an adenocarcinoma.[6] There are two subtypes: sporadic (that is, non-hereditary) and hereditary.[1] Both such subtypes are associated with mutations in the short-arm of chromosome 3, with the implicated genes being either tumour suppressor genes (VHL and TSC) or oncogenes (like c-Met).[1] ## Diagnosis[edit] The first steps taken to diagnose this condition are consideration of the signs and symptoms, and a medical history (the detailed medical review of past health state) to evaluate any risk factors. Based on the symptoms presented, a range of biochemical tests (using blood and/or urine samples) may also be considered as part of the screening process to provide sufficient quantitative analysis of any differences in electrolytes, kidney and liver function, and blood clotting times.[24] Upon physical examination, palpation of the abdomen may reveal the presence of a mass or an organ enlargement.[26] Although this disease lacks characterization in the early stages of tumor development, considerations based on diverse clinical manifestations, as well as resistance to radiation and chemotherapy are important. The main diagnostic tools for detecting renal cell carcinoma are ultrasound, computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the kidneys.[27] ### Classification[edit] Renal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derived from the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes.[24] Classification of the Common Histological Subtypes of Renal Cell Carcinoma[24] Renal Cell Carcinoma Subtype Frequency Genetic Abnormalities Characteristics Clear Cell Renal Cell Carcinoma (CCRCC) Generally the cells have a clear cytoplasm, are surrounded by a distinct cell membrane and contain round and uniform nuclei. 60–70% * Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs * Inactivation of von Hippel–Lindau (VHL) gene by mutation and promoter hypermethylation * Gain of chromosome 5q * Loss of chromosomes 8p, 9p, and 14q * In 2009–2010, five new frequently mutated genes were discovered in CCRCC; KDM6A/UTX, SETD2, KDM5C/JARID1C, and MLL2[28] * CCRCC is derived from the proximal convoluted tubule * Most commonly affects male patients in their sixties and seventies[29] * Majority of CCRCC arise sporadically[29] * Only 2 – 4% of the cases presenting as part of an inherited cancer syndrome[29] Papillary Renal Cell Carcinoma (PRCC) Type 1 PRCC consist of papillae covered with a single or double layer of small cuboid cells with scanty cytoplasm and Type 2 PRCC consist of papillae covered by large eosinophilic cells arranged in an irregular or pseudostratified manner. 10–15% * Trisomy of chromosomes 7 and 17, loss of chromosome Y in men in sporadic PRCC[30] * Trisomy of chromosome 7 in hereditary PRCC[31] * Gain of chromosomes 12, 16, and 20 * Rare mutations of Metproto-oncogene * PRCC is derived from the distal convoluted tubule * PRCCs most commonly affect males in their sixties and seventies[29] * Less aggressive tumour than clear cell RCC, with 5-year survival rates of 80% to 85%. * Majority of tumours occur sporadically, but some may develop in members of families with hereditary PRCC[29] Chromophobe Renal Cell Carcinoma (ChRCC) ChRCC consists of tumor cells with abundant eosinophilic cytoplasm (pale cells and eosinophilic cells with a perinuclear halo) and show mainly a solid structure. 3–5% * Loss of chromosomes Y, 1, 2, 6, 10, 13, 17, and 21 * ChRCC is derived from the cortical collecting duct * ChRCC has a much better prognosis than clear cell and papillary RCC, with 5-year survival rate of greater than 90%. * Most cases arise sporadically, while some familial cases are associated with Birt–Hogg–Dube (BHD) syndrome[29] Clinical, Pathological and Genetic Features of Uncommon RCC Subtypes Included in the 2004 WHO Classification of RCC Pathology[29][32] RCC subtype Clinical features Cell/Tissue Characteristics Genetics Prognosis Multilocular Cystic RCC * Variant of CCRCC (5% of CCRCC) * Mean age 51 years (range 20–76) * Male:female = 2–3:1 Clear cytoplasm, small dark nuclei 3p deletion as observed in CCRCC * Favorable * No local or distant metastasis after complete surgical removal Carcinoma of the Collecting Ducts of Bellini * Less than 1% of all renal tumors; arising in the collecting ducts of Bellini * Mean age 55 years (range 40–70) * Male:female = 2:1 High-grade tumor cells with eosinophilic cytoplasm Variable results: LOH on chromosomes 1q, 6p, 8p,9p, 13q, 19q32 and 21q; c-erB2 amplification associated with unfavorable outcome * Poor prognosis * 1/3 presenting with metastasis * 2/3 patients succumb to the disease within 2 years of diagnosis Medullary Carcinoma * Exceedingly rare; almost exclusively in patients with sickle cell hemoglobinopathies or traits * Majority are African-Americans * Mean age 19 years (5–69) * Male:female = 2:1 Haemorrhage and necrosis, high-grade tumour cells with eosinophilic cytoplasm Not well defined * Highly aggressive * 95% presenting with metastasis * Often succumb to the disease within 6 months of diagnosis Xp11.2 Translocation Carcinoma * Predominantly affecting children and young adults * Accounts for 40% of RCCs in this age group * Affects adult patients with a striking female predominance * May resemble PRCC * Clear and eosinophilic cells Chromosomal translocation involving TFE3 gene on Xp11.2 resulting in overexpression of the TFE3 protein * Present at advanced stage, but with indolent clinical course in children * Adult patients may pursue more aggressive course Mucinous Tubular Spindle Cell Carcinoma * Mean age 53 years (range 13–82) * Affects predominantly female patients (male:female = 1:4) incidental finding in most cases Tubules, extracellular mucin and spindle cells Not well defined; Losses involving chromosomes 1, 4, 6, 8, 9, 11, 13, 14, 15, 18, 22 reported; 3p alterations and gain of chromosome 7, and 17 not present * Favourable * Majority of patients remain disease free after surgical resection Post-Neuroblastoma Renal Cell Carcinoma * Mean age of RCC diagnosis is 13.5 years (range 2–35) Eosinophilic cells with oncocytoid features (same as CCRCC) Not well defined; Loss of multiple chromosomal loci observed Similar to other common RCC subtypes Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology.[33][34] Array-based karyotyping performs well on paraffin embedded tumours[35] and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumours. The 2004 World Health Organization (WHO) classification of genitourinary tumours recognizes over 40 subtypes of renal neoplasms. Since the publication of the latest iteration of the WHO classification in 2004, several novel renal tumour subtypes have been described:[36] * Clear cell papillary renal cell carcinoma and Clear cell renal cell carcinoma with smooth muscle stroma[37] * Mucinous tubular and spindle cell carcinoma (MTSCC) [36] * Multilocular cystic clear cell renal cell carcinoma [36] * Tubulocystic renal cell carcinoma * Thyroid-like follicular renal cell carcinoma * Acquired cystic kidney disease-associated renal cell carcinoma * Renal cell carcinoma with t(6;11) translocation (TFEB) * Hybrid oncocytoma/chromophobe renal cell carcinoma * Hereditary leiomyomatosis and renal cell carcinoma(HLRCC) ### Laboratory tests[edit] Laboratory tests are generally conducted when the patient presents with signs and symptoms that may be characteristic of kidney impairment. They are not primarily used to diagnose kidney cancer, due to its asymptomatic nature and are generally found incidentally during tests for other illnesses such as gallbladder disease.[38] In other words, these cancers are not detected usually because they do not cause pain or discomfort when they are discovered. Laboratory analysis can provide an assessment on the overall health of the patient and can provide information in determining the staging and degree of metastasis to other parts of the body (if a renal lesion has been identified) before treatment is given. #### Urine analysis[edit] The presence of blood in urine is a common presumptive sign of renal cell carcinoma. The haemoglobin of the blood causes the urine to be rusty, brown or red in colour. Alternatively, urinalysis can test for sugar, protein and bacteria which can also serve as indicators for cancer. A complete blood cell count can also provide additional information regarding the severity and spreading of the cancer.[39] #### Complete blood cell count[edit] The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells.[40] CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) should be considered. #### Blood chemistry[edit] Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levels of particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are found to be at abnormally high levels.[41] The staging of the cancer can also be determined by abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones.[42] In this case, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of the kidneys and can allow the doctor to decide upon further radiological tests. ### Radiology[edit] The characteristic appearance of renal cell carcinoma (RCC) is a solid renal lesion which disturbs the renal contour. It will frequently have an irregular or lobulated margin and may be seen as a lump on the lower pelvic or abdomen region. Traditionally, 85 to 90% of solid renal masses will turn out to be RCC but cystic renal masses may also be due to RCC.[43] However, the advances of diagnostic modalities are able to incidentally diagnose a great proportion of patients with renal lesions that may appear to be small in size and of benign state. Ten percent of RCC will contain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat).[44] Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one.[45] The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features.[46] The main imaging tests performed in order to identify renal cell carcinoma are pelvic and abdominal CT scans, ultrasound tests of the kidneys (ultrasonography), MRI scans, intravenous pyelogram (IVP) or renal angiography.[47] Among these main diagnostic tests, other radiologic tests such as excretory urography, positron-emission tomography (PET) scanning, ultrasonography, arteriography, venography, and bone scanning can also be used to aid in the evaluation of staging renal masses and to differentiate non-malignant tumours from malignant tumours. #### Computed tomography[edit] Contrast-enhanced computed tomography (CT) scanning is routinely used to determine the stage of the renal cell carcinoma in the abdominal and pelvic regions. CT scans have the potential to distinguish solid masses from cystic masses and may provide information on the localization, stage or spread of the cancer to other organs of the patient. Key parts of the human body which are examined for metastatic involvement of renal cell carcinoma may include the renal vein, lymph node and the involvement of the inferior vena cava.[48] According to a study conducted by Sauk et al., multidetector CT imaging characteristics have applications in diagnosing patients with clear renal cell carcinoma by depicting the differences of these cells at the cytogenic level.[49] #### Ultrasound[edit] Ultrasonographic examination can be useful in evaluating questionable asymptomatic kidney tumours and cystic renal lesions if Computed Tomography imaging is inconclusive. This safe and non-invasive radiologic procedure uses high frequency sound waves to generate an interior image of the body on a computer monitor. The image generated by the ultrasound can help diagnose renal cell carcinoma based on the differences of sound reflections on the surface of organs and the abnormal tissue masses. Essentially, ultrasound tests can determine whether the composition of the kidney mass is mainly solid or filled with fluid.[47] A Percutaneous biopsy can be performed by a radiologist using ultrasound or computed tomography to guide sampling of the tumour for the purpose of diagnosis by pathology. However this is not routinely performed because when the typical imaging features of renal cell carcinoma are present, the possibility of an incorrectly negative result together with the risk of a medical complication to the patient may make it unfavourable from a risk-benefit perspective.[50] However, biopsy tests for molecular analysis to distinguish benign from malignant renal tumours is of investigative interest.[50] #### Magnetic resonance imaging[edit] Magnetic Resonance Imaging (MRI) scans provide an image of the soft tissues in the body using radio waves and strong magnets. MRI can be used instead of CT if the patient exhibits an allergy to the contrast media administered for the test.[51][52] Sometimes prior to the MRI scan, an intravenous injection of a contrasting material called gadolinium is given to allow for a more detailed image. Patients on dialysis or those who have renal insufficiency should avoid this contrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis.[53] A bone scan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvement of these areas. MRI scans should also be considered to evaluate tumour extension which has grown in major blood vessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to the brain or spinal cord should the patient present symptoms that suggest this might be the case. #### Intravenous pyelogram[edit] Intravenous pyelogram (IVP) is a useful procedure in detecting the presence of abnormal renal mass in the urinary tract. This procedure involves the injection of a contrasting dye into the arm of the patient. The dye travels from the blood stream and into the kidneys which in time, passes into the kidneys and bladder. This test is not necessary if a CT or MRI scan has been conducted.[54] #### Renal angiography[edit] Renal angiography uses the same principle as IVP, as this type of X-ray also uses a contrasting dye. This radiologic test is important in diagnosing renal cell carcinoma as an aid for examining blood vessels in the kidneys. This diagnostic test relies on the contrasting agent which is injected in the renal artery to be absorbed by the cancerous cells.[55] The contrasting dye provides a clearer outline of abnormally-oriented blood vessels believed to be involved with the tumour. This is imperative for surgeons as it allows the patient's blood vessels to be mapped prior to operation.[48] ### Staging[edit] The staging of renal cell carcinoma is the most important factor in predicting its prognosis.[56] Staging can follow the TNM staging system, where the size and extent of the tumour (T), involvement of lymph nodes (N) and metastases (M) are classified separately. Also, it can use overall stage grouping into stage I–IV, with the 1997 revision of AJCC described below:[56] Stage I Tumour of a diameter of 7 cm (approx. 2 3⁄4 inches) or smaller, and limited to the kidney. No lymph node involvement or metastases to distant organs. Stage II Tumour larger than 7.0 cm but still limited to the kidney. No lymph node involvement or metastases to distant organs. Stage III any of the following Tumor of any size with involvement of a nearby lymph node but no metastases to distant organs. Tumour of this stage may be with or without spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the heart. Tumour with spread to fatty tissue around the kidney and/or spread into the large veins leading from the kidney to the heart, but without spread to any lymph nodes or other organs. Stage IV any of the following Tumour that has spread directly through the fatty tissue and the fascia ligament-like tissue that surrounds the kidney. Involvement of more than one lymph node near the kidney Involvement of any lymph node not near the kidney Distant metastases, such as in the lungs, bone, or brain. At diagnosis, 30% of renal cell carcinomas have spread to the ipsilateral renal vein, and 5–10% have continued into the inferior vena cava.[57] ### Histopathology[edit] Renal cell carcinoma Histopathologic types of kidney tumor, with relative incidences and prognoses, including renal cell carcinoma and its subtypes. Renal cell carcinoma The gross and microscopic appearance of renal cell carcinomas is highly variable. The renal cell carcinoma may present reddened areas where blood vessels have bled, and cysts containing watery fluids.[58] The body of the tumour shows large blood vessels that have walls composed of cancerous cells. Gross examination often shows a yellowish, multilobulated tumor in the renal cortex, which frequently contains zones of necrosis, haemorrhage and scarring. In a microscopic context, there are four major histologic subtypes of renal cell cancer: clear cell (conventional RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Sarcomatoid changes (morphology and patterns of IHC that mimic sarcoma, spindle cells) can be observed within any RCC subtype and are associated with more aggressive clinical course and worse prognosis. Under light microscopy, these tumour cells can exhibit papillae, tubules or nests, and are quite large, atypical, and polygonal. Recent studies have brought attention to the close association of the type of cancerous cells to the aggressiveness of the condition. Some studies suggest that these cancerous cells accumulate glycogen and lipids, their cytoplasm appear "clear", the nuclei remain in the middle of the cells, and the cellular membrane is evident.[59] Some cells may be smaller, with eosinophilic cytoplasm, resembling normal tubular cells. The stroma is reduced, but well vascularised. The tumour compresses the surrounding parenchyma, producing a pseudocapsule.[60] The most common cell type exhibited by renal cell carcinoma is the clear cell, which is named by the dissolving of the cells' high lipid content in the cytoplasm. The clear cells are thought to be the least likely to spread and usually respond more favourably to treatment. However, most of the tumours contain a mixture of cells. The most aggressive stage of renal cancer is believed to be the one in which the tumour is mixed, containing both clear and granular cells.[61] The recommended histologic grading schema for RCC is the Fuhrman system (1982), which is an assessment based on the microscopic morphology of a neoplasm with haematoxylin and eosin (H&E staining). This system categorises renal cell carcinoma with grades 1, 2, 3, 4 based on nuclear characteristics. The details of the Fuhrman grading system for RCC are shown below:[62] Grade Level Nuclear Characteristics Grade I Nuclei appear round and uniform, 10 μm; nucleoli are inconspicuous or absent. Grade II Nuclei have an irregular appearance with signs of lobe formation, 15 μm; nucleoli are evident. Grade III Nuclei appear very irregular, 20 μm; nucleoli are large and prominent. Grade IV Nuclei appear bizarre and multilobated, 20 μm or more; nucleoli are prominent. Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma.[24] However, a study by Delahunt et al. (2007) has shown that the Fuhrman grading is ideal for clear cell carcinoma but may not be appropriate for chromophobe renal cell carcinomas and that the staging of cancer (accomplished by CT scan) is a more favourable predictor of the prognosis of this disease.[63] In relation to renal cancer staging, the Heidelberg classification system of renal tumours was introduced in 1976 as a means of more completely correlating the histopathological features with the identified genetic defects.[64] ## Prevention[edit] The risk of renal cell carcinoma can be reduced by maintaining a normal body weight.[65] ## Management[edit] Micrograph of embolic material in a kidney removed because of renal cell carcinoma (cancer not shown). H&E stain The type of treatment depends on multiple factors and the individual, some of which include the stage of renal cell carcinoma (organs and parts of the body affected/unaffected), type of renal cell carcinoma, pre-existing or comorbid conditions and overall health and age of the person.[9][66] Every form of treatment has both risks and benefits; a health care professional will provide the best options that suit the individual circumstances. If it has spread outside of the kidneys, often into the lymph nodes, the lungs or the main vein of the kidney, then multiple therapies are used including surgery and medications. RCC is resistant to chemotherapy and radiotherapy in most cases but does respond well to immunotherapy with interleukin-2 or interferon-alpha, biologic, or targeted therapy. In early-stage cases, cryotherapy and surgery are the preferred options. ### Active surveillance[edit] Active surveillance or "watchful waiting" is becoming more common as small renal masses or tumours are being detected and also within the older generation when surgery is not always suitable.[67] Active surveillance involves completing various diagnostic procedures, tests and imaging to monitor the progression of the RCC before embarking on a more high risk treatment option like surgery.[67] In the elderly, patients with co-morbidities, and in poor surgical candidates, this is especially useful. ### Surgery[edit] Different procedures may be most appropriate, depending on circumstances. The recommended treatment for renal cell cancer may be nephrectomy or partial nephrectomy, surgical removal of all or part of the kidney.[3] This may include some of the surrounding organs or tissues or lymph nodes. If cancer is only in the kidneys, which is about 60% of cases, it can be cured roughly 90% of the time with surgery. Small renal tumors (< 4 cm) are treated increasingly by partial nephrectomy when possible.[68][69][70] Most of these small renal masses manifest indolent biological behavior with excellent prognosis.[71] Nephron-sparing partial nephrectomy is used when the tumor is small (less than 4 cm in diameter) or when the patient has other medical concerns such as diabetes or hypertension.[9] The partial nephrectomy involves the removal of the affected tissue only, sparing the rest of the kidney, Gerota's fascia and the regional lymph nodes. This allows for more renal preservation as compared to the radical nephrectomy, and this can have positive long term health benefits.[72] Larger and more complex tumors can also be treated with partial nephrectomy by surgeons with a lot of kidney surgery experience.[73] Surgical nephrectomy may be "radical" if the procedure removes the entire affected kidney including Gerota's fascia, the adrenal gland which is on the same side as the affected kidney, and the regional retroperitoneal lymph nodes, all at the same time.[9] This method, although severe, is effective. But it is not always appropriate, as it is a major surgery that contains the risk of complication both during and after the surgery and can have a longer recovery time.[74] It is important to note that the other kidney must be fully functional, and this technique is most often used when there is a large tumour present in only one kidney. In cases where the tumor has spread into the renal vein, inferior vena cava, and possibly the right atrium, this portion of the tumor can be surgically removed, as well. In cases of known metastases, surgical resection of the kidney ("cytoreductive nephrectomy") may improve survival,[75] as well as resection of a solitary metastatic lesion. Kidneys are sometimes embolized prior to surgery to minimize blood loss.[76] Surgery is increasingly performed via laparoscopic techniques. Commonly referred to as key hole surgery, this surgery does not have the large incisions seen in a classically performed radical or partial nephrectomy, but still successfully removes either all or part of the kidney. Laparoscopic surgery is associated with shorter stays in the hospital and quicker recovery time but there are still risks associated with the surgical procedure. These have the advantage of being less of a burden for the patient and the disease-free survival is comparable to that of open surgery.[3] For small exophytic lesions that do not extensively involve the major vessels or urinary collecting system, a partial nephrectomy (also referred to as "nephron sparing surgery") can be performed. This may involve temporarily stopping blood flow to the kidney while the mass is removed as well as renal cooling with an ice slush. Mannitol can also be administered to help limit damage to the kidney. This is usually done through an open incision although smaller lesions can be done laparoscopically with or without robotic assistance. Laparoscopic cryotherapy can also be done on smaller lesions. Typically a biopsy is taken at the time of treatment. Intraoperative ultrasound may be used to help guide placement of the freezing probes. Two freeze/thaw cycles are then performed to kill the tumor cells. As the tumor is not removed followup is more complicated (see below) and overall disease-free rates are not as good as those obtained with surgical removal. Surgery for metastatic disease: If metastatic disease is present surgical treatment may still a viable option. Radical and partial nephrectomy can still occur, and in some cases, if the metastasis is small this can also be surgically removed.[9] This depends on what stage of growth and how far the disease has spread. ### Percutaneous ablative therapies[edit] Percutaneous ablation therapies use image-guidance by radiologists to treat localized tumors if a surgical procedure is not a good option. Although the use of laparoscopic surgical techniques for complete nephrectomies has reduced some of the risks associated with surgery,[77] surgery of any sort in some cases will still not be feasible. For example, the elderly, people already suffering from severe renal dysfunction, or people who have several comorbidities, surgery of any sort is not warranted.[78] A probe is placed through the skin and into the tumor using real-time imaging of both the probe tip and the tumor by computed tomography, ultrasound, or even magnetic resonance imaging guidance, and then destroying the tumor with heat (radiofrequency ablation) or cold (cryotherapy). These modalities are at a disadvantage compared to traditional surgery in that pathologic confirmation of complete tumor destruction is not possible. Therefore, long-term follow-up is crucial to assess completeness of tumour ablation.[79][80] Ideally, percutaneous ablation is restricted to tumours smaller than 3.5 cm and to guide the treatment. However, there are some cases where ablation can be used on tumors that are larger.[78] The two main types of ablation techniques that are used for renal cell carcinoma are radio frequency ablation and cryoablation.[78] Radio frequency ablation uses an electrode probe which is inserted into the affected tissue, to send radio frequencies to the tissue to generate heat through the friction of water molecules. The heat destroys the tumor tissue.[9] Cell death will generally occur within minutes of being exposed to temperatures above 50 °C. Cryoablation also involves the insertion of a probe into the affected area,[9] however, cold is used to kill the tumor instead of heat. The probe is cooled with chemical fluids which are very cold. The freezing temperatures cause the tumor cells to die by causing osmotic dehydration, which pulls the water out of the cell destroying the enzyme, organelles, cell membrane and freezing the cytoplasm.[78] ### Targeted drugs[edit] Cancers often grow in an unbridled fashion because they are able to evade the immune system.[8] Immunotherapy is a method that activates the person's immune system and uses it to their own advantage.[8] It was developed after observing that in some cases there was spontaneous regression.[81] Immunotherapy capitalises on this phenomenon and aims to build up a person's immune response to cancer cells.[81] Other targeted therapy medications inhibit growth factors that have been shown to promote the growth and spread of tumours.[82][83] Most of these medications were approved within the past ten years.[84] These treatments are:[85] * Nivolumab[86] * Axitinib[87] * Sunitinib[88] * Cabozantinib[86] * Everolimus * Lenvatinib * Pazopanib * Bevacizumab * Sorafenib * Tivozanib * Temsirolimus[89] * Interleukin-2 (IL-2) has produced "durable remissions" in a small number of patients, but with substantial toxicity.[90] * Interferon-α Activity has also been reported for ipilimumab[91] but it is not an approved medication for renal cancer.[92] More medications are expected to become available in the near future as several clinical trials are currently being conducted for new targeted treatments,[93] including: atezolizumab, varlilumab, durvalumab, avelumab, LAG525, MBG453, TRC105, and savolitinib. ### Chemotherapy[edit] Chemotherapy and radiotherapy are not as successful in the case of RCC. RCC is resistant in most cases but there is about a 4–5% success rate, but this is often short-lived with more tumours and growths developing later.[9] ### Adjuvant and neoadjuvant therapy[edit] Adjuvant therapy, which refers to therapy given after a primary surgery, has not been found to be beneficial in renal cell cancer.[94] Conversely, neoadjuvant therapy is administered before the intended primary or main treatment. In some cases neoadjuvant therapy has been shown to decrease the size and stage of the RCC to then allow it to be surgically removed.[83] This is a new form of treatment and the effectiveness of this approach is still being assessed in clinical trials. ## Metastasis[edit] Metastatic renal cell carcinoma (mRCC) is the spread of the primary renal cell carcinoma from the kidney to other organs. 25–30% of people have this metastatic spread by the time they are diagnosed with renal cell carcinoma.[95] This high proportion is explained by the fact that clinical signs are generally mild until the disease progresses to a more severe state.[96] The most common sites for metastasis are the lymph nodes, lung, bones, liver and brain.[10] How this spread affects the staging of the disease and hence prognosis is discussed in the “Diagnosis” and “Prognosis” section. MRCC has a poor prognosis compared to other cancers although average survival times have increased in the last few years due to treatment advances. Average survival time in 2008 for the metastatic form of the disease was under a year[97] and by 2013 this improved to an average of 22 months.[98] Despite this improvement the 5 year survival rate for mRCC remains under 10%[99] and 20–25% of suffers remain unresponsive to all treatments and in these cases, the disease has a rapid progression.[98] The available treatments for RCC discussed in the “Treatment” section are also relevant for the metastatic form of the disease. Options include interleukin-2 which is a standard therapy for advanced renal cell carcinoma.[94] From 2007 to 2013, seven new treatments have been approved specifically for mRCC (sunitinib, temsirolimus, bevacizumab, sorafenib, everolimus, pazopanib and axitinib).[7] These new treatments are based on the fact that renal cell carcinomas are very vascular tumors – they contain a large number of blood vessels. The drugs aim to inhibit the growth of new blood vessels in the tumors, hence slowing growth and in some cases reducing the size of the tumors.[100] Side effects unfortunately are quite common with these treatments and include:[101] * Gastrointestinal effects – nausea, vomiting, diarrhea, anorexia * Respiratory effects – coughing, dyspnea (difficulty breathing) * Cardiovascular effects – hypertension (high blood pressure) * Neurological effects – intracranial hemorrhage (bleeding into the brain), thrombosis (blood clots) in the brain * Effects on the skin and mucus membranes – rashes, hand-foot syndrome, stomatitis * Bone marrow suppression – resulting in reduced white blood cells, increasing the risk of infections plus anemia and reduced platelets * Renal effects – impaired kidney function * Fatigue. Radiotherapy and chemotherapy are more commonly used in the metastatic form of RCC to target the secondary tumors in the bones, liver, brain and other organs. While not curative, these treatments do provide relief for suffers from symptoms associated with the spread of tumors.[98] ## Prognosis[edit] The prognosis is influenced by several factors, including tumour size, degree of invasion and metastasis, histologic type, and nuclear grade.[24] Staging is the most important factor in the outcome of renal cell cancer. The following numbers are based on patients first diagnosed in 2001 and 2002 by the National Cancer Data Base:[102] Stage Description 5 Year Survival Rate I Confined to the kidney 81% II Extend through the renal capsule, confined to Gerota's Fascia 74% III Include the renal vein, or the hilar lymph nodes 53% IV Includes tumors that are invasive to adjacent organs (except the adrenal glands), or distant metastases 8% A Korean study estimated a disease-specific overall 5-year survival rate of 85%.[103] Taken as a whole, if the disease is limited to the kidney, only 20–30% develop metastatic disease after nephrectomy.[104] More specific subsets show a five-year survival rate of around 90–95% for tumors less than 4 cm. For larger tumors confined to the kidney without venous invasion, survival is still relatively good at 80–85%.[citation needed] For tumors that extend through the renal capsule and out of the local fascial investments, the survivability reduces to near 60%.[citation needed] Factors as general health and fitness or the severity of their symptoms impact the survival rates. For instance, younger people (among 20–40 years old) have a better outcome despite having more symptoms at presentation, possibly due to lower rates spread of cancer to the lymph nodes (stage III). Histological grade is related to the aggressiveness of the cancer, and it is classified in 4 grades, with 1 having the best prognosis (5 year survival over 89%), and 4 with the worst prognosis (46% of 5 year survival). Some people have the renal cell cancer detected before they have symptoms (incidentally) because of the CT scan (Computed Tomography Imaging) or ultrasound. Incidentally diagnosed renal cell cancer (no symptoms) differs in outlook from those diagnosed after presenting symptoms of renal cell carcinoma or metastasis. The 5 year survival rate was higher for incidental than for symptomatic tumours: 85.3% versus 62.5%. Incidental lesions were significantly lower stage than those that cause symptoms, since 62.1% patients with incidental renal cell carcinoma were observed with Stage I lesions, against 23% were found with symptomatic renal cell carcinoma.[105] If it has metastasized to the lymph nodes, the 5-year survival is around 5% to 15%. For metastatic renal cell carcinoma, factors which may present a poor prognosis include a low Karnofsky performance-status score (a standard way of measuring functional impairment in patients with cancer), a low haemoglobin level, a high level of serum lactate dehydrogenase, and a high corrected level of serum calcium.[106][107] For non-metastatic cases, the Leibovich scoring algorithm may be used to predict post-operative disease progression.[108] Renal cell carcinoma is one of the cancers most strongly associated with paraneoplastic syndromes, most often due to ectopic hormone production by the tumour. The treatment for these complications of RCC is generally limited beyond treating the underlying cancer. ## Epidemiology[edit] The incidence of the disease varies according to geographic, demographic and, to a lesser extent, hereditary factors. There are some known risk factors, however the significance of other potential risk factors remains more controversial. The incidence of the cancer has been increasing in frequency worldwide at a rate of approximately 2–3% per decade[97] until the last few years where the number of new cases has stabilised.[16] The incidence of RCC varies between sexes, ages, races and geographic location around the world. Men have a higher incidence than women (approximately 1.6:1)[94] and the vast majority are diagnosed after 65 years of age.[94] Asians reportedly have a significantly lower incidence of RCC than whites and while African countries have the lowest reported incidences, African Americans have the highest incidence of the population in the United States.[16] Developed countries have a higher incidence than developing countries, with the highest rates found in North America, Europe and Australia / New Zealand[109] ## History[edit] Daniel Sennert made the first reference suggesting a tumour arising in the kidney in his text Practicae Medicinae, first published in 1613.[110] Miril published the earliest unequivocal case of renal carcinoma in 1810.[111] He described the case of Françoise Levelly, a 35-year-old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages of pregnancy.[110] Koenig published the first classification of renal tumours based on macroscopic morphology in 1826. Koenig divided the tumors into scirrhous, steatomatous, fungoid and medullary forms.[112] ### Hypernephroma controversy[edit] Following the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma. The pathogenesis of renal epithelial tumours was debated for decades. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphology of small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereas papillary tumours were derived from renal tissue.[110] In 1893, Paul Sudeck challenged the theory postulated by Grawitz by publishing descriptions of renal tumours in which he identified atypical features within renal tubules and noted a gradation of these atypical features between the tubules and neighboring malignant tumour. In 1894, Otto Lubarsch, who supported the theory postulated by Grawitz coined the term hypernephroid tumor, which was amended to hypernephroma by Felix Victor Birch-Hirschfeld to describe these tumours.[113] Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenal origin of renal tumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the term hypernephroma, with its associated adrenal connotation, persisted in the literature.[110] Foot and Humphreys, and Foote et al. introduced the term Renal Celled Carcinoma to emphasize a renal tubular origin for these tumours. Their designation was slightly altered by Fetter to the now widely accepted term Renal Cell Carcinoma.[114] Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure of clear cells from eight renal carcinomas. They found that the tumour cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat. They identified cytoplasmic membranes inserted perpendicularly onto the basement membrane with occasional cells containing microvilli along the free borders. They concluded that these features indicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one of the most debated issues in tumour pathology.[110][115] ## See also[edit] * Stauffer syndrome * Knudson hypothesis[116] * Interleukin-2 * Kidney cancer * Rapamycin * Vinblastine * Dysuria * Interferon ## References[edit] 1. ^ a b c d e f g Curti, B; Jana, BRP; Javeed, M; Makhoul, I; Sachdeva, K; Hu, W; Perry, M; Talavera, F (26 February 2014). Harris, JE (ed.). "Renal Cell Carcinoma". Medscape Reference. WebMD. Archived from the original on 7 March 2014. Retrieved 7 March 2014. 2. ^ "EAU Guidelines: Renal Cell Carcinoma". 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PMID 19015066. ## External links[edit] Classification D * ICD-10: C64 * ICD-9-CM: 189.0 * ICD-O: M8312/3 * OMIM: 144700 605074 * MeSH: D002292 * DiseasesDB: 11245 External resources * MedlinePlus: 000516 * eMedicine: med/2002 * v * t * e Tumors of the urinary and genital systems Kidney Glandular and epithelial neoplasm * Renal cell carcinoma * Renal oncocytoma Mixed tumor * Wilms' tumor * Mesoblastic nephroma * Clear-cell sarcoma of the kidney * Angiomyolipoma * Cystic nephroma * Metanephric adenoma by location * Renal medullary carcinoma * Juxtaglomerular cell tumor * Renal medullary fibroma Ureter * Ureteral neoplasm Bladder * Transitional cell carcinoma * Squamous-cell carcinoma * Inverted papilloma Urethra * Transitional cell carcinoma * Squamous-cell carcinoma * Adenocarcinoma * Melanoma Other * Malignant fibrous histiocytoma * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Renal cell carcinoma	c0007134	5,259	wikipedia	https://en.wikipedia.org/wiki/Renal_cell_carcinoma	2021-01-18T18:38:17	{"gard": ["13215"], "mesh": ["D002292"], "umls": ["C0007134"], "icd-9": ["189.0"], "icd-10": ["C64"], "orphanet": ["217071"], "wikidata": ["Q1164529"]}
For a phenotypic description and a discussion of genetic heterogeneity of bipolar disorder, see 125480. Bipolar disorder (BPAD) is a severe psychiatric disorder that manifests with alternating episodes of mania and depression. Age at onset (AAO) is a potential clinical marker of genetic heterogeneity in BPAD. Lin et al. (2005) sought to incorporate AAO as a covariate in linkage analyses of BPAD using 2 different methods in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified 2 loci, on 21q22.13 (lod = 3.29) and 18p11.2 (see 125480), with increased linkage among subjects who had early onset (AAO = 21 years or younger) and later onset (AAO = more than 21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (lod = 2.88). Lin et al. (2005) suggested that previous inconsistent linkage findings may have been due to differences in the AAO characteristics of the samples examined. Molecular Genetics McQuillin et al. (2006) found an association between bipolar disorder and a polymorphism (D543E) in exon 11 of the TRPM2 gene (603749) on chromosome 21q22.3 (p = 0.008). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MAJOR AFFECTIVE DISORDER 3	c1864994	5,260	omim	https://www.omim.org/entry/609633	2019-09-22T16:05:46	{"mesh": ["C566501"], "omim": ["609633"], "synonyms": ["Alternative titles", "BIPOLAR AFFECTIVE DISORDER, EARLY-ONSET"]}
LOC syndrome is a subtype of junctional epidermolysis bullosa (JEB, see this term) characterized by an altered cry in the neonatal period and by aberrant production of granulation tissue in particular affecting the upper airway tract, conjunctiva and periungual/subungual sites. ## Epidemiology Prevalence is unknown. Fewer than 50 cases have been reported to date, mostly in consanguineous families from the Punjabi region of Pakistan and India. ## Clinical description The condition is present at birth. Characteristic cutaneous findings are transient blisters leaving slowly healing erosions with exuberant granulation tissue formation, mainly localized to the head and neck, hands, feet, elbows and knees. Extracutaneous manifestations are always observed: the progressive laryngeal involvement frequently leads to fatal respiratory obstruction in infancy, and the chronic conjunctival lesions cause symblepharon formation, and also total palpebral occlusion and blindness. Enamel hypoplasia is also always present and nail dystrophies are common. ## Etiology The condition is associated with mutations in the alpha-3 chain of laminin-332 (LAMA3). ## Genetic counseling LOC syndrome follows an autosomal recessive pattern of inheritance. ## Prognosis Prognosis is poor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	LOC syndrome	c1328355	5,261	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2407	2021-01-23T18:19:45	{"gard": ["368"], "mesh": ["C537032"], "omim": ["245660"], "umls": ["C1328355"], "icd-10": ["Q81.8"], "synonyms": ["LOGIC syndrome", "Laryngeal and ocular granulation tissue in children from the Indian subcontinent syndrome", "Laryngo-onycho-cutaneous syndrome", "Shabbir syndrome"]}
Hemophilia B is a form of hemophilia (see this term) characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency. ## Epidemiology Prevalence is estimated at around 1 in 30,000 males. Hemophilia primarily affects males, but a symptomatic form of hemophilia B in female carriers (see this term) has also been described with a generally milder clinical picture. ## Clinical description In general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. The severity of the clinical manifestations depends on the extent of the factor IX deficiency. If the biological activity of factor IX is below 1%, the hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction (severe hemophilia B; see this term). If the biological activity of factor IX is between 1% and 5%, the hemophilia is moderately severe with abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia B; see this term). If the biological activity of factor IX is between 5 and 40%, the hemophilia is mild with abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia B; see this term). Bleeding most often occurs around the joints (hemarthroses) and in the muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a fairly frequent and highly characteristic sign of the disorder. ## Etiology Hemophilia B is caused by mutations in the F9 gene (Xq27) encoding coagulation factor IX. Diagnosis is suspected on the basis of coagulation tests revealing prolonged blood coagulation times and can be confirmed by specific measurements of factor IX levels. ## Differential diagnosis The differential diagnosis should include von Willebrand disease (see this term) and other coagulation anomalies leading to prolonged blood coagulation times. ## Antenatal diagnosis Prenatal diagnosis is feasible through molecular analysis of chorionic villus samples. Coagulation factor assays can also be carried out on venous and umbilical cord blood samples. ## Genetic counseling Hemophilia B is transmitted in an X-linked recessive manner. ## Management and treatment Treatment revolves around substitution therapy with plasma derivatives or genetically engineered recombinant alternatives. Treatment may be administered after a hemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers. ## Prognosis Historically, the disease course is severe and, left untreated, severe hemophilia B is generally fatal during childhood or adolescence. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to motor impairment with severe disability associated with stiffness, joint deformation and paralysis. However, current treatment approaches now allow these complications to be prevented and the prognosis is favorable: the earlier the substitutive therapy is received and the more adapted the treatment is to the clinical status of the patient, the better the prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hemophilia B	c0008533	5,262	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98879	2021-01-23T19:06:57	{"gard": ["8732"], "mesh": ["D002836"], "omim": ["306900"], "umls": ["C0008533"], "icd-10": ["D67"], "synonyms": ["Christmas disease", "Factor IX deficiency"]}
Koller et al. (1979) described an apparently 'new' dominant disorder characterized by cortical thickening of the diaphyses of long bones and bowing of femurs and tibias in a family from northern Norway. Six persons in 2 generations were affected. All 6 had ichthyosis and 3 also had an unusual proclivity to fractures. The patients had pain and weakness in the legs and a waddling gait, as in Engelmann disease (131300). No male-to-male transmission was observed and no affected male had children; hence, autosomal and X-linked inheritance could not be distinguished. Females and males were probably affected with equal severity. Skel \- Osteosclerosis \- Increased fractures Limbs \- Bowed femurs and tibias Radiology \- Cortical thickening of long bone diaphyses Inheritance \- Autosomal dominant Skin \- Ichthyosis ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	OSTEOSCLEROSIS WITH ICHTHYOSIS AND FRACTURES	c1833697	5,263	omim	https://www.omim.org/entry/166740	2019-09-22T16:36:50	{"mesh": ["C563483"], "omim": ["166740"], "synonyms": ["Alternative titles", "CORTICAL THICKENING OF LONG BONES WITH BOWING AND ICHTHYOSIS"]}
Craniosynostosis–anal anomalies–porokeratosis syndrome SpecialtyDermatology Craniosynostosis–anal anomalies–porokeratosis syndrome (also known as "CAP syndrome") is a cutaneous condition inherited in an autosomal recessive fashion.[1] ## See also[edit] * Cerebral dysgenesis–neuropathy–ichthyosis–keratoderma syndrome * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## External links[edit] Classification D * OMIM: 603116 * MeSH: C536789 This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Craniosynostosis–anal anomalies–porokeratosis syndrome	c1864186	5,264	wikipedia	https://en.wikipedia.org/wiki/Craniosynostosis%E2%80%93anal_anomalies%E2%80%93porokeratosis_syndrome	2021-01-18T18:43:18	{"mesh": ["C536789"], "umls": ["C1864186"], "orphanet": ["85199"], "wikidata": ["Q5182151"]}
A rare bacterial infectious disease caused by Francisella tularensis and characterized by six major clinical presentations: ulceroglandular, glandular, oropharyngeal, oculoglandular, pneumonic, or typhoidal, depending on the route of infection. Early flu-like symptoms are common to all forms and are accompanied/followed by either a skin inoculation ulcer with localized lymphadenopathy; isolated lymphadenopathy; chronic pharyngitis with cervical lymphadenopathy; conjunctivitis with localized lymphadenopathy; lung involvement; severe systemic disease with neurological symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tularemia	c0041351	5,265	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3392	2021-01-23T17:15:15	{"gard": ["396"], "mesh": ["D014406"], "umls": ["C0041351"], "icd-10": ["A21.0", "A21.1", "A21.2", "A21.3", "A21.7", "A21.8", "A21.9"]}
Ulegyria is a diagnosis used to describe a specific type of cortical scarring in the deep regions of the sulcus that leads to distortion of the gyri. Ulegyria is identified by its characteristic "mushroom-shaped" gyri, in which scarring causes shrinkage and atrophy in the deep sulcal regions while the surface gyri are spared.[1] This condition is most often caused by hypoxic-ischemic brain injury in the perinatal period.[2] The effects of ulegyria can range in severity, although it is most commonly associated with cerebral palsy, mental retardation and epilepsy. N.C. Bresler was the first to view ulegyria in 1899 and described this abnormal morphology in the brain as “mushroom-gyri."[1] Although ulegyria was first identified in 1899, there is still limited information known or reported about the condition. Gyrus vs. sulcus ## Contents * 1 Anatomy * 2 Causes * 2.1 Cerebral ischemia * 2.2 Cerebral hemorrhage * 2.3 Ascending intrauterine infections * 3 Signs and symptoms * 4 Similar conditions * 5 Detection * 6 Treatment * 7 References ## Anatomy[edit] Arteries supplying the brain The physical features of ulegyria consist of small radial scars which occupy the cortical sulci.[3] Overall, the physical structure of affected areas in the brain is described as a “mushroom”-like shape in which the gyri are unusually large and the sulci become wider deeper in the cortex. N.C. Bresler, the first person to view a brain with ulegyria in 1899, coined the phrase mushroom gyri. He also named the disorder, basing it off the Latin root ule, meaning scar.[1] This mushroom-like structure is the result of the lower parts of the ulegyria-affected area being more prone to deterioration, while the upper gyri are usually spared.[4] However, the entire affected area shrinks and presents brown coloration as a result of ulegyria. In addition, “islands” of neurons that are relatively unaffected can exist between ulegyria affected neurons.[5] Ulegyria can develop bilaterally or unilaterally, though the former is more commonly diagnosed.[6] Ulegyria can affect many parts of the brain including the cerebral cortex, parasagittal areas and posterior regions of the brain, such as the parietal and occipital lobes.[1] These areas are situated either near artery rich regions or near a major cerebral artery.[5] For instance, specifically in neonatal children, ulegyria-affected areas are found near the posterior cerebral artery or near the artery rich region between the middle and posterior regions of the brain, often referred to as watershed regions.[1][4][7] Neurons affected by ulegyria exhibit properties that differ from normally functioning neurons. For instance, ulegyria affected neurons experience gliosis in which glial cells, specifically astrocytes, build up near and around neurons. Ulegyria affected neurons also display decreases in their white matter content, showing signs of sclerosis, which is characterized by the deterioration of myelin in neurons. However, in regions of grey matter, large dense aggregates of myelin are present.[4] Ulegyria affected neurons also display metabolic disorders which could be linked to the disease phenylketonuria and disruptions in the urea cycle.[8] Hypoglycemia and hypoxia are also thought to accompany the symptoms of ulegyria-affected neurons as well.[2][9] ## Causes[edit] Microphotograph of HE stained section of human brain tissue upon acute ischemic stroke Ulegyria develops as a result of a brain injury called cerebral ischemia surrounding the time of an infant’s birth. Oftentimes, fetal hypoxic-ischemic brain injuries occur as a result of a pregnancy complications such as placental abruption, cord accident, or cardiovascular stress due to a difficult delivery.[10] A lack of oxygen to the brain contributes to the formation of lesions usually near the three main cerebral arteries, located near the parietal lobe and occipital lobes of the brain.[4] The cause of perinatal brain injuries includes: 1\. cerebral ischemia 2\. cerebral hemorrhage 3\. ascending intrauterine infections.[11] Some risk factors for perinatal brain injuries include: low birth weight, preterm birth, poor perinatal cardiorespiratory fitness, and artificial ventilation.[12] ### Cerebral ischemia[edit] Cerebral ischemia occurs when the brain is not receiving adequate oxygen to continue normal functions. When this occurs, the body makes restoring oxygenated blood flow to life-sustaining organs a priority. The brain alters the diameter of major blood vessels to redistribute blood to key organs such as the brain, heart, and adrenal glands. If sympathetic nervous system activation does not produce any improvement, oxygen levels will continue to fall and disruptions to metabolism, other cellular processes, and overall functioning will ensue. Another serious result of inefficient blood flow is that cells do not receive adequate amounts of glucose. An immediate effect of low intracellular glucose is reduced ATP production in the cell. This effectively inactivates the Na-K pump, leading to the uptake of calcium ions by the cell. Continued influx of calcium serves to constitutively activate downstream effectors, including lipases, proteases, and endonucleases, whose actions eventually destroy the cell skeleton.[11] Intracellular calcium concentrations are increased further due to the opening of glutamate-regulated ion channels. Ischemia causes anoxic cell depolarizations and it is this increase in membrane potential at the presynaptic cell that triggers the release of glutamate, an excitatory neurotransmitter.[13] Glucose deprivation in the brain for any amount of time has the potential to pose serious consequences, and the amount of time the brain spends under these anoxic conditions is directly related to accumulation of irreversible damage to protein biosynthesis pathways. Protein synthesis all over the body is severely inhibited and essentially comes to a standstill while the brain is suffering from acute oxygen deprivation.[13] Once oxygen sufficiently saturates the tissues again, protein biosynthesis returns to normal in non-vulnerable areas but remains at below normal levels in other areas. Insufficient protein synthesis in the brain is especially troubling in the fetal brain given the amount of growth and development that normally occurs. Areas particularly vulnerable to the damaging effects of hypoxic episodes include: the superior brainstem, the cerebellum, white matter and subcortical structures supplied by the branches of deep and superficial penetrating blood vessels.[10] Vulnerable areas where protein synthesis is interrupted usually indicate impending cell death in neurons. When oxygen levels return, oxygen radicals, nitric oxide and an imbalance of neurotransmitters cause further damage and lead to cellular death through apoptosis. Neuron cell death is responsible for gliosis and results in the mushroom appearance of areas and is characteristic of ulegyria.[13] ### Cerebral hemorrhage[edit] A cerebral hemorrhage is the result of immature blood vessels of a brain lesion bursting. The germinal matrix is a part of the brain that normally disappears as the fetal brain develops but during this process it is not unusual for changes in vessel volume to cause a vessel to burst. According to recent microscopic studies, the most common location for a cerebral hemorrhage is where the medullary veins drain to the terminal vein in the sub-ependymal region. It has been hypothesized that because pre-term babies don’t have fully developed sympathetic nervous systems, they cannot react as well to low oxygen saturation levels caused by the cerebral hemorrhage.[11] Although babies born at full-term are still susceptible to this, they are likely to respond better and thus, tend to have better outcomes in response to low-oxygen events. ### Ascending intrauterine infections[edit] Recent research has found a connection between intrauterine infections and inflammation in the mother and an increased likelihood of perinatal brain damage in the fetus. This study suggested that intrauterine infections in the mother could affect glial cells and toll-like receptors (TLRs) which are important in moderating the inflammatory response in the fetal brain.[14] When glial cells and TLRs are negatively affected they are not able to react to developing inflammation in the brain as well. The connection between ascending intrauterine infections and perinatal brain damage is a developing research theory but a more detailed explanation of the connection is not yet known. ## Signs and symptoms[edit] Ulegyria was found in about 1/3 of patients with defects caused by circulatory disease in the perinatal period.[15] Most clinical observations of the condition report mental retardation, cerebral palsy, and seizures as the main defects.[1][6][8][10][16] However, milder cases have been reported in which patients that exhibit ulegyria develop relatively normally.[1][2] The main movement disorders associated with ulegyria that are classified as cerebral palsy are choreoathetosis, dystonia, and ataxia.[10] It is suspected that ulegyria leads to epilepsy because malformation of the cortex obstructs the differentiation of neurons, glial cells, and synapses.[15] Parietal-occipital lobe epilepsy, which is often synonymous with posterior cortex epilepsy (PCE),[16] is the form of the disease seen in most cases involving ulegyria.[2] This type of epilepsy is very rare, making up about 5% of all reports of epilepsy. This form of the disease involves symptoms that would be expected from damage to the parietal and occipital lobes: seizures with visual hallucinations, visuospatial dysfunction, tingling, numbness, pain, and a burning sensation.[17] In addition to ulegyria, tumors and cortical dysplasia constitute the major causes of PCE.[13] Most of the epilepsy seen in conjunction with ulegyria is classified as medically refractory, meaning it is not responsive to treatment.[7] Patients usually present symptoms of epilepsy at an early age.[1] The severity of epilepsy has been shown to depend on this age of onset as well as the quantity of cortical lesions; earlier onset of epilepsy and a larger extent of lesions tends to mean more severe seizures.[1][7] ## Similar conditions[edit] Child presenting with seizures likely due to polymicrogyria (seen at arrow). Ulegyria is often confused with a similar distortion of the cortex known as polymicrogyria.[7] Polymicrogyria is characterized by excessive folding of the surface gyri and a thickening of the cerebral cortex,[18] rather than the sulcal scarring that is typical of ulegyria. In addition to morphological differences, the period in which polmicrogyria and ulegyria emerge is also different. Polymicrogyria typically forms while the embryo's central nervous system is maturing. Ulegyria is acquired later in development during the perinatal period after neuronal migration has already occurred. It is also suspected that polymicrogyra is genetically linked, whereas ulegyria is caused by environmental factors—namely lack of oxygen.[1] Polymicrogyria can lead to similar conditions that are linked to ulegyria such as mental retardation, cerebral palsy, and epilepsy. It has been observed that patients with polymicrogyria are not receptive to epilepsy surgery. However, responses of patients with ulegyria to similar surgeries are still not fully known, which makes distinction of these two disorders significant. In vivo neuroimaging techniques, namely MRI, have been instrumental in making this distinction. An MRI image of ulegyria is identified by mushroom shaped gyri, deformities in white matter, and localization mainly in the posterior cerebral region.[1] Polymicrogyria is typically recognized by a scalloped appearance at the bordering region between grey and white matter.[18] Although these distinctions have been made with many patients, there is still some difficulty in defining distinct boundaries between these two similar conditions.[7] ## Detection[edit] Primarily, the main method of detecting ulegyria is through the use of MRI screening for epilepsy. Normally an MRI of an ulegyria affected region will reveal groups of deteriorated neurons with gliosis present. In addition, unaffected gyri are also present in especially bilateral watershed regions indicating delayed effects of perinatal hypoxic damage.[4] However, there are three main criteria for diagnosing ulegyria using MRI in addition to the features mentioned above:[4] 1.The presence of a poorly demarcated lesion 2\. Atrophy and thinning of the cortex resulting in the characteristic “mushroom” like shape of ulegyria. 3\. Presence of white matter signal abnormalities as a result of FLAIR signaling (fluid attenuated inversion recovery). Another sign of ulegyria that is visible on an MRI scan is the presence of a widened subarachnoid space, signifying cortex atrophy. FLAIR signaling can help visualize the depths of the parietal-occipital sulci, which also allows ulegyria-affected gyri to be identified.[6] Though there is still confusion in differentiating ulegyria and polymicrogyria in patients, MRI allows for the proper identification in the majority of the cases. In addition, most of the current research regarding ulegyria is focused on improving this identification. Furthermore, MRI can diagnose whether ulegyria presence is unilateral or bilateral.[1] Electroencephalography, EEG, can also be used to screen for ulegyria, though MRI is still preferred. This is mainly done for epilepsy patients as abnormalities in EEG recordings indicate the presence of ulegyria in the area of the brain being tested.[7] For example, when EEG tests in epileptic patients show deviations in the frontal and central-parietal regions, ulegyria can be considered to be present in that area.[7] ## Treatment[edit] Presently, there is no well-defined treatment for ulegyria mainly because of the irreversible ischaemic damage done to neurons of an affected area. However, conditions associated with ulegyria, such as epilepsy and cerebral palsy, can be treated using the appropriate treatment. For instance, seizures caused by epilepsy, due to the presence of ulegyria in the occipital lobe, can be controlled using antiepileptic drugs in some patients.[1] In other patients, such as those who suffer from ulegyria in the posterior cortex, drugs are not effective and surgery of the area causing epilepsy is needed.[1][16] These treatments treat only the conditions but have no effect on the condition of ulegyria itself. ## References[edit] 1. ^ a b c d e f g h i j k l m n Gil-Nagel, A; García Morales, I; Jiménez Huete, A; Alvarez Linera, J; Del Barrio, A; Ruiz Ocaña, C; Muñoz, DG (2005). "Occipital lobe epilepsy secondary to ulegyria". Journal of Neurology. 252 (10): 1178–1185. doi:10.1007/s00415-005-0829-5. PMID 15806340. S2CID 28080071. 2. ^ a b c d Montassir, H; Maegaki, Y; Ohno, K; Ogura, K (2010). "Long term prognosis of symptomatic occipital lobe epilepsy secondary to neonatal hypoglycemia". Epilepsy Research. 88 (2–3): 93–99. doi:10.1016/j.eplepsyres.2009.10.001. PMID 19914803. S2CID 20982129. 3. ^ Christos, Panteliadis (2004). Cerebral Palsy: Principles and Management. New York: Thieme. p. 53. ISBN 978-3131400215. 4. ^ a b c d e f Singh, P; Kavita, S; Parambir, S; Munish, G. "Ulegyria-The 'Mushroom' Gyri". JK Science. 13 (1). 5. ^ a b Morys, J; Narkiewicz, O; Wisniewski, H (1993). "Neuronal loss in the human claustrum following ulegyria". Brain Research. 616 (1–2): 176–180. doi:10.1016/0006-8993(93)90207-4. PMID 8358611. S2CID 27261722. 6. ^ a b c Urbach, H (2005). "Imaging of the epilepsies". European Radiology. 15 (3): 494–500. doi:10.1007/s00330-004-2629-1. PMID 15678321. S2CID 5622991. 7. ^ a b c d e f g Villani, F; d'Incerti, L; Granata, T; Battaglia, G; Vitali, P; Chiapparini, L; Avanzini, G (2003). "Epileptic and imaging findings in perinatal hypoxic-ischemic encephalopathy with ulegyria". Epilepsy Res. 55 (3): 235–43. doi:10.1016/S0920-1211(03)00121-9. PMID 12972177. S2CID 41128348. 8. ^ a b Kim, H.-I.; Lee, M.-C.; Lee, J.-S.; Kim, H.-S.; Kim, M.-K.; Woo, Y.-J.; Kim, J.-H.; Jung, S; Palmini, A; Kim, Seung U. (2006). "Bilateral perisylvian ulegyria: Clinicopathological study of patients presenting with pseudobulbar palsy and epilepsy". Neuropathology. 26 (3): 236–242. doi:10.1111/j.1440-1789.2006.00659.x. PMID 16771181. S2CID 41661153. 9. ^ Armstrong, Dawna (2007). Pediatric Neuropathology: A Text-Atlas. New York: Springer. p. 92,126. ISBN 978-4431702467. 10. ^ a b c d Nikas, I; Dermentzoglou, V; Theofanopoulou, M; Theodoropoulos, V (2008). "Parasagittal Lesions and Ulegyria in Hypoxic-Ischemic Encephalopathy: Neuroimaging Findings and Review of the Pathogenesis". Journal of Child Neurology. 23 (1): 51–58. doi:10.1177/0883073807308694. PMID 18160553. S2CID 11346668. 11. ^ a b c Garnier, J; Garnier, Yves; Middelanis, Johannes; Berger, Richard (2003). "Perinatal Brain Damage-From pathophysiology to prevention". European Journal of Obstetrics and Gynecology and Reproductive Biology. 110: S70–S79. doi:10.1016/S0301-2115(03)00175-1. PMID 12965093. 12. ^ Love, S (2004). "Acute haemorrhagic and hypoxic-ischaemic brain damage in the neonate". Current Diagnostic Pathology. 10 (2): 106–115. doi:10.1016/j.cdip.2004.01.003. 13. ^ a b c d Berger, Richard; Garnier, Yves (2005). "Perinatal brain injury". Journal of Perinatal Medicine. 28 (4): 261–285. doi:10.1515/JPM.2000.034. PMID 11031697. S2CID 17726402. 14. ^ Yuan, Tian Ming; Sun, Yi; Zhan, Can-Yang; Yu, Hui-Min (2010). "Intrauterine infection/inflammation and perinatal brain damage: Role of glial cells and toll-like receptor signaling". Journal of Neuroimmunology. 229 (1–2): 16–25. doi:10.1016/j.jneuroim.2010.08.008. PMID 20826013. S2CID 37038841. 15. ^ a b Menkes, J. H.; Sarnat, H. B.; Maria, B. L. (2006). Child Neurology. Philadelphia: Lippincott. pp. 381–383. ISBN 978-0781751049. 16. ^ a b c Usui, N; Mihara, T; Baba, K; Matsuda, K; Tottori, T; Umeoka, S; Nakamura, F; Terada, K; Usui, K; Inoue, Yushi (2008). "Posterior cortex epilepsy secondary to ulegyria: Is it a surgically remediable syndrome?". Epilepsia. 49 (12): 1998–2007. doi:10.1111/j.1528-1167.2008.01697.x. PMID 18557774. S2CID 25979880. 17. ^ de Tisi, Jane; Bell, Gail S; Peacock, Janet L; McEvoy, Andrew W; Harkness, William FJ; Sander, Josemir W; Duncan, John S (2011). "The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study". The Lancet. 378 (9800): 1388–1395. doi:10.1016/S0140-6736(11)60890-8. PMID 22000136. S2CID 498402. 18. ^ a b Chang, B; Walsh, CA; Apse, K; Bodell, A; Pagon, RA; Adam, TD; Bird, CR; Dolan, K; Fong, MP; Stephens, K (1993). "Polymicrogyria Overview". GeneReviews. PMID 20301504. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Ulegyria	c0266488	5,266	wikipedia	https://en.wikipedia.org/wiki/Ulegyria	2021-01-18T18:33:10	{"umls": ["C0266488"], "icd-9": ["742.4"], "wikidata": ["Q7878831"]}
Melanocytic tumors of uncertain malignant potential (MELTUMP) are melanocytic lesions in the dermis that cannot be classified by morphology as either benign naevi (moles) or malignant melanomas because the mass shows features of both. Several lesion types may be classified as MELTUMPs: these include atypical melanocytic proliferations with features that may overlap with atypical Spitz naevi/tumors, dysplastic naevi, pigmented epithelioid melanocytoma, deep penetrating naevi, congenital neavi, cellular nodules in congenital naevi, possible naevoid melanomas, and cellular blue naevi.[1][2] A related category of melanocytic proliferation is superficial atypical melanocytic proliferations of uncertain significance (SAMPUS). This category, unlike MELTUMP, which implies as yet undetermined potential for metastases even after complete excision, signifies lesions without metastatic potential at time of excision but with potential to progress upon incomplete excision. The SAMPUS category includes certain atypical junctional melanocytic proliferations and proliferations in both the epidermis and papillary dermis that are not accompanied by intradermal tumorigenic architecture or cell mitosis.[1] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ a b Elder, David E.; Xiaowei Xu (October 2004). "The approach to the patient with a difficult melanocytic lesion". Pathology. 36 (5): 428–34. doi:10.1080/00313020412331283905. PMID 15370112. Retrieved 2007-02-27. 2. ^ Byrd, David R.; David E. Elder; James M. Grichnik; John M. Kirkwood; Merrick I. Ross (2006-08-01). "Melanoma Care Options" (PDF). Melanoma Care Coalition. pp. 6–8. Retrieved 2007-02-27. ## Further reading[edit] * Quatresooz P, Piérard-Franchimont C, Piérard GE (June 2008). "Highlighting the immunohistochemical profile of melanocytomas: review". Oncol. Rep. 19 (6): 1367–72. doi:10.3892/or.19.6.1367. PMID 18497938. * Murphy, George F. "Case 12: Melanocytic tumor of uncertain malignant potential (MELTUMP)". In Artur Zembowicz (ed.). Cases in Dermatopathology: Common Problems in Diagnosis of Pigmented Lesions. Los Gatos, California: Knowledge Books and Software. pp. 73–80. ISBN 1-74162-088-0. Retrieved 2007-02-27. * v * t * e Skin cancer of nevi and melanomas Melanoma * Mucosal melanoma * Superficial spreading melanoma * Nodular melanoma * lentigo * Lentigo maligna/Lentigo maligna melanoma * Acral lentiginous melanoma * Amelanotic melanoma * Desmoplastic melanoma * Melanoma with features of a Spitz nevus * Melanoma with small nevus-like cells * Polypoid melanoma * Nevoid melanoma * Melanocytic tumors of uncertain malignant potential Nevus/ melanocytic nevus * Nevus of Ito/Nevus of Ota * Spitz nevus * Pigmented spindle cell nevus * Halo nevus * Pseudomelanoma * Blue nevus * of Jadassohn–Tièche * Cellular * Epithelioid * Deep penetrating * Amelanotic * Malignant * Congenital melanocytic nevus (Giant * Medium-sized * Small-sized) * Balloon cell nevus * Dysplastic nevus/Dysplastic nevus syndrome * Acral nevus * Becker's nevus * Benign melanocytic nevus * Nevus spilus This article about a neoplasm is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Melanocytic tumors of uncertain malignant potential	None	5,267	wikipedia	https://en.wikipedia.org/wiki/Melanocytic_tumors_of_uncertain_malignant_potential	2021-01-18T18:43:57	{"umls": ["CL973832"], "wikidata": ["Q17141487"]}
Tuomaala and Haapanen (1968) described a Finnish family in which 2 sisters and a brother had an identical syndrome of congenital anodontia, small maxilla giving an impression of mandibular prognathism, short stature with particular shortening of the metacarpals and metatarsals, little hair growth, albinoidism, and multiple ocular abnormalities including strabismus, nystagmus, distichiasis, lenticular opacities, and high-grade myopia. The parents were not known to be related but came from the same parish in northeast Finland. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Ears \- Low-set ears Eyes \- Downslanting palpebral fissures \- Strabismus \- Thin eyelashes \- Distichiasis \- Myopia \- Irregular nystagmus \- Cataract \- Corneal opacities \- Tarsal hypoplasia Teeth \- Anodontia CHEST Breasts \- Small breast \- Hypoplastic nipples \- Unpigmented areola GENITOURINARY External Genitalia (Female) \- Hypoplastic labia SKELETAL Skull \- Hypoplastic maxilla Hands \- Short fingers \- Short metacarpals (3rd-5th) Feet \- Short toes (2nd-5th) \- Short metatarsals SKIN, NAILS, & HAIR Skin \- Albinoidism Hair \- Thin hair \- Absent pubic hair \- Absent axillary hair \- Thin eyelashes ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	BRACHYMETAPODY-ANODONTIA-HYPOTRICHOSIS-ALBINOIDISM	c1859385	5,268	omim	https://www.omim.org/entry/211370	2019-09-22T16:30:20	{"mesh": ["C565893"], "omim": ["211370"], "orphanet": ["2713"], "synonyms": ["Alternative titles", "ANODONTIA-HYPOTRICHOSIS SYNDROME", "OCULOOSTEOCUTANEOUS SYNDROME"]}
Hereditary coproporphyria (HCP) is a rare inherited form of liver (hepatic) porphyria, characterized by neurological symptoms in the form of episodes (acute attacks) of stomach pain, nausea, vomiting, weakness, numbness, and pain in the hands and feet (neuropathy). The porphyrias are a group of blood conditions caused by a lack of an enzyme in the body that makes heme, an important molecule that carries oxygen throughout the body and is vital for all of the body’s organs. Symptoms usually begin around 20-30 years of age, but have been reported at younger ages. Signs and symptoms present during the attacks may include body pain, nausea and vomiting, increased heart rate (tachycardia), and high blood pressure. Less common symptoms include seizures, skin lesions, and paralysis of the arms and legs, body trunk, and respiratory muscles. Most individuals with HCP do not have any signs or symptoms between attacks. HCP is caused by mutations in the CPOX gene and is inherited in an autosomal dominant manner.[1268] Diagnosis is based on the symptoms and specific blood, urine and stool testing. Treatment is based on preventing the symptoms. An acute attack requires hospitalization, medications, and treatment with heme therapy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hereditary coproporphyria	c0162531	5,269	gard	https://rarediseases.info.nih.gov/diseases/6619/hereditary-coproporphyria	2021-01-18T18:00:04	{"mesh": ["D046349"], "omim": ["121300"], "orphanet": ["79273"], "synonyms": ["Coproporphyria", "Coproporphyria hereditary", "Hereditary coproporphyria porphyria", "Porphyria hepatica coproporphyria", "Porphyria hepatica II", "HCP", "Coproporphyrinogen oxidase deficiency", "CPO deficiency", "CPRO deficiency", "CPX deficiency"]}
Histiocytosis-lymphadenopathy plus syndrome is a group of conditions with overlapping signs and symptoms that affect many parts of the body. This group of disorders includes H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (also known as familial sinus histiocytosis with massive lymphadenopathy or FSHML). These conditions were once thought to be distinct disorders; however, because of the overlapping features and shared genetic cause, they are now considered to be part of the same disease spectrum. While some affected individuals have signs and symptoms characteristic of one of these conditions, others have a range of features from two or more of the conditions. The pattern of signs and symptoms can vary, even within the same family. All of the conditions in the spectrum are characterized by histiocytosis, which is an overgrowth of immune system cells called histiocytes. These cells abnormally accumulate in one or more tissues in the body, which can lead to organ or tissue damage. The lymph nodes are commonly affected, leading to swelling of the lymph nodes (lymphadenopathy). Other areas of cell accumulation can include skin, kidneys, brain and spinal cord (central nervous system), or digestive tract. The spectrum is known as histiocytosis-lymphadenoapthy plus syndrome because the disorders that make up the spectrum can have additional signs and symptoms. H syndrome is named for the collection of symptoms - all starting with the letter H - that are commonly present. These include hyperpigmented skin lesions with excessive hair growth (hypertrichosis) and histiocyte accumulation, enlargement of the liver or liver and spleen (hepatomegaly or hepatosplenomegaly), heart abnormalities, hearing loss, reduced amounts of hormones that direct sexual development (hypogonadism), and short stature (reduced height). In some cases, hyperglycemia/diabetes mellitus may also be present. PHID is characterized by patches of hyperpigmented skin with hypertrichosis and the development of type 1 diabetes during childhood. Faisalabad histiocytosis is characterized by lymphadenopathy and swelling of the eyelids due to the accumulation of histiocytes. Affected individuals may also have joint deformities (contractures) in their fingers or toes, and hearing loss. Familial Rosai-Dorfman disease is characterized by lymphadenopathy, most often in the neck. Histiocytes can also accumulate in other parts of the body. Histiocytosis-lymphadenopathy plus syndrome is caused by mutations in the SLC29A3 gene. The condition is inherited in an autosomal recessive pattern. Treatment is aimed at treating the symptoms present in each individual. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Histiocytosis-lymphadenopathy plus syndrome	c1864445	5,270	gard	https://rarediseases.info.nih.gov/diseases/10239/histiocytosis-lymphadenopathy-plus-syndrome	2021-01-18T18:00:00	{"mesh": ["C538322"], "omim": ["602782"], "umls": ["C1864445"], "orphanet": ["168569"], "synonyms": ["HJCD", "Faisalabad histiocytosis", "H syndrome", "Histiocytosis with joint contractures and sensorineural deafness", "SLC29A3 spectrum disorder"]}
Degenerative disease that affects sheep and goats Not to be confused with Scrapy. Ewe with scrapie with weight loss and hunched appearance Same ewe as above with bare patches on rear end from scraping Scrapie (/ˈskreɪpi/) is a fatal, degenerative disease affecting the nervous systems of sheep and goats.[1] It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion.[2][3] Scrapie has been known since at least 1732 and does not appear to be transmissible to humans.[4][5] The name scrapie is derived from one of the clinical signs of the condition, wherein affected animals will compulsively scrape off their fleeces against rocks, trees or fences. The disease apparently causes an itching sensation in the animals. Other clinical signs include excessive lip smacking, altered gaits and convulsive collapse.[6] Scrapie is infectious and transmissible among conspecifics, so one of the most common ways to contain it (since it is incurable) is to quarantine and kill those affected. However, scrapie tends to persist in flocks and can also arise apparently spontaneously in flocks that have not previously had cases of the disease. The mechanism of transmission between animals and other aspects of the biology of the disease are only poorly understood, and are active areas of research. Recent studies suggest prions may be spread through urine and persist in the environment for decades.[7] Scrapie usually affects sheep around three to five years of age.[citation needed] The potential for transmission at birth and from contact with placental tissues is apparent.[citation needed] ## Contents * 1 Regulation * 2 Cause * 3 Transmission and pathogenesis * 4 Clinical signs and diagnosis * 5 Treatment and preventive action * 6 Transmission/exposure pathways * 6.1 Exposure through contaminated vaccines * 6.2 Exposure through contaminated soil * 6.3 Transmission summary * 7 Genetics * 8 See also * 9 References * 10 External links ## Regulation[edit] The disease has been notifiable in the EU since 1993, but unlike BSE, there was no evidence as of 1999 to suggest that scrapie is a risk to human health.[8][9][10][11] In July 2003, a Canadian Food Inspection Agency officer said that while scrapie shows up every year on Canadian farms, "We've had a lot of experience with scrapie and there's never been a link between scrapie and human illness."[12] As of 2004, the USDA made no mention of scrapie in its Sheep and Goats Death Loss circular.[13] Historically, scrapie had been considered to be an animal health issue. However, between 1996 and 1999 the UK Spongiform Encephalopathy Advisory Committee had been considering the control and eradication of scrapie in the UK also with public health in mind because of concern over five issues:[14] 1. Meat and bone meal (MBM), which was suspected to be the source of the BSE in cattle outbreak in the late 1990s, had also been fed to sheep and goats. 2. BSE had been transmitted to sheep following experimental oral exposure. 3. Transmissible spongiform encephalopathy (TSE) Infection was widespread through the carcasses of the sheep, unlike cattle infection which is limited to neural tissues. 4. Scrapie in sheep was underreported and it might be masking BSE – were it present in sheep. 5. Specified Risk Material (SRM) measures may not be adequate to control human exposure. ## Cause[edit] The cause of scrapie, as with other transmissible spongiform encephalopathies, is unknown and is a matter of debate;[15] the agent is very difficult to destroy with heat, radiation and disinfectants, does not evoke any detectable immune response, and has a long incubation period of between 18 months and 5 years.[16] The agent is thought to be much smaller than the smallest currently known virus and the prevailing theory is that it is caused by a misfolded protein called a prion. Prions multiply by causing normally folded proteins of the same type to take on their abnormal shape, which then go on to do the same, in a kind of chain reaction. These abnormal proteins are gradually accumulated in the body, especially in nerve cells, which subsequently die. ## Transmission and pathogenesis[edit] The primary mode of transmission is from mother to lamb through ingestion of placental or allantoic fluids.[citation needed] The agent can also enter through cuts in the skin. An experiment has shown lambs risk being infected through milk from infected ewes,[17] but the lambs in the experiment also infected each other, making the risk of infection difficult to assess. The experiment did not continue long enough to show if the lambs developed symptoms, but merely that the abnormal prion was present in their bodies. The pathogenesis of scrapie involves the lymphatic system. Once the agent is absorbed through the intestines, misfolded prions first appear and accumulate in the lymph nodes, especially in Peyer's patches at the small intestine.[18] Eventually, the infection invades the brain, often through the spinal cord or the medulla oblongata by creeping up the sympathetic and parasympathetic nervous system, respectively.[19] ## Clinical signs and diagnosis[edit] Changes are mild at first; slight behavioral changes and an increase in chewing movements may occur. Ataxia and neurological signs then develop, and affected sheep struggle to keep up with the flock.[20] Some sheep scratch excessively and show patches of wool loss and lesions on the skin. Scratching sheep over the rump area may lead to a nibbling reflex, which is characteristic for the condition.[20] Signs of a chronic systemic disease appear later, with weight loss, anorexia, lethargy, and death.[20] Post mortem examination is important for the diagnosis of scrapie. Histology of tissues shows accumulation of prions in the central nervous system, and immunohistochemical staining and ELISA can also be used to demonstrate the protein. ## Treatment and preventive action[edit] No treatment is available for affected sheep.[20] A test performed by sampling a small amount of lymphatic tissue from the third eyelid is now available.[21] In the UK, the Blair ministry implemented in 2001 a National Scrapie Plan, which encouraged breeding from sheep that are genetically more resistant to scrapie. This is intended to eventually reduce the incidence of the disease in the UK sheep population.[22][23] Scrapie occurs in Europe and North America, but to date, Australia and New Zealand (both major sheep-producing countries) are scrapie-free.[citation needed] In 2003, there was pressure from previously-sinistered Canadian husbandry practitioners on the Chretien government and their CFIA to implement their own national scrapie plan.[12] Breeds such as Cheviot and Suffolk are more susceptible to scrapie than other breeds.[24] Specifically, this is determined by the genes coding for the naturally occurring prion proteins. The most resistant sheep have a double set of ARR alleles, while sheep with the VRQ allele are the most susceptible.[25] A simple blood test reveals the allele of the sheep, and many countries are actively breeding away the VRQ allele. Out of fear of BSE, many European countries banned some traditional sheep or goat products made without removing the spinal cord, such as smalahove and smokie.[26] In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred billion (10−11) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrPSc. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals' brains were analysed once any symptoms became apparent. They could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals' lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared. After further development and testing, this method could be of great value in surveillance as a blood- or urine-based screening test for scrapie.[27][28] ## Transmission/exposure pathways[edit] Various studies have indicated prions (PrPSC) that infect sheep and goats with the fatal transmissible encephalopathy known as scrapie, are able to persist in soil for years without losing their pathogenic activity.[29] Dissemination of prions into the environment can occur from several sources: mainly, infectious placenta or amniotic fluid of sheep and possibly environmental contamination by saliva or excrement. Confirmatory testing for scrapie can only be achieved by applying immunohistochemistry of disease-associated prion protein (PrPSC) to tissues collected post mortem, including obex (a brainstem structure), retropharyngeal lymph node and palatine tonsil. A live animal diagnostic, not confirmatory, test was approved in 2008 for immunochemistry testing on rectal biopsy-derived lymphoid tissue by USDA. Human prion protein, residues 125–228, created from protein database (PDB) entry 1QM3. The coloring illustrates the subdomains, that are proposed to initiate the conversion from the normal cellular to the scrapie form by slow motions. Natural transmission of scrapie in the field seems to occur via the alimentary tract in the majority of cases, and scrapie-free sheep flocks can become infected on pastures where outbreaks of scrapie had been observed before. These findings point to a sustained contagion in the environment, notably in the soil.[30] Prion concentration in birth fluids does not alter the infectivity of the prions. Naturally or experimentally infected does and ewes transmit the infection to the lambs, even when placentas have little PrPSC. PrPSC is shed at a higher percentage in sheep placentas (52–72%) than in goat placenta (5–10%) in study trials at the USDA Agricultural Research Service.[31] Detectable PrPSC has been reported in the feces of sheep both in the terminal and the early preclinical stages of the disease, suggesting the prions are likely to be shed into the environment throughout the course of the disease. Several sources of prions in feces could be postulated, including environmental ingestion and swallowing infected saliva; however, the most likely source is shedding from the gut-associated lymphoid tissue. Ruminant animals have specialized Peyer's patches that, throughout the length of the ileum, amount to about 100,000 follicles, and all of these could be infected and shedding prions into the lumen.[32] Scrapie prions have been found in the Peyer's patches of naturally infected asymptomatic lambs as young as four months of age. ### Exposure through contaminated vaccines[edit] * Contaminated Louping-ill vaccine. Also known as the 1935 Moredun Louping-ill Vaccine Disaster..[33] More than 1,500 sheep developed scrapie following vaccination. "An investigation into the etiology of scrapie followed the vaccination of sheep for louping-ill virus with formalin-treated extracts of ovine lymphoid tissue unknowingly contaminated with scrapie prions (Gordon 1946). Two years later, more than 1500 sheep developed scrapie from this vaccine." "This vaccine was manufactured using formalised sheep brains contaminated with scrapie agent" [34] "At the 1946 National Veterinary Medical Association of Great Britain and Ireland Annual Congress, W. S. Gordon, PhD, presented evidence of scrapie transmission by way of a vaccine for louping-ill." "Dr. Gordon developed an effective vaccine to prevent louping-ill during 1931-32. After four years of field trials, his vaccine was produced in three batches for widespread use in 1935. The vaccine was made from brain, spinal cord, and spleen tissues taken from sheep five days after they had received an intracerebral inoculation of louping-ill virus. Formalin was added to the 10% saline suspension to inactivate the virus. During 1935 and 1936, no ill effects were noted in inoculated animals. Then two owners reported scrapie in their Blackface sheep who had been inoculated with louping-ill vaccine (batch 2) two and a half years earlier. Scrapie had not been seen in the Blackface breed before this. Upon investigation Dr. Gordon discovered that 8 lambs used to make batch 2 had been born to ewes who had been exposed to scrapie; some of the ewes developed scrapie in 1936-7. Dr. Gordon hypothesized that an "infective agent of scrapie" was present in the lambs' tissues used to make batch 2 and that this agent "could withstand a concentration of formalin...which inactivated the virus of louping ill; it could be transmitted by subcutaneous inoculation; it had an incubative period of two years or longer." A four-and-a-half-year experiment involving '788 sheep was initiated by the Animal Disease Research Association in 1938. The researchers found that 60% of normal sheep inoculated intracerebrally with saline suspensions of brain and spinal cord tissue taken from sheep with scrapie developed scrapie within those four-and-a-half-years. The incubation period was seven months and up. Only 30% of the sheep receiving a subcutaneous inoculation of the suspension developed scrapie in that time, and the incubation period in this group was 15 months and up. The researchers concluded that the infective agent was probably a filtrable virus." [35] * Contaminated Mycoplasma agalactiae vaccine. In 1997 and 1998 there was an outbreak of scrapie in sheep and goats in Italy, and the cause was attributed to the vaccine. "An accidental infection from a vaccine was suggested as the explanation for the sudden increase in outbreaks of scrapie in Italy in 1997 and 1998. This paper describes a recent outbreak of scrapie in sheep and goats which were exposed to the same vaccine. No ewes or goats had been imported into the herd since 1992, but a vaccine against Mycoplasma agalactiae had been administered twice, in 1995 and 1997. High rates of crude mortality and scrapie incidence were experienced by both species, all birth cohorts were involved and a large proportion of aged animals was affected. A pattern of brain lesions was observed, with slight differences between the sheep and goats, which was very similar to the pattern observed in animals previously exposed to the same vaccine but clearly different from that observed in the brains of sheep with scrapie in a flock not exposed to the vaccine. Regardless of their exposure status, genotype analysis of the sheep showed the presence of polymorphism only at codon 171. The patterns of both incidence and brain lesions provide evidence that the epidemic of scrapie was due to the use of the vaccine."[36] "An accidental intra- and interspecies transmission of scrapie occurred in Italy in 1997 and 1998 following exposure to a vaccine against Mycoplasma agalactiae. PrP(Sc) in affected sheep and goats, collected from a single flock exposed to vaccination 2 years earlier, was molecularly typed. In five animals with iatrogenic scrapie, a PrP(Sc) type with a 20 kDa core fragment was found in all areas of the brain investigated. In three sheep and one goat, this isoform co-occurred with a fully glycosylated isoform that had a protease-resistant backbone of 17 kDa, whereas in two sheep and four goats, the two PrP(Sc) types were detected in different regions of the brain. In sheep with natural field scrapie, a PrP(Sc) type with physico-chemical properties indistinguishable from the 20 kDa isoform was found. The present results suggest the co-presence of two prion strains in mammary gland and brain homogenates used for vaccination." [37][38] ### Exposure through contaminated soil[edit] Ingestion of soil by grazing sheep has been measured in two soil types, at two stocking rates, and over two grazing seasons. Animals ingested up to 400 g soil per kg of body weight between May and November. Rainfall and stocking rate emerged as factors influencing ingestion. The effect of soil type and vegetation type was less evident.[39] The average weight of an adult sheep is around 250 pounds.[40] If an adult sheep ate 400g/kg of soil as predicted by D. McGrath et al., then the average sheep would ingest about 45,000 g over six months, or 251 g per day. Assuming the soil was contaminated with prions (PrPSC) from feces or birth fluids, then potentially the sheep would become infected. The concentration of the prions in the soil is uncertain, and concentration is not directly proportional to infectivity. Factors affecting prion infectivity in the soil have been shown to include the length of time in the soil and the binding abilities of the soil. For a detailed risk assessment of scrapie-contaminated soil, it was of major importance to analyze whether the detectable PrPSc in the soil extracts still exhibited oral infectivity after incubation times up to 29 months. A bioassay with Syrian hamsters was performed by feeding the animals with contaminated soil or aqueous soil extracts that had been collected after soil incubation for 26 and 29 months, respectively. Hamsters fed with contaminated soil exhibited their first scrapie-associated symptoms at two weeks to six months (95% CI) after the first feeding. The hamsters reached the terminal stage of scrapie at five to 21 months (95% CI) after the first feeding. This indicated substantial amounts of persistent infectivity in soil that had been incubated for 26 and 29 months.[30] In Iceland in 1978, a program was implemented to eradicate scrapie, and affected flocks were culled, premises were disinfected, and sheep houses were burnt; after two to three years, the premises were restocked with lambs from scrapie-free areas. Between 1978 and 2004, scrapie recurred on 33 farms. Nine recurrences occurred 14–21 years after culling as a result of persistent environmental contamination with PrPSc.[41] The binding abilities of different soil types have been shown to enhance disease penetrance into a population. Soil containing the common clay mineral montmorillonite (Mte) and kaolinite (Kte) binds more effectively with the prions than soil containing quartz.[31] Enhanced transmissibility of soil-bound prions may explain the environmental spread of scrapie despite low levels shed into the environment. The mechanism by which Mte or other soil components enhances the transmissibility of particle bound prions remains to be clarified. Prion binding to Mte or other soil components may partially protect PrPSC from denaturation or proteolysis in the digestive tract, allowing more disease agent to be taken up from the gut. Adsorption of PrPSc soil may alter the aggregation state of the protein, shifting the size distribution toward more infectious prion protein particles, thereby increasing the infectious units. For prion disease to be transmitted via ingestion of prion contaminated soil, prions must also remain infectious by the oral route of exposure. Researchers at the University of Wisconsin investigated the oral infectivity of Mte-bound and soil-bound prions. The effects of prion source (via infected brain homogenate and purified PrPSc) and dose on penetrance (proportion of animals eventually exhibiting clinical signs of scrapie) and incubation period (time to onset of clinical symptoms) was evaluated. About 38% of animals receiving orally 200 ng of unbound, clarified PrPSc derived from soil exhibited clinical symptoms, with an incubation period for infected animals of 203 to 633 days. All animals orally dosed with an equivalent amount of Mte-bound PrPSc manifested disease symptoms in 195 to 637 days. By contrast, animals orally receiving Mte soil alone or one-tenth as much unbound clarified PrPSc (20 ng) remained asymptomatic throughout the course of the experiment. These data established that Mte-bound prions remain infectious via the oral route of exposure, and that the binding agent Mte increases disease penetrance, enhancing the efficiency of oral transmission.[42] Exposure through contaminated hay mites "With scrapie, the archetypical TSE, which is a natural disease in sheep and goats, the disease can appear suddenly in a flock in the absence of any known exposure to infected flocks (Palsson, 1979). Finally, fields in Iceland, that were left empty for up to 3 years after the destruction of scrapie-infected flocks, were repopulated with known scrapie-free sheep, and some of the sheep in this latter group subsequently developed scrapie (Palsson, 1979). This last 'experiment in nature' has yielded similar results a number of times in Iceland and in the United Kingdom. In one Icelandic farm, flocks have been eradicated three times; each time, the farm was left without sheep for 2 years, and after restocking with sheep from scrapie-free areas, the disease reappeared. Several years ago, a suggestion was made (S Sigurdarson, personal communication) that hay mites would be a good candidate as a vector for scrapie; this led to infection of mice with mite samples prepared from hay obtained from five Icelandic farms. Ten of these 71 mice became sick after injection with mite preparations from three of the five farms (Wisniewski et al, 1996; Rubenstein et al, 1998). The incubation periods ranged from 340 days to 626 days, and these mice had the protease-resistant form PrpSc, of a host-coded glycoprotein, PrPc . The protease-resistant form is a marker of TSE disease (Prusiner, 1991; Parchi et al, 1996). For some of these clinically positive mice, the banding pattern on WB analysis was unique (Wisniewski et al, 1996; Rubenstein et al, 1998)."[43] ### Transmission summary[edit] Prions (PrPSc) are shed from sheep and goats in birth fluids, feces and other excrement. The concentration of the prions is uncertain, but is not directly proportional to infectivity. Sheep ingest a considerable amount of soil, so soil represents a plausible environmental reservoir of scrapie prions, which can persist in the environment for years. Longevity of the prions and the attachment of soil particles likely influences the persistence and infectivity of prions in the environment.[citation needed] Effective methods of inactivating prions in the soil are currently lacking, and the effects of natural degradation mechanisms on prion infectivity are largely unknown. An improved understanding of the processes affecting the mobility, persistence and bioavailability of prions in soil is needed for the management of prion-contaminated environments. A system for estimating the prion-binding capacity of soil on farms using simple soil analysis may allow an estimate of the prion risk in the environment, and whether altering prion binding by the use of soil amendments may help to mitigate the infectious prions. Lichens, specifically, Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria, may have potential for reducing the number of prions because some lichen species contain proteases that show promise in breaking down the prion. Further work to clone and characterize the proteases, assess their effects on prion infectivity, and determine which component organism or organisms present in lichens produce or influence the protease activity is warranted and is currently under investigation.[44] ## Genetics[edit] The prion gene that codes for the prion protein is highly conserved in most mammals, meaning the gene is similar and present in most species of mammals. Three locations on the prion protein gene have been identified as highly polymorphic and may have an effect on scrapie: codons 136, 154, and 171.[45] Codon 154 has not shown any evidence of having a high effect on scrapie susceptibility, but is most likely having an effect on incubation time of the disease. Codons 136 and 171 are thought to control the incubation time as well as the susceptibility of the disease, and are the ones the USDA uses in its breeding standard.[46][47][48] Codon 171 has been determined to be the major genetic factor in scrapie susceptibility.[49][50] ## See also[edit] * Creutzfeldt–Jakob disease * Kuru * Transmissible mink encephalopathy * Virino * Rams (film), a 2016 Icelandic drama ## References[edit] 1. ^ Detwiler LA (1992). "Scrapie". Rev. Sci. Tech. Off. Int. Epiz. 11 (2): 491–537. doi:10.20506/rst.11.2.607. PMID 1617202. 2. ^ Hunter N (2007). "Scrapie: uncertainties, biology and molecular approaches" (PDF). Biochim. Biophys. Acta. 1772 (6): 619–28. doi:10.1016/j.bbadis.2007.04.007. PMID 17560089. 3. ^ "Safety & Availability (Biologics) - Bovine Spongiform Encephalopathy (BSE) Questions and Answers". FDA. 2019-05-22. 4. ^ National Scrapie Education Initiative. "Scrapie Fact Sheet". National Institute for Animal Agriculture. Retrieved 4 December 2011. 5. ^ Rolf, George. "From Sheep to Humans: Scrapie and Creutzfeldt–Jakob Disease". Ecclectica. Archived from the original on 27 August 2011. Retrieved 4 December 2011. 6. ^ Foster JD, Parnham D, Chong A, Goldmann W, Hunter N (2001). "Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats". Vet. Rec. 148 (6): 165–71. doi:10.1136/vr.148.6.165. PMID 11258721. S2CID 43497666. 7. ^ Detwiler LA, Baylis M (2003). "The epidemiology of scrapie" (PDF). Rev. Sci. Tech. Off. Int. Epiz. 22 (1): 121–43. doi:10.20506/rst.22.1.1386. PMID 12793776. 8. ^ Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P (1987) "The epidemiology of Creutzfeldt–Jakob disease: conclusion of a 15-year investigation in France and review of the world literature". Neurology, 37(6):895–904. 9. ^ Harries JR, Knight R, Will RG, Cousens SN, Smith PG, Mathews WB (1988) "Creutzfeldt–Jakob disease in England and Wales, 1980–1984: a case-control study of potential risk factors". Journal of Neurology Neurosurgery and Psychiatry, 51(9):1113–1119. 10. ^ Kondo K, Kuriowa Y (1982). "A case control study of Creutzfeldt-Jakob disease: association with physical injuries". Annals of Neurology, 11(4):377–381. 11. ^ World Health Organization, 1999. WHO consultation on public health and animal transmissible spongiform encephalopathies: epidemiology, risk and research requirements, with the participation of the Office International des Epizooties. http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000 Accessed 7 March 2005. http://www.who.int/csr/resources/publications/bse/en/whocdscsraph20002.pdf. 12. ^ a b "National scrapie plan urged". July 10, 2003. 13. ^ "Sheep and Goats Death Loss" (PDF). National Agricultural Statistics Service. 2005-05-06. Retrieved 2019-01-22. 14. ^ "National Scrapie Plan / Ram Genotyping Scheme Review / Benefits Review" (PDF). Department for the Environment, Food and Rural Affairs. December 2006. Archived from the original (PDF) on 2008-11-09. This article contains quotations from this source, which is available under the Open Government Licence v1.0. © Crown copyright. 15. ^ "USDA APHIS \| Scrapie". 16. ^ "Scrapie \| sheep disease". 17. ^ Konold Moore; Bellworthy Simmons (2008). "Evidence of scrapie transmission via milk". BMC Veterinary Research. 4: 16. doi:10.1186/1746-6148-4-16. PMC 2390527. PMID 18445253. 18. ^ Tarmen viktig for skrapesyke - forskning.no 19. ^ Van Keulen, L. J; Schreuder, B. E; Vromans, M. E; Langeveld, J. P; Smits, M. A (2000). "Pathogenesis of natural scrapie in sheep". Archives of Virology. Supplementum (16): 57–71. doi:10.1007/978-3-7091-6308-5_5. ISBN 978-3-211-83529-6. PMID 11214935. 20. ^ a b c d Scrapie reviewed and published by WikiVet, accessed 12 October 2011. 21. ^ O'Rourke KI, Duncan JV, Logan JR, et al. (2002). "Active surveillance for scrapie by third eyelid biopsy and genetic susceptibility testing of flocks of sheep in Wyoming". Clin. Diagn. Lab. Immunol. 9 (5): 966–71. doi:10.1128/CDLI.9.5.966-971.2002. PMC 120069. PMID 12204945. 22. ^ Atkinson, M. (2001). "National scrapie plan". The Veterinary Record. 149 (15): 462. PMID 11688751. 23. ^ "Letter from Franz FISCHLER, European Commission Directorate-General for Agriculture to The Right Hon Jack Straw MP Secretary of State for Foreign and Commonwealth Affairs regarding State aid N 544/2002 National Scrapie Plan for Great Britain: Phase 1 – Genotyping schemes to encourage breeding for genetic resistance" (PDF). 24. ^ Eddie Straiton, "Sheep Ailments - recognition and treatment", 7th edition (2001) ISBN 1-86126-397-X 25. ^ Synnøve Vatn, Lisbeth Hektoen, Ola Nafstad "Helse og Velferd hos sau" 1. utgave, Tun Forlag (2008) ISBN 978-82-529-3180-8 26. ^ Heim D, Kihm U (2003). "Risk management of transmissible spongiform encephalopathies in Europe". Rev. Sci. Tech. Off. Int. Epiz. 22 (1): 179–99. doi:10.20506/rst.22.1.1392. PMID 12793779. S2CID 20893064. 27. ^ "Detecting Prions in Blood" (PDF). Microbiology Today.: 195. August 2010. Retrieved 2011-08-21. 28. ^ Richard Rubenstein; Binggong Chang; Perry Gray; Martin Piltch; Marie S. Bulgin; Sharon Sorensen-Melson; Michael W. Miller. "SOFIA: An Assay Platform for Ultrasensitive Detection of PrPSc in Brain and Blood" (PDF). SUNY Downstate Medical Center. Archived from the original (PDF) on 2012-02-05. Retrieved 2011-08-19. "SOFIA: An Assay Platform for Ultrasensitive Detection of PrPSc in Brain and Blood". Prion. 5: 138–139. April 2011 – via Ovid. 29. ^ Saunders, Samuel E.; Shannon L. Bartelt-Hunt; Jason C. Bartz (2008). "Prions in the environment". Prion. 2 (4): 162–169. doi:10.4161/pri.2.4.7951. PMC 2658766. PMID 19242120. 30. ^ a b Seidel, Bjoern; Thomzig A; Buschmann A; Groschup M; Peters R; Beekes M; Terytze K (9 May 2007). "Scrapie Agent (Strain 263K) Can Transmit Disease via the Oral Route after Persistence in Soil Over Years". PLOS One. 2 (5): e435. Bibcode:2007PLoSO...2..435S. doi:10.1371/journal.pone.0000435. PMC 1855989. PMID 17502917. 31. ^ a b O'Rourke, Catherine. "PP-USDA ARS". Missing or empty `\|url=` (help) 32. ^ Terry, Linda; et al. (18 May 2011). "Detection of Prions in the faeces of sheep naturally infected with classical scrapie". Veterinary Research. 42 (65): 65. doi:10.1186/1297-9716-42-65. PMC 3112104. PMID 21592355. 33. ^ Kim, Kiheung (2006-11-22). The Social Construction of Disease: From Scrapie to Prion. Routledge. ISBN 9781134237135. 34. ^ DETWILER, L.A. "Scrapie (USDA publication)" (PDF). 35. ^ "Scrapie: Scrapie transmission via vaccine - Shorts at The Medical Dictionary". the-medical-dictionary.com. Retrieved 2018-04-13. 36. ^ Caramelli, M.; Ru, G.; Casalone, C.; Bozzetta, E.; Acutis, P. L.; Calella, A.; Forloni, G. (2001-04-28). "Evidence for the transmission of scrapie to sheep and goats from a vaccine against Mycoplasma agalactiae". The Veterinary Record. 148 (17): 531–536. doi:10.1136/vr.148.17.531. PMID 11354646. S2CID 41220613. 37. ^ Zanusso, Gianluigi; Casalone, Cristina; Acutis, Pierluigi; Bozzetta, Elena; Farinazzo, Alessia; Gelati, Matteo; Fiorini, Michele; Forloni, Gianluigi; Sy, Man Sun (April 2003). "Molecular analysis of iatrogenic scrapie in Italy". The Journal of General Virology. 84 (Pt 4): 1047–1052. doi:10.1099/vir.0.18774-0. ISSN 0022-1317. PMID 12655108. S2CID 25077051. 38. ^ Agrimi, U.; Ru, G.; Cardone, F.; Pocchiari, M.; Caramelli, M. (1999-02-13). "Epidemic of transmissible spongiform encephalopathy in sheep and goats in Italy". Lancet. 353 (9152): 560–561. doi:10.1016/S0140-6736(98)04545-0. ISSN 0140-6736. PMID 10028993. S2CID 8624669. 39. ^ McGrath, D; et al. (1982). "Soil Ingestion by Grazing Sheep". Irish Journal of Agriculture. 40. ^ "Livestock Slaughter 2010 Summary". United States Department of Agriculture, National Agricultural Statistics Service. April 2011. Retrieved June 19, 2020. 41. ^ Georgsson, Gudmundu; et al. (2006). "Infectious agent of sheep scrapie may persist in the environment for at least 16 years". Journal of General Virology. 87 (12): 3737–3740. doi:10.1099/vir.0.82011-0. PMID 17098992. 42. ^ Pederson, Joel; et al. (July 2007). "Oral transmissibility of prion disease is enhanced by binding to soil particles". PLOS Pathog. 3 (7): e93. doi:10.1371/journal.ppat.0030093. PMC 1904474. PMID 17616973. 43. ^ Carp, Richard I.; Meekerl, Harry C.; Rubenstein, Richard; Sigurdarson, Sigurdur; Papini, Michael; Kascsak, Richard J.; Kozlowski, Piotr B.; Wisniewski, Henryk M. (January 2000). "Characteristics of scrapie isolates derived from hay mites". Journal of Neurovirology. 6 (2): 137–144. doi:10.3109/13550280009013157. PMID 10822327. S2CID 16441609. 44. ^ Johnson, CJ; et al. (2011). "Degradation of the disease-associated prion protein by a serine protease from lichens". PLOS ONE. 6 (5): e19836. Bibcode:2011PLoSO...619836J. doi:10.1371/journal.pone.0019836. PMC 3092769. PMID 21589935. 45. ^ Laplanche, J.L.; Chatelain, J.; Westaway, D.; Thomas, S.; Dussaucy, M.; Brugere-Picoux, J.; Launay, J.M. (January 1993). "PrP Polymorphisms Associated with Natural Scrapie Discovered by Denaturing Gradient Gel Electrophoresis". Genomics. 15 (1): 30–37. doi:10.1006/geno.1993.1006. ISSN 0888-7543. PMID 8094373. 46. ^ Goldmann, W.; Hunter, N.; Foster, J. D.; Salbaum, J. M.; Beyreuther, K.; Hope, J. (1990-04-01). "Two alleles of a neural protein gene linked to scrapie in sheep". Proceedings of the National Academy of Sciences. 87 (7): 2476–2480. Bibcode:1990PNAS...87.2476G. doi:10.1073/pnas.87.7.2476. ISSN 0027-8424. PMC 53712. PMID 1969635. 47. ^ Goldmann, Wilfred; Hunter, Nora; Benson, Grace; Foster, James D.; Hope, James (1991). "Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene". Journal of General Virology. 72 (10): 2411–2417. doi:10.1099/0022-1317-72-10-2411. PMID 1681027. 48. ^ "Scrapie Eradication Uniform Methods and Rules" (PDF). 49. ^ Clouscard, C.; Beaudry, P.; Elsen, J. M.; Milan, D.; Dussaucy, M.; Bounneau, C.; Schelcher, F.; Chatelain, J.; Launay, J. M. (1995). "Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie". Journal of General Virology. 76 (8): 2097–2101. doi:10.1099/0022-1317-76-8-2097. PMID 7636494. 50. ^ Westaway, D.; Zuliani, V.; Cooper, C. M.; Costa, M. Da; Neuman, S.; Jenny, A. L.; Detwiler, L.; Prusiner, S. B. (1994-04-15). "Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie". Genes & Development. 8 (8): 959–969. doi:10.1101/gad.8.8.959. ISSN 0890-9369. PMID 7926780. ## External links[edit] Wikimedia Commons has media related to Scrapie. * Article about scrapie and the aforementioned diagnostic test * UK government scrapie information * UK government National Scrapie Plan * Scrapie research at the Institute for Animal Health (UK) * Sheep genetics research at the Institute for Animal Health (includes photo of a sheep with scrapie) * Scrapie in the United States * US Department of Agriculture video of infected sheep demonstrating Hopping Gait * Striking a Nerve: Prions Not the Last Word in TSEs – opinion article by Frank Bastian that proposes a different causation for scrapie and other prion diseases * v * t * e Prion diseases and transmissible spongiform encephalopathy Prion diseases in humans inherited/PRNP: * fCJD * Gerstmann–Sträussler–Scheinker syndrome * Fatal familial insomnia sporadic: * sCJD * Sporadic fatal insomnia * Variably protease-sensitive prionopathy acquired/ transmissible: * iCJD * vCJD * Kuru Prion diseases in other animals * Bovine spongiform encephalopathy * Camel spongiform encephalopathy * Scrapie * Chronic wasting disease * Transmissible mink encephalopathy * Feline spongiform encephalopathy * Exotic ungulate encephalopathy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Scrapie	c0036457	5,271	wikipedia	https://en.wikipedia.org/wiki/Scrapie	2021-01-18T18:37:13	{"mesh": ["D012608"], "umls": ["C0036457"], "wikidata": ["Q170102"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Cyclic vomiting syndrome" – news · newspapers · books · scholar · JSTOR (February 2018) (Learn how and when to remove this template message) This article's tone or style may not reflect the encyclopedic tone used on Wikipedia. See Wikipedia's guide to writing better articles for suggestions. (February 2018) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Cyclic vomiting syndrome Other namesCyclical vomiting syndrome SpecialtyPediatrics Cyclic vomiting syndrome (CVS) is a chronic functional condition of unknown pathogenesis. CVS is characterized as recurring episodes lasting a single day to multiple weeks. Each episode is divided into four phases: inter-episodic, prodrome, vomiting, and recovery. Inter-episodic phase (symptom free phase), is characterized as no discernible symptoms, normal everyday activities can occur, and this phase typically lasts one week to one month. The prodrome phase is known as the pre-emetic phase, characterized by the initial feeling of an approaching episode, still able to keep down oral medication. Emetic or vomiting phase is characterized as intense persistent nausea, and repeated vomiting typically lasting hours to days. Recovery phase is typically the phase where vomiting ceases, nausea diminishes or is absent, and appetite returns. This syndrome is most commonly seen in children usually between ages 3 and 7, however adult diagnosis is quite common.[1] This disorder is thought to be closely related to migraines and family history of migraines.[2][3] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Diagnostic criteria * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 History * 8 See also * 9 References * 10 Further reading * 11 External links ## Signs and symptoms[edit] Adults Children Mean age of diagnosis 29–34 years old 3–7 years old Mean duration of episodes 3–6 days few hours to 4 days Mean Inter-episodic duration 1–3 months 1 week to 1 month Presence of Prodrome phase common common Recovery time lasting several days lasting hours to days Vomiting universal up to 6 times an hour universal up to 6 times an hour Abdominal pain common (57-70)% common (68-80)% UGI Complications common (38%) common (22-32)% Headaches common common Fever not common not common Dehydration needing IV fluids common common with longer attacks Family history with migraines common (30-70)% common (40-89)% Psychiatric disorders common common Inter-episodic nausea/pain common rare Mitochondrial DNA disorders not reported reported Cannabis use reported not reported Unpleasant triggers common (67%) common harder to pinpoint Sufferers may vomit or retch 6–12 times in an hour and an episode may last from a few hours to over three weeks and in some cases months, with a median episode duration of 41 hours.[4] Acid, bile and, if the vomiting is severe, blood may be vomited. Some sufferers will ingest water to reduce the irritation of bile and acid on the esophagus during emesis. Between episodes, the sufferer is usually normal and healthy otherwise but can be in a weak state of fatigue or experience muscle pain. In approximately half of cases the attacks, or episodes, occur in a time-related manner. Each attack is stereotypical; that is, in any given individual, the timing, frequency and severity of attacks is similar. Some sufferers experience episodes that progressively get worse when left untreated, occurring more frequently with reduced symptom free phase.[5] Episodes may happen every few days, every few weeks or every few months, for some happening at common uniform times typically mornings.[5] For other sufferers, there is not a pattern in time that can be recognized. Some sufferers have a warning of an episodic attack; they may experience a prodrome, some documented prodromal symptoms include: unusually intense nausea and pallor, excess salivation, sweating, flushing, rapid/irregular heartbeat, diarrhea, anxiety/panic, food aversion, restlessness/insomnia, irritability, depersonalization, fatigue/listlessness, intense feelings of being hot or chilled, intense thirst, shivering/shaking, retching, tachypnea, abdominal pain/cramping, limb paresthesias, hyperesthesia, photophobia, phonophobia, headache, and dyspnea, heightened sensitivity, especially to light, though sensitivity to smell, sound, pressure, and temperature, as well as oncoming muscle pain and fatigue, are also reported by some patients. Some prodromal symptoms are present inter-episodically as well as during acute phases of illness. The majority of sufferers can identify triggers that may precede an attack. The most common are various foods, infections (e.g., colds), menstruation, extreme physical exertion, lack of sleep, and psychological stresses, both positive and negative.[citation needed] A sufferer may also be light-sensitive (photophobic), sound-sensitive (phonophobic) or, less frequently, temperature- or pressure-sensitive during an attack.[6] Some sufferers also have a strong urge to bathe in warm or cold water. Some sufferers experience insomnia, diarrhea (GI complications), hot and cold flashes, and excessive sweating before an episode. Some sufferers report that they experience a restless sensation or stinging pain along the spine, hands, and feet followed by weakness in both legs. Some of these symptoms may be due to dehydration or hypokalemia from excessive vomiting, rather than the underlying cause of CVS. ## Genetics[edit] There is no known genetic pathogenesis for CVS. Recent studies suggest many affected individuals have a family history of related conditions, such as migraines, psychiatric disorders and gastrointestinal disorders. Inheritance is thought to be maternal, a possible genetic mitochondrial inheritance. Adolescents show higher possible mitochondrial inheritance and maternal inheritance than found in adults. Single base-pair and DNA rearrangements in the mitochondrial DNA (mtDNA) have been associated with these traits.[7][8] ## Diagnosis[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Cyclic vomiting syndrome" – news · newspapers · books · scholar · JSTOR (February 2018) (Learn how and when to remove this template message) The cause of CVS has not been determined and there are no diagnostic tests for CVS. Several other medical conditions, such as cannabinoid hyperemesis syndrome (CHS), can mimic the same symptoms, and it is important to rule these out. If all other possible causes have been excluded, a diagnosis of CVS using Rome criteria by a physician may be appropriate.[5] Once formal investigations to rule out gastrointestinal or other causes have been conducted, these tests do not need to be repeated in the event of future episodes.[6] ### Diagnostic criteria[edit] Although there are differences[example needed] between early-onset CVS (babies and children) and late-onset CVS (in adults),[5] there are established criteria to aid in diagnosis of CVS, namely: 1. A history of three or more periods of intense, acute nausea and unremitting vomiting, as well as pain in some cases, lasting hours to days and even weeks or months[9] 2. Intervening symptom-free or reduced-symptom intervals, lasting weeks to months 3. There are repeated cycles of periods (of varying duration) with intense/acute nausea, with or without vomiting, with or without severe pain, followed by periods of reduced symptoms, followed by gradual increase in CVS symptoms until it peaks (peak intensity is generally relative to cycle intensity). 4. Exclusion of metabolic, gastrointestinal, genitourinary or central nervous system structural or biochemical disease, e.g., individuals with specific physical causes (such as intestinal malrotation) ## Treatment[edit] Treatment for cyclic vomiting syndrome depends on the evident phase of the disorder.[citation needed] Because the symptoms of CVS are similar (or perhaps identical) to those of the disease well-identified as "abdominal migraine," prophylactic migraine medications, such as topiramate and amitriptyline, have seen recent success in treatment for the prodrome, and vomiting, phases, reducing the duration, severity, and frequency of episodes.[10] Therapeutic treatment for the prodromal phase, characterized by the anticipation of an episode, consists of sumatriptan (nasal or oral) an anti-migraine medication, anti-inflammatory drugs to reduce abdominal pain, and possible anti-emetic drugs. These options may be helpful in preventing an episode or reducing the severity of an attack.[citation needed] The most common therapeutic strategies for those already in the vomiting phase are maintenance of salt balance by appropriate intravenous fluids and, in some cases, sedation. Having vomited for a long period prior to attending a hospital, patients are typically severely dehydrated. For a number of patients, potent anti-emetic drugs such as ondansetron (Zofran) or granisetron (Kytril), and dronabinol (Marinol) may be helpful in either preventing an attack, aborting an attack, or reducing the severity of an attack. Many patients seek comfort during episodes by taking prolonged showers and baths typically quite hot. The use of a heating pad may also help reduce abdominal pain.[2] Lifestyle changes may be recommended, such as extended rest, reduction of stress, frequent small meals, abstain from fasting, and possibly cessation of cannabis use. A diet change may be recommended avoid food allergens, eliminating trigger foods such as chocolates, cheese, beer, and red wine.[11][3] Some patients experience relief from inhaled isopropyl alcohol.[12] ## Prognosis[edit] Fitzpatrick et al. (2007) identified 41 children with CVS. The mean age of the sample was 6 years at the onset of the syndrome, 8 years at first diagnosis, and 13 years at follow-up. As many as 39% of the children had resolution of symptoms immediately or within weeks of the diagnosis. Vomiting had resolved at the time of follow-up in 61% of the sample. Many children, including those in the remitted group, continued to have somatic symptoms such as headaches (in 42%) and abdominal pain (in 37%).[13] Most children who have this disorder miss on average 24 school days a year.[11] The frequency of episodes is higher for some people during times of excitement.[11] Charitable organizations to support sufferers and their families and to promote knowledge of CVS exist in several countries. Complications can include dehydration, dental caries, or an esophageal tear.[14] ## Epidemiology[edit] The average age at onset is 3–7 years, with described cases as young as 6 days and as old as 73 years.[15] Typical delay in diagnosis from onset of symptoms is 3 years.[15] Females show a slight predominance over males.[15] One study found that 3 in 100,000 five-year-olds are diagnosed with the condition.[16] Two studies on childhood CVS suggest nearly 2% of school-age children may have CVS.[17][18] ## History[edit] Cyclic vomiting syndrome was first described in France by Swiss physician Henri Clermond Lombard[19] and first described in the English language by pediatrician Samuel Gee in 1882.[20] It has been suggested that Charles Darwin's adult illnesses may have been due to this syndrome.[21][further explanation needed] ## See also[edit] * Migraine ## References[edit] 1. ^ Lee LY, Abbott L, Mahlangu B, Moodie SJ, Anderson S (September 2012). "The management of cyclic vomiting syndrome: a systematic review". European Journal of Gastroenterology & Hepatology. 24 (9): 1001–6. doi:10.1097/MEG.0b013e328355638f. PMID 22634989. S2CID 19343777. 2. ^ a b Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ (December 2005). "Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management". BMC Medicine. 3 (1): 20. doi:10.1186/1741-7015-3-20. PMC 1326207. PMID 16368014. 3. ^ a b Abell TL, Adams KA, Boles RG, Bousvaros A, Chong SK, Fleisher DR, et al. (April 2008). "Cyclic vomiting syndrome in adults". Neurogastroenterology and Motility. 20 (4): 269–84. doi:10.1111/j.1365-2982.2008.01113.x. hdl:2027.42/72300. PMID 18371009. 4. ^ Li BU, Fleisher DR (August 1999). "Cyclic vomiting syndrome: features to be explained by a pathophysiologic model". Digestive Diseases and Sciences. 44 (8 Suppl): 13S–18S. doi:10.1023/A:1026662402734. PMID 10490033. S2CID 295292. 5. ^ a b c d Bhandari S, Jha P, Thakur A, Kar A, Gerdes H, Venkatesan T (April 2018). "Cyclic vomiting syndrome: epidemiology, diagnosis, and treatment". Clinical Autonomic Research. 28 (2): 203–209. doi:10.1007/s10286-018-0506-2. PMID 29442203. S2CID 3324893. 6. ^ a b Lindley KJ, Andrews PL (September 2005). "Pathogenesis and treatment of cyclical vomiting". Journal of Pediatric Gastroenterology and Nutrition. 41 Suppl 1 (Suppl 1): S38-40. doi:10.1097/01.scs.0000180299.04731.cb. PMID 16131963. S2CID 25060114. 7. ^ "What is cyclic vomiting syndrome?". 8. ^ Venkatesan T, Zaki EA, Kumar N, Sengupta J, Ali M, Malik B, et al. (October 2014). "Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome". BMC Gastroenterology. 14 (1): 181. doi:10.1186/1471-230X-14-181. PMC 4287476. PMID 25332060. 9. ^ Sagar RC, Sood R, Gracie DJ, Gold MJ, To N, Law GR, Ford AC (January 2018). "Cyclic vomiting syndrome is a prevalent and under-recognized condition in the gastroenterology outpatient clinic" (PDF). Neurogastroenterology and Motility. 30 (1): e13174. doi:10.1111/nmo.13174. PMID 28745840. S2CID 11299617. 10. ^ Paul SP, Barnard P, Soondrum K, Candy DC (May 2012). "Antimigraine (low-amine) diet may be helpful in children with cyclic vomiting syndrome". Journal of Pediatric Gastroenterology and Nutrition. 54 (5): 698–9. doi:10.1097/MPG.0b013e31824ca0a2. PMID 22302150. 11. ^ a b c Li BU, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, et al. (September 2008). "North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome". Journal of Pediatric Gastroenterology and Nutrition. 47 (3): 379–93. doi:10.1097/MPG.0b013e318173ed39. PMID 18728540. S2CID 3910188. 12. ^ "Inhaled Isopropyl Alcohol Superior to Oral Ondansetron as an Antiemetic". New England Journal of Medicine Journal Watch jwatch.org. 2018-03-09. 13. ^ Fitzpatrick E, Bourke B, Drumm B, Rowland M (April 2008). "The incidence of cyclic vomiting syndrome in children: population-based study". The American Journal of Gastroenterology. 103 (4): 991–5, quiz 996. PMID 18070235. 14. ^ "Cyclical vomiting syndrome". NHS Gov.UK. 2017-10-18. 15. ^ a b c Li BU, Misiewicz L (September 2003). "Cyclic vomiting syndrome: a brain-gut disorder". Gastroenterology Clinics of North America. 32 (3): 997–1019. doi:10.1016/S0889-8553(03)00045-1. PMID 14562585. 16. ^ Drumm BR, Bourke B, Drummond J, McNicholas F, Quinn S, Broderick A, et al. (October 2012). "Cyclical vomiting syndrome in children: a prospective study". Neurogastroenterology and Motility. 24 (10): 922–7. doi:10.1111/j.1365-2982.2012.01960.x. PMID 22762244. 17. ^ Abu-Arafeh I, Russell G (November 1995). "Cyclical vomiting syndrome in children: a population-based study". Journal of Pediatric Gastroenterology and Nutrition. 21 (4): 454–8. doi:10.1097/00005176-199511000-00014. PMID 8583299. S2CID 20399340. 18. ^ Cullen KJ, Ma Cdonald WB (August 1963). "The periodic syndrome: its nature and prevalence". The Medical Journal of Australia. 50 (2): 167–73. doi:10.5694/j.1326-5377.1963.tb24739.x. PMID 14024194. 19. ^ Lombard HC (1861). "Description d'une névrose de la digestion, caractérisée par des crises périodiques de vomissements et une profonde modification de l'assimilation". Gazette Médicale de Paris: 312. 20. ^ Gee S (1882). "On fitful or recurrent vomiting". St Bartholomew Hospital Reports. 18: 1. 21. ^ Hayman JA (December 2009). "Darwin's illness revisited". BMJ. 339: b4968. doi:10.1136/bmj.b4968. PMID 20008377. S2CID 32616636. ## Further reading[edit] * Abu-Arafeh I, Russell G (November 1995). "Cyclical vomiting syndrome in children: a population-based study". Journal of Pediatric Gastroenterology and Nutrition. 21 (4): 454–8. doi:10.1097/00005176-199511000-00014. PMID 8583299. S2CID 20399340. * Fleisher DR (1995). "The cyclic vomiting syndrome described". Journal of Pediatric Gastroenterology and Nutrition. 21 Suppl 1 (Suppl 1): S1-5. doi:10.1097/00005176-199501001-00003. PMID 8708859. S2CID 9994376. * Fleisher DR (July 2008). "Empiric guidelines for the management of cyclic vomiting syndrome". Child Health Publications. University of Missouri Library System. hdl:10355/5142. * Rasquin-Weber A, Hyman PE, Cucchiara S, Fleisher DR, Hyams JS, Milla PJ, Staiano A (September 1999). "Childhood functional gastrointestinal disorders". Gut. 45 Suppl 2 (Suppl 2): II60-8. doi:10.1136/gut.45.2008.ii60. PMC 1766693. PMID 10457047. * Raucci U, Borrelli O, Di Nardo G, Tambucci R, Pavone P, Salvatore S, Baldassarre ME, Cordelli DM, Falsaperla R, Felici E, et al. (November 2020). "Cyclic vomiting syndrome in children". Frontiers in Neurology. doi:10.3389/fneur.2020.583425. PMC 7667239. PMID 33224097. * Terzaghi M, Sartori I, Rustioni V, Manni R (January 2009). "Cyclic vomiting syndrome in adults: disregarding a possible epileptic component?". Neurogastroenterology and Motility. 21 (1): 95–6. doi:10.1111/j.1365-2982.2008.01211.x. PMC 2886424. PMID 19140956. ## External links[edit] * Cyclic Vomiting Syndrome Emedicine article * CVS page at the US National Digestive Diseases Clearinghouse, NIH Publication No. 04-4548 * Cyclic Vomiting Syndrome on rarediseases.org Classification D * ICD-9-CM: 536.2 G43.A0 * OMIM: 500007 * MeSH: C536228 * DiseasesDB: 34706 External resources * eMedicine: article/933135 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Cyclic vomiting syndrome	c0152164	5,272	wikipedia	https://en.wikipedia.org/wiki/Cyclic_vomiting_syndrome	2021-01-18T19:05:40	{"gard": ["6230"], "mesh": ["C536228"], "umls": ["C0152164", "C1838992", "C1838991"], "icd-9": ["536.2"], "icd-10": ["G43.A0"], "wikidata": ["Q1857905"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (February 2019) Opioid-induced endocrinopathy (OIE) is a complication of chronic opioid treatment.[1][2][3] It is a common name for all hypothalamo-pituitary axis disorders, which can be observed mostly after long term use of opioids, both as a treatment and as a substance of abuse.[1] The effect of opioids on hormonal levels can be measured immediately after the application of the opioid.[1] The onset of deficit mostly comes after longer time of use of high doses, but sometimes coexisting factor like cancer disease,[4][5] pain disease or other medicines may accelerate the progress.[1] ## Pathophysiology[edit] Opioid-induced hypogonadism, caused by negative effect of opioids on hypothalamo-pituitary gonadal axis is most often ( 21-86% of opioid users).[6] Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic–pituitary–gonadal (HPG) and hypothalamic–pituitary–adrenal (HPA) axes as well as testosterone production within the testes.[6] Opioid-induced hypogonadism and direct negative effect of opioids to bone formatting leads to osteoporosis.[1] The opioid effect on adrenal hormone production, somatostatin and thyreoid levels is less common, but should be considered as well due to the serious impact on the patients total health.[1] Effect on hypothalamic–pituitary–adrenal axis is well described both after short acting and long acting treatment with opioids, resulting in cortisol deficit. It might lead to the problems in stress situations, immunodeficiency and Addison crisis.[1] Opioid-induced hyperprolactemia can lead to the painful growth of breast (gynecomastia), milk production (galactorhea) and hypogonadism.[1] Opioid-induced defect of hypothalamic–pituitary–somatotropic axis leads to growth hormone deficiency which in adults results in cognitive dysfunction, mainly affecting visuospatial memory and orientation.[7] ## Symptoms[edit] Testosterone deficit at men leads to erectile problems, infertility, depression, anxiety, night sweat and hot flushes. Premenopausal women due to the low estrogen levels struggle of irregular menstruation, infertility or complete menopause. Postmenopausal women might have lower levels of dehydroxyepiandosterone, LH and FSH as well leading to fatigue and depressions.[1] Fatigue, higher incidence of infection diseases, problems with wound healing and total exhaustion during infects or Addison crisis are symptoms of cortisol deficit.[1] Pathological fractures in early age at opioid users must indicate bone density evaluation and osteoporosis suspition.[1] Desorientation in the previously well known surrounding can be the symptom of GH deficit.[7] ## Treatment[edit] If cessation or decreasing of doses of opioids is possible, endocrinopathy can be reversed. If the treatment with opioid cannot be disrupted due to the serious reasons, for example in substitution program or due to the severe pain or cancer, the hormonal substitution should be considered.[1] It seems like opioids with partial antagonistic action, like buprenorphine, effect hormonal levels less.[1] ## References[edit] 1. ^ a b c d e f g h i j k l m Fountas, Athanasios; Chai, Shu Teng; Kourkouti, Chrysoula; Karavitaki, Niki (October 2018). "MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids". European Journal of Endocrinology. 179 (4): R183–R196. doi:10.1530/EJE-18-0270. ISSN 0804-4643. PMID 30299887. 2. ^ Colameco, Stephen; Coren, Joshua S. (January 2009). "Opioid-induced endocrinopathy". The Journal of the American Osteopathic Association. 109 (1): 20–25. ISSN 1945-1997. PMID 19193821. 3. ^ Rhodin, Annica; Stridsberg, Mats; Gordh, Torsten (June 2010). "Opioid Endocrinopathy: A Clinical Problem in Patients With Chronic Pain and Long-term Oral Opioid Treatment". The Clinical Journal of Pain. 26 (5): 374–380. doi:10.1097/AJP.0b013e3181d1059d. ISSN 0749-8047. PMID 20473043. 4. ^ Buss, Tomasz; Leppert, Wojciech (February 2014). "Opioid-Induced Endocrinopathy in Cancer Patients: An Underestimated Clinical Problem". Advances in Therapy. 31 (2): 153–167. doi:10.1007/s12325-014-0096-x. ISSN 0741-238X. PMID 24497073. 5. ^ Merdin, Alparslan; Merdin, Fatma Avci; Gündüz, Şeyda; Bozcuk, Hakan; Coşkun, Hasan Şenol (May 2016). "Opioid endocrinopathy: A clinical problem in patients with cancer pain". Experimental and Therapeutic Medicine. 11 (5): 1819–1822. doi:10.3892/etm.2016.3156. ISSN 1792-0981. PMC 4840782. PMID 27168810. 6. ^ a b Coluzzi, F.; Billeci, D.; Maggi, M.; Corona, G. (December 2018). "Testosterone deficiency in non-cancer opioid-treated patients". Journal of Endocrinological Investigation. 41 (12): 1377–1388. doi:10.1007/s40618-018-0964-3. ISSN 1720-8386. PMC 6244554. PMID 30343356. 7. ^ a b Rhodin, A.; von EHREN, M.; Skottheim, B.; Grönbladh, A.; Ortiz-Nieto, F.; Raininko, R.; Gordh, T.; Nyberg, F. (July 2014). "Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids: GH improves cognition in pain patient". Acta Anaesthesiologica Scandinavica. 58 (6): 759–765. doi:10.1111/aas.12309. PMC 4265204. PMID 24712862. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Opioid-induced endocrinopathy	None	5,273	wikipedia	https://en.wikipedia.org/wiki/Opioid-induced_endocrinopathy	2021-01-18T18:56:21	{"wikidata": ["Q61861225"]}
Dislocation of hip (coxofemoral luxation) may occur in domestic animals. It is a not rare condition, usually unilateral, in: * cattle, among others, after calving. * dogs, resulting from trauma or as a complication of hip dysplasia. The same illness also exists in human medicine. The condition can be observed after the forced traction of fetus while delivery, slip of animal on a floor. More commonly seen in animals with poor nutrient ration at end stage of gestation which results in osteoporosis of bones & joints due go which acetabulum notch become shallow and femur comes out if it while delivery, ketonemia also has adverse effect on coxo-femoral luxation ## Contents * 1 Symptoms * 2 Treatment * 3 Literature * 4 See also ## Symptoms[edit] In dogs, it occurs mainly in an upwards and forwards direction. Hence, the affected leg is shortened, and the greater trochanter prominent. In cattle, it occurs mainly craniodorsally or caudoventrally, but other directions are possible. A typical stance is seen in craniodorsal luxations, with a shortened limb, and a protrusion of greater trochanter. ## Treatment[edit] Attempts in reduction in cattle are generally not successful. Affected animals, at least not too heavy ones, can live with the disease for a long time because of the formation of a sort of pseudo-joint in the hip. Dogs with hip dysplasia and unilateral dislocation can live if the other leg is not too severely hit. Then there is a severe muscular atrophy of the thigh. Compensation occurs with musculation of the shoulders. ## Literature[edit] This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (April 2014) (Learn how and when to remove this template message) * Hip dislocation in cattle * P. Greenough, F. Weaver & A. Weaver; Lameness in cattle, Wright Scientica, Bristol, 1981, ISBN 0-7216-5205-0, p. 269–273. * G. Rosenberger, Krankheiten des Rindes, Verlag Parey, Berlin, 1978, ISBN 3-489-61716-9, s. 463–466. * Hip dislocation in dogs * H.J. Christoph; Diseases of dogs, Pergamon Press, New York, 1975, ISBN 0-08-015800-5, p. 406–410. ## See also[edit] * Hip dysplasia (canine) This veterinary medicine–related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Dislocation of hip in animals	None	5,274	wikipedia	https://en.wikipedia.org/wiki/Dislocation_of_hip_in_animals	2021-01-18T18:54:33	{"wikidata": ["Q5282338"]}
Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay, intellectual disability, progressive liver damage, skin lesions, and brittle hair. The condition is caused by mutations in the ASL gene and is inherited in an autosomal recessive pattern. Long-term management includes dietary restriction of protein and supplementation with arginine. Acute crises may be treated by discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen scavenging therapy. If ammonia levels do not normalize, hemodialysis may be necessary. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Argininosuccinic aciduria	c0268547	5,275	gard	https://rarediseases.info.nih.gov/diseases/5843/argininosuccinic-aciduria	2021-01-18T18:02:03	{"mesh": ["D056807"], "omim": ["207900"], "umls": ["C0268547"], "orphanet": ["23"], "synonyms": ["Arginino succinase deficiency", "Inborn error of urea synthesis, arginino succinic type", "Urea cycle disorder, arginino succinase type", "Argininosuccinate lyase deficiency", "ASL deficiency", "ASA deficiency", "Argininosuccinicaciduria", "Argininosuccinate acidemia", "Argininosuccinic acid lyase deficiency"]}
Osteogenesis imperfecta (OI) comprises a heterogeneous group of genetic disorders characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity. ## Epidemiology Prevalence is estimated at between 1/10,000 and 1/20,000. ## Clinical description Age at diagnosis depends on the severity of the disease. Five clinically distinct types of OI have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Osteogenesis imperfecta type II is lethal, type III is severe, types IV and V are moderate, and type I is mild (see these terms). Type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Patients with type IV have moderately short stature, mild to moderate scoliosis, grayish or white sclera, and DI. Type V is characterized by mild to moderate short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplastic callus, white sclera, and no DI. Other genetically different types have been observed (types VI to IX) but they are not clinically different from types II-IV. ## Etiology In 95% of cases, OI is caused by mutations in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1collagen. These mutations can cause all five clinical types of OI. Transmission is autosomal dominant. Autosomal recessive forms of OI are also observed and are caused by mutations in the LEPRE1, CRTAP, and PPIB genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms are always severe forms with severe hypotonia. ## Diagnostic methods Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of wormian-like bones. Bone densitometry confirms the low bone mass. ## Differential diagnosis Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia (see these terms), non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia. The presence of several fractures should not lead to the assumption of child abuse. ## Antenatal diagnosis Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified. ## Management and treatment Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (centro-medullary osteosynthesis). Early physiotherapy improves autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity. ## Prognosis Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Osteogenesis imperfecta	c0023931	5,276	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=666	2021-01-23T18:39:14	{"gard": ["1017"], "mesh": ["D010013"], "omim": ["166200", "166210", "166220", "166230", "259420", "259440", "610682", "610915", "610967", "610968", "613848", "613849", "613982", "614856", "615066", "615220", "616229", "616507"], "umls": ["C0023931", "C0029434", "C0268360", "C1859069"], "icd-10": ["Q78.0"], "synonyms": ["Brittle bone disease", "Glass bone disease", "Lobstein disease", "OI", "Osteopsathyrosis", "Porak and Durante disease"]}
Infectious disease in humans This article needs to be updated. Please update this article to reflect recent events or newly available information. (July 2014) Psittacosis Direct fluorescent antibody stain of a mouse brain impression smear showing C. psittaci SpecialtyInfectious medicine Pulmonology Psittacosis—also known as parrot fever, and ornithosis—is a zoonotic infectious disease in humans caused by a bacterium called Chlamydia psittaci and contracted from infected parrots, such as macaws, cockatiels, and budgerigars, and from pigeons, sparrows, ducks, hens, gulls and many other species of birds. The incidence of infection in canaries and finches is believed to be lower than in psittacine birds. In certain contexts, the word is used when the disease is carried by any species of birds belonging to the family Psittacidae, whereas ornithosis is used when other birds carry the disease.[1] ## Contents * 1 In humans * 1.1 Signs and symptoms * 1.2 Transmission route * 1.3 Diagnosis * 1.4 Treatment * 1.5 Epidemiology * 2 In birds * 2.1 Signs * 2.2 Diagnosis * 2.3 Epidemiology * 2.4 Treatment * 3 Use as a biological weapon * 4 Notable casualties * 5 References * 6 External links ## In humans[edit] ### Signs and symptoms[edit] In humans, after an incubation period of 5–19 days, the symptoms of the disease range from inapparent illness to systemic illness with severe pneumonia. It presents chiefly as an atypical pneumonia. In the first week of psittacosis, the symptoms mimic typhoid fever, prostrating high fevers, joint pains, diarrhea, conjunctivitis, nose bleeds, and low level of white blood cells.[2] Rose spots called Horder's spots can appear.[3] Spleen enlargement is common towards the end of the first week. It may become a serious lung infection. Diagnosis can be suspected in case of respiratory infection associated with splenomegaly and/or epistaxis. Headache can be so severe that it suggests meningitis and some nuchal rigidity is not unusual. Towards the end of the first week, stupor or even coma can result in severe cases. The second week is more akin to acute bacteremic pneumococcal pneumonia with continuous high fevers, headaches, cough, and dyspnea. X-rays show patchy infiltrates or a diffuse whiteout of lung fields. Complications in the form of endocarditis, liver inflammation, inflammation of the heart's muscle, joint inflammation, keratoconjunctivitis (occasionally extranodal marginal zone lymphoma of the lacrimal gland/orbit)[citation needed], and neurologic complications (brain inflammation) may occasionally occur. Severe pneumonia requiring intensive-care support may also occur. Fatal cases have been reported (less than 1% of cases). ### Transmission route[edit] The Chlamydia psittaci bacterium that causes psittacosis can be transmitted by mouth-to-beak contact, or through the airborne inhalation of feather dust, dried faeces, or the respiratory secretions of infected birds.[4] Person-to-person transmission is possible, but rare.[4] ### Diagnosis[edit] Blood analysis usually shows a normal white cell count, but marked leukocytosis is occasionally apparent. Liver enzymes are abnormal in half of the patients, with mild elevation of AST. The erythrocyte sedimentation rate and C-reactive protein can be markedly elevated. Differential diagnosis must be made with typhus, typhoid, and atypical pneumonia by Mycoplasma, Legionella, or Q fever. Exposure history is paramount to diagnosis. Diagnosis involves microbiological cultures from respiratory secretions of patients or serologically with a fourfold or greater increase in antibody titers against C. psittaci in blood samples combined with the probable course of the disease. Typical inclusions called "Leventhal-Cole-Lillie bodies"[5] can be seen within macrophages in BAL (bronchoalveolar lavage) fluid. Culture of C. psittaci is hazardous and should only be carried out in biosafety laboratories. ### Treatment[edit] The infection is treated with antibiotics; tetracyclines and chloramphenicol are the choice for treating patients.[6] Most people respond to oral therapy doxycycline, tetracycline hydrochloride, or chloramphenicol palmitate. For initial treatment of severely ill patients, doxycycline hyclate may be administered intravenously. Remission of symptoms is usually evident within 48–72 hours. However, relapse can occur, and treatment must continue for at least 10–14 days after fever subsides. ### Epidemiology[edit] Psittacosis was first reported in Europe in 1879.[7] In 1929, a highly publicized outbreak of psittacosis hit the United States. Although not the first report of psittacosis in the United States, it was the largest up to that time. It led to greater controls on the import of pet parrots.[7] The aftermath of the outbreak and how it was handled led to the establishment of the National Institutes of Health.[8] From 2002 through 2009, 66 human cases of psittacosis were reported to the Centers for Disease Control and Prevention,[citation needed] and most resulted from exposure to infected pet birds, usually cockatiels, parakeets, and macaws. Many more cases may occur that are not correctly diagnosed or reported. Bird owners, pet shop employees, zookeepers, and veterinarians are at risk of the infection. Some outbreaks of psittacosis in poultry-processing plants have been reported. ## In birds[edit] An immature little blue heron with psittacosis In birds, Chlamydia psittaci infection is referred to as avian chlamydiosis. Infected birds shed the bacteria through feces and nasal discharges, which can remain infectious for several months. Many strains remain quiescent in birds until activated under stress. Birds are excellent, highly mobile vectors for the distribution of chlamydial infection because they feed on, and have access to, the detritus of infected animals of all sorts. ### Signs[edit] C. psittaci in birds is often systemic and infections can be inapparent, severe, acute, or chronic with intermittent shedding. Signs in birds include "inflamed eyes, difficulty in breathing, watery droppings, and green urates."[9] ### Diagnosis[edit] Initial diagnosis may be by symptoms, but is usually confirmed by an antigen and antibody test. A polymerase chain reaction-based test is also available. Although any of these tests can confirm psittacosis, false negatives are possible, so a combination of clinical and laboratory tests is recommended before giving the bird a clean bill of health.[9] It may die within three weeks. ### Epidemiology[edit] Infection is usually by the droppings of another infected bird, though it can also be transmitted by feathers and eggs,[10] and is typically either inhaled or ingested.[9] C. psittaci strains in birds infect mucosal epithelial cells and macrophages of the respiratory tract. Septicaemia eventually develops and the bacteria become localized in epithelial cells and macrophages of most organs, conjunctiva, and gastrointestinal tract. It can also be passed in the eggs. Stress commonly triggers onset of severe symptoms, resulting in rapid deterioration and death. C. psittaci strains are similar in virulence, grow readily in cell culture, have 16S-rRNA genes that differ by <0.8%, and belong to eight known serovars. All should be considered to be readily transmissible to humans. C. psittaci serovar A is endemic among psittacine birds and has caused sporadic zoonotic disease in humans, other mammals, and tortoises. Serovar B is endemic among pigeons, has been isolated from turkeys, and has also been identified as the cause of abortion in a dairy herd. Serovars C and D are occupational hazards for slaughterhouse workers and for people in contact with birds. Serovar E isolates (known as Cal-10, MP, or MN) have been obtained from a variety of avian hosts worldwide, and although they were associated with the 1920s–1930s outbreak in humans, a specific reservoir for serovar E has not been identified. The M56 and WC serovars were isolated during outbreaks in mammals. ### Treatment[edit] Treatment is usually with antibiotics, such as doxycycline or tetracycline, and can be administered through drops in the water or injections.[10] Many strains of C. psittaci are susceptible to bacteriophages. ## Use as a biological weapon[edit] Psittacosis was one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program.[11] ## Notable casualties[edit] Lena Rose Pepperdine died in 1930 of parrot fever. She was the first wife of George Pepperdine, the founder of Pepperdine University.[12] ## References[edit] * The initial content for this article was adapted from sources available at https://www.cdc.gov. 1. ^ "ornithosis" at Dorland's Medical Dictionary[dead link] 2. ^ Dugdale, David. "Psittacosis". MediLine Plus. Retrieved 9 September 2012. 3. ^ "Horder's spots". GPnotebook. 4. ^ a b Australian Guidelines for the Prevention and Control of Infection in Healthcare (PDF). National Health and Medical Research Council. May 2019. p. 274. ISBN 978-1-86496-028-0. Retrieved 23 January 2020. 5. ^ Saif, Y. M. (2003). Diseases of poultry. Ames, Iowa: Iowa State Press. p. 863. ISBN 0-8138-0423-X. 6. ^ Gregory DW, Schaffner W (1997). "Psittacosis". Semin Respir Infect. 12 (1): 7–11. PMID 9097370. 7. ^ a b Potter ME, Kaufmann AK, Plikaytis BD (February 1983). "Psittacosis in the United States, 1979". MMWR Morb. Mortal. Wkly. Rep. 32 (1): 27SS–31SS. PMID 6621602. 8. ^ "In 1929, Parrot Fever Gripped The Country". National Public Radio All Things Considered. May 31, 2009. 9. ^ a b c "Winged Wisdom Pet Bird Magazine - Zoonotic (Bird-Human) Diseases: Psittacosis, Salmonellosis". Archived from the original on 2007-11-01. Retrieved 2007-12-29. 10. ^ a b "PSITTACOSIS DISEASE - Pet Birds, Pet Parrots, Exotic Birds". Archived from the original on 2007-11-29. Retrieved 2007-12-29. 11. ^ "Chemical and Biological Weapons: Possession and Programs Past and Present", James Martin Center for Nonproliferation Studies, Middlebury College, April 9, 2002, accessed November 14, 2008. 12. ^ "Lena Rose Baker Pepperdine (1888-1930) - Find A..." www.findagrave.com. Retrieved 10 September 2018. ## External links[edit] Classification D * ICD-10: A70 * ICD-9-CM: 073 * MeSH: D009956 * DiseasesDB: 2375 External resources * MedlinePlus: 000088 * eMedicine: med/1951 * Patient UK: Psittacosis * Psittacosis on Birds n Ways * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill fever) Authority control * NDL: 00568816 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Psittacosis	c0029291	5,277	wikipedia	https://en.wikipedia.org/wiki/Psittacosis	2021-01-18T18:58:38	{"gard": ["7492"], "mesh": ["D009956"], "umls": ["C0029291"], "wikidata": ["Q164727"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Eclabium" – news · newspapers · books · scholar · JSTOR (July 2018) (Learn how and when to remove this template message) Eclabium means the turning outwards of the lip. Eclabium comes from the Greek word "ek" meaning "out," and the Latin word "labium"[1] meaning "lip." This deformation occurs in most babies born with Harlequin type ichthyosis,[2] caused by genetic defects.[3] Eclabium can severely impact the quality of life. There are ways to predict if a child will have this condition before they are born through genetic testing.[4] For patients who suffer from eclabium due to improper wound healing, there are different treatment options available to restore the lips back to normal or at least to the point where they are not a hazard to the patients quality of life. Periodontitis can also cause eclabium. As eclabium is a symptom, it is treated by addressing its cause. When the underlying disease is treated, the eclabium tends to go away as well. ## Contents * 1 Classification * 2 Causes * 2.1 Mechanisms * 3 Signs and symptoms * 4 Diagnosis * 5 Prevention * 6 Treatment * 7 Prognosis and Epidemiology * 8 Research * 9 References ## Classification[edit] It is commonly classified as a congenital malformation (birth defect)[3] however it can also result from improper healing of a wound.[5] ## Causes[edit] Harlequin ichthyosis Causes of Eclabium include but are not limited to * General Ichthyosis.[6] * Congenital ichthyosis[7] * Lamellar ichthyosis[8] * Harlequin type Ichthyosis[9] * Scarring after trauma, such as surgery * Gingivitis/periodontitis[10] Periodontitis ### Mechanisms[edit] Disease causing variants in adenosine triphosphate binding cassette transporter protein (A12 gene)[11] on chromosome 2 carries information for lipid transportation to keratinocytes[12] in the cutaneous layer.[13] The malfunction of this gene causes scaly tight skin. The tightening of the skin pulls the eyes and lips back causing Eclabium and Ectropion. This disease has a Rare autosomal recessive mode of inheritance.[14] At times the skin does not heal properly after surgery or a wound. Improper healing of a wound on or near the lips can cause eclabium. All wounds heal[15] in 3 parts: contraction, connective tissue matrix deposition and epithelialization. If any one of those parts is disrupted, it can become a cause of eclabium True homozygous versus compound heterozygous for the ABCA 12 gene. ## Signs and symptoms[edit] Diseases that cause eclabium have the following signs and symptoms * Tight scaly skin [16](Ichthyosis) * Absence of ABCA12 gene[17] (Ichthyosis) * Swollen or puffy gums (Periodontitis/Gingivitis) * Purulent drainage from lips[18] (Improper Wound healing) * Wide mouth which causes difficulty feeding and suckling * Difficulty in feeding causes lack of adequate nutrition, dehydration[19] and even death * Skin that is more prone to infection * Hindered pulmonary ventilation Hindered pulmonary ventilation[20] ## Diagnosis[edit] Eclabium is very clearly visible and a medical professional can identify it easily. In some cases it can be diagnosed beforehand. For example, when there has been a surgery[21] by the lip or gums, abnormal healing can be very likely. When the tissue does not heal properly it can result in the outward turning of the lip. Also, If a mother tests positive for a mutation in the ABCA12 gene,[22] Eclabium as a result of Ichthyosis can be present in the child. Ichthyosis is characterized by tight scaly skin along with ectropion[23] which is outward turning of eyelids. If the skin is tight enough to be pulling on the eyes then it is safe to diagnose that the tight skin is also pulling on the lips making them turn outward If a patient is diagnosed with periodontitis[24] it can cause swelling of the gums which in turn causes the outward turning of the lip. ## Prevention[edit] To prevent Eclabium, testing for the mutation for ABCA12 gene can be done on the mother to see if the unborn child has the gene. This allows the parents to make a decision accordingly because most children with ABCA12 gene mutation[22] will have Eclabium. Healing of wounds near lips or gums should be carefully monitored to prevent severe Eclabium. If the improper healing [15] is caught at the right time it can become imperative to prevent the Eclabium as soon as possible. Basic dental hygiene[25] can help prevent periodontitis. Basic dental hygiene includes brushing and flossing as well as regular dentist visits. If periodontitis is prevented, it reduces the chances of Eclabium caused by poor dental hygiene. ## Treatment[edit] Chlorhexidine for treating Periodontitis To reduce the tightness and dehydration of the skin, Lubricant ointment[2] has been used. When the skin becomes less tense, it doesn't pull at the lips as much causing a reduction in the Eclabium. Once the skin is loose enough the Eclabium subsides. Eclabium can be a life long disorder But drug treatment for the causing disease would heal the lips as well.For example for harlequin ichthyosis drugs such as Tazarotene[26] and isotretinoin [27] have been used to help the skin heal and loosen up which helps the Eclabium heal. But sometimes surgery might become necessary to correct the disorder. Lateral columella base-labrum transposition flap [28] results in soft linear scars without hyperplasia.[29] It is an easy, minimally invasive and nearly no secondary malformation method. a type of flap used is the Limberg/Rhomboid flap.[28] The flap is made up of Cutaneous tissue[13] to close defects anywhere on the body. If the Eclabium is caused by periodontitis,[24] treatment includes removal of plaque and calculus from the teeth, antimicrobial mouth rinse such as chlorhexidine,[30] antiseptic chips/gels. When the swelling in the gums reduces it will no longer push on lips making them turn outwards. ## Prognosis and Epidemiology[edit] Unfortunately, most conditions that cause Eclabium, such as ichthyosis, have a very high mortality rate with worldwide figure approaching 50 percent. However, Eclabium caused by improper wound healing is usually reversible through another corrective surgery and has little to no mortality. Scarring can occur from surgery to correct eclabium. Some patients might get further cosmetic surgery[28] to fix the scarring. Eclabium caused by Periodontitis is almost always treatable and if it has advanced severely, surgery can help to treat it. It does not cause death but it can become very painful and decrease the quality of life if left untreated. It can affect anyone who does not follow good oral hygeine. It currently affects 20-50% of the global population[31] but only a small portion of cases become severe enough to cause Eclabium. Eclabium caused by Harlequin Ichthyosis is more severe. Its prognosis is very poor.[32] Most affected babies do not survive the first week of life. Survival rates based on the severity of the case have varied from 10 months to 25 years with supportive treatment. The oldest person in the united states with Harlequin Ichthyosis is 23 year old Stephanie turner.[33] She was also the first person to have a child with this condition. She has two children and neither have the condition. There is a 25% chance of this condition reoccurring in the mothers next pregnancy. Genetic counseling[34] is highly recommended for couples who have the mutated ABCA12 gene.[17] ## Research[edit] A research study conducted in 2019 on a pregnant couple with a child that has Harlequin Ichthyosis[2] talked about characteristic sonographic features. Eclabium and Ectropion[23] can be seen in the ultrasound. The mouth is persistently open and restriction of limb movement is also seen.[35] Another Research was inducted on the use of retinoids[36] and whether or not they are the only way to treat Harlequin Ichthyosis.[2] The research titled survival without systemic retinoids mentions how the chances of survival are very low regardless of retinoid treatment. According to this study two neonates were able to survive with intensive care but no retinoids.[37] Further research on the types of Ichthyosis and receiving genetic counseling[34] for the condition is still being reviewed. The importance of neonatologist,[38] a pediatric dermatologist,[39] a geneticist [40] and other specialists is discussed in this study. Their involvement can help better the treatment plan for Harlequin Ichthyosis patients and help ease symptoms such as Eclabium.[41] ## References[edit] 1. ^ "Labium". Wikipedia. 7 August 2013. Retrieved 15 December 2020. 2. ^ a b c d "Harlequin-type ichthyosis". Wikipedia. 4 December 2020. Retrieved 15 December 2020. 3. ^ a b "Birth defect". Wikipedia. 30 November 2020. Retrieved 15 December 2020. 4. ^ Rathore, Swati; David, Liji Sarah; Beck, Manisha Madhai; Bindra, Mandeep Singh; Arunachal, Gautham (November 2015). "Harlequin Ichthyosis: Prenatal Diagnosis of a Rare Yet Severe Genetic Dermatosis". Journal of Clinical and Diagnostic Research : JCDR. pp. QD04–QD06. doi:10.7860/JCDR/2015/15250.6705. 5. ^ "Wound healing". Wikipedia. 14 December 2020. 6. ^ Salehin, Shahrbanoo; Azizimoghadam, Ahmad; Abdollahimohammad, Abdolghani; Babaeipour-Divshali, Mohammad (November 2013). "Harlequin ichthyosis: Case report". Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences. pp. 1004–1005. 7. ^ "Congenital ichthyosiform erythroderma". Wikipedia. 21 November 2020. Retrieved 16 December 2020. 8. ^ "Lamellar ichthyosis". Wikipedia. 5 December 2020. Retrieved 16 December 2020. 9. ^ "Harlequin-type ichthyosis". Wikipedia. 4 December 2020. Retrieved 16 December 2020. 10. ^ "Gingivitis". Wikipedia. 16 December 2020. Retrieved 16 December 2020. 11. ^ kelsell, David (May 2005). "Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis". AJHJ. 76 (5): 794–803. PMC 1199369. 12. ^ "Keratinocyte". Wikipedia. 3 December 2020. Retrieved 16 December 2020. 13. ^ a b "Skin". Wikipedia. 13 December 2020. Retrieved 16 December 2020. 14. ^ "Human genetics". Wikipedia. 2 December 2020. Retrieved 16 December 2020. 15. ^ a b "Wound healing". Wikipedia. 14 December 2020. Retrieved 16 December 2020. 16. ^ Craiglow, Brittany G. (1 February 2013). "Ichthyosis in the newborn". Seminars in Perinatology. 37 (1): 26–31. doi:10.1053/j.semperi.2012.11.001. PMC 3758581. 17. ^ a b "ABCA12". Wikipedia. 10 December 2020. Retrieved 16 December 2020. 18. ^ Pippi, Roberto (2017). "Post-Surgical Clinical Monitoring of Soft Tissue Wound Healing in Periodontal and Implant Surgery". International Journal of Medical Sciences. 14 (8): 721–728. doi:10.7150/ijms.19727. 19. ^ "Dehydration". Wikipedia. 16 December 2020. Retrieved 16 December 2020. 20. ^ "Breathing". Wikipedia. 11 December 2020. Retrieved 16 December 2020. 21. ^ "Lip reconstruction", Wikipedia, 2020-01-06, retrieved 2020-12-16 22. ^ a b Thomas, Anna C.; Cullup, Tom; Norgett, Elizabeth E.; Hill, Tara; Barton, Stephanie; Dale, Beverly A.; Sprecher, Eli; Sheridan, Eamonn; Taylor, Aileen E.; Wilroy, Robert S.; DeLozier, Celia. "ABCA12 is the major harlequin ichthyosis gene". The Journal of Investigative Dermatology. 126 (11): 2408–2413. doi:10.1038/sj.jid.5700455. ISSN 1523-1747. PMID 16902423. 23. ^ a b "Ectropion", Wikipedia, 2020-08-19, retrieved 2020-12-16 24. ^ a b "Periodontal disease", Wikipedia, 2020-12-13, retrieved 2020-12-16 25. ^ "Oral hygiene". Wikipedia. 16 December 2020. 26. ^ "Tazarotene", Wikipedia, 2020-12-06, retrieved 2020-12-16 27. ^ "Isotretinoin", Wikipedia, 2020-12-07, retrieved 2020-12-16 28. ^ a b c "Flap (surgery)", Wikipedia, 2020-10-18, retrieved 2020-12-16 29. ^ "Hyperplasia", Wikipedia, 2020-05-20, retrieved 2020-12-16 30. ^ Brookes, Zoë L.S.; Bescos, Raul; Belfield, Louise A.; Ali, Kamran; Roberts, Anthony. "Current uses of chlorhexidine for management of oral disease: a narrative review". Journal of Dentistry. 103: 103497. doi:10.1016/j.jdent.2020.103497. ISSN 0300-5712. PMC 7567658. PMID 33075450. 31. ^ Nazir, Muhammad Ashraf (2017). "Prevalence of periodontal disease, its association with systemic diseases and prevention". International Journal of Health Sciences. 11 (2): 72–80. ISSN 1658-3639. PMC 5426403. PMID 28539867. 32. ^ Shruthi, Belide; Nilgar, B.R.; Dalal, Anita; Limbani, Nehaben (2017-06-01). "Harlequin ichthyosis: A rare case" (PDF). Journal of Turkish Society of Obstetric and Gynecology. 14 (2): 138–140. doi:10.4274/tjod.63004. PMC 5558415. PMID 28913151. 33. ^ "Harlequin Ichthyosis – A Case Report – Irish Medical Journal". Retrieved 2020-12-16. 34. ^ a b "Genetic counseling", Wikipedia, 2020-12-01, retrieved 2020-12-16 35. ^ Brandão, Pedro; Seco, Sandra; Loureiro, Teresa; Ramalho, Carla (2019). "Prenatal sonographic diagnosis of Harlequin ichthyosis". Journal of Clinical Ultrasound. 47 (4): 228–231. doi:10.1002/jcu.22675. ISSN 1097-0096. 36. ^ "Retinoid", Wikipedia, 2020-10-22, retrieved 2020-12-16 37. ^ Sharma, Amit; Rozzelle, Arlene; Jahnke, Marla N.; Desai, Jagdish; Shwayder, Tor A.; Kisseih, Esther; Bryant, Justin R.; Agarwal, Prashant (2019). "ABCA12 homozygous mutation in harlequin ichthyosis: Survival without systemic retinoids". Pediatric Dermatology. 36 (3): 339–341. doi:10.1111/pde.13770. ISSN 1525-1470. 38. ^ "Neonatology", Wikipedia, 2020-11-26, retrieved 2020-12-16 39. ^ "Dermatology", Wikipedia, 2020-12-14, retrieved 2020-12-16 40. ^ "Geneticist", Wikipedia, 2020-12-05, retrieved 2020-12-16 41. ^ Pinkova, Blanka; Buckova, Hana; Borska, Romana; Fajkusova, Lenka (2020-12-14). "Types of congenital nonsyndromic ichthyoses". Biomedical Papers. 164 (4): 357–365. doi:10.5507/bp.2020.050. * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease Category:Lip disorders [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Eclabium	c3550430	5,278	wikipedia	https://en.wikipedia.org/wiki/Eclabium	2021-01-18T18:47:50	{"umls": ["C3550430"], "wikidata": ["Q5332940"]}
Consumption of urine This article is part of a series on Alternative medicine General information * Alternative medicine * Alternative veterinary medicine * Quackery (Health fraud) * History of alternative medicine * Rise of modern medicine * Pseudoscience * Antiscience * Skepticism * Skeptical movement * National Center for Complementary and Integrative Health * Terminology of alternative medicine * Therapeutic nihilism Fringe medicine and science * Acupressure * Acupuncture * Alkaline diet * Anthroposophic medicine * Apitherapy * Applied kinesiology * Aromatherapy * Auriculotherapy * Bates method * Black salve * Bodywork * Bonesetter * Bowen technique * Breathwork * Fake COVID-19 treatments * Cancer treatments * Charcoal cleanse * Chiropractic * Chiropractic treatment techniques * Vertebral subluxation * Christian Science * Chromotherapy * Colon cleansing * Coffee enema * Colorpuncture * Colloidal silver * Craniosacral therapy * Crystal healing * Cupping therapy * Dental amalgam controversy * Detoxification * Foot detox * Ear candling * Energy medicine * Esoteric energy * Therapeutic touch * Fabunan Antiviral Injection * Facilitated communication * Feldenkrais Method * Functional medicine * Hair analysis * Herbal medicine * Holistic dentistry * Hologram bracelet * Homeopathy * Bach flower remedies * Biological terrain assessment * Hypnotherapy * Iridology * Ionized jewelry * Jilly Juice * Lightning Process * Lymphotherapy * Medical intuitive * Mesmerism * Magnet therapy * Manual therapy * Megavitamin therapy * Mind–body interventions * MMS * Myofascial release * NAET * Naturopathy * Oil pulling * Orgone * Orthomolecular medicine * Orthopathy * Osteomyology * Osteopathy * Ozone therapy * Parapsychology * Phrenology * Psychic surgery * Psychodermatology * Radionics * Rapid prompting method * RBOP * Reiki * Reflexology * Rolfing * Scientific racism * ThetaHealing * Thought Field Therapy * Urophagia * Vaginal steaming * Vision therapy * Vitalism * Young blood transfusion * Zero balancing Conspiracy theories (list) * Big Pharma conspiracy theory * HIV/AIDS denialism * OPV AIDS hypothesis * Anti-vaccination * Vaccines and autism * MMR vaccine and autism * Water fluoridation controversy * GMO conspiracy theories * Misinformation related to the COVID-19 pandemic Classifications * Alternative medical systems * Mind–body intervention * Biologically-based therapy * Manipulative methods * Energy therapy Traditional medicine * African * Muti * Southern Africa * Ayurveda * Ayurvedic acupressure * Dosha * Maharishi Vedic Approach to Health * Balneotherapy * Brazilian * Bush medicine * Cambodian * Chinese * Blood stasis * Chinese herbology * Dit Da * Gua sha * Gill plate trade * Meridian * Moxibustion * Pressure point * Qi * San Jiao * Tui na * Zang-fu * Chumash * Curandero * Faith healing * Iranian * Jamu * Kambo * Japanese * Korean * Mien Shiang * Mongolian * Prophetic medicine * Shamanism * Shiatsu * Siddha * Sri Lankan * Thai massage * Tibetan * Unani * Vietnamese Diagnoses * Adrenal fatigue * Aerotoxic syndrome * Candida hypersensitivity * Chronic Lyme disease * Electromagnetic hypersensitivity * Heavy legs * Leaky gut syndrome * Multiple chemical sensitivity * Wilson's temperature syndrome * v * t * e Urophagia is the consumption of urine. Urine was used in several ancient cultures for various health, healing, and cosmetic purposes; urine drinking is still practiced today, though no health benefit to it has been proven. In extreme cases, people drink urine if no other potable fluid is available, although numerous credible sources (including the US Army Field Manual) advise against it. Urine is also consumed as a sexual activity. ## Contents * 1 Reasons for urophagia * 1.1 As an emergency survival technique * 1.2 Folk medicine * 1.3 Sexual practice * 2 Health warnings * 3 References * 4 External links ## Reasons for urophagia[edit] ### As an emergency survival technique[edit] Survival guides such as the US Army Field Manual,[1] the SAS Survival Handbook,[2] and others[3][better source needed] generally advise against drinking urine for survival. These guides state that drinking urine tends to worsen rather than relieve dehydration due to the salts in it, and that urine should not be consumed in a survival situation, even when no other fluid is available. While some people in dire straits have drunk urine, whether this actually helped or hindered their situation is unclear. In one incident, Aron Ralston drank urine when trapped for several days with his arm wedged under a boulder.[4] Survivalist television host Bear Grylls drank urine and encouraged others to do so on several episodes on his TV shows.[5][6][7] ### Folk medicine[edit] Further information: Urine therapy In various cultures, alternative medicine applications exist of urine from humans, or animals such as camels or cattle, for medicinal or cosmetic purposes, including drinking of one's own urine, but no evidence supports their use.[8][9] ### Sexual practice[edit] Further information: Urolagnia Some people are sexually aroused by urine, which can include the drinking of their own or other people's urine. ## Health warnings[edit] The World Health Organization cautions that the drinking of urine carries health risks.[10][8][failed verification] ## References[edit] 1. ^ "Water Procurement" (PDF). US Army Field Manual. 2. ^ Wiseman, John "Lofty". The SAS Survival Handbook. p. 42. "Warning: Urine and sea-water. Never drink either – Never!" 3. ^ "Equipped to Survive – A Survival Primer". Retrieved May 26, 2016. 4. ^ Mark Jenkins. "Aron Ralston – Between a Rock and the Hardest Place". Outside Online. Retrieved 26 May 2016. 5. ^ Singh, Anita (May 31, 2014). "Bear Grylls: Kids, please don't drink your own urine". The Telegraph. 6. ^ Loughrey, Clarisse (December 18, 2015). "Obama refused to drink his own urine..." The Independent. 7. ^ Thistlethwaite, Felicity (February 26, 2015). "Stars vomit profusely after drinking their own urine...,". Daily Express. 8. ^ a b Why You Definitely Shouldn't Drink Your Own Pee, Gizmodo, 22 Oct 2014 9. ^ Maxine Frith (21 February 2006). "Urine: The body's own health drink?". The Independent. Retrieved 2016-09-26. 10. ^ http://skepdic.com/urine.html Urine Therapy: Skeptic's Dictionary entry ## External links[edit] * [1] Urine Therapy explained by Boulder resident Brother Sage [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Urophagia	None	5,279	wikipedia	https://en.wikipedia.org/wiki/Urophagia	2021-01-18T18:28:47	{"wikidata": ["Q1779312"]}
A rare, congenital disorder of glycosylation caused by mutations in the COG2 gene and characterized by normal presentation at birth, followed by progressive deterioration with postnatal microcephaly, developmental delay, intellectual disability, seizures, spastic quadriplegia, liver dysfunction, hypocupremia and hypoceruloplasminemia in the first year of life. Diffuse cerebral atrophy and thin corpus callosum may be observed on brain MRI. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	COG2-CDG	c4479353	5,280	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435934	2021-01-23T17:23:28	{"omim": ["617395"], "icd-10": ["E77.8"], "synonyms": ["COG2-related congenital disorder of glycosylation"]}
A number sign (#) is used with this entry because Hurthle cell tumors are associated with chromosomal abnormalities or mutations in the RAS gene (190020), the PAX8/PPARG fusion gene (see 167415), or the NDUFA13 gene (609435). Description Hurthle cell carcinoma of the thyroid accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms (Sanders and Silverman, 1998). Hurthle cell tumors, also known as oxyphil cell tumors, are composed of cells with increased numbers of mitochondria, which corresponds morphologically to their voluminous, granular, eosinophilic cytoplasm (Maximo et al., 2005). Cytogenetics Chromosomal aberrations by comparative genomic hybridization (CGH) are common in Hurthle cell neoplasms. However, the relationship between the chromosomal aberrations by CGH and tumor behavior was obscure. Wada et al. (2002) investigated chromosomal aberrations in primary Hurthle cell neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the aberrations identified with tumor node metastasis stage, tumor differentiation, capsular invasion, and tumor recurrence. Chromosomal aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15) of adenomas. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Five of the 8 (63%) patients with aberrations developed recurrence, whereas 0 of 5 patients without aberrations developed recurrence. The authors concluded that chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q in Hurthle cell carcinomas are associated with tumor recurrence. They also concluded that such chromosomal aberrations may be predictive for recurrent disease in patients with Hurthle cell thyroid carcinoma. Mapping Both papillary and follicular thyroid carcinomas may subsequently acquire further somatic genetic changes, which can result in tumor dedifferentiation and clinical progression. Certain chromosomal regions seem to be preferentially involved, suggesting that they may harbor tumor suppressor genes. The 17p13 region has been suggested to harbor a novel oncogene or tumor suppressor gene that plays a role in thyroid carcinoma progression. Farrand et al. (2002) studied a large cohort of clinically and histologically well characterized tumors, mainly typical follicular thyroid carcinoma and oxyphilic follicular thyroid carcinoma (Hurthle cell carcinoma), using a series of well mapped and closely spaced microsatellite markers. They confirmed a high 17p13 LOH rate in follicular thyroid carcinomas (18 of 20) and Hurthle cell carcinomas (13 of 19) and showed an association between 17p13 LOH and advanced tumor grade. In the Hurthle cell carcinomas the authors identified a narrow minimal common deleted region between D17S1308 (285 kb from pter) and D17S695 (696 kb from pter). This region was flanked centromerically by a breakpoint cluster, further suggesting nonrandom deletion. Farrand et al. (2002) concluded that these data suggest that a tumor suppressor gene, involved in Hurthle cell carcinoma pathogenesis, is contained within the D17S1308-D17S695 interval. Molecular Genetics Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (e.g., 190020) mutations and PAX8-PPARG (see 167415) rearrangements for galectin-3 (153619) and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations. Nikiforova et al. (2003) concluded that follicular thyroid carcinomas can develop through different molecular pathways. While conventional follicular thyroid carcinomas develop through at least 2 distinct and nonoverlapping molecular pathways initiated by RAS point mutation or PAX8-PPARG rearrangement, Hurthle cell tumors have a low frequency of both of these genetic alterations and apparently require a unique set of mutations for their development. In a man with papillary thyroid carcinoma composed predominantly of Hurthle cells, Maximo et al. (2005) identified a heterozygous germline mutation (609435.0001) in the NDUFA13 gene, which they called GRIM19. Heterozygous somatic mutations were identified in 3 of 26 additional sporadic Hurthle cell tumors. There was no associated loss of heterozygosity at the GRIM19 locus, suggesting either a dominant-negative mechanism or haploinsufficiency. The 4 tumors with GRIM19 mutations had significantly higher levels of ICAM1 (147840) expression in tumor tissue versus normal tissue compared to tumors without GRIM19 mutations. Maximo et al. (2005) postulated that loss of GRIM19 function may lead to mitochondrial defects and mitochondrial excess observed in Hurthle cell tumors or to defects in apoptosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	THYROID CARCINOMA, HURTHLE CELL	c0238463	5,281	omim	https://www.omim.org/entry/607464	2019-09-22T16:09:14	{"doid": ["8161"], "mesh": ["D000077273"], "omim": ["607464"], "orphanet": ["146"], "synonyms": ["Alternative titles", "HURTHLE CELL THYROID NEOPLASIA"]}
Leukoplakia Other namesLeucoplakia,[1] leukokeratosis,[1] idiopathic leukoplakia,[2] leukoplasia,[1] idiopathic keratosis,[3] idiopathic white patch[3] Leukoplakia on the inside of the cheek SpecialtyOtolaryngology, dentistry SymptomsFirmly attached white patch on a mucous membrane, changes with time[4][5][6] ComplicationsSquamous cell carcinoma[4] Usual onsetAfter 30 years old[4] CausesUnknown[6] Risk factorsSmoking, chewing tobacco, excessive alcohol, betel nuts[4][7] Diagnostic methodMade after other possible causes ruled out, tissue biopsy[6] Differential diagnosisYeast infection, lichen planus, keratosis due to repeated minor trauma[4] TreatmentClose follow up, stop smoking, limit alcohol, surgical removal[4] FrequencyUp to 8% of men over 70[6] Leukoplakia is a firmly attached white patch on a mucous membrane which is associated with increased risk of cancer.[4][5] The edges of the lesion are typically abrupt and the lesion changes with time.[4][6] Advanced forms may develop red patches.[6] There are generally no other symptoms.[8] It usually occurs within the mouth, although sometimes mucosa in other parts of the gastrointestinal tract, urinary tract, or genitals may be affected.[9][10][11] The cause of leukoplakia is unknown.[6] Risk factors for formation inside the mouth include smoking, chewing tobacco, excessive alcohol, and use of betel nuts.[4][7] One specific type is common in HIV/AIDS.[12] It is a precancerous lesion, a tissue alteration in which cancer is more likely to develop.[4] The chance of cancer formation depends on the type, with between 3–15% of localized leukoplakia and 70–100% of proliferative leukoplakia developing into squamous cell carcinoma.[4] Leukoplakia is a descriptive term that should only be applied after other possible causes are ruled out.[6] Tissue biopsy generally shows increased keratin build up with or without abnormal cells, but is not diagnostic.[4][6] Other conditions that can appear similar include yeast infections, lichen planus, and keratosis due to repeated minor trauma.[4] The lesions from a yeast infection can typically be rubbed off while those of leukoplakia cannot.[4][13] Treatment recommendations depend on features of the lesion.[4] If abnormal cells are present or the lesion is small surgical removal is often recommended; otherwise close follow up at three to six month intervals may be sufficient.[4] People are generally advised to stop smoking and limit the drinking of alcohol.[3] In potentially half of cases leukoplakia will shrink with stopping smoking;[5] however, if smoking is continued up to 66% of cases will become more white and thick.[6] The percentage of people affected is estimated at 1–3%.[4] Leukoplakia becomes more common with age, typically not occurring until after 30.[4] Rates may be as high as 8% in men over the age of 70.[6] ## Contents * 1 Classification * 1.1 Mouth * 1.1.1 Homogenous leukoplakia * 1.1.2 Non-homogenous leukoplakia * 1.1.2.1 Proliferative verrucous leukoplakia * 1.1.2.2 Erythroleukoplakia * 1.1.3 Sublingual keratosis * 1.1.4 Candidal leukoplakia * 1.1.5 Oral hairy leukoplakia * 1.1.6 Syphilitic leukoplakia * 1.2 Esophagus * 1.3 Bladder * 1.4 Anal canal * 2 Signs and symptoms * 3 Causes * 3.1 Tobacco * 3.2 Alcohol * 3.3 Sanguinaria * 3.4 Ultraviolet radiation * 3.5 Micro-organisms * 3.6 Epithelial atrophy * 3.7 Trauma * 4 Pathophysiology * 4.1 Tumor suppressor genes * 5 Diagnosis * 5.1 Definition * 5.2 Biopsy * 5.3 Histologic appearance * 5.4 Differential diagnosis * 6 Management * 6.1 Predisposing factors and review * 6.2 Surgery * 6.3 Medications * 7 Prognosis * 8 Epidemiology * 9 Etymology * 10 History * 11 References * 12 External links ## Classification[edit] Leukoplakia in the lower labial sulcus Leukoplakia of the soft palate Exophytic leukoplakia on the buccal mucosa Leukoplakia on the side of tongue Leukoplakia could be classified as mucosal disease, and also as a premalignant condition. Although the white color in leukoplakia is a result of hyperkeratosis (or acanthosis), similarly appearing white lesions that are caused by reactive keratosis (smoker's keratosis or frictional keratoses e.g. morsicatio buccarum) are not considered to be leukoplakias.[14] Leukoplakia could also be considered according to the affected site, e.g. oral leukoplakia, leukoplakia of the urinary tract, including bladder leukoplakia or leukoplakia of the penis, vulvae, cervix or vagina.[15][16] Leukoplakia may also occur in the larynx, possibly in association with gastro-esophageal reflux disease.[17] Oropharyngeal leukoplakia is linked to the development of esophageal squamous cell carcinoma,[17] and sometimes this is associated with tylosis, which is thickening of the skin on the palms and soles of the feet (see: Leukoplakia with tylosis and esophageal carcinoma). Dyskeratosis congenita may be associated with leukoplakia of the oral mucosa and of the anal mucosa.[17] ### Mouth[edit] Within the mouth, leukoplakia is sometimes further classified according to the site involved, e.g. leukoplakia buccalis (leukoplakia of the buccal mucosa) or leukoplakia lingualis (leukoplakia of the lingual mucosa). There are two main clinical variants of oral leukoplakia, namely homogenous leukoplakia and non-homogenous (heterogenous) leukoplakia, which are described below. The word leukoplakia is also included within the nomenclature of other oral conditions which present as white patches, however these are specific diagnoses which are generally considered separate from leukoplakia, with the notable exception of proliferative verrucous leukoplakia, which is a recognized sub-type of leukoplakia. #### Homogenous leukoplakia[edit] Homogenous leukoplakia (also termed "thick leukoplakia")[2] is usually well defined white patch of uniform, flat appearance and texture, although there may be superficial irregularities.[2][8] Homogenous leukoplakia is usually slightly elevated compared to surrounding mucosa, and often has a fissured, wrinkled or corrugated surface texture,[2] with the texture generally consistent throughout the whole lesion. This term has no implications on the size of the lesion, which may be localized or extensive.[2] When homogenous leukoplakia is palpated, it may feel leathery, dry, or like cracked mud.[2] #### Non-homogenous leukoplakia[edit] Non-homogenous leukoplakia is a lesion of non-uniform appearance. The color may be predominantly white or a mixed white and red. The surface texture is irregular compared to homogenous leukoplakia, and may be flat (papular), nodular or exophytic.[8][14] "Verrucous leukoplakia" (or "verruciform leukoplakia") is a descriptive term used for thick, white, papillary lesions. Verrucous leukoplakias are usually heavily keratinized and are often seen in elderly people. Some verrucous leukoplakias may have an exophytic growth pattern,[2] and some may slowly invade surrounding mucosa, when the term proliferative verrucous leukoplakia may be used. Non-homogeneous leukoplakias have a greater risk of cancerous changes than homogeneous leukoplakias.[8] ##### Proliferative verrucous leukoplakia[edit] Proliferative verrucous leukoplakia (PVL) is a recognized high risk subtype of non-homogenous leukoplakia.[18] It is uncommon, and usually involves the buccal mucosa and the gingiva (the gums).[19] This condition is characterized by (usually) extensive, papillary or verrucoid keratotic plaques that tends to slowly enlarge into adjacent mucosal sites.[1][2] An established PVL lesion is usually thick and exophytic (prominent), but initially it may be flat.[19] Smoking does not seem to be as strongly related as it is to leukoplakia generally, and another dissimilarity is the preponderance for women over 50.[19] There is a very high risk of dysplasia and transformation to OSCC or to verrucous carcinoma.[2] ##### Erythroleukoplakia[edit] Erythroleukoplakia ("speckled leukoplakia"), left commissure. Biopsy showed mild epithelial dysplasia and candida infection. Antifungal medication may turn this type of lesion into a homogenous leukoplakia (i.e. the red areas would disappear) Erythroleukoplakia (also termed speckled leukoplakia, erythroleukoplasia or leukoerythroplasia) is a non-homogenous lesion of mixed white (keratotic) and red (atrophic) color. Erythroplakia (erythroplasia) is an entirely red patch that cannot be attributed to any other cause. Erythroleukoplakia can therefore be considered a variant of either leukoplakia or erythroplakia since its appearance is midway between.[20] Erythroleukoplakia frequently occurs on the buccal mucosa in the commisural area (just inside the cheek at the corners of the mouth) as a mixed lesion of white nodular patches on an erythematous background,[20] although any part of the mouth may be affected. Erythroleukoplakia and erythroplakia have a higher risk of cancerous changes than homogeneous leukoplakia.[20] #### Sublingual keratosis[edit] Homogenous leukoplakia in the floor of the mouth in a smoker. Biopsy showed hyperkeratosis Sometimes leukoplakia of the floor of mouth or under the tongue is called sublingual keratosis,.[18] though this is not universally accepted to be a distinct clinical entity from idiopathic leukoplakia generally,[18] as it is distinguished from the latter by location only.[3] Usually sublingual keratoses are bilateral and possesses a parallel-corrugated, wrinkled surface texture described as "ebbing tide".[3] #### Candidal leukoplakia[edit] Candidal leukoplakia is usually considered to be a largely historical synonym for a type of oral candidiasis, now more commonly termed chronic hyperplastic candidiasis, rather than a subtype of true leukoplakia.[21] However, some sources use this term to refer to leukoplakia lesions that become colonized secondarily by Candida species, thereby distinguishing it from hyperplastic candidiasis.[18] #### Oral hairy leukoplakia[edit] Oral hairy leukoplakia is a corrugated ("hairy") white lesion on the sides of the tongue caused by opportunistic infection with Epstein-Barr virus on a systemic background of immunodeficiency, almost always human immunodeficiency virus (HIV) infection.[14] This condition is not considered to be a true idiopathic leukoplakia since the causative agent has been identified. It is one of the most common oral lesions associated with HIV infection, along with pseudomembraneous candidiasis.[12] The appearance of the lesion often heralds the transition from HIV to acquired immunodeficiency syndrome (AIDS).[12] #### Syphilitic leukoplakia[edit] This term refers to a white lesion associated with syphilis, specifically in the tertiary stage of the infection.[14] It is not considered to be a type of idiopathic leukoplakia, since the causative agent Treponema pallidum is known. It is now rare, but when syphilis was more common, this white patch usually appeared on the top surface of the tongue and carried a high risk of cancerous changes.[18] It is unclear if this lesion was related to the condition itself or whether it was caused by the treatments for syphilis at the time.[22] ### Esophagus[edit] Leukoplakia of the esophagus is rare compared to oral leukoplakia. The relationship with esophageal cancer is unclear because the incidence of esophageal leukoplakia is so low. It usually appears as a small, nearly opaque white lesion that may resemble early esophageal squamous cell carcinoma. The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and possible dysplasia.[23] ### Bladder[edit] In the context of lesions of the mucous membrane lining of the bladder, leukoplakia is a historic term for a visualized white patch which histologically represents keratinization in an area of squamous metaplasia. The symptoms may include frequency, suprapubic pain (pain felt above the pubis), hematuria (blood in the urine), dysuria (difficult urination or pain during urination), urgency, and urge incontinence. The white lesion may be seen during cystoscopy, where it appears as a whitish-gray or yellow lesion, on a background of inflamed urothelium and there may be floating debris in the bladder. Leukoplakia of the bladder may undergo cancerous changes, so biopsy and long term follow up are usually indicated.[24] ### Anal canal[edit] Leukoplakia of the anal canal is rare.[25] It may extend up to the anorectal junction. On digital examination it feels hard and granular, and at proctoscopy it appears as white plaques which may be diffuse, circumferential, or circumscribed. The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and acanthosis. It may be asymptomatic, with symptoms due to other lesions such as hemorrhoids or fissures. Progression to anal stenosis has been described. The malignant potential is seemingly low, and few cases of anal carcinoma have been reported associated with anal leukoplaka.[26] ## Signs and symptoms[edit] Most cases of leukoplakia cause no symptoms,[8] but infrequently there may be discomfort or pain.[2] The exact appearance of the lesion is variable. Leukoplakia may be white, whitish yellow or grey.[27] The size can range from a small area to much larger lesions.[27] The most common sites affected are the buccal mucosa, the labial mucosa and the alveolar mucosa,[28] although any mucosal surface in the mouth may be involved.[2] The clinical appearance, including the surface texture and color, may be homogenous or non-homogenous (see: classification). Some signs are generally associated with a higher risk of cancerous changes (see: prognosis). Leukoplakia may rarely be associated with esophageal carcinoma.[29]:805 ## Causes[edit] The exact underlying cause of leukoplakia is largely unknown,[1] but it is likely multifactorial, with the main factor being the use of tobacco.[27] Tobacco use and other suggested causes are discussed below. The mechanism of the white appearance is thickening of the keratin layer, called hyperkeratosis. The abnormal keratin appears white when it becomes hydrated by saliva, and light reflects off the surface evenly.[27] This hides the normal pink-red color of mucosae (the result of underlying vasculature showing through the epithelium).[1] A similar situation can be seen on areas of thick skin such as the soles of the feet or the fingers after prolonged immersion in water. Another possible mechanism is thickening of the stratum spinosum, called acanthosis.[27] ### Tobacco[edit] Tobacco smoking or chewing is the most common causative factor,[27] with more than 80% of persons with leukoplakia having a positive smoking history.[1] Smokers are much more likely to suffer from leukoplakia than non-smokers.[1] The size and number of leukoplakia lesions in an individual is also correlated with the level of smoking and how long the habit has lasted for.[1] Other sources argue that there is no evidence for a direct causative link between smoking and oral leukoplakia.[30] Cigarette smoking may produce a diffuse leukoplakia of the buccal mucosa, lips, tongue and rarely the floor of mouth.[27] Reverse smoking, where the lit end of the cigarette is held in the mouth is also associated with mucosal changes.[27] Tobacco chewing, e.g. betel leaf and areca nut, called paan, tends to produce a distinctive white patch in a buccal sulcus termed "tobacco pouch keratosis".[1] In the majority of persons, cessation triggers shrinkage or disappearance of the lesion, usually within the first year after stopping.[1][27] ### Alcohol[edit] Although the synergistic effect of alcohol with smoking in the development of oral cancer is beyond doubt, there is no clear evidence that alcohol is involved in the development of leukoplakia, but it does appear to have some influence.[27] Excessive use of a high alcohol containing mouth wash (> 25%) may cause a grey plaque to form on the buccal mucosa, but these lesions are not considered true leukoplakia.[1] ### Sanguinaria[edit] Sanguinaria (Bloodroot) is a herbal extract which is included in some toothpastes and mouthwashes. Its use is strongly associated with development of leukoplakia, usually in the buccal sulcus.[31] This type of leukoplakia has been termed "sanguinaria associated keratosis" and more than 80% of people with leukoplakia in the vestibule of the mouth have used this substance. Upon stopping contact with the causative substance, the lesions may persist for years. Although this type of leukoplakia may show dysplasia, the potential for malignant transformation is unknown.[1] ### Ultraviolet radiation[edit] Ultraviolet radiation is believed to be a factor in the development of some leukoplakia lesions of the lower lip, usually in association with actinic cheilitis.[1] ### Micro-organisms[edit] Candida in its pathogenic hyphal form is occasionally seen in biopsies of idiopathic leukoplakia. It is debated whether candida infection is a primary cause of leukoplakia with or without dysplasia, or a superimposed (secondary) infection that occurs after the development of the lesion. It is known that Candida species thrive in altered tissues.[27] Some leukoplakias with dysplasia reduce or disappear entirely following use of antifungal medication.[1] Smoking, which as discussed above can lead to the development of leukoplakia, can also promote oral candidiasis.[1] Candida in association with leukoplakia should not be confused with white patches which are primarily caused by candida infection, such as chronic hyperplastic candidiasis ("candidal leukoplakia").[18] The involvement of viruses in the formation of some oral white lesions is well established, e.g. Epstein-Barr virus in oral hairy leukoplakia (which is not a true leukoplakia). Human papilloma virus (HPV), especially HPV 16 and 18,[1] is sometimes found in areas of leukoplakia, however since this virus can be coincidentally found on normal, healthy mucosal surfaces in the mouth, it is unknown if this virus is involved in the development of some leukoplakias.[27] In vitro experimentation has demonstrated that HPV 16 is capable of inducing dysplastic changes in previously normal squamous epithelium.[1] ### Epithelial atrophy[edit] Leukoplakia is more likely to develop in areas of epithelial atrophy. Conditions associated with mucosal atrophy include iron deficiency, some vitamin deficiencies, oral submucous fibrosis, syphilis and sideropenic dysphagia.[27] ### Trauma[edit] Another very common cause of white patches in the mouth is frictional or irritational trauma leading to keratosis. Examples include nicotine stomatitis, which is keratosis in response to heat from tobacco smoking (rather than a response to the carcinogens in tobacco smoke). The risk of malignant transformation is similar to normal mucosa. Mechanical trauma, e.g. caused by a sharp edge on a denture, or a broken tooth, may cause white patches which appear very similar to leukoplakia. However, these white patches represent a normal hyperkeratotic reaction, similar to a callus on the skin, and will resolve when the cause is removed.[1] Where there is a demonstrable cause such as mechanical or thermal trauma, the term idiopathic leukoplakia should not be used. ## Pathophysiology[edit] ### Tumor suppressor genes[edit] Tumor suppressor genes are genes involved in the regulation of normal cell turnover and apoptosis (programmed cell death).[27] One of the most studied tumor suppressor genes is p53, which is found on the short arm of chromosome 17. Mutation of p53 can disrupt its regulatory function and lead to uncontrolled cell growth.[27] Mutations of p53 have been demonstrated in the cells from areas of some leukoplakias, especially those with dysplasia and in individuals who smoke and drink heavily.[27] ## Diagnosis[edit] ### Definition[edit] Leukoplakia is a diagnosis of exclusion, meaning that which lesions are included depends upon what diagnoses are currently considered acceptable.[27] Accepted definitions of leukoplakia have changed over time and are still controversial.[28] It is possible that the definition will be further revised as new knowledge becomes available.[27] In 1984 an international symposium agreed upon the following definition: "a whitish patch or plaque, which cannot be characterized clinically or pathologically as any other disease, and is not associated with any physical or chemical agent except the use of tobacco."[27] There were, however, problems and confusion in applying this definition.[27] At a second international symposium held in 1994, it was argued that, whilst tobacco was a likely causative factor in the development of leukoplakia, some white patches could be linked directly to the local effects of tobacco by virtue of their disappearance following smoking cessation, suggesting that this kind of white patch represents a reactive lesion to local tissue irritation rather than a lesion caused by carcinogens in cigarette smoke, and could be better termed to reflect this etiology, e.g. smokers' keratosis.[27] The second international symposium therefore revised the definition of leukoplakia to: "a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion." In the mouth, the current definition of oral leukoplakia adopted by the World Health Organization is "white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer".[32] However, this definition is inconsistently applied in the medical literature, and some refer to any oral white patch as "leukoplakia".[3] The term has been incorrectly used for white patches of any cause (rather than specifically referring to idiopathic white patches) and also to refer only to white patches which have a risk of cancerous changes.[3] It has been suggested that leukoplakia is an unhelpful term since there is so much inconsistency surrounding its use,[3] and some clinicians now avoid using it at all.[28] ### Biopsy[edit] Microscopic examination of keratinocytes scraped from the buccal mucosa Tissue biopsy is usually indicated[5] to rule out other causes of white patches and also to enable a detailed histologic examination to grade the presence of any epithelial dysplasia. This is an indicator of malignant potential and usually determines the management and recall interval. The sites of a leukoplakia lesion that are preferentially biopsied are the areas that show induration (hardening) and erythroplasia (redness), and erosive or ulcerated areas. These areas are more likely to show any dysplasia than homogenous white areas.[5] Brush biopsy/exfoliative cytology is an alternative to incisional biopsy,[5] where a stiff brush is scraped against the lining of the mouth to remove a sample of cells. This is then made into a smear which can be examined microscopically. Sometimes the biopsy site can be selected with adjunct methods which aim to highlight areas of dysplasia. Toluidine blue staining, where the dye is preferentially retained by dysplastic tissue, is sometimes used, but there is high false positive rate.[3] Other methods involve the use of illuminescence, relying on either the property of normal autoflorescent molecules in mucosa such as collagen and keratin which is lost from areas of dysplasia or carcinoma under blue light, or by initially staining of the mucosa with toluidine blue or dilute acetic acid and examination under white light.[3] ### Histologic appearance[edit] Leukoplakia has a wide range of possible histologic appearances. The degree of hyperkeratosis, epithelial thickness (acanthosis/atrophy), dysplasia and inflammatory cell infiltration in the underlying lamina propria are variable.[27] In mucous membranes, hyperkeratosis can be defined as "an increase in the thickness of the keratin layer of the epithelium, or the presence of such a layer in a site where none would normally be expected."[20] In leukoplakia, the hyperkeratosis varies in thickness, and may be either ortho- or para-keratosis, (depending upon whether cell nuclei are lost or retained in the superficial layers respectively), or a mixture of both in different areas of the lesion.[27][33] The epithelium may show hypertrophy (e.g. acanthosis) or atrophy. Red areas within leukoplakia represent atrophic or immature epithelium which has lost the ability to keratinize.[1] The transition between the lesion and normal surrounding mucosa may be well demarcated, or poorly defined. Melanin, a pigment naturally produced in oral mucosa, can leak from cells and give a grey color to some leukoplakia lesions.[27] Hyperkeratosis and altered epithelial thickness may be the only histologic features of a leukoplakia lesion, but some show dysplasia. The word "dysplasia" generally means "abnormal growth", and specifically in the context of oral red or white lesions refers to microscopic changes ("cellular atypia") in the mucosa that indicate a risk of malignant transformation.[3] When dysplasia is present, there is generally an inflammatory cell infiltration in the lamina propria.[33] The following are commonly cited as being possible features of epithelial dysplasia in leukoplakia specimens:[3][27] * Cellular pleomorphism, in which cells are of abnormal and different shapes. * Nuclear atypia, in which the nuclei of cells varies in size, any may be increased in size relative to the cytoplasm, shape, and may stain more intensely. There may also be more prominent nucleoli. * Increased number of cells seen undergoing mitosis, including both normal and abnormal mitoses. Abnormal mitosis may be abnormally located, e.g. occurring in suprabasal cells (cell layers more superficial to the basal cell layer) or of abnormal form, e.g. "tri-radiate mitoses" (a cell splitting into 3 daughter cells rather than only 2) * Loss the normal organization of the epithelial layers. The distinction between the epithelial layers may be lost. Normally stratified squamous epithelium shows progressive changes in the form of cells from the basal to the superficial layers, with cells becoming more flat ("squames") towards the surface as a continuous maturation process. In dysplastic epithelium, cells may become vertically orientated rather than becoming flat towards the surface. * There may be abnormal keratinization, where keratin is formed below the normal keratin layer. This can occur in individual cells or groups of cells, forming an intraepithelial keratin pearl. There may be an increase in number of basal cells, and they may lose their cellular orientation (losing their polarity and long axis). * Alteration of the normal epithelial-connective tissue architecture - the rete pegs may become "drop shaped". wider at their base than more superficially. Generally dysplasia is subjectively graded by pathologists into mild, moderate or severe dysplasia. This requires experience as it is a difficult skill to learn. It has been shown that there is high degree of inter-observer variation and poor reproducibility in how dysplasia is graded.[34] Severe dysplasia is synonymous with the term carcinoma in situ, denoting the presence of neoplastic cells which have not yet penetrated the basement membrane and invaded other tissues. ### Differential diagnosis[edit] Cause Diagnosis Normal anatomic variation Fordyce's spots (Fordyce's granules) Developmental White sponge nevus Leukoedema Pachyonychia congenita Dyskeratosis congenita Tylosis Hereditary benign intraepithelial dyskeratosis Darier's disease (follicular keratosis) Traumatic Frictional keratosis (e.g. morsicatio buccarum, linea alba, factitious injury) Chemical burn Infective Oral candidiasis Oral hairy leukoplakia Syphlytic leukoplakia Immunologic Lichen planus Lichenoid reaction (e.g. Lupus erythematosus, Graft versus host disease, Drug-induced lichenoid reaction) Psoriasis Idiopathic and smoking related Leukoplakia Smoker's keratosis (Stomatitis nicotina) Others e.g. Smokeless tobacco keratosis ("tobacco pouch keratosis") Neoplastic Oral squamous cell carcinoma Carcinoma in situ Other Oral keratosis of kidney failure Skin graft There are many known conditions which present with a white lesion of the oral mucosa, but the majority of oral white patches have no known cause.[3] These are termed leukoplakia once other likely possibilities have been ruled out. There are also few recognized subtypes of leukoplakia, described according to the clinical appearance of the lesion. Almost all oral white patches are usually the result of keratosis.[3] For this reason oral white patches are sometimes generally described as keratoses, although a minority of oral white lesions are not related to hyperkeratosis, e.g. epithelial necrosis and ulceration caused by a chemical burn (see: Oral ulceration#Chemical injury).[3] In keratosis, the thickened keratin layer absorbs water from saliva in the mouth and appears white in comparison with normal mucosa. Normal oral mucosa is a red-pink color due to the underlying vasculature in the lamina propria showing through the thin layer of epithelium. Melanin produced in the oral mucosa also influences the color, with a darker appearance being created by higher levels of melanin in the tissues (associated with racial/physiologic pigmentation, or with disorders causing melanin overproduction such as Addison's disease).[27] Other endogenous pigments can be overproduced to influence the color, e.g. bilirubin in hyperbilirubinemia or hemosiderin in hemochromatosis, or exogenous pigments such as heavy metals can be introduced into the mucosa, e.g. in an amalgam tattoo. Almost all white patches are benign, i.e. non-malignant. The differential diagnosis of a white lesion in the mouth can be considered according to a surgical sieve (see table).[3][27][35][33] Leukoplakia cannot be rubbed off the mucosa,[13] distinguishing it readily from white patches such as pseudomembraneous candidiasis, where a white layer can be removed to reveal an erythematous, sometimes bleeding surface underneath. The white color associated with leukoedema disappears when the mucosa is stretched. A frictional keratosis will generally be adjacent to a sharp surface such as a broken tooth or rough area on a denture and will disappear when the causative factor is removed. Some have a suggested as general rule that any lesion that does not show signs of healing within 2 weeks should be biopsied.[35] Morsicatio buccarum and linea alba are located at the level of the occlusal plane (the level at which the teeth meet). A chemical burn has a clear history of placing an aspirin tablet (or other caustic substance such as eugenol) against the mucosa in an attempt to relieve toothache. Developmental white patches usually are present from birth or become apparent earlier in life, whilst leukoplakia generally affects middle aged or elderly people. Other causes of white patches generally require pathologic examination of a biopsy specimen to distinguish with certainty from leukoplakia. ## Management[edit] A systematic review found that no treatments commonly used for leukoplakia have been shown to be effective in preventing malignant transformation. Some treatments may lead to healing of leukoplakia, but do not prevent relapse of the lesion or malignant change.[8] Regardless of the treatment used, a diagnosis of leukoplakia almost always leads to a recommendation that possible causative factors such as smoking and alcohol consumption be stopped,[35] and also involves long term review of the lesion,[35] to detect any malignant change early and thereby improve the prognosis significantly. ### Predisposing factors and review[edit] Beyond advising smoking cessation, many clinicians will employ watchful waiting rather than intervene. Recommended recall intervals vary. One suggested program is every 3 months initially, and if there is no change in the lesion, then annual recall thereafter. Some clinicians use clinical photographs of the lesion to help demonstrate any changes between visits. Watchful waiting does not rule out the possibility of repeated biopsies.[3] If the lesion changes in appearance repeat biopsies are especially indicated.[2] Since smoking and alcohol consumption also places individuals at higher risk of tumors occurring in the respiratory tract and pharynx, "red flag" symptoms (e.g. hemoptysis \- coughing blood) often trigger medical investigation by other specialties.[3] ### Surgery[edit] Surgical removal of the lesion is the first choice of treatment for many clinicians. However, the efficacy of this treatment modality cannot be assessed due to insufficient available evidence.[8] This can be carried out by traditional surgical excision with a scalpel, with lasers, or with eletrocautery or cryotherapy.[35] Often if biopsy demonstrates moderate or severe dysplasia then the decision to excise them is taken more readily. Sometimes white patches are too large to remove completely and instead they are monitored closely. Even if the lesion is completely removed, long term review is still usually indicated since leukoplakia can recur, especially if predisposing factors such as smoking are not stopped.[2] ### Medications[edit] Many different topical and systemic medications have been studied, including anti-inflammatories, antimycotics (target Candida species), carotenoids (precursors to vitamin A, e.g. beta carotene), retinoids (drugs similar to vitamin A), and cytotoxics, but none have evidence that they prevent malignant transformation in an area of leukoplakia.[8]Vitamins C and E have also been studied with regards a therapy for leukoplakia.[2] Some of this research is carried out based upon the hypothesis that antioxidant nutrients, vitamins and cell growth suppressor proteins (e.g. p53) are antagonistic to oncogenesis.[2] High doses of retinoids may cause toxic effects.[8] Other treatments that have been studied include photodynamic therapy.[8] ## Prognosis[edit] White patch on left buccal mucosa. Biopsy showed early squamous cell carcinoma. The lesion is suspicious because of the presence of nodules Nodular leukoplakia in right commissure. Biopsy showed severe dysplasia The annual malignant transformation rate of leukoplakia rarely exceeds 1%,[8] i.e. the vast majority of oral leukoplakia lesions will remain benign.[30] A number of clinical and histopathologic features are associated with varying degrees of increased risk of malignant transformation, although other sources argue that there are no universally accepted and validated factors which can reliably predict malignant change.[30] It is also unpredictable to an extent if an area of leukoplakia will disappear, shrink or remain stable.[36] * Presence and degree of dysplasia (mild, moderate or severe/carcinoma in situ). While the degree of dysplasia has been shown to be an important predictor of malignant change,[3] many have challenged its use due to the low predictive value from the lack of objectivity of grading dysplasia.[37][38][39] While 10% of leukoplakia lesions show dysplasia when biopsied,[8] as many as 18% of oral lesions undergo malignant change in the absence of dysplasia.[40] * Leukoplakia located on the floor of the mouth, the posterior and lateral tongue, and the retromolar areas (the region behind the wisdom teeth) have higher risk, whereas white patches in areas such as the top surface of the tongue and the hard palate do not have significant risk.[3] Although these "high risk" sites are recognized, statistically, leukoplakia is more common on the buccal mucosa, alveolar mucosa, and the lower labial mucosa.[28] Leukoplakia of the floor of the mouth and tongue accounts for over 90% of leukoplakias showing dysplasia or carcinoma on biopsy.[2] This is thought to be due to pooling of saliva in the lower part of the mouth, exposing these areas to more carcinogens held in suspension. * Red lesions (erythroplasia) and mixed red and white lesions (erythroleukoplakia/"speckled leukoplakia") have a higher risk of malignant change than homogenous leukoplakia.[14] * Verrucous or nodular areas have a higher risk.[3] * Although smoking increases risk of malignant transformation, smoking also causes many white patches with no dysplasia.[3] This means that statistically, white patches in non smokers have a higher risk.[2] * Older people with white patches are at higher risk.[3] * Larger white patches are more likely to undergo malignant transformation than smaller lesions.[3] * White patches which have been present for a long period of time have higher risk.[3] * Persons with a positive family history of cancer in the mouth.[3] * Candida infection in the presence of dysplasia has a small increased risk.[3] * A change in the appearance of the white patch, apart from a change in the color, has a higher risk.[3] Changes in the lesion such as becoming fixed to underlying tissues, ulceration, cervical lymphadenopathy (enlargement of lymph nodes in the neck), and bone destruction may herald the appearance of malignancy.[27] * White patches present in combination with other conditions that carry a higher risk (e.g. oral submucous fibrosis), are more likely to turn malignant.[3] * Although overall, oral cancer is more common in males, females with white patches are at higher risk than men.[3] ## Epidemiology[edit] The prevalence of oral leukoplakia varies around the world, but generally speaking it is not an uncommon condition.[8] Reported prevalence estimates range from less than 1% to more than 5% in the general population.[8] Leukoplakia is therefore the most common premalignant lesion that occurs in the mouth.[36] Leukoplakia is more common in middle-aged and elderly males.[28] The prevalence increases with increasing age.[2] In areas of the world where smokeless tobacco use is common, there is a higher prevalence.[2] In the Middle East region, the prevalence of leukoplakia is less than 1% (0.48%).[41] ## Etymology[edit] The word leukoplakia means "white patch",[3] and is derived from the Greek words λευκός - "white" and πλάξ - "plate".[42] ## History[edit] The term leukoplakia was coined in 1861 by Karl Freiherr von Rokitansky, who used it to refer to white lesions of the urinary tract.[24] In 1877 Schwimmer first used the term for an oral white lesion.[28] It is now thought that this white lesion on the tongue represented syphilitic glossitis,[28] a condition not included in the modern definitions of oral leukoplakia. Since then, the word leukoplakia has been incorporated into the names for several other oral lesions (e.g. candidal leukoplakia, now more usually termed hyperplastic candidiasis).[3] In 1930 it was shown experimentally that leukoplakia could be induced in rabbits that were subjected to tobacco smoke for 3 minutes per day.[43] According to one source from 1961, leukoplakia can occur on multiple different mucous membranes of the body, including in the urinary tract, rectum, vagina, uterus, vulva, paranasal sinuses, gallbladder, esophagus, eardrums, and pharynx.[24] Generally, oral leukoplakia is the only context where the term is in common usage in modern medicine. In 1988, a case report used the term acquired dyskeratotic leukoplakia to refer to an acquired condition in a female where dyskeratotic cells were present in the epithelia of the mouth and genitalia.[44]:480[29]:806 ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t Neville BW; Damm DD; Allen CM; Bouquot JE. (2002). Oral & maxillofacial pathology (2. ed.). Philadelphia: W.B. Saunders. pp. 337–345. ISBN 978-0-7216-9003-2. 2. ^ a b c d e f g h i j k l m n o p q r s Greenberg MS, Glick M (2003). Burket's oral medicine diagnosis & treatment (10th ed.). Hamilton, Ont.: BC Decker. pp. 87, 88, 90–93, 101–105. ISBN 978-1-55009-186-1. 3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af Odell W (2010). Clinical problem solving in dentistry (3rd ed.). Edinburgh: Churchill Livingstone. pp. 209–217. ISBN 978-0-443-06784-6. Archived from the original on 2017-09-10. 4. ^ a b c d e f g h i j k l m n o p q r Villa A, Woo SB (April 2017). "Leukoplakia-A Diagnostic and Management Algorithm". Journal of Oral and Maxillofacial Surgery. 75 (4): 723–734. doi:10.1016/j.joms.2016.10.012. PMID 27865803. 5. ^ a b c d e f Scully C, Porter S (July 2000). "ABC of oral health. Swellings and red, white, and pigmented lesions". BMJ. 321 (7255): 225–8. doi:10.1136/bmj.321.7255.225. PMC 1118223. 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"The carcinogenic effects of tobacco" (PDF). World Health Organization. Archived (PDF) from the original on 1 November 2013. Retrieved 30 April 2013. 44. ^ Weedon D; Strutton G; Rubin AI (2010). Weedon's skin pathology (3rd ed.). [Edinburgh]: Churchill Livingstone/Elsevier. ISBN 978-0-7020-3485-5. ## External links[edit] Classification D * ICD-10: K13.2, N48.0, N88.0, N89.4, N90.4 * ICD-9-CM: 528.6, 530.83, 607.0, 622.2, 623.1, 624.0 * MeSH: D007971 * DiseasesDB: 7438 External resources * MedlinePlus: 001046 * Patient UK: Leukoplakia * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Tumors of lip, oral cavity and pharynx / head and neck cancer Oral cancer Salivary gland malignant epithelial tumors * Acinic cell carcinoma * Mucoepidermoid carcinoma * Adenoid cystic carcinoma * Salivary duct carcinoma * Epithelial-myoepithelial carcinoma * Polymorphous low-grade adenocarcinoma * Hyalinizing clear cell carcinoma benign epithelial tumors * Pleomorphic adenoma * Warthin's tumor ungrouped: * Oncocytoma Tongue * Leukoplakia * Rhabdomyoma * Oropharynx * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder Wikimedia Commons has media related to Leukoplakia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Leukoplakia	c0023531	5,282	wikipedia	https://en.wikipedia.org/wiki/Leukoplakia	2021-01-18T18:36:18	{"gard": ["6897"], "mesh": ["D007971"], "umls": ["C0023531"], "icd-9": ["528.6", "622.2", "607.0", "530.83", "624.0", "623.1"], "icd-10": ["N88.0", "N90.4", "K13.2", "N48.0", "N89.4"], "wikidata": ["Q838145"]}
Terry's nails Terry's nails SpecialtyInternal medicine, Dermatology Diagnostic methodPhysical examination Differential diagnosisLiver failure, cirrhosis, diabetes mellitus, congestive heart failure, hyperthyroidism, or malnutrition TreatmentDirected at underlying condition Terry's nails is a physical condition in which a person's fingernails or toenails[1]:659 appear white with a characteristic "ground glass" appearance without any lunula.[2] The condition is thought to be due to a decrease in vascularity and an increase in connective tissue within the nail bed.[3] It frequently occurs in the setting of liver failure, cirrhosis, diabetes mellitus, congestive heart failure, hyperthyroidism, or malnutrition. Eighty percent of patients with severe liver disease have Terry's nails, but they are also found in people with kidney failure, in patients with congestive heart failure[4] and are described as a brown arc near the ends of the nails.[5] The recognition of characteristic nail patterns, such as Terry's nails, may be a helpful herald for early diagnosis of systemic diseases.[4] This finding was named for Richard Terry.[6] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ Stulberg, Daniel L.; Linford, Sean; Fawcett, Robert S. (2004-03-15). "Nail Abnormalities: Clues to Systemic Disease - March 15, 2004". American Family Physician. 69 (6): 1417–1424. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1029. ISBN 978-1-4160-2999-1. 4. ^ a b Nia, AM; Ederer, S; Dahlem, KM; Gassanov, N; Er, F (July 2011). "Terry's nails: a window to systemic diseases". The American Journal of Medicine. 124 (7): 602–4. doi:10.1016/j.amjmed.2010.11.033. PMID 21683827. 5. ^ Examination Medicine. Nicolas J Tally. MacLennan and Petty Pty Ltd. 2003 6. ^ Terry, Richard (10 April 1954). "White nails in hepatic cirrhosis". Lancet. 266 (6815): 757–9. doi:10.1016/s0140-6736(54)92717-8. PMID 13153107. * v * t * e Symptoms and signs relating to skin and subcutaneous tissue Disturbances of skin sensation * Hypoesthesia * Paresthesia * Formication * Hyperesthesia * Hypoalgesia * Hyperalgesia Circulation * Cyanosis * Pallor * Livedo * Livedo reticularis * Flushing * Petechia * Blanching Edema * Peripheral edema * Anasarca Other * Rash * Desquamation * Induration * Diaphoresis * Mass * Neck mass Skin * Asboe-Hansen sign * Auspitz's sign * Borsari's sign * Braverman's sign * Crowe sign * Dennie–Morgan fold * Darier's sign * Fitzpatrick's sign * Florid cutaneous papillomatosis * Gottron's sign * Hutchinson's sign * Janeway lesion * Kerr's sign * Koebner's phenomenon * Koplik's spots * Leser-Trelat sign * Nikolsky's sign * Pastia's sign * Russell's sign * Wickham striae * Wolf's isotopic response * Munro's microabscess Nails * Aldrich-Mees' lines * Beau's lines * Muehrcke's lines * Terry's nails This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Terry's nails	None	5,283	wikipedia	https://en.wikipedia.org/wiki/Terry%27s_nails	2021-01-18T19:01:09	{"wikidata": ["Q7704017"]}
Part of a series on Doping in sport Substances and types * Anabolic steroids * Blood doping * Gene doping * Cannabinoids * Diuretics * Painkillers * Sedatives * Stem cell doping * Stimulants * Beta2-adrenergic agonist * Clenbuterol * Ephedrine * EPO * Human growth hormone * Methylhexanamine * SARMs * Stanozolol * Tetrahydrogestrinone Terminology * Abortion doping * Biological passport * Blood-spinning * Doping test * Performance-enhancing drugs * Repoxygen * Stem cell doping * Whizzinator History * Olympics * Tour de France (1998, 1999, 2007) * Auto racing * BALCO scandal * Clemson University steroid scandal * U of South Carolina steroid scandal * Dubin Inquiry * Association Football * China * East Germany * Russia * United States * Festina affair * Floyd Landis case * Game of Shadows * Juiced * L.A. Confidentiel * Lance Armstrong * History of allegations * Doping case * Operación Puerto * Operation Aderlass * Doping in American football * Steroid use in baseball * Barry Bonds perjury case * Mitchell Report * Biogenesis scandal Doping-related lists * Doping cases in Sport * Athletics * Cycling * Doping at the Olympic Games * Doping at the World Championships in Athletics * Stripped Olympic medals * Stripped European Athletics C'ships medals * Drugs banned from the Olympics * MLB players suspended for doping * MLB players in the Mitchell Report Anti-doping bodies * World Anti-Doping Agency * International Testing Agency * List of national anti-doping organizations * Australian Sports Anti-Doping Authority * French Anti-Doping Agency * National Anti-Doping Agency * Russian Anti-Doping Agency * UK Anti-Doping * United States Anti-Doping Agency * v * t * e Systematic doping in Russian sports has resulted in 47 Olympic and tens of world championships medals being stripped from Russian athletes—the most of any country, more than four times the number of the runner-up, and more than 30% of the global total. Russia also has the most athletes that have been caught doping at the Olympic Games, with more than 200.[1] Russian doping is distinct from doping in other countries because in Russia steroids and other drugs were supplied to athletes by the state. Due to widespread doping violations, including an attempt to sabotage ongoing investigations by the manipulation of computer data, in 2019 the World Anti-Doping Agency banned Russia from all major sporting events for four years.[2] That ban was later reduced to two years in 2020 by the Court of Arbitration for Sport (CAS) following an appeal by Russia. The country will also be allowed to compete as "Russia" but with a neutral flag.[3] ## Contents * 1 Background: Soviet era * 2 Timeline * 2.1 Doping issues from 2008 to 2009 * 2.2 2010–2014: allegations of state-sponsored doping and 2014 ARD documentary * 2.3 2015 * 2.4 2016 * 2.4.1 January to May 2016 * 2.4.2 June 2016 * 2.4.3 July 2016 * 2.4.4 August to September 2016 * 2.4.5 October to December 2016 * 2.5 2017 * 2.5.1 January to October 2017 * 2.5.2 November to December 2017 * 2.5.3 Official sanctions * 2.5.4 Reaction in Russia * 2.6 2018 * 2.6.1 January to February 2018 * 2.6.2 May to August 2018 * 2.6.3 September 2018 * 2.6.4 November to December 2018 * 2.7 2019 * 2.7.1 January 2019 * 2.7.2 February to March 2019 * 2.7.3 June to July 2019 * 2.7.4 September to December 2019 * 2.8 2020 * 2.8.1 January to April 2020 * 2.8.2 July to December 2020 * 3 International competitions * 3.1 Russian hosting * 3.2 Russian participation * 4 Media coverage * 5 Reactions * 5.1 International * 5.2 In Russia * 5.2.1 2017 Sochi bans * 5.3 2018 Olympic ban * 6 Statistics * 6.1 Stripped Olympic medals * 7 Hashtag controversy * 8 See also * 9 References * 10 External links ## Background: Soviet era[edit] See also: Doping at the Olympic Games § 1980 Moscow Moscow Olympics has been called the "Chemists' Games" According to British journalist Andrew Jennings, a KGB colonel stated that the agency's officers had posed as anti-doping authorities from the International Olympic Committee (IOC) to undermine doping tests and that Soviet athletes were "rescued with [these] tremendous efforts".[4] On the topic of the 1980 Summer Olympics, a 1989 Australian study said "There is hardly a medal winner at the Moscow Games, certainly not a gold medal winner, who is not on one sort of drug or another: usually several kinds. The Moscow Games might as well have been called the Chemists' Games."[4] Documents obtained in 2016 revealed the Soviet Union's plans for a statewide doping system in track and field in preparation for the 1984 Summer Olympics in Los Angeles. Dated prior to the country's decision to participate in the 1984 Summer Olympics boycott, the document detailed the existing steroids operations of the program, along with suggestions for further enhancements.[5] The communication, directed to the Soviet Union's head of track and field, was prepared by Dr. Sergei Portugalov of the Institute for Physical Culture. Portugalov was also one of the main figures involved in the implementation of the Russian doping program prior to the 2016 Summer Olympics.[5] ## Timeline[edit] ### Doping issues from 2008 to 2009[edit] In 2008, seven Russian track and field athletes were suspended ahead of the Summer Olympics in Beijing for manipulating their urine samples.[6] Multiple Russian biathletes were involved in doping offences in run-up to the 2010 Olympics.[7][8] The president of the International Biathlon Union, Anders Besseberg, said, "We are facing systematic doping on a large scale in one of the strongest teams of the world."[9] Reviewing 7289 blood samples from 2737 athletes from 2001 to 2009, a report found that the number of suspicious samples from "Country A" notably exceeded other countries.[10] One of the authors said that Country A was Russia.[9] In October 2009, IAAF general secretary Pierre Weiss wrote to Valentin Balakhnichev that blood samples from Russian athletes "recorded some of the highest values ever seen since the IAAF started testing" and that tests from the 2009 World Championships "strongly suggest a systematic abuse of blood doping or EPO-related products".[11] ### 2010–2014: allegations of state-sponsored doping and 2014 ARD documentary[edit] Yuliya Stepanova In 2010, an employee at the Russian Anti-Doping Agency (RUSADA), Vitaly Stepanov, began sending information to the World Anti-Doping Agency (WADA) alleging that RUSADA was enabling systemic doping in athletics.[12][13] He said that he sent two hundred emails and fifty letters over the course of three years.[14] In December 2012, Darya Pishchalnikova sent an email to WADA containing details of an alleged state-run doping program in Russia. According to The New York Times, the email reached three top WADA officials but the agency decided not to open an inquiry but instead forwarded her email to Russian sports officials.[9] In April 2013, having failed a doping test for the second time (after a previous two-year doping ban in 2008–2010), Pishchalnikova was banned by the Russian Athletics Federation (RusAF) for ten years, in a move that was likely in retaliation. Her results from May 2012 were annulled, thus setting her on track to lose her Olympic medal.[15] British journalist Nick Harris said that he contacted the IOC with allegations about Grigory Rodchenkov's laboratory in Moscow in early July 2013.[16] According to Stepanov, "Even at WADA there were people who didn't want this story out," but he said that a person at the organization put him in contact with the German broadcaster ARD.[12] WADA's chief investigator Jack Robertson believed that the organization was reluctant to take action and that media attention was necessary, so he obtained the permission of WADA's director-general, David Howman,[17] to approach an investigative reporter called Hajo Seppelt, who had previously reported on doping in East Germany and other countries. In December 2014, ARD aired Seppelt's documentary, "Geheimsache Doping: 'Wie Russland seine Sieger macht'" ("The Doping Secret: 'How Russia Creates its Champions'"), which uncovered alleged Russian state involvement in systematic doping, describing it as "East German-style".[18] In the documentary, Stepanov and his wife Yuliya Stepanova (née Rusanova), claimed that Russian athletics officials had supplied banned substances in exchange for 5% of an athlete's earnings and had also falsified tests in cooperation with doping control officers.[19][20] It included conversations that had been secretly recorded by Stepanova, e.g. Russian athlete Mariya Savinova saying that contacts at a Moscow drug-testing laboratory had covered up her doping.[21] Russian long-distance runner Liliya Shobukhova allegedly paid 450,000 euros to cover up her positive doping result.[19] According to the allegations, Dr. Sergei Portugalov of the Institute for Physical Culture, who stands accused of organising state-sponsored doping in the Soviet Union, dating back to the early 1980s, was also involved in the recent Russian doping programme.[5] ### 2015[edit] See also: Russia at the 2012 Summer Olympics § Russian doping scandal In January 2015, then-All-Russia Athletic Federation President Valentin Balakhnichev resigned as treasurer of the International Association of Athletics Federations (IAAF).[22] Dick Pound led the 2015 WADA investigation and became a vocal critic of the IOC's indecision In response to the ARD documentary, WADA commissioned an investigation headed by former anti-doping agency President Dick Pound, the report of which was published on 9 November 2015.[23][24] The 335-page document, described as "damning" by The Guardian,[25] reported widespread doping and large-scale cover-ups by the Russian authorities. It stated that the Federal Security Service (FSB) had regularly visited and questioned laboratory staff and instructed some of them not to cooperate with the WADA investigation.[23]:196–197 Two staff members said that they suspected that the offices and telephones were bugged.[23]:196–197 The report recommended that ARAF be declared non-compliant with respect to the World Anti-Doping Code and that the IOC should not accept any 2016 Summer Olympics entries from ARAF until compliance was reached.[23][26] A day later, WADA suspended the Moscow Anti-doping Center, prohibiting the laboratory "from carrying out any WADA-related anti-doping activities including all analyses of urine and blood samples".[27] On 13 November, the IAAF council voted 22–1 in favour of prohibiting Russia from world track and field events with immediate effect.[28] Under other penalties against the ARAF, Russia has been also prohibited from hosting the 2016 World Race Walking Team Championships (Cheboksary) and 2016 World Junior Championships (Kazan), and ARAF must entrust doping cases to Court of Arbitration for Sport.[28] ARAF accepted the indefinite IAAF suspension and did not request a hearing.[29] ARAF's efforts towards regaining full IAAF membership will be monitored by a five-person IAAF team.[30] On 18 November 2015 WADA suspended RUSADA, meaning that Russia does not have a functioning NADO for any sport.[31][32] In November 2015, France began a criminal investigation into former IAAF president Lamine Diack, alleging that in 2011 he accepted a 1 million euro bribe from the ARAF to cover up positive doping results of at least six Russian athletes.[33] ### 2016[edit] #### January to May 2016[edit] In January 2016, the IAAF gave lifetime bans to the former head of the Russian athletics federation, Valentin Balakhnichev, and a top Russian coach, Aleksey Melnikov.[34] In mid-January, WADA released the second report by its independent commission.[35] The following month, the United Kingdom Anti-Doping (UKAD) agency was tasked to oversee testing in Russia.[36] Two former directors of RUSADA, Vyacheslav Sinev and Nikita Kamaev, both died unexpectedly in February 2016.[37] The Sunday Times reported that Kamaev had approached the newspaper shortly before his death planning to publish a book on "the true story of sport pharmacology and doping in Russia since 1987".[38] Grigory Rodchenkov, the director of a prominent laboratory who has been described by WADA as "the heart of Russian doping", was fired by Russian authorities and fled in fear of his safety to the United States, where he shared information[39] with the help of filmmaker Bryan Fogel, which was documented in the film Icarus. In March 2016, German broadcaster ARD aired a documentary called "Russia's Red Herrings", alleging that athletes were alerted about testing plans and offered banned substances by individuals at RUSADA and ARAF.[40] According to a May 2016 report in The New York Times, whistleblower Grigory Rodchenkov said that doping experts collaborated with Russia's intelligence service on a state-sponsored doping programme in which urine samples were switched through a hole in the laboratory's wall.[41] He said that at least fifteen medalists at the 2014 Winter Olympics were involved.[41] On 19 May, WADA appointed Richard McLaren to lead an investigation into the 2014 Winter Olympics in Sochi.[42] On 15 March 2016, The International Olympic Committee announced that they were re-analyzing stored urine samples from the 2008 and 2012 Olympics using more advanced analytical methods to detect banned substances that would have gone unnoticed at the time of competition. Specific sports and countries were targeted, including in particular athletes likely to compete in Rio who also competed in London 2012 and Beijing 2008. Athletes from the 2006 and 2010 Winter Olympics were also being targeted as urine samples can only be stored for 10 years.[43] The re-analysis programme would eventually conclude in November 2017. Away from the Olympics, Russian heavyweight boxer Alexander Povetkin and tennis player Maria Sharapova would both fail drug tests in March and May respectively, both testing positive for Meldonium. Russian-Finnish footballer Roman Eremenko would also fail a drugs test later on in the year. #### June 2016[edit] An ARD documentary in June 2016 implicated Russian sports minister Vitaly Mutko in covering up doping by a football player at FK Krasnodar.[44] In the same month, IAAF deputy general secretary Nick Davies was provisionally suspended over allegations that he took money to delay naming Russian athletes.[45] According to the BBC, emails from July 2013 showed that Davies had discussed how to delay or soften an announcement on Russians who had tested positive.[46] Vitaly Mutko, The Minister of Sport, Tourism and Youth of Russia In June 2016, WADA released a report stating that the work of its Doping Control Officers (DCO) had been limited by a "significant amount of unavailable athlete reports and missed tests", insufficient or incorrect athlete location information, and little information about the location or date of competitions. Some athletes named military cities requiring special permission to enter as their location and some national championships, including Olympic qualifiers, were held in cities with restricted access due to civil conflicts, preventing testing of the competitors.[47] WADA also reported intimidation of DCOs by armed Federal Security Service (FSB) agents; "significant delays" before being allowed to enter venues; consistent monitoring by security staff; delays in receiving athlete lists; and opening of sample packages by Russian customs.[47] 90% of Russian athletes did not respond or "emphatically" refused when WADA requested to interview them as part of its investigation.[48] Director general David Howman stated, "It was the very right time for those who considered themselves clean [to approach WADA]. They had nine months, plenty of time, and none came forward."[48] On 17 June, the IAAF Council held an extraordinary meeting "principally to give the Russian Athletics Federation (RusAF) a further opportunity to satisfy the Reinstatement Conditions for IAAF Membership".[49] A task force chaired by Rune Andersen recommended against reinstating Russia after reporting that criteria had not been met and that there were "detailed allegations, which are already partly substantiated, that the Russian authorities, far from supporting the anti-doping effort, have in fact orchestrated systematic doping and the covering up of adverse analytical findings".[49] The IAAF voted unanimously to uphold its ban.[50] A week later, the International Weightlifting Federation (IWF) decided to give a one-year ban to Russia, along with two other countries; on 3 August 2016 the IOC ratified the decision, and Russia's weightlifting team missed the 2016 Summer Olympics.[51][52] #### July 2016[edit] Headquarters of the Russian Olympic Committee in Moscow See also: McLaren Report On 18 July 2016, Richard McLaren, a Canadian attorney retained by WADA to investigate Rodchenkov's allegations, published a 97-page report covering significant state-sponsored doping in Russia.[53][54] Although limited by a 57-day time frame, the investigation found corroborating evidence after conducting witness interviews, reviewing thousands of documents, analysis of hard drives, forensic analysis of urine sample collection bottles, and laboratory analysis of individual athlete samples, with "more evidence becoming available by the day".[53]:5 The report concluded that it was shown "beyond a reasonable doubt" that Russia's Ministry of Sport, the Centre of Sports Preparation of the National Teams of Russia, the Federal Security Service (FSB), and the WADA-accredited laboratory in Moscow had "operated for the protection of doped Russian athletes" within a "state-directed failsafe system" using "the disappearing positive [test] methodology" (DPM) after the country's poor medal count during the 2010 Winter Olympic Games in Vancouver.[55][56] McLaren stated that urine samples were opened in Sochi in order to swap them "without any evidence to the untrained eye".[53] The official producer of BEREG-KIT security bottles used for anti-doping tests, Berlinger Group, stated, "We have no knowledge of the specifications, the methods or the procedures involved in the tests and experiments conducted by the McLaren Commission."[57] According to the McLaren report, the DPM operated from "at least late 2011 to August 2015".[53]:35 It was used on 643 positive samples, a number that the authors consider "only a minimum" due to limited access to Russian records.[53]:39 The system covered up positive results in a wide range of sports:[53]:41 * Athletics (139) * Weightlifting (117) * Non-Olympic sports (37) * Paralympic sport (35) * Wrestling (28) * Canoe (27) * Cycling (26) * Skating (24) * Swimming (18) * Ice hockey (14) * Skiing (13) * Football (11) * Rowing (11) * Biathlon (10) * Bobsleigh (8) * Judo (8) * Volleyball (8) * Boxing (7) * Handball (7) * Taekwondo (6) * Fencing (4) * Triathlon (4) * Modern pentathlon (3) * Shooting (3) * Beach volleyball (2) * Curling (2) * Basketball (1) * Sailing (1) * Snowboard (1) * Table tennis (1) * Water polo (1) In response to these findings, WADA announced that RUSADA should be regarded as non-compliant with respect to the World Anti-Doping Code and recommended that Russian athletes be banned from competing at the 2016 Summer Olympics.[58] The IOC decided to decline 2016 Summer Olympics accreditation requests by Russian sports ministry officials and any individuals implicated in the report, to begin re-analysis and a full inquiry into Russian competitors at the Sochi Olympics, and to ask sports federations to seek alternative hosts for major events that had been assigned to Russia.[59][60] On 21 July 2016, the Court of Arbitration for Sport (CAS) turned down an appeal by the Russian Olympic Committee and 68 Russian athletes.[61] The following day, the International Paralympic Committee began suspension proceedings against the National Paralympic Committee of Russia.[62] On 24 July, the IOC rejected WADA's recommendation to ban Russia from the Summer Olympics and announced that a decision would be made by each sport federation. With each positive decision having to be approved by a CAS arbitrator.[63] WADA's president Craig Reedie said, "WADA is disappointed that the IOC did not heed WADA's Executive Committee recommendations that were based on the outcomes of the McLaren Investigation and would have ensured a straight-forward, strong and harmonized approach."[64] On the IOC's decision to exclude Stepanova, WADA director general Olivier Niggli stated that his agency was "very concerned by the message that this sends whistleblowers for the future".[64] On 30 July 2016 the IOC announced that a final decision on each athlete would be made by a newly established IOC panel consisting of Ugur Erdener, Claudia Bokel, and Juan Antonio Samaranch Jr.[65] #### August to September 2016[edit] See also: Russia at the 2016 Summer Olympics and Russia at the 2016 Summer Paralympics Originally Russia submitted a list of 389 athletes for the Rio Olympics competition. On 7 August 2016, the IOC cleared 278 athletes, while 111 were removed because of the scandal (including 67 athletes removed by IAAF before the IOC's decision).[66] Yulia Efimova, who had been banned for doping, competed in Rio Critics noted that Kuwaitis were banned from competing under their own flag (for a non-doping related matter) while Russians were permitted to do so. Due to governmental interference, Kuwaiti competitors were permitted to enter only as independent athletes. Dick Pound stated, "It is not a consistent standard which is being applied now. Not all Kuwait athletes banned from competing in Rio under their own flag were supporters of the regime, and not all South African athletes were supporters of apartheid, but the greater good called for South Africa to be expelled."[67] Germany's Deutsche Welle wrote of "troublesome questions, like why Kuwait's Olympic federation faced a ban from Rio, while Russia's did not. Kuwait's tiny team [...] was suspended because of improper political conduct by the government; Russia's was not, after systematically organizing a doping program for many of its competitors."[68] Having sent samples for forensic analysis, the International Paralympic Committee (IPC) found evidence that the Disappearing Positive Methodology (DPM) was in operation at the 2014 Winter Paralympics in Sochi.[69] On 7 August 2016, the IPC's Governing Board voted unanimously to ban the entire Russian team from the 2016 Summer Paralympics, citing the Russian Paralympic Committee's (RPC) inability to enforce the IPC's Anti-Doping Code and the World Anti-Doping Code, which is "a fundamental constitutional requirement".[69] IPC President Sir Philip Craven described the Russian anti-doping system as "entirely compromised" and 18 July 2016 as "one of the darkest days in the history of all sport", and stated that the Russian government had "catastrophically failed its Para athletes".[70] IPC Athletes' Council Chairperson Todd Nicholson said that Russia had used athletes as "pawns" in order to "show global prowess".[71] On 23 August 2016, the Court of Arbitration for Sport dismissed Russia's appeal, stating that the IPC's decision was "made in accordance with the IPC Rules and was proportionate in the circumstances" and that Russia "did not file any evidence contradicting the facts on which the IPC decision was based".[72] The Federal Supreme Court of Switzerland rejected another appeal by Russia, saying that the RPC "needed to demonstrate it had fulfilled its obligations in upholding... anti-doping protocols, and that its interests in an immediate lifting of its suspension outweigh the International Paralympics Committee's interests in fighting doping and in the integrity of athletics. It did not succeed in this in any way."[73] Rejecting an appeal by ten athletes, a German court stated that the IPC had no obligation to allow them to compete and that the committee had "comprehensibly justified" its decision.[74] In an interview with NRK, WADA's director general Olivier Niggli said that "Russia is threatening us and our informers", mentioning daily hacking attempts and bugging of houses. He said that the agency had "a pretty good suspicion" that the hackers were Russian and that Western governments were already familiar with them.[75] He stated, "I think this will cease if they stop looking at us as an enemy, and instead accept that there is a problem that we must work together to solve. But for the moment they are sending out completely the wrong signals."[75] #### October to December 2016[edit] See also: McLaren Report In October 2016, Russia's sports minister Vitaly Mutko was promoted to deputy prime minister amid allegations that Mutko had covered up a doping violation.[76] On 3 November 2016, Russia approved an anti-doping law targeting coaches.[77] On 15 November 2016, Berlinger introduced a new design for doping sample bottles. A spokesman later said, "We work with forensic specialists from different nations. We want to always stay a little bit ahead of those cheating but you cannot avoid a system like the Russians built up."[78] On 7 December 2016, Yelena Isinbayeva became the chair of the supervisory board of the Russian Anti-Doping Agency.[79] On 9 December 2016, McLaren published the second part of his report. The report claimed that from 2011 to 2015, more than 1,000 Russian competitors in various sports (including summer, winter, and Paralympic sports) benefited from the cover-up.[80][81][82][83] However, McLaren later walked back from that assertion when the cases went to court, rephrasing it as not a fact but only a possibility, as recorded on page 68 of the CAS verdict for Alexander Legkov: "Prof. McLaren went on to explain that, in this respect, if his investigation obtained evidence that a particular athlete may have benefited from the scheme, then 'It didn't mean that they did benefit. It didn't mean that they committed [an] anti-doping rule violation.'"[84] Emails indicate that those who might have benefited from a cover-up included five blind powerlifters, who may have been given drugs without their knowledge, and a fifteen-year-old.[85] An IAAF taskforce announced that Russia could not be reinstated because the country still had no functional drug-testing agency and had not accepted the findings of investigations.[36] ### 2017[edit] #### January to October 2017[edit] In February 2017, All-Russia Athletic Federation vice-president Andrey Silnov held a press conference in Moscow alongside a former Soviet athlete who said that East German successes due to state-sponsored doping are legitimate results of "good pharmacology" and should not be condemned.[86] Later that month, WADA stated that evidence against many individuals named in the McLaren report might be insufficient because the Moscow laboratory had disposed of doping samples and Russian authorities were not answering requests for additional evidence.[87][88] An IAAF taskforce chaired by Rune Andersen published an interim report in April 2017.[89] President Sebastian Coe stated, "There is testing but it is still far too limited. The Russian investigative committee is still refusing to hand over athlete biological passport samples for independent testing from labs, we still have got athletes in closed cities that are difficult or impossible to get to, the ongoing employment of coaches from a tainted system, and we have got the head coach of RUSAF effectively refusing to sign their own pledge to clean athletics."[90] The report also noted the case of whistleblower Andrei Dmitriev, who had fled Russia after being threatened with imprisonment.[89] Coe said, "Anyone with information about a system which has failed to protect the goals and aspirations of clean athletes must feel it is safe to speak out."[91] Andersen questioned the selection of Yelena Isinbayeva, who had called for whistleblower Yuliya Stepanova to be "banned for life",[92] as the chair of RUSADA's supervisory board. Andersen stated, "It is difficult to see how this helps to achieve the desired change in culture in track and field, or how it helps to promote an open environment for Russian whistleblowers", noting that Isinbayeva had called a WADA report "groundless" without reading it, publicly criticised whistleblowers (Dmitriev and the Stepanovs), and had not signed a pledge for clean sport or endorsed a Russian anti-doping group.[89] In September 2017, WADA rejected Russia's claims that WADA should be held responsible for Rodchenkov, noting that Russia had chosen to appoint him as head of the Moscow laboratory. The organisation also stated, "WADA would expect the Russian authorities to take responsibility for this deliberate system of cheating that was uncovered by the McLaren Investigation – as is stipulated within RUSADA's Roadmap to Compliance – rather than continually shifting the blame onto others."[93] Seventeen national anti-doping organisations criticised the IOC for a "continuing refusal to hold Russia accountable for one of the biggest doping scandals in sports history" and "dereliction of duty [sending] a cynical message that those of favored, insider nations within the Olympic Movement will never be punished or held accountable".[94] They stated that cases had been "shut prematurely before the IOC or IFs have obtained complete evidence from the Moscow laboratory or interviewed the relevant witnesses".[94] An additional 20 NADOs have signed on.[95] #### November to December 2017[edit] See also: Oswald Commission In November 2017, the IOC disciplinary commission headed by Denis Oswald imposed its first sanctions after a year-long Sochi investigation. As of 22 December 2017, 43 Russian athletes had been sanctioned and 13 medals had been stripped. On 10 November 2017, the day after Vladimir Putin accused the U.S. of stirring up problems for Russian athletes,[96] WADA said in a news release that it had obtained an electronic file that contained "all testing data" from January 2012 to August 2015 – thousands of drug screenings run on Russian athletes. The database, which the Russian authorities were unwilling to share with antidoping investigators, arrived through a whistleblower.[97] The head of the Russian Ski Association, Yelena Välbe, told the press that "whistleblowers are traitors to their country" shortly thereafter.[98] Russia's ski team coach went even further and accused Ilia Chernousov (a skier who won a bronze medal in the 50 km freestyle event) of "leaking information" to WADA.[99] On 11 November 2017, it was revealed that Grigory Rodchenkov had provided new evidence of Russian state-sponsored doping to the IOC, noting that he would consider going public if the Schmid Commission did not give due weight to his evidence in any public findings.[citation needed] On 16 November 2017, WADA announced that Russia remained non-compliant with its Code.[100] On 26 November 2017, IAAF decided to maintain Russia's ban from international track and field competitions, saying the country had not done enough to tackle doping.[101] In an interview with the New York Times, Rodchenkov reported that Yuri Nagornykh, the deputy minister of sport, had asked him to incriminate a Ukrainian athlete, Vita Semerenko, during a competition in Moscow leading up to the Olympics. Rodchenkov did not comply, convincing the minister that a retest of the drug sample would show the drugs had been spiked into the sample rather than passed through a human body. "I could not have done this to an innocent athlete," he said. "During my career, I reported many Dirty Samples as clean, but never the other way around."[102] #### Official sanctions[edit] Approved OAR logo On 5 December 2017, the IOC announced that the Russian Olympic Committee had been suspended with immediate effect from the 2018 Winter Olympics, but their concession was to allow those Russian athletes with no previous drug violations and a consistent history of drug testing to compete under the Olympic Flag as an "Olympic Athlete from Russia" (OAR).[103] Under the terms of the IOC's edict, no Russian government officials were permitted to attend the Games, and neither the Russian flag nor the Russian national anthem would be featured; the Olympic Flag and Olympic Anthem were to be used instead. On 20 December 2017, the IOC proposed an alternative logo for the OAR athletes' uniforms (shown on right).[104] IOC President Thomas Bach said that "after following due process [the IOC] has issued proportional sanctions for this systematic manipulation while protecting the clean athletes."[105] As of January 2018, the IOC had identified 43 Russian athletes from the 2014 Winter Olympics in Sochi that it intended to ban from competing in the 2018 Winter Olympics and all other future Olympic Games as part of the Oswald Commission. All but one of those athletes appealed against their bans to the Court of Arbitration for Sport (CAS). The court overturned the sanctions on 28 of the appellants, resulting in their Sochi medals and results being reinstated, but the court ruled that there was sufficient evidence against eleven of the athletes to uphold their Sochi sanctions. The IOC issued a statement saying "the result of the CAS decision does not mean that athletes from the group of 28 will be invited to the Games. Not being sanctioned does not automatically confer the privilege of an invitation" and that "this [case] may have a serious impact on the future fight against doping". The IOC found it imperative to point out that the CAS Secretary General "insisted that the CAS decision does not mean that these 28 athletes are innocent" and that they would consider an appeal against the court's decision. The court also downgraded the punishment by deciding that the 39 athletes should only be banned from the 2018 Games, not all future Olympic Games. The remaining three Russian athletes did not appeal their decisions until March 2020 and in September 2020, two of the athletes were cleared of doping whilst the remaining athlete was found guilty, however all three had their life bans overturned.[106][107] After the partially successful appeal, 47 Russian athletes and coaches launched a further appeal to the CAS, in a final attempt to secure an invitation to the Games. This appeal was dismissed on 9 February 2018, the day of the opening ceremony, a decision that was welcomed by the IOC.[108] An original pool of 500 Russian athletes was put forward for consideration for the 2018 Games and 111 of those athletes were immediately eliminated from the pool; this included the 43 athletes who had been sanctioned by the Oswald Commission.[109] The remaining 389 athletes were required to meet a number of pre-games conditions, such as a further round of tests and re-analysis of stored samples, and they would only be considered for invitation to the Games providing these requirements were met. The final number of neutral Russian athletes that were invited to compete was 169.[110] However, speed skater Olga Graf chose not to compete, stating that "the sport has become a bargaining chip in dirty political games",[111] bringing the eventual total to 168. #### Reaction in Russia[edit] In the past, the President of Russia, Vladimir Putin, and other government officials had stated that it would be a humiliation for Russia if its athletes were not allowed to compete at the Olympics under the Russian flag.[112] However, despite rumours to the contrary, his spokesman Dmitry Peskov later revealed that no boycott had been discussed leading up to the IOC's announcement.[103] After the IOC decision was made public, Ramzan Kadyrov, the Head of Chechnya, announced that no Chechen athletes would be allowed to compete under a neutral flag.[113] On 6 December 2017, Putin confirmed that the Russian government would not prevent any of its athletes from participating at the 2018 Games as individuals, despite there being calls from other leading Russian politicians for a boycott.[114][115] Gennady Zyuganov, leader of the Communist Party of the Russian Federation, put forward a proposal to send fans to the Games with a Soviet Victory Banner.[116] Russian Minister of Foreign Affairs, Sergey Lavrov, commented that the United States "fears honest competition",[117] affirming Vladimir Putin's position that the United States used its influence within the IOC to "orchestrate the doping scandal".[118] According to Komsomolskaya Pravda, a popular Russian tabloid newspaper, 86% of the Russian population opposed participation in the Winter Olympics under a neutral flag.[119] Many Russians believed that the IOC was retaliating against Russia for their discriminatory anti-gay law which provoked considerable controversy with the IOC during the 2014 Winter Olympics when it was hosted in Sochi, Russia.[119] ### 2018[edit] #### January to February 2018[edit] In January 2018, it was reported that all leading Russian athletes avoided meeting doping officers and passing anti-doping tests in a track and field competition in Irkutsk.[120] During the Pyeongchang Winter Olympics in February 2018, two Russian athletes from the Olympic Athletes from Russia (OAR) delegation failed doping tests and were disqualified: curler Aleksandr Krushelnitckii[121] who won a bronze medal in the mixed doubles event; and bobsleigh pilot Nadezhda Sergeeva[122] who finished twelfth in the two-woman event. The IOC expressed their disappointment at the positive doping tests and stated that the OAR team would consequently not be allowed to parade under the Russian flag at the closing ceremony.[123] Despite the two disqualifications, the IOC announced on 28 February that it had chosen to reinstate Russia's Olympic membership, just days after the end of the Winter Games, as no more cases of doping had been found in the delegation. The surprise decision to lift the suspension provoked anger among the international sporting community.[124] The IOC had planned all along to reinstate Russia after the Games provided there were no more failed tests. Their statement read "The suspension of the Russian Olympic Committee is automatically lifted with immediate effect."[125][126] #### May to August 2018[edit] In the buildup to the 2018 FIFA World Cup hosted by Russia, lab director and whistleblower Grigory Rodchenkov said that he recognised one of Russia's players as a doper in one of his own doping programmes.[127] FIFA had opened an inquiry into Russian doping in football after the McLaren report was published with 33 Russian footballers named in it,[128] but said in May that they had found 'insufficient evidence' of doping but said that some cases with players unrelated to the World Cup were ongoing. The tournament eventually concluded with no players failing a drugs test. A few months after the tournament had concluded in September, the father of Russian player Denis Cheryshev said that his son had been taking growth hormone during the tournament. He was later cleared of doping by anti-doping authorities.[129] On 20 July, the Athletics Integrity Unit (AIU) released details of 120 doping cases with some 85 of the cases involving Olympic and World Championships medallists and almost half (47.5%) involving Russians.[130] On 27 July, 10 days before the start of the 2018 European Athletics Championships, the IAAF announced that despite making improvements in key areas, Russia would still remain suspended from international athletics competitions.[131] 29 Russian athletes still competed in the championships as Authorised Neutral Athletes,[132] and Russia eventually topped the medal table of the inaugural European Championships. #### September 2018[edit] The World-Anti Doping Agency voted on 20 September whether or not to re-instate the Russian Anti-Doping Agency after they were suspended in 2015. A WADA compliance review committee had recommended that RUSADA be re-instated, which sparked anger from international athletes and officials. One of the members of the six-person review committee, Beckie Scott, the chair of WADA'S athletes commission, left her role on the committee in protest over the recommendation to reinstate RUSADA and the vice president of the agency, Linda Helleland, said that she would vote against their re-admission.[133] A group of athletes from UK-Anti-Doping had earlier called for Russia to remain banned until it had overhauled its Anti-Doping System, saying that Russia's re-admission would be "a catastrophe for clean sport"[134] and a member of US Anti-Doping Agency was quoted as saying 'frankly, it stinks to high heaven'.[135] The former head of the Moscow laboratory turned whistle-blower Grigory Rodchenkov said that lifting Russia's ban would be a 'catastrophe'.[136] WADA had insisted that Russia meet two criteria before RUSADA could be re-admitted; accept the findings of the McLaren Report and grant access to Moscow's anti-doping laboratory. The compliance review committee had reviewed a letter from the Russian Sports Ministry that said it had 'sufficiently acknowledged the issues identified in Russia' and that they agree to accept the two remaining conditions'.[137] WADA voted unanimously to re-instate the Russian Anti-Doping Agency at their congress in the Seychelles, going against the wishes of numerous national Anti-Doping agencies around the world.[138] The lawyer for whistle-blower Grigory Rodchenkov called it "the greatest treachery against clean athletes in Olympic history" whilst US Anti-Doping Agency head Travis Tygart said the decision is "bewildering and inexplicable" and a "devastating blow to the world's clean athletes". The decision received so much criticism that the head of WADA, Craig Reedie, had to publicly defend the decision[139][140] as he came under mounting criticism.[141] With RUSADA now re-instated, the Russian Athletics Federation launched a legal challenge to the IAAF to overturn their ban from athletics competitions from which they were still suspended.[142] The IAAF, however, refused the request,[143] which was later withdrawn by the Russian athletics federation. By 26 September 2018, 77 Russians were serving doping bans in the sport of athletics including 72 athletes and five coaches and athlete support personnel.[144] #### November to December 2018[edit] It was announced in November that the International Olympic Committee would further re-analyse stored samples from the 2012 Olympics, testing for all banned substances. This came after 48 adverse analytical findings were found in previous re-analysis of samples with 22 of them being Russian[145] On 14 December 2018, Hugo Lowell at The i newspaper reported from Moscow that officials at the Russian Ministry of Sport were still reluctant to cooperate fully with WADA over turning over the testing data from its anti-doping laboratory.[146] WADA subsequently released a statement that said their Expert Team had flown to extract the data. Later, it emerged that WADA was unsuccessful in retrieving the data because their equipment had allegedly not been properly certified. The reinstatement of RUSADA prompted allegations of bullying and a call for reform within the World Anti-Doping Agency,[147] however the IAAF decided to uphold Russia's suspension from athletics into 2019 with 63 Russians cleared to compete as neutral athletes for the year.[148][149][150] A team of five WADA experts traveled to Moscow on 17 December expected to be given full access to the laboratory, but on arrival they were refused full access which put RUSADA on the brink of being suspended once more with their president Yuri Ganus appealing to Vladimir Putin personally for a resolution.[151][152] ### 2019[edit] #### January 2019[edit] WADA had set Russia a strict deadline to hand over data from their Moscow laboratory by 31 December, a deadline which they evidently missed.[153] There were calls for the WADA compliance review committee to meet immediately to consider their next steps, however they decided to meet much later on 14 January which caused anger among the international community with 16 national anti-doping bodies calling for Russia's suspension once more. WADA president Dick Pound described the reaction to their decision as like a 'lynch mob'.[154][155] WADA eventually gained full access to the Moscow laboratory on 10 January, 10 days after the initial deadline. The WADA president described it as a 'major breakthrough for clean sport' and said that they were now starting their second phase of authentication and review of the data that had been collected to make sure that it had not been compromised and to build strong cases against Russian athletes that might have doped. WADA eventually managed to retrieve 2262 samples from the Moscow lab.[156][157] Despite missing the deadline, RUSADA was still deemed compliant and was not punished.[158] The Institute of National Anti-Doping Organisations (iNADO) said that 'Russia has been granted more chances and, ultimately, leniency than any individual athlete or small country could expect to receive. This is very troubling'.[159] #### February to March 2019[edit] It was announced on 8 February that the International Paralympic Committee would now re-instate Russia by 15 March after they were suspended in July 2016. They stated that 69 of the 70 reinstatement criteria had been met with the last criterion being to accept the findings of the McLaren report.[160] Meanwhile, Russia's ban in athletics was upheld by the IAAF 'until further notice' stating that there were two outstanding issues that needed to be resolved.[161] On 19 March, France issued arrest warrants for two former Russian athletics officials as part of an investigation into a doping cover-up. The former head of Russian athletics Valentin Balakhnichev and the ex-coach of the Russian athletics team Alexei Melnikov, who were both banned from the sport for life in 2016, were targeted.[162] #### June to July 2019[edit] Russia's 2008 Olympic high jump champion Andrey Silnov stepped down from his position as the vice-president of the Russian Athletics Federation in June after it was reported that he was under investigation for a possible doping violation following a re-analysis of his sample from 2013.[163] It was also reported that seven Russian track and field athletes, including athletes from the national team, were caught training in Kyrgyzstan with Vladimir Kazarin, a coach who was banned from the sport for life in 2017 for doping offences.[164] With all of that in mind, Russia was in danger of remaining suspended for the 2019 World Athletics Championships in September after the IAAF voted to uphold their ban, the 11th time they had done so.[165] In July 2019 Reuters reported that two Olympic Russian boxers competed in 2018 while serving doping bans applied by RUSADA. Reuters said this indicated an inconsistency in Russia's reform of its anti-doping practices. After Reuters notified it of the two cases RUSADA said it would investigate.[166] The first cases of possible Anti-Doping violations against Russian athletes' samples taken from the Moscow Laboratory were handed over to the individual sporting federations in July.[167] WADA said that the data of 43 athletes had been handed over out of a target pool of 298 athletes. The first sporting federation to suspend athletes from the data received was the International Weightlifting Federation who suspended 12 Russian weightlifters including Olympic, World and European medalists.[168] #### September to December 2019[edit] On 21 September, it was widely reported that some of the data retrieved from the Moscow laboratory may have been manipulated and tampered with before it was retrieved by the World Anti-Doping Agency. This meant that Russia would remain suspended from the then-upcoming 2019 World Athletics Championships, and faced a possible ban from hosting and competing in all major sporting events including the upcoming 2020 Olympics and possibly the 2022 Olympics, 2022 FIFA World Cup and the 2024 Olympics.[169][170][171][172] Two months later on 21 November, a number of Russian athletics officials were suspended for obstructing and failing to co-operate with an investigation into the whereabouts of high-jumper Danil Lysenko. President of the Russian Athletics Federation Dmitry Shlyakhtin was suspended along with 6 others associated with RusAF, including the athlete and his coach.[173] WADA then recommended that Russia be declared non-compliant once more and banned from hosting sporting events for four years.[174][175] On 9 December, WADA banned Russia from major international sporting events for four years, on charges of tampering with doping-related reports. Russia will be barred from hosting, participating in, or establishing bids for international sporting events during this period. As before, WADA will allow cleared Russian athletes to compete neutrally, but not under the Russian flag. This will not affect Russia's co-hosting of UEFA Euro 2020, as WADA does not recognize UEFA as a "major event organization" covered by the ban.[176] In regard to this sanction, WADA president Craig Reedie said that "For too long, Russian doping has detracted from clean sport". He also added that "Russia was afforded every opportunity to get its house in order and rejoin the global anti-doping community for the good of its athletes and of the integrity of sport, but it chose instead to continue in its stance of deception and denial".[177] Russia appealed the decision to the Court of Arbitration for Sports (CAS).[178] ### 2020[edit] #### January to April 2020[edit] In January 2020, WADA suspended the Moscow laboratory from carrying out its only remaining accreditation, analysis of blood samples. The Moscow laboratory had been allowed to carry out analysis of blood samples since May 2016 as "practically impossible for laboratories to interfere with the blood variables of samples due to the nature of the analytical equipment and the athlete biological passport principles in place".[179] In March, World Athletics announced that no more than 10 Russian track and field athletes would be allowed to compete as neutrals at the summer's Olympics. It also fined the Russian athletics federation $10 million due to the obstruction and forgery of documents relating to the doping case of Danil Lysenko and stated that all Russian neutrals would be banned if half of the fine was not paid by 1 July. The 2020 Summer Olympics were later delayed until 2021 due to the ongoing COVID-19 pandemic.[180] On 30 April, WADA announced that they had completed their 'painstaking' investigation of the 298 Russian athletes whose data they had received from the Moscow laboratory in January 2019. The first data was handed over in July and a total of 27 international sporting federations and one major event organisation received the data in order to decide on possible anti-doping violations being brought forward.[181] #### July to December 2020[edit] The Russian athletics federation failed to pay half of its $10 million World Athletics fine by 1 July. RusAF's chief, Yevgeny Yurchenko, stated that the federation did not have the sufficient funds to pay the fine.[182] RusAF avoided expulsion from World Athletics after the Russian Sports Minister Oleg Matytsin made an 'unconditional' guarantee to pay the fine by a new deadline of August 15. Russia paid the fine of $5 million and $1.31 million in costs three days before the set deadline and avoided expulsion by doing so.[183] In a case that was described as 'almost identical' to that of Danil Lysenko, Russian figure skater Maria Sotskova was handed a 10-year ban from the sport by RUSADA for submitting a forged medical document in relation to her three missed doping tests and the presence of a prohibited substance in her body.[184] The Court of Arbitration for Sport, on review of Russia's appeal of its case from WADA, ruled on December 17, 2020 to reduce the penalty that WADA had placed. Instead of banning Russia from sporting events, the ruling allowed Russia to participate at the Olympics and other international events, but for a period of two years, the team cannot use the Russian name, flag, or anthem and must present themselves as "Neutral Athlete" or "Neutral Team". The ruling does allow for team uniforms to display "Russia" on the uniform but only up to equal predominance as the "Neutral Athlete/Team" designation, as well as the use of the Russian flag colors within the uniform's design.[185] ## International competitions[edit] ### Russian hosting[edit] Vladimir Putin at the 2018 FIFA World Cup opening ceremony Although the IOC stated in July 2016 that it would ask sports federations to seek alternative hosts,[59] Russia has retained hosting rights for some major international sports events, including the 2017 FIFA Confederations Cup, 2018 FIFA World Cup, and 2019 Winter Universiade. In September 2016, Russia was awarded hosting rights for the 2021 World Biathlon Championships because the IOC's recommendation did not apply to events that had already been awarded or planned bids from the country.[186] Olympic medalists Steven Holcomb, Matthew Antoine, Martins Dukurs, and Lizzy Yarnold questioned the decision to hold the FIBT World Championships 2017 in Sochi, with boycotts considered by Austria, Latvia, and South Korea.[187] Latvia's skeleton team confirmed that it would boycott if Sochi remained the host, saying that the "Olympic spirit was stolen in 2014."[188] On 13 December 2016, the International Bobsleigh and Skeleton Federation announced that it would relocate the event. Some athletes were concerned that they might unwittingly ingest a banned substance if the host tampered with food or drinks,[187] while others "were worried about the evidence that Russian laboratories had been opening tamper-proof bottles. If they have opened these bottles to help their athletes, what is to stop them also opening them to tamper with samples from any athlete in the competition?"[189] Biathlon teams from the Czech Republic and Great Britain decided to boycott a 2016–17 Biathlon World Cup stage in Tyumen.[190] On 22 December 2016, Russia announced it would not host the World Cup event or the 2017 Biathlon Junior World Championships in Ostrov.[191] The same day, the International Skating Union decided to relocate a speed skating event, the 2016–17 ISU Speed Skating World Cup stage in Chelyabinsk, due to "a substantial amount of critical evidence and the uncertainty relating to the attendance of the athletes".[192] Russia was later removed as host of the 2016–17 FIS Cross-Country World Cup final stage[193][194] and 2021 World Biathlon Championships in Tyumen.[195] On 22 December 2017, it was reported that FIFA fired Jiri Dvorak, a doctor, who had been investigating doping in Russian football. However, FIFA stated that removal of Dvorak was unrelated to his investigation of doping in Russian sports.[196] ### Russian participation[edit] See also: Olympic Athletes from Russia at the 2018 Winter Olympics 19 national anti-doping organisations recommended suspending Russia from participation in all sports. Russia was suspended from athletics, weightlifting, Paralympic sport competitions, but has continued its participation in other sports.[citation needed] The IAAF permitted Russians who have undergone testing by non-Russian agencies to compete as neutral athletes.[90] The Russian flag, national colours, and anthem were banned.[197] There were calls to ban Russia from participating in the 2018 Winter Olympics and 2018 Winter Paralympics or to allow Russian athletes to compete only as neutrals.[198][199][200] ## Media coverage[edit] This section needs expansion. You can help by adding to it. (December 2017) Russian doping has been featured in several documentaries broadcast in Germany, France, and the United States: * Geheimsache Doping: Wie Russland seine Sieger macht (The Doping Secret: How Russia Creates Champions), ARD / Das Erste, aired 3 December 2014[19] * Geheimsache Doping. Im Schattenreich der Leichtathletik (The Doping Secret: The Shadowy World of Athletics), ARD / Das Erste, aired 1 August 2015[201] * Geheimsache Doping: Russlands Täuschungsmanöver (The Doping Secret: Russia's Red Herrings), ARD / Westdeutscher Rundfunk, aired 6 March 2016[40][202] * Russia's Dark Secret, 60 Minutes / CBS News, aired 8 May 2016[203] * Plus vite, plus haut, plus dopés (Faster, higher, more doped), Arte in partnership with Le Monde, aired 7 June 2016[204] * Icarus, Netflix, directed by Bryan Fogel, 2017[205] * Inside edge on Amazon prime ## Reactions[edit] ### International[edit] Some athletes from other countries have criticised WADA, alleging that the agency has been reluctant to investigate Russia despite multiple tips over several years.[9] WADA officials stated that the agency lacked the authority to carry out its own investigations until 2015.[14][206] Arne Ljungqvist, WADA's former vice chairman, commented that "WADA always had an excuse as to why they wouldn't move forward. They expected Russia to clean up themselves."[9] In June 2016, The Guardian reported that a letter approved by over twenty athletes' groups from multiple sports and countries as well as the chairs of the IOC's and WADA's athletes committees, Claudia Bokel and Beckie Scott, had been sent to IOC president Thomas Bach and WADA head Craig Reedie; the letter criticised the organisations for inaction and silence until the media became involved and said that athlete confidence in the anti-doping system had been "shattered".[207] On 18 July 2016, WADA's Athlete Committee stated, "Although we have known of the allegations, to read the report today, to see the weight of the evidence, and to see the scale of doping and deception is astounding."[208] The athlete committee,[208] the Institute of National Anti-Doping Organizations,[209] and the leaders of anti-doping agencies in Austria, Canada, Denmark, Egypt, Finland, Germany, Japan, the Netherlands, New Zealand, Norway, Spain, Sweden, Switzerland, and the United States called for Russia to be banned from the 2016 Olympics in Rio.[210] After Bach delayed a decision on whether to ban the entire Russian team, IOC member Dick Pound said, "the IOC is for some reason very reluctant to think about a total exclusion of the Russian team. But we've got institutionalized, government-organised cheating on a wide scale across a whole range of sports in a country. You've got to keep from turning [zero tolerance] into: 'We have zero tolerance except for Russia.'"[211] Bruce Arthur of the Toronto Star said, "If the threshold Russia established is not high enough to merit a total ban from an Olympic Games, it's a remarkable precedent to set."[212] Former IOC vice president, Kevan Gosper of Australia, said, "we have to be very careful [about making] the wrong move with an important country like Russia", to which Richard Hind of The Daily Telegraph (Sydney) responded, "And there is the IOC in a nutshell. There are nations, and there are 'important nations'. Not everyone pees in the same specimen jar."[213] The IOC's decision on 24 July 2016 was criticised by athletes[214][215][216][217][218] and writers.[219][220][221][222][223][224] It received support from the European Olympic Committees, which said that Russia is "a valued member".[214] Cam Cole of Canada's National Post said that the IOC had "caved, as it always does, defaulting to whatever compromise it could safely adopt without offending a superpower".[223] Expressing disappointment, a member of the IOC Athletes' Commission, Hayley Wickenheiser, wrote, "I ask myself if we were not dealing with Russia would this decision to ban a nation [have] been an easier one? I fear the answer is yes."[216] Writing for Deutsche Welle in Germany, Olivia Gerstenberger said that Bach had "flunked" his first serious test, adding, "With this decision, the credibility of the organization is shattered once more, while that of state-sponsored doping actually receives a minor boost."[225] Bild (Germany) described Bach as "Putin's poodle".[221] Paul Hayward, chief sports writer of The Daily Telegraph (UK), remarked, "The white flag of capitulation flies over the International Olympic Committee. Russia's deep political reach should have told us this would happen."[219] Leaders of thirteen national anti-doping organisations wrote that the IOC had "violated the athletes' fundamental rights to participate in Games that meet the stringent requirements of the World Anti-Doping Code" and "[demonstrated that] it lacks the independence required to keep commercial and political interests from influencing the tough decisions necessary to protect clean sport".[226] WADA's former chief investigator, Jack Robertson, said "The anti-doping code is now just suggestions to follow or not" and that "WADA handed the IOC that excuse [not enough time before the Olympics] by sitting on the allegations for close to a year."[17] McLaren was dissatisfied with the IOC's handling of his report, saying "It was about state-sponsored doping and the misrecording of doping results and they turned the focus into individual athletes and whether they should compete. [...] it was a complete turning upside down of what was in the report and passing over responsibility to all the different international federations."[227][228] ### In Russia[edit] Vladimir Putin awards Alexandr Zubkov at the ceremonies for Russian athletes, 24 February 2014. Zubkov would be stripped of his gold medals 3.5 years later. Some Russians described the allegations as an anti-Russian plot while others stated that Russia was "just doing what the rest of the world does".[229][230][231] Russian President Vladimir Putin said that Russia had "never supported any violations in sport, we have never supported it at the state level, and we will never support this"[232] and that the allegations were part of an "anti-Russia policy" by the West.[233] Aleksei Pushkov, chairman of Russia's parliamentary foreign affairs committee, said that the IAAF's decision to uphold its ban was "an act of political revenge against Russia for its independent foreign policy".[233] A member of Russia's parliament, Vadim Dengin, stated, "The entire doping scandal is a pure falsification, invented to discredit and humiliate Russia."[234] After the Court of Arbitration for Sport turned down an appeal by Russian athletes, pole vaulter Yelena Isinbayeva wrote, "Let all those pseudo-clean foreign athletes breathe a sigh of relief and win their pseudo gold medals in our absence. They always did fear strength."[235] The Ministry of Foreign Affairs called the ruling a "crime against sport".[236] A poll by the Levada Center found that 14% of Russians believed that the country's athletes had doped in Sochi, 71% did not believe WADA's reports, and 15% decided not to answer.[237] A spokesman for Putin called Stepanova a "Judas".[238] The Russian media have also criticised the Stepanovs. Yuliya Stepanova said, "All the news stories call me a traitor and not just traitor but a traitor to the Motherland."[12] Vitaly Stepanov said, "I wasn't trying to expose Russia, I was trying to expose corrupt sports officials that are completely messing up competitions not just inside the country but globally."[13] Frankfurter Allgemeine Zeitung reported that the Russian media portrayed the German documentaries as "part of a Western conspiracy with the aim of weakening the great nation that Vladimir Putin lifted from its knees".[239] Hajo Seppelt had the "impression that he and the Stepanovs were being styled as enemies of the state".[239] Dick Pound described Russia's response as "a bit like when you get stopped for speeding on the freeway by the police and you say 'Why me? Everyone else was doing it'."[240] He stated that if Russia's authorities had "responded to their issues they could easily have enough time to sort everything out in time for Rio. But instead, they played the role of victims, claiming there was a plot against them for too long."[240] Leonid Bershidsky, a Russian writer for Bloomberg View, wrote that Russia's "officials need to understand that "whataboutism" doesn't avert investigations".[230] The Moscow correspondent of Deutsche Welle, Juri Rescheto, wrote that the response he saw in Russia "shows that the country is living in a parallel universe" and seeks to blame others.[241] Writing for The New York Times, Andrew E. Kramer said that Russia responded to the IAAF's decision against reinstatement with "victimhood" reflecting a "culture of grievances that revolves around perceived slights and anti-Russian conspiracies taking place in the outside world, particularly in Western countries".[233] The newspaper's editorial board also saw a "narrative of victimization" in Russia, and wrote that it resembled how the Soviet Union would respond to a punishment – by saying that it was "politically motivated, always a provocation, never justified. [Even] though the Cold War is long over, President Vladimir Putin remains stuck in the same, snarling defensive crouch in his responses to any accusations of Russian foul play".[242] Andrew Osborn of Reuters wrote that the Russian government had "deftly deflected the blame by passing it off as a Western Cold War-style plot to sabotage Russia's international comeback".[243] In response to Russia's opinion that the allegations were "politically motivated", WADA's former chief investigator, Jack Robertson, said that he saw politics "when Craig Reedie tried to intervene by writing emails to the Russian ministry to console them".[17] Match TV said that Americans had orchestrated the doping scandal, and modern pentathlon champion Aleksander Lesun called it an unfair "attack", because "Doping is in all countries and there are violators everywhere."[244] Following the IOC's announcement on 24 July 2016, Russian sports minister Vitaly Mutko said it was "a just and fair decision and we hope every federation will take the same kind of decision. Doping is a worldwide evil, not only of Russia."[245] The Russian media's reaction was "nearly euphoric at points".[244] A reporter from Russian state-owned television told IOC President Thomas Bach that "It looked like you personally were helping us," and asked whether the doping investigation was a "political attack" on Russian athletes.[246] After Russian athletes said that McLaren was about "politics" rather than sport, the British biathlon association stated that their comments were "brain-washed, deluded and dishonest" and decided to boycott an event in Russia.[247] Russia's Deputy Prime Minister Vitaly Mutko said that athletes should be "punished" for calls to boycott.[191] On 7 December 2017, it was reported that Russian oligarch Mikhail Prokhorov paid a Russian Olympic athlete millions of rubles in hush money not to reveal Russia's elaborate doping scheme. Prokhorov had run the Russian Biathlon Union from 2008 to 2014 and offered legal services to disqualified Russian biathletes.[248] In Russia, the December 2019 sanction was received with outrage. President Vladimir Putin slammed the decision as a "politically motivated" ruling that "contradicted" the Olympic Charter. "There is nothing to reproach the Russian Olympic Committee for and if there is no reproach towards this committee, the country should take part in competitions under its own flag," Putin said. Russian Prime Minister Dmitry Medvedev also said the ban was politically motivated. "This is the continuation of this anti-Russian hysteria that has already become chronic," Medvedev told domestic press.[177] #### 2017 Sochi bans[edit] See also: Oswald Commission The fallout from the IOC bans of Russian athletes caught doping at the Sochi Olympics, which left previous Russian whistleblowers in fear of their own personal safety, has been likened to a "witch-hunt" within the Russian winter sports community.[249] On 9 November 2017, Vladimir Putin called the decisions to ban Russian athletes for doping violations an attempt by the U.S. to undermine his nation and affect the Russian presidential election in March.[250] According to Russian news agency TASS, the Russian sports minister Pavel Kolobkov said that the investigative committee had found no evidence that the state was operating a doping system; that same committee was seeking whistleblower Grigory Rodchenkov's extradition from the United States, where he is in witness protection. Despite reassurances from Russian officials that no doping system existed, IOC official Dick Pound said: "empirical evidence is totally to the contrary, so I think what we're seeing in the Russian press is for domestic consumption."[95] On 17 November 2017, top Russian Olympic official Leonid Tyagachev said that Grigory Rodchenkov, who had alleged that Russia was running a systematic doping programme, "should be shot for lying, like Stalin would have done".[251] ### 2018 Olympic ban[edit] The IOC's decision was criticized by Jack Robertson, primary investigator of the Russian doping programme on behalf of WADA, who said that the IOC had issued "a non-punitive punishment meant to save face while protecting the [IOC’s] and Russia’s commercial and political interests". He also emphasized that Russian whistleblowers provided empirical evidence that "99 per cent of [their] national-level teammates were doping." According to Robertson, "[WADA] has discovered that when a Russian athlete [reaches] the national level, he or she [has] no choice in the matter: [it is] either dope, or you’re done"; he added "There is currently no intelligence I have seen or heard about that indicates the state-sponsored doping program has ceased."[252] It was also reported that Russian officials intensively lobbied U.S. politicians in an apparent attempt to achieve the extradition to Russia of the main whistleblower, Grigory Rodchenkov.[253] On 6 December 2017 Vladimir Putin announced his decision "not to prevent individual Russian athletes" from participating at the 2018 Winter Games. He also stated that he is pleased the IOC Inquiry Commission chaired by Samuel Schmid "didn't find any proof that the Russian government was involved in a doping conspiracy".[254] However, the Inquiry Commission only said that there's not enough evidence to claim that highest Russian state authorities were involved. The fact that Russian Ministry of Sport and Federal Security Service were part of the scheme was never in doubt.[255] Deputy (member) of the Russian State Duma and former professional boxer Nikolai Valuev has said that Russia should go to the Olympics and "tear everyone apart to spite these bastards who want to kill our sport".[256] Despite the "Olympic Athletes from Russia" (OAR) designation, many Russian fans still attended the 2018 Games, wearing the Russian colours and chanting "Russia!" in unison, in an act of defiance against the ban.[257] Justin Peters of Slate magazine wrote during the Games that the IOC "ended up with a situation that seemed to negate the entire point of the sanctions against Russia. The IOC did not want there to be a Russian Olympic team at the Pyeongchang Games… [yet] arenas are full of teams of Russian Olympians… [this is] a half-hearted wrist slap issued by an entity that appears more interested in saving face than in protecting athletes".[258] The CAS decision to overturn the life bans of 28 Russian athletes and restore their medals met fierce criticism among Olympic officials, including IOC president Thomas Bach who described the decision as "extremely disappointing and surprising". Grigory Rodchenkov's lawyer has stated that "the CAS decision would allow doped athletes to escape without punishment"[259] and also that "[the CAS decision] provides yet another ill-gotten gain for the corrupt Russian doping system generally, and Putin specifically".[260] ## Statistics[edit] WADA publishes annual summaries of anti-doping rule violations (ADRV). Russia ranked first in the world for ADRVs during 2013, 2014, and 2015.[261] Anti-doping rule violations[261] Year Russian ADRV Total world ADRV Russian proportion Russian rank As of 2013 225 1,953 11.5% 1 15 May 2015 2014 148 1,647 9% 1 21 February 2016 2015 176 1,901 9.3% 1 31 January 2017 ### Stripped Olympic medals[edit] See also: List of stripped Olympic medals Due to doping violations, Russia has been stripped of 43 Olympic medals – the most of any country, four times the number of the runner-up, and more than a third of the global total. It was the leading country in terms of the number of medals removed due to doping at the 2002 Winter Olympics (5 medals), the 2006 Winter Olympics (1 medal), the 2008 Summer Olympics (14 medals), the 2012 Summer Olympics (13 medals), 2014 Winter Olympics (4 medals) and the joint most at the 2004 Summer Olympics (3 medals) and the 2016 Summer Olympics (1 medal). The 43 revoked medals include 11 Golds, 21 Silvers, and 11 Bronzes. Olympics Athlete Medal Event Ref 2002 Winter Olympics Olga Danilova Gold Cross-country skiing, women's 5 km + 5 km combined pursuit [262] Silver Cross-country skiing, women's 10 km classical [262] Larisa Lazutina Gold Cross-country skiing, women's 30 km classical [262][263] Silver Cross-country skiing, women's 15 km freestyle [264] Silver Cross-country skiing, women's 5 km + 5 km combined pursuit [264] 2004 Summer Olympics Irina Korzhanenko Gold Athletics, women's shot put [265] Svetlana Krivelyova Bronze Athletics, women's shot put [266] Oleg Perepetchenov Bronze Weightlifting, men's 77 kg [267] 2006 Winter Olympics Olga Medvedtseva Silver Biathlon, women's individual [268] 2008 Summer Olympics Relay team (Yuliya Chermoshanskaya) Gold Athletics, women's 4 × 100 m relay [269] Relay team (Anastasiya Kapachinskaya, Tatyana Firova) Silver Athletics, women's 4 × 400 m relay [271] Maria Abakumova Silver Athletics, women's javelin throw [272] Relay team (Denis Alexeev) Bronze Athletics, men's 4 × 400 m relay [272] Yekaterina Volkova Bronze Athletics, women's 3000 m steeplechase [274] Anna Chicherova Bronze Athletics, women's high jump [276] Khadzhimurat Akkayev Bronze Weightlifting, men's 94 kg [277] Dmitry Lapikov Bronze Weightlifting, men's 105 kg [277] Marina Shainova Silver Weightlifting, women's 58 kg [271] Nadezhda Evstyukhina Bronze Weightlifting, women's 75 kg [271] Khasan Baroyev Silver Wrestling, men's Greco-Roman 120 kg [277] Tatyana Lebedeva Silver Athletics, women's triple jump [278] Silver Athletics, women's long jump [278] Tatyana Chernova Bronze Athletics, Women's heptathlon [279] 2012 Summer Olympics Tatyana Lysenko Gold Athletics, women's hammer throw [280] Yuliya Zaripova Gold Athletics, women's 3000 m steeplechase [281][282] Sergey Kirdyapkin Gold Athletics, men's 50 km walk [283] Tatyana Chernova Bronze Athletics, women's heptathlon [284] Darya Pishchalnikova Silver Athletics, women's discus throw [285] Yevgeniya Kolodko Silver Athletics, women's shot put [286] Olga Kaniskina Silver Athletics, women's 20 km walk [287] Apti Aukhadov Silver Weightlifting, men's 85 kg [288] Aleksandr Ivanov Silver Weightlifting, men's 94 kg [282] Natalia Zabolotnaya Silver Weightlifting, women's 75 kg [282] Svetlana Tsarukayeva Silver Weightlifting, women's 63 kg Relay (Antonina Krivoshapka, Yulia Gushchina) Silver Athletics, women's 4 × 400 m relay [289][290] Mariya Savinova Gold Athletics, women's 800 m 2014 Winter Olympics Two-man (Alexandr Zubkov, Alexey Voyevoda) Gold Bobsleigh, Two-man [291][292] Four-man (Alexandr Zubkov, Alexey Voyevoda) Gold Bobsleigh, Four-man [291][292][293] Olga Vilukhina Silver Biathlon, Women's sprint [293] Relay team (Olga Vilukhina, Yana Romanova, Olga Zaitseva) Silver Biathlon, Women's relay [294][295] 2016 Summer Olympics Mikhail Aloyan Silver Boxing, men's flyweight [296] ## Hashtag controversy[edit] Further information: Internet Research Agency According to Reuters, Russian trolls were involved in spreading Twitter hashtag #NoRussiaNoGames following the announcement from IOC that Russia was suspended from the 2018 Winter Olympics. One of the accounts identified by Reuters as driving activity around #NoRussiaNoGames was @ungestum, which lists its location as the Russian city of Orenburg. The account has sent 238 tweets consisting of just the hashtag to other users since the ban was announced, indicating that these were computer-generated. The campaign was also highly promoted by a group of at least five accounts which tweeted the hashtag numerous times along with the links that were not related to Russian-language news articles, and repeatedly reposted tweets from each other. One of those accounts, @03_ppm, has sent at least 275 such tweets.[297] ## See also[edit] * Doping in sport * Doping at the Olympics * List of stripped Olympic medals * Icarus ## References[edit] 1. ^ https://www.wada-ama.org/en/media/news/2019-12/wada-executive-committee-unanimously-endorses-four-year-period-of-non-compliance 2. ^ https://time.com/5746344/russia-banned-olympics-2019/ 3. ^ https://www.wsj.com/articles/sports-court-ruling-on-russian-doping-scheme-11608217781 4. ^ a b Hunt, Thomas M. (2011). Drug Games: The International Olympic Committee and the Politics of Doping. University of Texas Press. p. 66. ISBN 978-0-29273957-4. 5. ^ a b c Ruiz, Rebecca R. (13 August 2016). "The Soviet Doping Plan: Document Reveals Illicit Approach to '84 Olympics". The New York Times. ISSN 0362-4331. Retrieved 3 September 2016. 6. ^ "Dobriskey slams 'Russian seven'". 28 November 2008 – via news.bbc.co.uk. 7. ^ "In Biathlon, Concerns About Russia's program". nytimes.com. 22 February 2010. 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"IOC abdicates its responsibility in Russian doping case on the wings of money and mythology". National Post. 224. ^ Hines, Nico (24 July 2016). "Spineless IOC Surrenders Olympic Integrity to Russia Forever". The Daily Beast. 225. ^ Gerstenberger, Olivia (24 July 2016). "Opinion: A non-decision from the IOC". Deutsche Welle. Archived from the original on 25 July 2016. 226. ^ National Anti-Doping Organisations of Austria, Canada, Denmark, Finland, Germany, Japan, Netherlands, New Zealand, Norway, Poland, Sweden, Switzerland, US (31 July 2016). "Russian doping scandal: 'When it mattered most, the IOC failed to lead'". The Guardian.CS1 maint: multiple names: authors list (link) 227. ^ Kelso, Paul (16 September 2016). "Investigator who exposed Russian doping hits out at IOC". Sky News. 228. ^ Ford, Bonnie D. (15 March 2017). "Are Russian authorities ready to cooperate in drug scandal investigation?". ESPN. 229. ^ MacFarquhar, Neil (21 July 2016). "A Doping Scandal Appears Unlikely to Tarnish Russia's President". The New York Times. 230. ^ a b Bershidsky, Leonid (10 November 2015). "Doping Shows Russia Is Rotten, But Not Hopeless". Bloomberg View. 231. ^ Grohmann, Karolos; Stubbs, Jack (14 August 2016). "Russia athletics suffers final disgrace as last competitor barred". Reuters. 232. ^ Ferguson, Kate (18 June 2016). "Vladimir Putin insists 'Russia does not support doping'". The Scotsman. 233. ^ a b c Kramer, Andrew E. (17 June 2016). "Olympic Ban Adds to Russia's Culture of Grievances". The New York Times. 234. ^ Nemtsova, Anna (17 June 2016). "Russia: America and the West 'Invented' Olympic Doping Scandal to 'Humiliate' Us". The Daily Beast. 235. ^ McGowan, Tom; Sinnott, John (21 July 2016). "Russia Olympic ban: Six questions answered". CNN. 236. ^ "Rio Olympics 2016: Russia fails to overturn athlete ban for next month's Games". BBC News. 21 July 2016. 237. ^ "Most Russians Unconvinced by WADA Doping Reports – Poll". The Moscow Times. 29 July 2016. 238. ^ "IAAF Taskforce: Interim report to IAAF Council, 17 June 2016" (PDF). IAAF. 17 June 2016. 239. ^ a b Schmidt, Friedrich; Hanfeld, Michael (11 June 2016). "Stell dir vor, das russische Staatsfernsehen kommt" [When Russian TV shows up]. Frankfurter Allgemeine Zeitung (in German). 240. ^ a b Majendie, Matt (16 June 2016). "Dick Pound warns of chaos if IOC overrule IAAF over Russia's bid for Olympic Games". London Evening Standard. 241. ^ Rescheto, Juri (9 June 2016). "Opinion: Russia's parallel universe". Deutsche Welle. 242. ^ "Russia Blames Others for Its Doping Woes". The New York Times. 29 August 2016. 243. ^ Osborn, Andrew (22 July 2016). "Doping scandal rocks Russian sport but Putin's ratings look safe". Reuters. 244. ^ a b Luhn, Alec (24 July 2016). "Russia greets IOC decision on Rio Games with relief and jubilation". The Guardian. 245. ^ "US doping chief says IOC have left a 'confusing mess'". www.rte.ie. Archived from the original on 25 July 2016. 246. ^ Powell, Michael (4 August 2016). "I.O.C. Chief Thomas Bach Supports a Peculiar Form of Justice on Doping". The New York Times. 247. ^ "GBR Lead Boycott of WC 8 in Tyumen RUS". British Biathlon. 21 December 2016. 248. ^ "Mikhail Prokhorov, Nets owner, paid Russian Olympic athlete millions of rubles to keep quiet amid doping scandal: report". Daily News (New York). 7 December 2017. Retrieved 13 December 2017. 249. ^ "Russian sports gripped by distrust, anger ahead of key doping vote". CBC. 14 November 2017. Retrieved 14 November 2017. 250. ^ "Putin: Doping allegations 'US plot against Russian election'". BBC News. 9 November 2017. Retrieved 14 November 2017. 251. ^ "Russian Olympic official says doping whistleblower should be executed". The Guardian. 17 November 2017. Retrieved 23 November 2017. 252. ^ "The 2018 Winter Olympics Are Already Tainted". The New York Times. 27 December 2017. Retrieved 27 December 2017. 253. ^ "IOC accused of cowardice for failing to address Russian retaliation against Rodchenkov". Inside the Games. 26 December 2017. Retrieved 27 December 2017. 254. ^ "Путин считает важным, что в заключении МОК нет выводов о господдержке допинга в России". Тасс. 255. ^ "IOC suspends Russian NOC and creates a path for clean individual athletes to compete in PyeongChang 2018 under the Olympic Flag". Olympic. 5 December 2017. 256. ^ "Валуев: нужно ехать на Олимпиаду и рвать всех назло этим гадам". Спорт FM. 23 December 2017. Archived from the original on 24 December 2017. Retrieved 24 December 2017. 257. ^ Ortiz, Eirk (14 February 2018). "Russian fans spurn 'stupid' ban on athletes at Olympic Games". NBC News. 258. ^ Peters, Justin (12 February 2018). ""Olympic Athletes From Russia" Is a Craven Euphemism for a Craven Olympic Games". Slate. Archived from the original on 16 February 2018. Retrieved 17 February 2018. 259. ^ "IOC Chief Disappointed by Court Lifting Doping Ban on Russians". RFERL. 4 February 2018. Retrieved 4 February 2018. 260. ^ "28 Russians have Olympic doping bans lifted". NBC Sorts. 1 February 2018. Retrieved 4 February 2018. 261. ^ a b * "2013 Anti-Doping Rule Violations (ADRVs) Report" (PDF). World Anti-Doping Agency. 26 June 2015. p. 63. * "2014 Anti-Doping Rule Violations (ADRVs) Report" (PDF). World Anti-Doping Agency. 4 May 2016. p. 55. * "2015 Anti-Doping Rule Violations (ADRVs) Report" (PDF). World Anti-Doping Agency. 3 April 2017. p. 58. 262. ^ a b c "Muehlegg, Lazutina test positive, stripped of golds". ESPN.com. Associated Press. 24 February 2002. 263. ^ "Drugs test denies Lazutina gold". BBC News. 24 February 2002. 264. ^ a b "Lazutina loses Olympic medals". BBC News. 29 June 2003. 265. ^ "Shot-put champion will lose gold". CNN. 22 August 2004. 266. ^ "Four Athens competitors stripped of medals". Al Jazeera. 5 December 2012. 267. ^ "Russian weightlifter, Oleg Perepetchenov, stripped of Athens bronze medal". Reuters. 12 February 2013. 268. ^ "Russian Woman Stripped of Biathlon Medal". NBCSports.com. Associated Press. 16 February 2006. Archived from the original on 19 May 2011. Retrieved 8 December 2016. 269. ^ "IOC sanctions Yulia Chermoshanskaya for failing anti-doping test at Beijing 2008". 25 January 2017. 270. ^ "IOC sanctions three athletes for failing anti-doping tests at Beijing 2008". International Olympic Committee. 19 August 2016. Retrieved 19 August 2016. 271. ^ a b c "IOC sanctions six athletes for failing anti-doping tests at Beijing 2008". International Olympic Committee. 31 August 2016. Retrieved 31 August 2016. 272. ^ a b "IOC sanctions four athletes for failing anti-doping tests at Beijing 2008 and London 2012". International Olympic Committee. 13 September 2016. Retrieved 13 September 2016. 273. ^ "9 Olympians, including 6 medallists, caught for Beijing doping". cbc.ca. 26 October 2016. Retrieved 27 October 2016. 274. ^ "IOC sanctions nine athletes for failing anti-doping tests at Beijing 2008". International Olympic Committee. 26 October 2016. Retrieved 26 October 2016. 275. ^ "Russian Chicherova stripped of 2008 Olympics high jump medal". reuters.com. 6 October 2016. Retrieved 13 October 2016. 276. ^ "IOC sanctions Anna Chicherova for failing anti-doping test at Beijing 2008". 25 January 2017. 277. ^ a b c "IOC sanctions 16 athletes for failing anti-doping tests at Beijing 2008". International Olympic Committee. 17 November 2016. Retrieved 18 November 2016. 278. ^ a b "IOC sanctions two athletes for failing anti-doping test at Beijing 2008". 31 May 2017. 279. ^ "IOC sanctions two athletes for failing anti-doping test at Beijing 2008 and London 2012". 18 May 2017. 280. ^ "IOC sanctions Tatyana Lysenko for failing anti-doping test at London 2012". 25 January 2017. 281. ^ "The decisions of the Lausanne (Switzerland) Court of Arbitration for Sport regarding the Russian Athletes". 16 March 2016. Archived from the original on 25 June 2016. Retrieved 8 December 2016. 282. ^ a b c "IOC sanctions 12 athletes for failing anti-doping test at London 2012". International Olympic Committee. 21 November 2016. Retrieved 21 November 2016. 283. ^ "London 2012 50km walk men - Olympic Athletics". 3 June 2017. 284. ^ Sean, Ingle (29 November 2016). "Jessica Ennis-Hill in line for 2011 gold as Chernova is stripped of world title". The Guardian. 285. ^ "Russia's Pishchalnikova given 10-year doping ban". Reuters. 1 May 2013. Retrieved 1 May 2013. 286. ^ "IOC sanctions Evgeniia Kolodko for failing anti-doping test at London 2012". olympic.org. 20 August 2016. Retrieved 21 August 2016. 287. ^ "London 2012 20km race walk women - Olympic Athletics". 3 June 2017. 288. ^ "IOC sanctions two athletes for failing anti-doping test at London 2012". International Olympic Committee. 18 October 2016. Retrieved 18 October 2016. 289. ^ "IOC sanctions three athletes for failing anti-doping tests at London 2012". International Olympic Committee. 1 February 2017. Retrieved 1 February 2017. 290. ^ "More Russian track athletes banned for doping at London Olympics - CBC Sports". 291. ^ a b "IOC sanctions four Russian athletes as part of Oswald Commission findings". 24 November 2017. 292. ^ a b "Russian bobsledder banned over doping". France 24. 18 December 2017. Archived from the original on 19 December 2017. Retrieved 19 December 2017. 293. ^ a b "IOC sanctions five Russian athletes and publishes first full decision as part of the Oswald Commission findings". 27 November 2017. Archived from the original on 28 January 2017. Retrieved 9 December 2016. 294. ^ "IOC sanctions five Russian athletes and publishes first full decision as part of the Oswald Commission findings". International Olympic Committee. 27 November 2017. Retrieved 27 November 2017. 295. ^ "IOC sanctions three Russian athletes as part of Oswald Commission findings". 1 December 2017. 296. ^ "CAS to strip Olympic medals from Russian boxer, Romanian weightlifter". espn.com. 8 December 2016. Retrieved 9 December 2016. 297. ^ "#NoRussiaNoGames: Twitter 'bots' boost Russian backlash against Olympic ban". 9 December 2017 – via Reuters. ## External links[edit] * Russian Athletes Disappear From Competition After Doping Agency Arrives The Moscow Times, 2018 * v * t * e Doping in Russia Russia at Olympics * 2012 Summer Olympics * 2014 Winter Olympics * Paralympics * 2016 Summer Olympics * Paralympics * 2018 Winter Olympics * Paralympics * 2020 Summer Olympics * Paralympics Investigations * Garcia Report * WADA investigation * McLaren Report * Oswald Commission Organisations * ROC * IOC * RUSADA * WADA * ARAF * IAAF * FSB * Ministry of Sport (Russia) Involved people * Thomas Bach * Bryan Fogel * Richard McLaren * Vitaly Mutko * Denis Oswald * Dick Pound * Grigory Rodchenkov * Hajo Seppelt * Yuliya Stepanova * James Walden Related articles * Meldonium * Icarus (2017 film) * List of stripped Olympic medals * Doping at the Olympic Games * Houston Astros sign stealing scandal * v * t * e Olympic Games scandals and controversies By year * 2008 (summer) * 2010 (winter) * 2012 (summer) * 2014 (winter) * 2016 (summer) * 2018 (winter) * 2020 (summer) * 2022 (winter) * 2024 (summer) Boycotts * 1936 * 1956 * 1964 * 1976 * 1980 * 1984 * 1988 Alternative competitions * People's Olympiad (1936) * Games of the New Emerging Forces (1963) * Liberty Bell Classic (1980) * Friendship Games (1984) * Goodwill Games (1986–2001) Events * Football match between Peru and Austria (1936) * "Blood in the Water" water polo match (1956) * Tlatelolco massacre (1968) * Black Power salute (1968) * Munich massacre (1972) * Basketball gold medal match controversy (1972) * Black Power salute (1972) * Kozakiewicz's gesture (1980) * Centennial Olympic Park bombing (1996) * Winter Olympic bid scandal (1998) * Figure-skating judging scandal (2002) * Underage gymnasts controversy (2008) * Death of Nodar Kumaritashvili (2010) * One minute of silence campaign (2012) * LGBT rights protests (2014) * Sochi Ladies' singles judging controversy (2014) * Russian doping scandal (2015–present) * Ireland Summer Olympics ticket scandal (2016) * Death of Bahman Golbarnezhad (2016) * Lochtegate (2016) * Rule 40 (2016) * Impact of COVID-19 (2019–present) * List of stripped Olympic medals * Doping at the Olympic Games * Apartheid-era South Africa and the Olympics [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Doping in Russia	None	5,284	wikipedia	https://en.wikipedia.org/wiki/Doping_in_Russia	2021-01-18T18:45:30	{"wikidata": ["Q44013763"]}
In utero onset was noted by Badr El-Din (1960), who described the condition in sibs as a familial convulsive disorder. Other features were mental retardation, generalized hypertonus, reflex myoclonus, and death in the first year. Winkelman and Moore (1942) described a single case with antenatal onset. Liu and Sylvester (1960) reported a disorder beginning near or before birth and characterized by mental deterioration, fits, spasticity, paralysis, deafness, and blindness. The parents were not related and 2 brothers were affected. The condition could, of course, be X-linked as well as autosomal recessive. Intrauterine convulsions also occur in pyridoxine dependency (Bejsovec et al., 1967); see 266100. Growth \- Death in infancy Neuro \- Prenatal onset seizures \- Mental retardation \- Generalized hypertony \- Reflex myoclonus Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CONVULSIVE DISORDER, FAMILIAL, WITH PRENATAL OR EARLY ONSET	c1857575	5,285	omim	https://www.omim.org/entry/217200	2019-09-22T16:29:25	{"mesh": ["C565678"], "omim": ["217200"]}
Pang et al. (1986) described 2 sisters with lid retraction on adduction, the classic sign of levator-oculomotor synkinesis. In both women the left eye was involved. There was no history of trauma or ocular surgery and there were no complaints of diplopia. Both sisters had good visual acuity and full ocular motility. Each exhibited 2 mm of left upper lid elevation on adduction and 2 to 6 mm with elevation on adduction with depression. One sister showed 1 mm of ptosis in straight ahead gaze in the involved eye; this increased to almost 2 mm on abduction but full levator function was observed. Four other family members in 3 generations in a pattern consistent with autosomal dominant inheritance were described. The family showed 1 instance of male-to-male transmission and 2 instances of failure of penetrance in transmitting females. The levator muscle is involved in 2 other forms of congenital synkinesis: the Duane retraction syndrome (126800) and the Marcus Gunn jaw-winking phenomenon (154600). Eyes \- Eyelid retraction on adduction Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	LEVATOR-MEDIAL RECTUS SYNKINESIS	c1835403	5,286	omim	https://www.omim.org/entry/151610	2019-09-22T16:38:57	{"mesh": ["C563625"], "omim": ["151610"], "synonyms": ["Alternative titles", "OCULOMOTOR-LEVATOR SYNKINESIS"]}
A psychological disorder derived from parental depression Paternal depression Other namesPostpartum depression, Postnatal depression SpecialtyPsychiatry SymptomsAnxiety, extreme sadness, substance abuse, irritability, violence, risky behavior, anger attacks ComplicationsRelationships with partner and children Usual onsetEarly pregnancy to years postpartum CausesUnclear Risk factorsPrior mental disorder and drug abuse, bipolar disorder, family history of depression, psychological stress, upholding multiple social roles, lack of support Diagnostic methodBased on severity of symptoms Differential diagnosisBaby blues TreatmentCounselling, medications, electroconvulsive therapy (ECT) MedicationAntidepressants Paternal depression is a psychological disorder derived from parental depression. Paternal depression affects the mood of men; fathers and caregivers in particular. 'Father' may refer to the biological father, foster parent, social parent, step-parent or simply the carer of the child. This mood disorder exhibits symptoms similar to postpartum depression (PPD) including anxiety, insomnia, irritability, consistent breakdown and crying episodes, and low energy.[1] This may negatively impact family relationships and the upbringing of children.[2] Parents diagnosed with parental depression often experience increased stress and anxiety levels during early pregnancy, labor and postpartum.[2] Those with parental depression may have developed it early on but some are diagnosed later on from when the child is a toddler up until a young adult. The causes of paternal depression are unclear; however, previous experiences of mental disorders and family history can contribute to the development of paternal depression.[3] Other factors including stress overload, sleep deprivation and unhappy relationships with one's partner or children may also affect its prevalence.[4] Although symptoms of feeling down, baby blues and a lack of sleep are common amongst new parents, a diagnosis of depression is appropriate when symptoms are severe and ongoing.[5] Most health literature provides studies and research on maternal depression and women with postnatal depression.[6] However, there is limited information about men and mental illness. Modern society and culture have changed social stigma of men with mental illness due to changes in gender role perspectives.[7] ## Contents * 1 Signs and symptoms compared to women * 2 Causes * 3 Prevalence * 3.1 Men in the U.S. * 4 Treatment * 4.1 Psychotherapy * 4.2 Antidepressants * 4.3 Self-care * 5 Society and culture * 5.1 Stigma of men with mental illness * 6 References ## Signs and symptoms compared to women[edit] When comparing the anxiety level of first-time parents, women tend to have higher levels of anxiety. This is applicable to women immediately after birth and in the first three trimesters.[6] Compared to women, men experience greater anxiety levels within the first 3 months of childbirth and develop paternal depression as the children grows older.[5] Although depression can affect individuals in different ways, there are some gender differences between parents. Women tend to have similar depressive symptoms over all three trimesters, however in men, there are significant changes between the 1st and 2nd trimester, but not between the 2nd trimester to 3 months postpartum.[6] Women are also more likely to experience symptoms such as developing an eating disorder, irritability, crying episodes, extreme sadness, bipolar disorder and low energy levels.[8] Men are more likely to experience substance abuse, a higher frequency of irritability, anger attacks and becoming abusive and violent. Men may also partake in risk-taking behaviour such as drink driving. Despite common symptoms of loss of appetite and insomnia, women are more likely to display atypical behaviours such as oversleeping and overeating.[9] Fatal suicide attempts are also more often associated with fathers rather than with mothers.[10] Prevalence of depressive symptoms in men and women from pregnancy to 3-months postpartum[6] ## Causes[edit] In general, the causes of maternal and paternal depression are similar. Common causes include having limited emotional and social support, experiencing financial stress, having an unsatisfying relationship with one's partner, finding difficulty adjusting to parenting, unexpected events in child development and personal histories of mental disorders and drug abuse.[3] According to a study conducted in 2005, 65% of males identified with depressive symptoms when the child was 8 weeks old.[4] The causes of paternal depression include stress overload, caring responsively to the children, undertaking multiple family and social roles and a decrease in direct father to child interaction.[4] Fathers of young boys are most vulnerable to paternal depression during the child's early and behavioural development. This is caused by young boys having the tendency to be hyperactive and harder to discipline.[4] This causes the father to be concerned and frustrated. There is a positive correlation between a boy's misbehaviour and depression in fathers.[4] ## Prevalence[edit] ### Men in the U.S.[edit] Studies show that 14.1% of men suffer from postpartum depression.[11] Outside of the U.S. 8.2% of men experience depressive symptoms. The observation of postpartum depression could be categorised into the time blocks of paternal depression: first trimester to 6 months gestational age, >6 months to birth, immediate postpartum to 3 months postpartum, >3 to 6 months postpartum and >6 to 12 months postpartum.[11] During the period of 3 to 6 months postpartum, the highest rate of 25.6% was recorded in men whilst the lowest occurred during the first three months of postpartum at 7.7%. The high levels of depression during the 3 to 6 months postpartum period is also similar amongst women.[11] These results could be explained by the strenuousness of 3 to 6 months newborn care. ## Treatment[edit] Treatment for paternal depression depends on the severity of it.[5] Light to moderate symptoms could be treated at home. This includes being well-rested, getting alone time, eating a well-balanced diet with adequate amounts of water and exercise, accepting social support from partner, friends and family.[12] Joining local community groups and creating bonds with other fathers experiencing similar symptoms will decrease stress and create a sense of relief. However, treatment of mild to severe depression would require further action. Outlines some of the common treatment available for PPD, excluding psychotherapy and antidepressants.[13][12][14] Treatments offered for parents with depression are similar to other mental disorders. This includes taking antidepressants or receiving psychotherapy.[15] Those experiencing moderate paternal depression should seek therapy from a mental health professional. This may be a psychiatrist, counselor or psychologist. However, if experiencing intense depression, medical intervention may be necessary.[16] Consult your health professional about medication including mood stabilizers. Other methods to recovery include electroconvulsive therapy (ECT).[17] This releases short electrical currents to the brain, allowing it to relax. It is recommended when all other procedures are ineffective. There are other alternatives to treatment. This includes self-care in the form of relaxation, massage, herbal medicine and chiropractic services.[14] ### Psychotherapy[edit] Psychotherapy aids PPD treatment by approaching it with psychological, rather than biological, intervention.[18] Many parents with PPD prefer psychological treatment as it limits any potential side affects that will influence the child. Common therapy styles include interpersonal therapy, cognitive-behavioural therapy, psychodynamic psychotherapy and non-directive counseling.[19] Therapy could be conducted individually or couple therapy is also an option. This is practical in addressing support at home along with your relationship with your partner.[20] In general, therapy may take anywhere between a few weeks to months to be effective. However, severe symptoms will require intense psychotherapy which may take up to years.[18] ### Antidepressants[edit] Pharmacological treatment such as antidepressant medication is a growing method of treatment with a recent increase in literature surrounding the topic.[21][22] This is given to those that experience severe PPD as it balances the chemicals in the brain that affect mood.[23] Mothers tend to avoid antidepressants with many fearing its impact on breast milk.[19][24] However, it is an effective way in treating depression amongst fathers. There are several factors that the father may want to consider; this includes metabolic changes, mood changes, memory loss, drowsiness and possible side effects influencing child care. Medication needs to be under the supervision of a medical professional and is proven to be even more effective when accompanied with psychotherapy.[20] ### Self-care[edit] There are a number of ways to treat PPD at home. These methods are recommended for those with moderate PPD. However, severe PPD will require intensive intervention. The following practices will promote a healthier and positive lifestyle and are beneficial to anyone: talking to loved ones, taking alone time, getting sufficient amounts of rest, exercising regularly and eating a balanced diet.[24] Not skipping meals, prioritising sleep and getting outside will improve mental health and increase feelings of satisfaction and fulfilment.[20] ## Society and culture[edit] Main article: Mental disorders and gender Further information: Gender roles The increase of paternal depression could be explained by women's increasing input into social roles.[25] Women contributing to the workforce leads to more fathers becoming involved with family life. This increases the possibility of developing paternal depression. Paternal depression is a frequently neglected topic.[16] It challenges social normalities of gender roles, the stereotypes of fatherhood, masculinity and social stigma on men with mental health.[25] The progressive perception of fathers being the primary parent leads to further increase in father involvement. National policies have not progressed with the changes in gender roles. This includes the difficulties in receiving of paternal leave and receiving custody.[26] This is influenced by the limited studies on fathers and depression. However, the recent increase of research into paternal depression shows society's views on increasing gender equality in social roles and the changing culture on masculine and feminine concepts.[7] ### Stigma of men with mental illness[edit] How the stigma of men with mental illness influence the prevalence of seeking treatment[27] There is often stigma around mental illness, especially for men. Severe stigma usually takes forms of discrimination, prejudice and stereotypes. These categorise how society view mental disorders. Paired with gender roles and the concepts of masculinity and femininity, society views men with mental impairments as weak and vulnerable and not the stereotypical alpha male.[7] This then affects how men view their own mental disability, influencing the seeking of treatment and acceptance of the illness.[16] This cause and effect relationship can create a cycle, leading men to be disheartened and ashamed of reaching out. According to the Australian Black Dog Institute, it is estimated that 72% of men do not seek treatment for mental disorders.[27] ## References[edit] 1. ^ Mickelson KD, Biehle SN, Chong A, Gordon A (2017-03-01). "Perceived Stigma of Postpartum Depression Symptoms in Low-Risk First-Time Parents: Gender Differences in a Dual-Pathway Model". Sex Roles. 76 (5): 306–318. doi:10.1007/s11199-016-0603-4. S2CID 147479681. 2. ^ a b Delrosario, G. A.; Chang, A. C.; Lee, E. D. (2013). "Wolters Kluwer Health - Article Landing Page". JAAPA. 26 (2): 50–4. doi:10.1097/01720610-201302000-00009. PMID 23409386. S2CID 7842384. Retrieved 2019-05-13. 3. ^ a b "beyondblue". www.beyondblue.org.au. Retrieved 2019-05-13. 4. ^ a b c d e Ramchandani P, Stein A, Evans J, O'Connor TG (2005-06-25). "Paternal depression in the postnatal period and child development: a prospective population study". Lancet. 365 (9478): 2201–5. doi:10.1016/S0140-6736(05)66778-5. PMID 15978928. S2CID 34516133. 5. ^ a b c Kanopy (Firm), Recognizing and treating postpartum depression., OCLC 897768040 6. ^ a b c d Figueiredo B, Conde A (July 2011). "Anxiety and depression symptoms in women and men from early pregnancy to 3-months postpartum: parity differences and effects". Journal of Affective Disorders. 132 (1–2): 146–57. doi:10.1016/j.jad.2011.02.007. hdl:1822/41604. PMID 21420178. 7. ^ a b c Boysen GA (2017-01-02). "Exploring the relation between masculinity and mental illness stigma using the stereotype content model and BIAS map". The Journal of Social Psychology. 157 (1): 98–113. doi:10.1080/00224545.2016.1181600. PMID 27110638. S2CID 13093367. 8. ^ Nierenberg, Cari; October 27, Contributing writer; ET, 2016 03:22am. "7 Ways Depression Differs in Men and Women". Live Science. Retrieved 2019-05-13. 9. ^ Silverstein B, Angst J (2015). "Evidence for Broadening Criteria for Atypical Depression Which May Define a Reactive Depressive Disorder". Psychiatry Journal. 2015: 575931. doi:10.1155/2015/575931. PMC 4516843. PMID 26258131. 10. ^ England MJ, Sim LJ, editors (2009). Depression in Parents, Parenting, and Children : Opportunities to Improve Identification, Treatment, and Prevention. National Academies Press (US). OCLC 971082452.CS1 maint: multiple names: authors list (link) 11. ^ a b c Bond S (September 2010). "Men suffer from prenatal and postpartum depression, too; rates correlate with maternal depression". Journal of Midwifery & Women's Health. 55 (5): e65-6. doi:10.1016/j.jmwh.2010.06.015. PMID 20732656. 12. ^ a b "Postpartum Depression: A Guide to Symptoms & Treatment". PsyCom.net - Mental Health Treatment Resource Since 1986. Retrieved 2019-05-16. 13. ^ "Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey". Complementary Therapies in Medicine. 7 (3): 191–192. 1990–1999. doi:10.1016/s0965-2299(99)80132-0. ISSN 0965-2299. 14. ^ a b Hendrick, Victoria (August 2003). "Alternative Treatments for Postpartum Depression". Psychiatric Times. 15. ^ "Postpartum depression - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2019-05-16. 16. ^ a b c Cameron EE, Hunter D, Sedov ID, Tomfohr-Madsen LM (June 2017). "What do dads want? Treatment preferences for paternal postpartum depression". Journal of Affective Disorders. 215: 62–70. doi:10.1016/j.jad.2017.03.031. PMID 28319693. 17. ^ Verwijk E, Comijs HC, Kok RM, Spaans HP, Stek ML, Scherder EJ (November 2012). "Neurocognitive effects after brief pulse and ultrabrief pulse unilateral electroconvulsive therapy for major depression: a review". Journal of Affective Disorders. 140 (3): 233–43. doi:10.1016/j.jad.2012.02.024. PMID 22595374. 18. ^ a b "Postpartum Depression Treatment, Screening, Causes & Symptoms". MedicineNet. Retrieved 2019-05-27. 19. ^ a b Fitelson E, Kim S, Baker AS, Leight K (December 2010). "Treatment of postpartum depression: clinical, psychological and pharmacological options". International Journal of Women's Health. 3: 1–14. doi:10.2147/IJWH.S6938. PMC 3039003. PMID 21339932.CS1 maint: uses authors parameter (link) 20. ^ a b c Melinda (2018-11-02). "Postpartum Depression and the Baby Blues - HelpGuide.org". Retrieved 2019-05-27. 21. ^ Payne JL (September 2007). "Antidepressant use in the postpartum period: practical considerations". The American Journal of Psychiatry. 164 (9): 1329–32. doi:10.1176/appi.ajp.2007.07030390. PMID 17728416. 22. ^ Battle CL, Zlotnick C, Pearlstein T, Miller IW, Howard M, Salisbury A, Stroud L (2008–2010). "Depression and breastfeeding: which postpartum patients take antidepressant medications?". Depression and Anxiety. 25 (10): 888–91. doi:10.1002/da.20299. PMC 3918906. PMID 17431885. 23. ^ "Postpartum depression: Symptoms, causes, and diagnosis". Medical News Today. Retrieved 2019-05-27. 24. ^ a b "Treatment". nhs.uk. 2018-10-03. Retrieved 2019-05-27. 25. ^ a b Fisher SD (2016-02-16). "Paternal Mental Health: Why Is It Relevant?". American Journal of Lifestyle Medicine. 11 (3): 200–211. doi:10.1177/1559827616629895. PMC 6125083. PMID 30202331. 26. ^ Qadar, By Sana (2019-05-05). "Three fathers' experiences taking parental leave - ABC Life". www.abc.net.au. Retrieved 2019-05-13. 27. ^ a b Australia. Department of Health and Ageing. Australia. Department of Health and Ageing. Health Priorities and Suicide Prevention Branch. (2013). National mental health report 2013 : tracking progress of mental health reform in Australia, 1993-2011. Dept. of Health and Ageing. ISBN 9781742419251. OCLC 948775488. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Paternal depression	None	5,287	wikipedia	https://en.wikipedia.org/wiki/Paternal_depression	2021-01-18T19:08:24	{"wikidata": ["Q64485022"]}
Bech-Hansen et al. (1981) studied a family in which members had had a diversity of neoplasms over 6 generations (originally reported by Blattner et al., 1979). Two members had neoplasms of possible radiogenic origin. Gamma-irradiation survival studies of cultured skin fibroblasts in these 2 patients and in 3 other relatives, but not their spouses, over 3 generations demonstrated resistance to cell killing. Radioresistance, as well as radiosensitivity (e.g., in ataxia-telangiectasia and xeroderma pigmentosum to gamma- and UV-irradiation, respectively), measured in vitro may be a marker for increased cancer risk. Thus, one subset of 'cancer families,' such as that described by Li and Fraumeni (1969), may represent this category. Oncology \- Familial cancer \- Possible radiogenic tumor origin Lab \- In vitro resistance to cell killing by gamma-irradiation Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CANCER, FAMILIAL, WITH IN VITRO RADIORESISTANCE	c1861915	5,288	omim	https://www.omim.org/entry/114450	2019-09-22T16:43:52	{"mesh": ["C566179"], "omim": ["114450"]}
For references, see 152200. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	LIPOPROTEIN TYPES--Lt SYSTEM	c1835359	5,289	omim	https://www.omim.org/entry/152300	2019-09-22T16:38:49	{"omim": ["152300"]}
Cotton and Harris (1962) reported a brother and sister with pyridoxine-responsive sideroblastic anemia. Inheritance was not consistent with the more common X-linked form (XLSA; 300751) and autosomal recessive inheritance was proposed. Kasturi et al. (1982) reported severe sideroblastic anemia with moderate hepatosplenomegaly in 2 male and 2 female sibs from a Libyan family. The disorder was pyridoxine-responsive. The parents were not consanguineous, but Kasturi et al. (1982) suggested autosomal recessive inheritance. Inheritance \- Autosomal recessive \- X-linked form more common Heme \- Anemia, pyridoxine-responsive \- Microcytosis \- Hypochromia \- Ringed sideroblasts in marrow ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ANEMIA, SIDEROBLASTIC, PYRIDOXINE-RESPONSIVE, AUTOSOMAL RECESSIVE	c1859787	5,290	omim	https://www.omim.org/entry/206000	2019-09-22T16:31:05	{"mesh": ["C565954"], "omim": ["206000"], "synonyms": ["Alternative titles", "ANEMIA, CONGENITAL SIDEROBLASTIC, B6-RESPONSIVE"]}
Junctional epidermolysis bullosa, Herlitz-type is a severe subtype of junctional epidermolysis bullosa (JEB, see this term) characterized by blisters and extensive erosions, localized to the skin and mucous membranes. ## Epidemiology Reported incidence ranges are 1/2,500,000 and 1/1,470,000 live births in the United States and Italy, respectively, and 1/250,000 live births in the Netherlands. According to data from U.S. and Italian EB registries, about 20% of patients with JEB have the more severe Herlitz type. ## Clinical description The condition is present at birth. Exuberant granulation tissue is a characteristic manifestation, which usually arises within the first several months to one to two years of life, and may involve the skin (around nail folds, in a mask-like distribution on the face, and at sites of friction, such as shoulders and buttocks), and the upper airways. Involvement of mucous membranes may affect the entire gastrointestinal (GI) tract, genitourinary tract, and respiratory tract to the bronchioles. However, the most significant and frequent mucosal lesions are those in the upper part of the GI and respiratory tracts. The numerous erosions and ulcerations of the oral mucosa severely hamper feeding, and involvement of the laryngotracheal mucosa, manifesting as hoarseness, dyspnea and stridor, may lead to acute respiratory failure requiring tracheostomy. Other constant features include nail anomalies with paronychia, various degrees of onychodystrophy and nail shedding. Dental abnormalities, when survival enables their observation, include regularly marked hypoplasia or complete absence of enamel. Frequent ocular lesions comprise corneal blisters, erosions and scarring and ectropion formation. Failure to thrive is an almost constant finding in JEB-H, and multifactorial anemia is also common. ## Etiology JEB-H is caused by mutations in one of the three laminin-332 coding genes: LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31). In most cases, null mutations are found on both alleles of the causative gene. ## Diagnostic methods In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone, a negative immunofluorescence staining for laminin-332 is typical of JEB-H. However, in rare cases the staining is strongly reduced and thus does not enable differentiation of JEB-H from JEB non-Herlitz (see this term). In these cases, genetic testing, showing null mutations in one of the three genes encoding laminin-332, is necessary to confirm the diagnosis. ## Antenatal diagnosis Genetic testing allows prenatal diagnosis for pregnancies at increased risk. ## Genetic counseling The condition follows an autosomal recessive pattern of inheritance. ## Prognosis Prognosis is poor and most JEB-H patients die in the first few years of life, with the major causes of death being failure to thrive, respiratory failure, sepsis, and pneumonia. In addition, squamous cell carcinomas may arise in a minority of JEB-H patients (4.5% according to data from the U.S. National EB Registry). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Junctional epidermolysis bullosa, generalized severe	c0079683	5,291	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79404	2021-01-23T18:44:20	{"gard": ["2153"], "mesh": ["D016109"], "omim": ["226700"], "umls": ["C0079683"], "icd-10": ["Q81.1"], "synonyms": ["Epidermolysis bullosa letalis", "JEB, generalized severe", "JEB-H", "Junctional epidermolysis bullosa generalisata gravis", "Junctional epidermolysis bullosa, Herlitz type", "Junctional epidermolysis bullosa, Herlitz-Pearson type"]}
Isolated delta-storage pool disease is a rare, isolated, constitutional thrombocytopenia disorder characterized by defective formation and/or malfunction of platelet dense granules, as well as melanosomes in skin cells, resulting in variable manifestations ranging from mild bleeding and easy bruising to moderate mucous/cutaneous hemorrhagic diathesis and bleeding complications after surgery. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Isolated delta-storage pool disease	None	5,292	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=248340	2021-01-23T17:24:19	{"icd-10": ["D69.1"], "synonyms": ["Isolated delta-SPD", "Isolated dense-SPD", "Isolated dense-storage pool disease"]}
Urachal cancer is a type of bladder cancer, making up less than 1% of all bladder cancers. The urachus is a structure normally only present during development in the womb that connects the bellybutton and the bladder. This connection normally disappears before birth, but in some people remains. Urachal cancers are usually diagnosed in adults in their 50's and 60's and may develop at the dome or anterior wall of the bladder, along the midline of the body (including the belly button), and between the pubis symphasis and the bladder. Most urachal cancers are adenocarcinomas (cancers that develop from gland cells). Others may be sarcomas (which develop from connective tissue - such as leiomyosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma), small cell carcinomas, transitional cell cancer, and mixed neoplasias. Most individuals with urachal cancer have symptoms of with hematuria (blood in urine). Other symptoms may include abdominal pain, a palpable abdominal mass, mucinuria, and bacteriuria. Treatment usually involved surgery to remove the cancer. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Urachal cancer	c2931202	5,293	gard	https://rarediseases.info.nih.gov/diseases/7836/urachal-cancer	2021-01-18T17:57:13	{"mesh": ["C536475"], "umls": ["C2931202"], "synonyms": ["Urachal carcinoma"]}
Van den Bosch syndrome is characterized by intellectual deficit, choroideremia, acrokeratosis verruciformis, anhidrosis, and skeletal deformities. It has been observed in a single kindred. The syndrome is transmitted as an X-linked recessive trait and may be caused by a small X-chromosome deletion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Van den Bosch syndrome	c0796192	5,294	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3417	2021-01-23T19:10:51	{"gard": ["5453"], "mesh": ["C563129"], "omim": ["314500"], "umls": ["C0796192"]}
A rare, systemic, autoimmune disease characterized by inflammation in any organ system, with onset prior to adulthood, presenting highly variable clinical manifestations, which usually have a more aggressive course and higher rate of major organ involvement than adult-onset systemic lupus erythematosus, resulting in potential damage to a variety of organs (e.g. the skin, kidneys, lungs, nervous system). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pediatric systemic lupus erythematosus	None	5,295	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93552	2021-01-23T17:17:55	{"icd-10": ["M32.0", "M32.1", "M32.8", "M32.9"], "synonyms": ["SLE, pediatric onset"]}
Brazilian hemorrhagic fever, caused by the Sabia virus (a newly discovered arenavirus), is a viral hemorrhagic fever, believed to originate from Sao Paulo, Brazil, with only 3 reported cases (2 of which were due to laboratory accidents) to date, characterized by fever, nausea vomiting myalgia tremors, and hemorragic manifestations such as conjunctival petechia and haematemesis, leading potentially to shock, coma and death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Brazilian hemorrhagic fever	c0343633	5,296	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319239	2021-01-23T18:37:08	{"umls": ["C0343633"], "icd-10": ["A96.8"], "synonyms": ["Sabia hemorrhagic fever"]}
MEN type 2A (Sipple syndrome) Other namesMEN2 Bilateral pheochromocytomas associated with Multiple endocrine neoplasia type 2 SpecialtyOncology Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary thyroid carcinoma",[1] "PTC syndrome,"[1] and "Sipple syndrome"[1]) is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant (cancer). They generally occur in endocrine organs (e.g. thyroid, parathyroid, and adrenals), but may also occur in endocrine tissues of organs not classically thought of as endocrine.[2] MEN2 is a sub-type of MEN (multiple endocrine neoplasia) and itself has sub-types, as discussed below. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Genetics * 4 Diagnosis * 4.1 Differences in presentation * 4.2 Classification * 5 Management * 6 Prognosis * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] MEN2 can present with a sign or symptom related to a tumor or, in the case of multiple endocrine neoplasia type 2b, with characteristic musculoskeletal and/or lip and/or gastrointestinal findings.[citation needed] Medullary thyroid carcinoma (MTC) represents the most frequent initial diagnosis. Occasionally pheochromocytoma or primary hyperparathyroidism may be the initial diagnosis. Pheochromocytoma occurs in 33-50% of MEN2 cases.[3] In MEN2A, primary hyperparathyroidism occurs in 10–50% of cases and is usually diagnosed after the third decade of life. Rarely, it may present in childhood or be the sole clinical manifestation of this syndrome.[citation needed]MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20–50% of cases and with primary hyperparathyroidism in 5–20% of cases.[citation needed] MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with marfanoid habitus and with mucosal and digestive neurofibromatosis. In familial isolated medullary thyroid carcinoma the other components of the disease are absent.[citation needed] In a review of 85 patients 70 had MEN2A and 15 had MEN2B.[3] The initial manifestation of MEN2 was medullary thyroid carcinoma in 60% of patients, medullary thyroid carcinoma synchronous with pheochromocytoma in 34% and pheochromocytoma alone in 6%. 72% had bilateral pheochromocytomas. ## Causes[edit] The table in the multiple endocrine neoplasia article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin. A database of MEN-implicated RET mutations is maintained by the University of Utah Department of Physiology.[4] The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM # 164761 lists the syndromes associated with the RET gene. ## Genetics[edit] Most cases of multiple endocrine neoplasia type 2 are inherited in an autosomal dominant pattern. When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations. ## Diagnosis[edit] Diagnosis is suspected when a patient with family history of two of the three classical tumors (medullary thyroid cancer, pheochromocytoma, parathyroid adenoma) or MEN2 presents with one of the classical tumors. It is confirmed by genetic testing for mutation in RET gene.[5] ### Differences in presentation[edit] As noted, all types of MEN2 include pheochromocytoma and medullary thyroid carcinoma. MEN2A is additionally characterized by the presence of parathyroid hyperplasia. MEN2B is additionally characterized by the presence of mucocutaneous neuroma, gastrointestinal symptoms (e.g. constipation and flatulence), and muscular hypotonia. MEN2B can present with a Marfanoid habitus.[6] ### Classification[edit] Before gene testing was available, the type and location of tumors determined which type of MEN2 a person had. Gene testing now allows a diagnosis before tumors or symptoms develop. A table in the multiple endocrine neoplasia article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes MEN2A, MEN2B and familial medullary thyroid cancer (FMTC). The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma. A variant of MEAs 2A was described in 1989.[7] This variant also has patches of cutaneous amyloidosis in the mid/upper back and is inherited in an autosomal dominat fashion.[8] ## Management[edit] Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.[citation needed] ## Prognosis[edit] Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects. ## See also[edit] * Multiple endocrine neoplasia * Multiple endocrine neoplasia type 1 * Multiple endocrine neoplasia type 2b * Multiple mucosal neuromata ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Moline J, Eng C (2011). "Multiple endocrine neoplasia type 2: an overview". Genet. Med. 13 (9): 755–64. doi:10.1097/GIM.0b013e318216cc6d. PMID 21552134. S2CID 22402472. 3. ^ a b Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA, Jimenez C (2013) The characterization of pheochromocytoma and its impact on overall survival in Multiple Endocrine Neoplasia type 2. J Clin Endocrinol Metab 4. ^ "MEN2 Database". University of Utah. 5. ^ "Multiple Endocrine Neoplasia Type 2". Cancer.Net. 2012-06-25. Retrieved 2018-01-15. 6. ^ Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB (January 2008). "Failure to recognize multiple endocrine neoplasia 2B: more common than we think?". Ann. Surg. Oncol. 15 (1): 293–301. doi:10.1245/s10434-007-9665-4. PMID 17963006. S2CID 2564555. 7. ^ Donovan DT, Levy ML, Furst EJ, Alford BR, Wheeler T, Tschen JA, Gagel RF (1989) Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: a new variant. Henry Ford Hosp Med J 37(3-4):147-150 8. ^ Jabbour SA, Davidovici BB, Wolf R (2006) Rare syndromes. Clin Dermatol 24(4):299-316 ## External links[edit] * MEN2 (RET) gene variant database * GeneReview/NIH/UW entry on Multiple Endocrine Neoplasia Type 2 Classification D * ICD-10: D44.8 * ICD-9-CM: 258.02 * OMIM: 171400 * MeSH: D018813 * DiseasesDB: 7984 External resources * MedlinePlus: 000399 * eMedicine: med/1520 * GeneReviews: Multiple Endocrine Neoplasia Type 2 * v * t * e Disorders involving multiple endocrine glands * Autoimmune polyendocrine syndrome * APS1 * APS2 * Carcinoid syndrome * Multiple endocrine neoplasia * 1 * 2A * 2B * Progeria * Werner syndrome * Acrogeria * Metageria * Woodhouse–Sakati syndrome * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Multiple endocrine neoplasia type 2	c1833921	5,297	wikipedia	https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_2	2021-01-18T18:50:13	{"gard": ["4881"], "mesh": ["C536911", "D018813"], "umls": ["C1833921"], "orphanet": ["247698", "653"], "wikidata": ["Q604075"]}
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-like (DBAL) is caused by homozygous mutation in the EPO gene (133170) on chromosome 7q21. One such family has been reported. Clinical Features Kim et al. (2017) reported a 6-year-old boy, born of consanguineous Turkish parents, who was diagnosed with severe red cell hypoplastic anemia requiring regular transfusions at 1 year of age. Bone marrow analysis showed selective absence of erythroid precursors and progenitors, consistent with a provisional diagnosis of Diamond-Blackfan anemia (see, e.g., DBA1, 105650). Serum EPO levels were inappropriately increased even when he received transfusions. At age 6 years, he underwent bone marrow transplant and achieved full donor chimerism, but still required transfusions. He subsequently died of transplant complications. A younger sib was subsequently diagnosed clinically and molecularly with the same disorder; she was successfully treated with recombinant EPO. Clinical Management Kim et al. (2017) reported successful treatment of a child with DBAL using recombinant EPO. Inheritance The transmission pattern of DBAL in the family reported by Kim et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 sibs, born of consanguineous parents, with DBAL, Kim et al. (2017) identified a homozygous missense mutation in the EPO gene (R150Q; 133170.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Mutations in genes known to be involved in DBA were excluded in the proband. In vitro functional expression studies using recombinant wildtype and mutant EPO showed that the R150Q mutation only mildly affected overall affinity to the EPO receptor (EPOR; 133171), but significantly altered the kinetics of binding to the receptor, with significantly faster dissociation compared to wildtype. Studies on cultured erythroid cells and CD34+ hematopoietic stem cells showed that increased concentration of the R150Q mutated protein was unable to compensate for the defect in erythropoiesis. Intracellular flow cytometry and Western blot analysis examining downstream EPO receptor pathways showed a selective decrease in JAK2 (147796)-mediated phosphorylation of STAT1 (600555) and STAT3 (102582). Further studies indicated that the R150Q mutant had reduced ability to promote dimerization of the EPO receptor, resulting in decreased JAK2 activation, even at maximally potent concentrations, and impaired downstream signal transduction. Kim et al. (2017) discussed the role of functional selectivity and biased agonists in receptor signaling. INHERITANCE \- Autosomal recessive HEMATOLOGY \- Anemia, red cell, hypoplastic \- Selective absence of red cell precursors and progenitors seen on bone marrow biopsy LABORATORY ABNORMALITIES \- Increased serum erythropoietin (EPO) MISCELLANEOUS \- Onset in infancy \- Favorable response to treatment with recombinant EPO \- One consanguineous Turkish family has been reported (last curated March 2018) MOLECULAR BASIS \- Caused by mutation in the erythropoietin gene (EPO, 133170.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DIAMOND-BLACKFAN ANEMIA-LIKE	c4693556	5,298	omim	https://www.omim.org/entry/617911	2019-09-22T15:44:28	{"omim": ["617911"]}
Congenital deafness with vitiligo and achalasia is a syndrome characterized by deafness present from birth (congenital), associated with short stature, vitiligo, muscle wasting and achalasia (swallowing difficulties). The condition was described in a brother and sister born to first cousin parents. It is believed to be inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital deafness with vitiligo and achalasia	c1857339	5,299	gard	https://rarediseases.info.nih.gov/diseases/1705/congenital-deafness-with-vitiligo-and-achalasia	2021-01-18T18:01:10	{"mesh": ["C565642"], "omim": ["221350"], "orphanet": ["3239"], "synonyms": ["Deafness vitiligo achalasia"]}

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