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This article is about a vasculitis syndrome caused by ADA2 gene mutations. For the metabolic disorder caused by different ADA gene mutations, see Adenosine deaminase deficiency. Adenosine deaminase 2 deficiency Other namesDADA2 Autosomal recessive pattern is the inheritance manner of this condition SpecialtyMedical genetics CausesMutations in the ADA2 gene Adenosine deaminase 2 deficiency (DADA2) is a vasculitis syndrome.[1][2] It is due to mutations in the ADA2 gene which encodes the adenosine deaminase 2 protein. The clinical features of this condition are protean and it may be easily missed. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 Epidemiology * 7 History * 8 References ## Signs and symptoms[edit] The age of onset of symptoms is variable: 24% of reported patients present before 1 year of age. 77% present before the age 10 years. Adult onset has also been described. 5-10% die from this disease by the age of 30 years.[citation needed] Like all vasculitis syndromes the features depend on which is organ is involved. Most commonly the gut, kidney and liver are affected. It may manifest as lacunar and/or hemorrhagic strokes, cutaneous lesions or polyarteritis nodosa.[3] Hypertension and hepatosplenomegaly may occur. It may affect the skin (livedo reticularis and livedo racemosa) or brain (stroke).[4] Polyarteritis nodosa in children is also known to occur.[5] Other conditions associated with this syndrome include hypogammaglobulinemia, pure red cell aplasia,[6] immune thrombocytopenia and neutropenia. ## Genetics[edit] The ADA2 gene is located in the long arm of chromosome 22 (22q11.1).[citation needed] Over 60 pathogenic mutations have been recognised in ADA2. In all clinical cases to date both copies of the gene have been mutated implying a recessive inheritance.[citation needed] ## Pathophysiology[edit] This is not understood. The gene is expressed in myeloid cells and macrophages but its function is not known.[citation needed] ## Diagnosis[edit] ### Differential diagnosis[edit] This includes common variable immunodeficiency,[7] bone marrow failure and idiopathic aplastic anemia. ## Treatment[edit] Thalidomide, tumour necrosis factor antibodies and in severe cases bone marrow transplantation have been used successfully.[8][9] ## Epidemiology[edit] This is a rare condition with less than 200 cases reported.[9] ## History[edit] This condition was first reported in 2014.[10] ## References[edit] 1. ^ Meyts, Isabelle; Aksentijevich, Ivona (2018-06-27). "Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment". Journal of Clinical Immunology. 38 (5): 569–578. doi:10.1007/s10875-018-0525-8. ISSN 0271-9142. PMC 6061100. PMID 29951947. 2. ^ Giannelou, Angeliki; Zhou, Qing; Kastner, Daniel L. (December 2014). "When less is more: primary immunodeficiency with an autoinflammatory kick". Current Opinion in Allergy and Clinical Immunology. 14 (6): 491–500. doi:10.1097/ACI.0000000000000117. ISSN 1473-6322. PMC 4212813. PMID 25337682. 3. ^ Aksentijevich I, Sampaio Moura N, Barron K (2019) Adenosine Deaminase 2 Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, (eds) GeneReviews: University of Washington, Seattle 4. ^ Nanthapisal, Sira; Murphy, Claire; Omoyinmi, Ebun; Hong, Ying; Standing, Ariane; Berg, Stefan; Ekelund, Maria; Jolles, Stephen; Harper, Lorraine (September 2016). "Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases" (PDF). Arthritis & Rheumatology. 68 (9): 2314–2322. doi:10.1002/art.39699. ISSN 2326-5205. PMID 27059682. S2CID 7585215. 5. ^ Caorsi, Roberta; Penco, Federica; Schena, Francesca; Gattorno, Marco (2016-09-08). "Monogenic polyarteritis: the lesson of ADA2 deficiency". Pediatric Rheumatology Online Journal. 14 (1): 51. doi:10.1186/s12969-016-0111-7. ISSN 1546-0096. PMC 5015262. PMID 27609179. 6. ^ Claassen D, Boals M, Bowling KM, Cooper GM, Cox J, Hershfield M, Lewis S, Wlodarski M, Weiss MJ, Estepp JH (2018) Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia. Cold Spring Harb Mol Case Stud 4(6) 7. ^ Springer JM, Gierer SA, Jiang H, Kleiner D, Deuitch N, Ombrello AK, Grayson PC, Aksentijevich I (2018) Deficiency of adenosine deaminase 2 in adult siblings: Many years of a misdiagnosed disease With severe consequences. Front Immunol 9:1361 8. ^ Caorsi, Roberta; Penco, Federica; Grossi, Alice; Insalaco, Antonella; Omenetti, Alessia; Alessio, Maria; Conti, Giovanni; Marchetti, Federico; Picco, Paolo (October 2017). "ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study". Annals of the Rheumatic Diseases. 76 (10): 1648–1656. doi:10.1136/annrheumdis-2016-210802. ISSN 1468-2060. PMID 28522451. S2CID 39815969. 9. ^ a b Hashem, Hasan; Kelly, Susan J.; Ganson, Nancy J.; Hershfield, Michael S. (2017-10-05). "Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders". Current Rheumatology Reports. 19 (11): 70. doi:10.1007/s11926-017-0699-8. ISSN 1534-6307. PMID 28983775. S2CID 207339894. 10. ^ Zhou, Qing; Yang, Dan; Ombrello, Amanda K.; Zavialov, Andrey V.; Toro, Camilo; Zavialov, Anton V.; Stone, Deborah L.; Chae, Jae Jin; Rosenzweig, Sergio D. (2014-03-06). "Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2". New England Journal of Medicine. 370 (10): 911–920. doi:10.1056/nejmoa1307361. ISSN 0028-4793. PMC 4193683. PMID 24552284. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Adenosine deaminase 2 deficiency	c0031036	6,900	wikipedia	https://en.wikipedia.org/wiki/Adenosine_deaminase_2_deficiency	2021-01-18T18:37:43	{"gard": ["12383"], "mesh": ["D010488"], "umls": ["C0031036"], "orphanet": ["404553"], "wikidata": ["Q55603216"]}
A number sign (#) is used with this entry because of evidence that long QT syndrome-5 (LQT5) is caused by heterozygous mutation in the KCNE1 gene (176261) on chromosome 21q22. Digenic inheritance has also been reported; see MOLECULAR GENETICS. Description Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999). For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500). Molecular Genetics In affected members of 2 families with long QT syndrome, Splawski et al. (1997) identified heterozygosity for different missense mutations in the KCNE1 gene (176261.0003-176261.0004). Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2; SCN5A, 600163; KCNE1; and KCNE2 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). ### Acquired Long QT Syndrome Paulussen et al. (2004) screened 5 congenital long QT syndrome-associated genes (KCNQ1, KCNH2, SCN5A, KNCE1, and KCNE2) in 32 individuals with drug-induced long QT syndrome and identified 3 heterozygous mutations in 4 patients that were not found in 32 healthy controls (see, e.g., 176261.0005). ### Digenic Inheritance Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance). Millat et al. (2006) suggested that because double heterozygosity appears to be more common than expected, molecular diagnosis should be performed on all LQTS-related genes, even after a single mutation has been identified. Genotype/Phenotype Correlations Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 176261.0005). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Prolonged QT interval on EKG \- Syncope \- Torsade de pointes \- Ventricular fibrillation \- Sudden cardiac death MISCELLANEOUS \- Homozygous mutation of KCNE1 causes Jervell and Lange-Nielsen syndrome ( 176261.0001 ) \- Genetic heterogeneity (see LQT1 192500 ) \- Patients with more severe phenotype have been reported with mutations in more than 1 LQT-related gene \- GEI (gene-environment interaction) - association of cardiac events with drug administration MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, Isk-related subfamily, member 1 gene (KCNE1, 176261.0003 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	LONG QT SYNDROME 5	c1141890	6,901	omim	https://www.omim.org/entry/613695	2019-09-22T15:57:49	{"doid": ["0110647"], "omim": ["613695"], "orphanet": ["768", "101016"], "genereviews": ["NBK1129"]}
A number sign (#) is used with this entry because of evidence that Saul-Wilson syndrome (SWILS) is caused by recurrent de novo heterozygous missense mutations in the COG4 (606976) gene on chromosome 16q22. Description Saul-Wilson syndrome is a rare skeletal dysplasia with characteristic dysmorphic and radiographic findings, as well as early developmental delay, primarily involving speech, with eventual normal cognition. Clinical findings include marked short stature, prominent forehead with an enlarged anterior fontanel, prominent eyes with cataracts, narrow nasal bridge with a convex nasal ridge, micrognathia, clubfoot, brachydactyly, and short distal phalanges of fingers. Radiographic changes include platyspondyly, irregular end plates of vertebral bodies, and hypoplasia of the odontoid process with cervical instability in the spine, coxa valga, overtubulation, metaphyseal flaring and megaepiphyses in the long bones, while the hands and feet exhibit short phalanges, metacarpals and metatarsals, cone-shaped epiphyses of phalanges, and accessory ossification centers of metacarpals and metatarsals (summary by Ferreira et al., 2018). Clinical Features Saul (1982) described a 7-year 10-month-old white boy who was born at 34 months' gestation with normal weight, open bulging fontanels, and a left calcaneovalgus deformity. He developed short stature, borderline microcephaly, distinctive facial features including a sharp narrow face, frontal bossing, metopic depression, blue sclerae, bilateral cataracts, and opalescent teeth, pectus carinatum, upper lumbar lordosis, short hands with blunted fingers, and bilateral bowed legs. He had delayed growth, late onset of speech, and delayed gross motor development. Radiographic features included a few wormian bones, widened clavicles, dysplastic L-1 vertebra, nonunion or pseudoarthrosis of the left tibia and fibula, and mild distal phalangeal tufting. Fibroblast enzymes, including arylsulfatase A, alpha-mannosidase, alpha-fucosidase, beta-galactosidase, N-acetyl-beta-glucosaminidase, beta-glucuronidase, prolyl hydroxylase, and lysyl hydroxylase were all normal, as was the sweat chloride. Saul and Wilson (1990) provided follow-up on the boy (patient 1) previously reported by Saul (1982) and reported an unrelated boy (patient 2) with similar features. At age 16 years, patient 1 showed resolution of his early delay in language and gross motor development and was doing well in school. His height, weight and occipitofrontal circumference (OFC) were all well below the 3rd centile for age but were proportionate. Patient 2 was born at 36 weeks' gestation and weighed only 1.5 kg. Neonatal abnormalities included large anterior fontanel, bilateral clubfoot, contractures of the knees and elbows, and poor feeding. In early childhood he had recurrent otitis media and several episodes of pneumonia requiring hospitalization. His psychomotor development was delayed. At age 9 years he had a vocabulary of only a few words; when excited, he hand flapped. Hearing tests were normal. His height, weight, and OFC were all well below the 3rd centile for age but proportionate. Craniofacial manifestations included frontal prominence with slight metopic depression, a small recessed midface with a narrow nasal root, beaked nose, and prominent eyes. The chin was small and teeth were crowded and slightly opalescent. Chest was narrow superiorly but flared at the costal margins. All major joints had full range of motion except the ankles of which there was slight limitation. Hands and fingers were short and the fingers were broad distally. Nails were short and broad. X-rays showed short phalanges with widening of the distal phalanges, several coned epiphyses, and sclerotic epiphyses with a normal bone age. Hip radiographs showed coxa valga. Both patients had mild widening of the medial ends of the clavicles as well as several vertebral irregularities, including a dysplastic L-1 in patient 2. Hersh et al. (1994) reported 2 additional unrelated patients with similar clinical and radiographic features. Patient 1 was a girl who was noted at birth to have a large anterior fontanel, sparse scalp hair, a high forehead, slight exophthalmos, beaked nose, micrognathia, and clubfeet. In infancy, she had hypotonia and recurrent otitis media. She developed cataracts at age 3. An MRI at age 2 years documented a syrinx of the lower spinal cord and tethered cord necessitating surgical treatment. The patient walked at age 2 years and acquired normal speech and language. At age 4.5 years, her height, weight, and OFC were all less than the 5th centile. Facial features included prominent forehead with shallow supraorbital ridges, midface hypoplasia, micrognathia, and blue sclerae. She had slightly prominent ears, a narrow nasal root, a beaked nose, and bifid uvula. Dentition was normal. She had pectus excavatum. She had brachydactyly with short hands and short midfinger length. There was blunting of the fingertips, and talipes equinovarus was present with atrophy of the gastrocnemius muscles. The elbows were prominent and extension was limited to 165 degrees. There was an exaggerated lumbar lordosis and capillary hemangioma. Skeletal survey documented moderate flattening of the vertebral bodies. The first lumbar vertebra was hypoplastic with a wedge-shaped appearance. There was hypoplasia of the odontoid process, and a coxa valga deformity was present bilaterally. There was overtubulation of the long bones, with relative flare of the metaphyses. The metacarpals, metatarsals, and phalanges were short. Several epiphyses of the fingers were cone shaped, and ivory epiphyses were present in the distal phalanges of the fingers. Patient 2 was a boy born at 36 weeks' gestation with height, weight, and OFC at the 50th centile. He had wide anterior fontanel, a prominent nasal bridge, micrognathia, and mild symmetrical rhizomelic shortness of all limbs. Skeletal survey disclosed platyspondyly with mild coronal clefting. There was rhizomelic and mesomelic shortness of long bones. He had multiple episodes of otitis media as well as multiple hospitalizations for aspiration pneumonia. Gastroesophageal reflux was identified and a fundal plication was performed. Growth hormone studies were normal. Audiometry studies showed mild mixed bilateral hearing loss, and there was evidence of global developmental delay with greater speech delay. Iliac crest bone biopsy showed normal resting cartilage, but some chondrocytes appeared to have large inclusion bodies within them. At age 5 years, the patient's height and weight were at the 50th percentile for a 9-month-old infant, and OFC was at the 50th centile for an 18 month old. He had a striking facial appearance with frontal bossing, downslanting palpebral fissures, blue sclerae, shallow orbits with prominent eyes, narrow nasal root with beaked nose, and micrognathia. There was a mild lenticular opacity in the left eye. He had pectus carinatum. There was mild lower thoracic scoliosis and accentuated lumbar lordosis. There was evidence of metatarsus adductus, and his fingers were short with squared distal phalanges. There was limitation of movement at the elbow joint. Ferreira et al. (2018) reported 14 patients with Saul-Wilson syndrome, including patient 2 in the report of Saul and Wilson (1990) and patient 1 in the report of Hersh et al. (1994). The patients ranged in age from 18 months to 39 years, were of various ethnicity, and included 6 females. Birth weight Z score ranged from -1.2 to -3.8, birth length Z score from -0.7 to -5.1, and birth OFC Z score from -0.8 to -3.9. Current weight Z scores ranged from -1.1 to -5.8, height Z score from -3.5 to -9.8, and OFC Z score from +0.8 to -5. Ferreira et al. (2018) noted that all 14 patients had prominent forehead, prominent veins, prominent eyes, overtubulation of the long bones, metaphyseal long bone flaring, megaepiphyses, coxa valga, and short metatarsals, metacarpals, and phalanges. Most patients had anterior fontanel enlargement or delayed closure, dens hypoplasia, micrognathia, neutropenia, cataracts, hearing loss that was bilateral sensorineural, mixed, or conductive, irregular vertebral bodies, many of which were described as mild and some only at an older age, cone-shaped epiphyses, pseudoepiphyses of the metacarpals, ivory epiphyses of the phalanges, and clubfoot. Molecular Genetics In 14 patients with Saul-Wilson syndrome, including patient 2 in the report of Saul and Wilson (1990) and patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified 2 different de novo heterozygous mutations in the COG4 gene, c.1546G-A (606976.0005) and c.1546G-C (606976.0006), both of which give rise to an identical missense mutation (G516R). The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Compared to control cell lines, fibroblasts from affected individuals showed normal mRNA expression and protein level of COG4 and other COG subunits, confirming that the variant leads to production of a stable protein. Protein modeling predicted the loss of a loop structure in the mutant protein; however, binding of COG4 to other COG subunits was not altered. Pathogenesis Ferreira et al. (2018) found that Golgi morphology was significantly altered in fibroblasts of 3 patients with Saul-Wilson syndrome with only 51.1% (n=237, patient 1.1), 52.8% (n=254, patient 4.1), and 54.9% (n=268, patient 5.1) of the Golgi complexes exhibiting normal morphology in contrast to 93.9% in control fibroblasts. Abnormal Golgi morphology was defined as colocalization of GM130 (GOLGA2; 602580) and TGN46 (TGOLN2; 603062), suggesting collapse of the cis- and trans-Golgi stacks. The Golgi volume in patient cells was significantly decreased compared to that of control cells (P less than 0.0001). The nuclear volume was also decreased (P = 0.0016). Ferreira et al. (2018) found that unlike patients with CDG2J (613489) due to biallelic mutation in COG4 who demonstrate delayed response to brefelden A treatment, patients with SWILS have significantly faster brefeldin A-induced retrograde transport. Animal Model Ferreira et al. (2018) used CRISPR/Cas9 to knock out cog4 in zebrafish and found that the cog4-null mutants had inner ear, growth, and skeletal defects. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Prenatal growth retardation \- Postnatal growth retardation HEAD & NECK Head \- Prominent forehead \- Large anterior fontanel Face \- Micrognathia \- Prominent veins \- Progeroid appearance Ears \- Hearing loss, sensorineural, mixed or conductive Eyes \- Prominent eyes \- Blue sclerae \- Retinal pigmentary changes \- Night blindness \- Cataracts Nose \- Narrow nasal bridge \- Convex nasal ridge CHEST External Features \- Pectus excavatum \- Pectus carinatum SKELETAL Spine \- Platyspondyly \- Dens hypoplasia Pelvis \- Coxa valga Limbs \- Overtubulation of long bones \- Metaphyseal flaring of long bones \- Megaepiphyses of the long bones \- Dysplastic proximal radius Hands \- Short metacarpals \- Short distal phalanges \- Cone-shaped epiphyses of phalanges Feet \- Talipes equinovarus (clubfoot) \- Short metatarsals NEUROLOGIC Central Nervous System \- Developmental delay \- Motor delay \- Speech delay \- Normal cognition HEMATOLOGY \- Neutropenia MOLECULAR BASIS \- Caused by mutation in the component of oligomeric Golgi complex 4 gene (COG4, 606976.0005 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SAUL-WILSON SYNDROME	c1300285	6,902	omim	https://www.omim.org/entry/618150	2019-09-22T15:43:21	{"omim": ["618150"], "orphanet": ["85172"], "synonyms": ["Alternative titles", "MICROCEPHALIC OSTEODYSPLASTIC DYSPLASIA"]}
Events resembling an epileptic seizure, but without the electrical discharges associated with epilepsy "PNES" redirects here. For the Pakistani international school network abbreviated PNES, see Pakistan National English School. Psychogenic non-epileptic seizures SpecialtyNeurology, psychiatry Psychogenic non-epileptic seizures (PNES) are events resembling an epileptic seizure, but without the characteristic electrical discharges associated with epilepsy.[1] They are of psychological origin, and are one type of non-epileptic seizure mimics.[2][3] PNES are also known less specifically as non-epileptic attack disorder (NEAD) and functional neurological symptom disorder.[1][4] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Risk factors * 4 Diagnosis * 4.1 Distinguishing features * 5 Treatment * 6 Prognosis * 7 Epidemiology * 7.1 Children * 8 History * 9 Society and culture * 10 Terminology * 11 References * 12 External links ## Signs and symptoms[edit] People present with episodes that resemble seizures, and most have received a diagnosis of epilepsy and treatment for it.[5][6][7] Most commonly the episodes in question are convulsive (whole body shaking) and resemble generalized tonic-clonic (“grand mal”) seizures, but they can be less dramatic and mimic milder types of seizures (partial seizures, absence seizures, myoclonic seizures).[citation needed] ## Causes[edit] The cause is by definition psychological, and can be categorized into several psychiatric diagnoses.[3] In the vast majority of people, the production of seizure-like symptoms is not under voluntary control, meaning that the person is not faking;[5][8] symptoms which are feigned or faked voluntarily would fall under the categories of factitious disorder or malingering.[9] ## Risk factors[edit] Most people with PNES (75%) are women, with onset in the late teens to early twenties being typical.[10] A number of studies have also reported a high incidence of abnormal personality traits or personality disorders in people with PNES such as borderline personality.[11] However, again, when an appropriate control group is used, the incidence of such characteristics is not always higher in PNES than in similar illnesses arising due to organic disease (e.g., epilepsy).[12][13][14][15][16] Other risk factors for PNES include having a diagnosis of epilepsy, having recently had a head injury or recently undergone neurosurgery.[17] ## Diagnosis[edit] The differential diagnosis of PNES firstly involves ruling out epilepsy as the cause of the seizure episodes, along with other organic causes of non-epileptic seizures, including syncope, migraine, vertigo, anoxia, hypoglycemia, and stroke. However, between 5-20% of people with PNES also have epilepsy.[18] Frontal lobe seizures can be mistaken for PNES, though these tend to have shorter duration, stereotyped patterns of movements and occurrence during sleep.[10] Next, an exclusion of factitious disorder (a subconscious somatic symptom disorder, where seizures are caused by psychological reasons) and malingering (simulating seizures intentionally for conscious personal gain – such as monetary compensation or avoidance of criminal punishment) is conducted. Finally other psychiatric conditions that may superficially resemble seizures are eliminated, including panic disorder, schizophrenia, and depersonalisation disorder.[10] The most definitive test to distinguish epilepsy from PNES is long term video-EEG monitoring, with the aim of capturing one or two episodes on both video recording and EEG simultaneously (some clinicians may use suggestion to attempt to trigger an episode).[19] Additional clinical criteria are usually considered in addition to video-EEG monitoring when diagnosing PNES.[20] EEG-video monitoring will usually answer the following questions:[21] 1. Is it epilepsy? 2. If not, is it psychogenic? 3. If not psychogenic, what other seizure mimic is it? 4. If epilepsy, what type? 5. If focal epilepsy, where is the focus? By recording the event in question on video and EEG simultaneously, a clear diagnosis can usually be obtained.[22] Laboratory testing can detect rising blood levels of serum prolactin if samples are taken in the right time window after most tonic-clonic or complex partial epileptic seizures. However, due to false positives and variability in results, this test is relied upon less frequently.[10] ### Distinguishing features[edit] Some features are more or less likely to suggest PNES but they are not conclusive and should be considered in the broader clinical picture. Features that are common in PNES but rarer in epilepsy include: biting the tip of the tongue, seizures lasting more than 2 minutes (easiest factor to distinguish), seizures having a gradual onset, a fluctuating course of disease severity, the eyes being closed during a seizure, and side to side head movements. Features that are uncommon in PNES include automatisms (automatic complex movements during the seizure), severe tongue biting, biting the inside of the mouth, and incontinence.[10] If a person with suspected PNES has an episode during a clinical examination, there are a number of signs that can be elicited to help support or refute the diagnosis of PNES. Compared to people with epilepsy, people with PNES will tend to resist having their eyes forced open (if they are closed during the seizure), will stop their hands from hitting their own face if the hand is dropped over the head, and will fixate their eyes in a way suggesting an absence of neurological interference.[10] Mellers et al. warn that such tests are neither conclusive nor impossible for a determined person with factitious disorder to "pass" through faking convincingly. ## Treatment[edit] People with PNES have typically carried a diagnosis of epilepsy for roughly 7 years, so an understanding of the new diagnosis is crucial for their treatment, which requires their active participation.[23] There are a number of recommended steps to explain to people their diagnosis in a sensitive and open manner. A negative diagnosis experience may cause frustration and could cause a person to reject any further attempts at treatment.[10] Ten points recommended to explain the diagnosis to the person and their caregivers are: 1. Reasons for concluding they do not have epilepsy 2. What they do have (describe dissociation) 3. Emphasise they are not suspected of "putting on" the attacks 4. They are not 'mad' 5. Triggering "stresses" may not be immediately apparent. 6. Relevance of aetiological factors in their case 7. Maintaining factors 8. May improve after correct diagnosis 9. Caution that anticonvulsant drug withdrawal should be gradual 10. Describe psychological treatment Psychotherapy is the most frequently used treatment, which might include cognitive behavioral therapy, insight-orientated therapy, and/or group work.[10] There is also some evidence supporting selective serotonin reuptake inhibitor antidepressants.[24] Mental health professionals typically show little interest in this category of psychiatric diseases and people frequently find themselves stuck between psychiatry and neurology with no one to turn to for treatment.[5][25] ## Prognosis[edit] Though there is limited evidence, outcomes appear to be relatively poor with a review of outcome studies finding that two thirds of people with PNES continue to experience episodes and more than half are dependent on social security at three-year followup.[26] This outcome data was obtained in a referral-based academic epilepsy center and loss to follow-up was considerable; the authors point out ways in which this may have biased their outcome data. Outcome was shown to be better in people with higher IQ,[27] social status,[28] greater educational attainments,[29] younger age of onset and diagnosis,[29] attacks with less dramatic features,[29] and fewer additional somatoform complaints.[29] ## Epidemiology[edit] The number of people with PNES ranges from 2 to 33 per 100,000.[30] Although the rate in the general population are difficult to determine, it remains the most frequent non-epileptic condition seen in epilepsy centers. At epilepsy centers PNES is found in 20-40% of inpatients. Like other somatic symptom disorders, PNES are most common in young adults and women.[31] The number of people with PNES in those with functional neurological disorder is higher.[32] ### Children[edit] PNES are seen in children after the age of 8, and occur equally among boys and girls before puberty. Diagnostic and treatment principles are similar to those for adults, except that in children there is a broader differential diagnosis of seizures so that other possible diagnoses specific to children may be considered.[33] ## History[edit] Hystero-epilepsy is a historical term that refers to a condition described by 19th-century French neurologist Jean-Martin Charcot[34] where people with neuroses "acquired" symptoms resembling seizures as a result of being treated on the same ward as people who genuinely had epilepsy. ## Society and culture[edit] PNES rates and presenting symptoms are somewhat dependent on the culture and society. In some cultures, they, like epilepsy, are thought of as a curse or a demonic possession.[35] In cultures with a solid establishment of evidence-based medicine, they are considered a subtype of a larger category of psychiatric disease. ## Terminology[edit] Terminology varies somewhat, although PNES has become the most widely accepted term. The use of older terms including pseudoseizures and hysterical seizures are discouraged.[36] In the English language, the word “seizure” usually refers to epileptic events, so some prefer to use more general terms like "events," "attacks," or "episodes," as the term “seizures” may cause confusion with epilepsy.[37][38] PNES may also be referred to as "non-epileptic attack disorder" or "functional seizures," though those terms do not clearly indicate a psychological origin and therefore include other (non psychological) causes of epilepsy mimics. Within DSM IV the attacks are classified as a somatoform disorder, whilst in ICD 10 the term dissociative convulsions is used, classified as a conversion disorder.[10] In DSM-5 PNES is also known as functional neurological symptom disorder and is classified as a conversion disorder, which falls under the diagnostic category of somatic symptom disorders.[4] ## References[edit] 1. ^ a b Devinsky, Orrin; Gazzola, Deana; LaFrance, W. Curt (2011-04-01). "Differentiating between nonepileptic and epileptic seizures". Nature Reviews. Neurology. 7 (4): 210–220. doi:10.1038/nrneurol.2011.24. ISSN 1759-4766. PMID 21386814. 2. ^ Joseph H. Ricker; Reilly R. Martinez, eds. (October 2003). Differential Diagnosis in Adult Neuropsychological Assessment. Springer Publishing Company. p. 109. ISBN 978-0-8261-1665-9. 3. ^ a b Benbadis, Selim R (6 December 2017). "Psychogenic Nonepileptic Seizures: Background, Pathophysiology, Etiology". Medscape. Retrieved 14 April 2018. 4. ^ a b Bajestan, Sepideh N; LaFrance, W. Curt (October 2016). "Clinical Approaches to Psychogenic Nonepileptic Seizures". FOCUS. 14 (4): 422–431. doi:10.1176/appi.focus.20160020. PMC 6519589. 5. ^ a b c Benbadis, SR (February 2005). "The problem of psychogenic symptoms: is the psychiatric community in denial?". Epilepsy & Behavior. 6 (1): 9–14. doi:10.1016/j.yebeh.2004.10.009. PMID 15652726. 6. ^ Benbadis, SR (June 2013). "Nonepileptic behavioral disorders: diagnosis and treatment". Continuum (Minneapolis, Minn.). 19 (3 Epilepsy): 715–29. doi:10.1212/01.CON.0000431399.69594.de. PMID 23739106. 7. ^ LaFrance, W. Curt; Baker, Gus A.; Duncan, Rod; Goldstein, Laura H.; Reuber, Markus (November 2013). "Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: A staged approach". Epilepsia. 54 (11): 2005–2018. doi:10.1111/epi.12356. PMID 24111933. 8. ^ Brown, RJ; Reuber, M (April 2016). "Psychological and psychiatric aspects of psychogenic non-epileptic seizures (PNES): A systematic review" (PDF). Clinical Psychology Review. 45: 157–82. doi:10.1016/j.cpr.2016.01.003. PMID 27084446. 9. ^ Bass, C; Halligan, P (2016). Factitious disorders and malingering in relation to functional neurologic disorders. Handbook of Clinical Neurology. 139. pp. 509–520. doi:10.1016/B978-0-12-801772-2.00042-4. ISBN 9780128017722. PMID 27719868. 10. ^ a b c d e f g h i Mellers, JD (August 2005). "The approach to patients with "non-epileptic seizures"". Postgraduate Medical Journal. 81 (958): 498–504. doi:10.1136/pgmj.2004.029785. PMC 1743326. PMID 16085740. 11. ^ Galimberti, Carlo Andrea; Ratti, Maria Teresa; Murelli, Rosanna; Marchioni, Enrico; Manni, Raffaele; Tartara, Amelia (1 March 2003). "Patients with psychogenic nonepileptic seizures, alone or epilepsy-associated, share a psychological profile distinct from that of epilepsy patients". Journal of Neurology. 250 (3): 338–346. doi:10.1007/s00415-003-1009-0. PMID 12638026. 12. ^ Salmon, Peter; Al-Marzooqi, Suad M.; Baker, Gus; Reilly, James (July 2003). "Childhood Family Dysfunction and Associated Abuse in Patients With Nonepileptic Seizures". Psychosomatic Medicine. 65 (4): 695–700. doi:10.1097/01.PSY.0000075976.20244.D8. PMID 12883124. 13. ^ Brown, Richard J.; Bouska, Julia F.; Frow, Anna; Kirkby, Antonia; Baker, Gus A.; Kemp, Steven; Burness, Christine; Reuber, Markus (October 2013). "Emotional dysregulation, alexithymia, and attachment in psychogenic nonepileptic seizures". Epilepsy & Behavior. 29 (1): 178–183. doi:10.1016/j.yebeh.2013.07.019. PMID 23973643. 14. ^ Dimaro, Lian V.; Dawson, David L.; Roberts, Nicole A.; Brown, Ian; Moghaddam, Nima G.; Reuber, Markus (April 2014). "Anxiety and avoidance in psychogenic nonepileptic seizures: The role of implicit and explicit anxiety" (PDF). Epilepsy & Behavior. 33: 77–86. doi:10.1016/j.yebeh.2014.02.016. PMID 24632427. 15. ^ Strutt, Adriana M.; Hill, Stacy W.; Scott, Bonnie M.; Uber-Zak, Lori; Fogel, Travis G. (October 2011). "Motivation, psychopathology, locus of control, and quality of life in women with epileptic and nonepileptic seizures". Epilepsy & Behavior. 22 (2): 279–284. doi:10.1016/j.yebeh.2011.06.020. PMID 21788158. 16. ^ Thompson, Alexander W.; Hantke, Nathan; Phatak, Vaishali; Chaytor, Naomi (January 2010). "The Personality Assessment Inventory as a tool for diagnosing psychogenic nonepileptic seizures". Epilepsia. 51 (1): 161–164. doi:10.1111/j.1528-1167.2009.02151.x. PMC 2844915. PMID 19490032. 17. ^ Wilshire, C. E.; Ward, T. (29 September 2016). "Psychogenic Explanations of Physical Illness: Time to Examine the Evidence". Perspectives on Psychological Science. 11 (5): 606–631. doi:10.1177/1745691616645540. PMID 27694458. 18. ^ Martin R, Burneo JG, Prasad A, Powell T, Faught E, Knowlton R, Mendez M, Kuzniecky R (2003). "Frequency of epilepsy in patients with psychogenic seizures monitored by video-EEG". Neurology. 61 (12): 1791–2. doi:10.1212/01.wnl.0000098890.13946.f5. PMID 14694050. 19. ^ Asano, E; Pawlak, C; Shah, A; Shah, J; Luat, AF; Ahn-Ewing, J; Chugani, HT (2005). "The diagnostic value of initial video-EEG monitoring in children--review of 1000 cases". Epilepsy Res. 66 (1–3): 129–35. doi:10.1016/j.eplepsyres.2005.07.012. PMID 16157474. 20. ^ Bowman, E. S.; Coons, P. M. (2000). "The differential diagnosis of epilepsy, pseudoseizures, dissociative identity disorder, and dissociative disorder not otherwise specified". Bulletin of the Menninger Clinic. 64 (2): 164–180. PMID 10842446. 21. ^ Benbadis, Selim R. "EEG Video Monitoring". Medscape. Retrieved 1 April 2018. 22. ^ Benbadis SR; LaFrance Jr WC (2010). "Chapter 4. Clinical Features and the Role of Video-EEG Monitoring". In Schachter, SC; LaFrance Jr, WC (eds.). Gates and Rowan's Nonepileptic Seizures (3rd ed.). Cambridge; New York: Cambridge University Press. pp. 38–50. 23. ^ Reuber, Markus; Elger, Christian E. (June 2003). "Psychogenic nonepileptic seizures: review and update". Epilepsy & Behavior. 4 (3): 205–216. doi:10.1016/S1525-5050(03)00104-5. PMID 12791321. 24. ^ LaFrance WC, Jr; Reuber, M; Goldstein, LH (March 2013). "Management of psychogenic nonepileptic seizures". Epilepsia. 54 Suppl 1: 53–67. doi:10.1111/epi.12106. PMID 23458467. 25. ^ Benbadis, Selim R (February 2013). "Mental health organizations and the ostrich policy". Neuropsychiatry. 3 (1): 5–7. doi:10.2217/NPY.12.74. 26. ^ Reuber M, Elger CE (2003). "Psychogenic nonepileptic seizures: review and update". Epilepsy & Behavior. 4 (3): 205–216. doi:10.1016/S1525-5050(03)00104-5. PMID 12791321. 27. ^ McDade (1992). "Non-epileptic seizures: management and predictive factors of outcome". Seizure. 1 (1): 7–10. doi:10.1016/1059-1311(92)90047-5. PMID 1344323. 28. ^ Kanner (1999). "Psychiatric and neurologic predictors of psychogenic pseudoseizure outcome". Neurology. 53 (5): 933–938. doi:10.1212/wnl.53.5.933. PMID 10496249. 29. ^ a b c d Reuber, Markus (March 2003). "Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients". Annals of Neurology. 53 (3): 305–311. doi:10.1002/ana.3000. PMID 12601698. 30. ^ Asadi-Pooya, Ali A.; Sperling, Michael R. (May 2015). "Epidemiology of psychogenic nonepileptic seizures". Epilepsy & Behavior. 46: 60–65. doi:10.1016/j.yebeh.2015.03.015. PMID 25882323. 31. ^ Asadi-Pooya, Ali A.; Sperling, Michael R. (May 2015). "Epidemiology of psychogenic nonepileptic seizures". Epilepsy & Behavior. 46: 60–65. doi:10.1016/j.yebeh.2015.03.015. PMID 25882323. 32. ^ Dekker, Marieke C. J.; Urasa, Sarah J.; Kellogg, Marissa; Howlett, William P. (March 2018). "Psychogenic non-epileptic seizures among patients with functional neurological disorder: A case series from a Tanzanian referral hospital and literature review". Epilepsia Open. 3 (1): 66–72. doi:10.1002/epi4.12096. PMC 5839312. PMID 29588989. 33. ^ Benbadis, Selim R. (August 2007). "Differential Diagnosis of Epilepsy". CONTINUUM: Lifelong Learning in Neurology. 13: 48–70. doi:10.1212/01.CON.0000284534.43272.1c. 34. ^ Gamgee, A (Oct 12, 1878). "An Account of a Demonstration on the Phenomena of Hystero-Epilepsy Given by Professor Charcot: And on the Modification which they Undergo under the Influence of Magnets and Solenoids". British Medical Journal. 2 (928): 545–8. doi:10.1136/bmj.2.928.545. PMC 2221928. PMID 20748992. 35. ^ Asadi-Pooya, AA; Valente, K; Alessi, R; Tinker, J (October 2017). "Semiology of psychogenic nonepileptic seizures: An international cross-cultural study". Epilepsy & Behavior. 75: 210–212. doi:10.1016/j.yebeh.2017.08.016. PMID 28865883. 36. ^ Diagnosis and management of dissociative seizures, John DC Mellers, The National Society for Epilepsy, September 2005. 37. ^ Benbadis, SR (6 July 2010). "Psychogenic nonepileptic "seizures" or "attacks"? It's not just semantics: attacks". Neurology. 75 (1): 84–6. doi:10.1212/WNL.0b013e3181e6216f. PMID 20603487. 38. ^ LaFrance WC, Jr (6 July 2010). "Psychogenic nonepileptic "seizures" or "attacks"? It's not just semantics: seizures". Neurology. 75 (1): 87–8. doi:10.1212/WNL.0b013e3181e62181. PMC 2906405. PMID 20603488. ## External links[edit] Classification D * ICD-10: F44.5 * ICD-9-CM: 300.11, 780.39 External resources * eMedicine: article/1184694 * 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 * 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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 * t * e Seizures and epilepsy Basics * Seizure types * Aura (warning sign) * Postictal state * Epileptogenesis * Neonatal seizure * Epilepsy in children Management * Anticonvulsants * Investigations * Electroencephalography * Epileptologist Personal issues * Epilepsy and driving * Epilepsy and employment Seizure types Focal Seizures Simple partial Complex partial Gelastic seizure Epilepsy Temporal lobe epilepsy Frontal lobe epilepsy Rolandic epilepsy Nocturnal epilepsy Panayiotopoulos syndrome Vertiginous epilepsy Generalised * Tonic–clonic * Absence seizure * Atonic seizure * Automatism * Benign familial neonatal seizures * Lennox–Gastaut syndrome * Myoclonic astatic epilepsy * Epileptic spasms Status epilepticus * Epilepsia partialis continua * Complex partial status epilepticus Myoclonic epilepsy * Progressive myoclonus epilepsy * Dentatorubral–pallidoluysian atrophy * Unverricht–Lundborg disease * MERRF syndrome * Lafora disease * Juvenile myoclonic epilepsy Non-epileptic seizure * Febrile seizure * Psychogenic non-epileptic seizure Related disorders * Sudden unexpected death in epilepsy * Todd's paresis * Landau–Kleffner syndrome * Epilepsy in animals Organizations * Citizens United for Research in Epilepsy (US) * Epilepsy Action (UK) * Epilepsy Action Australia * Epilepsy Foundation (US) * Epilepsy Outlook (UK) * Epilepsy Research UK * Epilepsy Society (UK) [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Psychogenic non-epileptic seizure	c1142430	6,903	wikipedia	https://en.wikipedia.org/wiki/Psychogenic_non-epileptic_seizure	2021-01-18T18:48:56	{"gard": ["13028"], "icd-9": ["300.11", "780.39"], "icd-10": ["F44.5"], "wikidata": ["Q4162371"]}
A rare neurologic disease characterized by the chronic consequences of bilirubin toxicity in the globus pallidus, sub-thalamic nuclei, and other brain regions, after exposure to high levels of unconjugated bilirubin in the neonatal period. Symptoms begin after the acute phase of bilirubin encephalopathy in the first year of life, evolve slowly over several years, and include mild to severe extrapyramidal disturbances (especially dystonia and athetosis), auditory neuropathy spectrum disorder, and oculomotor and dental abnormalities. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Chronic bilirubin encephalopathy	None	6,904	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=529808	2021-01-23T18:50:48	{"synonyms": ["BIND", "Bilirubin-induced neurological dysfunction", "CBE", "KSD", "Kernicterus spectrum disorder"]}
A rare, axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of variable onset and severity. Patients present with postural instability, gait and running difficulties, decreased deep tendon reflexes, foot deformities, fine motor impairment, and distal sensory impairment. Dysarthria, dysphagia, and mild cognitive and behavioral abnormalities have also been 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Autosomal dominant Charcot-Marie-Tooth disease type 2Y	c4225244	6,905	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435387	2021-01-23T17:30:02	{"omim": ["616687"], "icd-10": ["G60.0"], "synonyms": ["Autosomal dominant Charcot-Marie-Tooth disease type 2 due to VCP mutation", "CMT2 due to VCP mutation", "CMT2Y"]}
A number sign (#) is used with this entry because of evidence that familial myoclonus-2 (MYOCL2) is caused by heterozygous mutation in the SCN8A gene (600702) on chromosome 12q13. One such family has been reported. For a discussion of genetic heterogeneity of familial myoclonus, see MYOCL1 (614937). Clinical Features Wagnon et al. (2018) reported a 3-generation family in which 5 individuals had onset of isolated action-induced nonepileptic myoclonus affecting the upper limb in the first decade. Two patients were examined and the other 3 were reportedly affected with a similar disorder. The 2 patients had onset at age 5 and 7 years, and had no other neurologic findings, particularly no dystonia, seizures, or cognitive impairment. The disorder was nonprogressive. Electrophysiologic studies of 1 patient in the first decade showed evidence of subcortical origin, but not cortical origin. The 35-year-old proband reported that the myoclonus was responsive to alcohol, suggesting cerebellar involvement. Inheritance The transmission pattern of MYOCL2 in the family reported by Wagnon et al. (2018) was consistent with autosomal dominant inheritance. Molecular Genetics In 3 affected members of a family with MYOCL2, Wagnon et al. (2018) identified a heterozygous missense mutation in the SCN8A gene (P1719R; 600702.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who agreed to testing. In vitro functional expression studies in transfected neuron-derived cells showed that the mutation caused a partial loss of function, manifest as decreased inward sodium current compared to controls. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Myoclonic seizures, isolated \- Possible subcortical origin \- No dystonia \- No seizures MISCELLANEOUS \- Onset in the first decade \- Nonprogressive disorder \- Alcohol may alleviate the symptoms \- One family has been reported (last curated March 2019) MOLECULAR BASIS \- Caused by mutation in the sodium channel, voltage gated, type VIII, alpha polypeptide gene (SCN8A, 600702.0012 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MYOCLONUS, FAMILIAL, 2	None	6,906	omim	https://www.omim.org/entry/618364	2019-09-22T15:42:24	{"omim": ["618364"]}
Multicentric reticulohistiocytosis SpecialtyDermatology Multicentric reticulohistiocytosis is a multisystem disease beginning usually around the age of 50 years, and is twice as common in women.[1]:718[2] ## See also[edit] * Reticulohistiocytosis * List of cutaneous conditions ## 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. ^ 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 External resources * eMedicine: article/283885 * v * t * e Histiocytosis WHO-I/Langerhans cell histiocytosis/ X-type histiocytosis * Letterer–Siwe disease * Hand–Schüller–Christian disease * Eosinophilic granuloma * Congenital self-healing reticulohistiocytosis WHO-II/non-Langerhans cell histiocytosis/ Non-X histiocytosis * Juvenile xanthogranuloma * Hemophagocytic lymphohistiocytosis * Erdheim-Chester disease * Niemann–Pick disease * Sea-blue histiocyte * Benign cephalic histiocytosis * Generalized eruptive histiocytoma * Xanthoma disseminatum * Progressive nodular histiocytosis * Papular xanthoma * Hereditary progressive mucinous histiocytosis * Reticulohistiocytosis (Multicentric reticulohistiocytosis, Reticulohistiocytoma) * Indeterminate cell histiocytosis WHO-III/malignant histiocytosis * Histiocytic sarcoma * Langerhans cell sarcoma * Interdigitating dendritic cell sarcoma * Follicular dendritic cell sarcoma Ungrouped * Rosai–Dorfman disease 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Multicentric reticulohistiocytosis	c0311284	6,907	wikipedia	https://en.wikipedia.org/wiki/Multicentric_reticulohistiocytosis	2021-01-18T18:29:48	{"gard": ["7103"], "umls": ["C0311284"], "orphanet": ["139436"], "wikidata": ["Q15731494"]}
For a phenotypic description and discussion of genetic heterogeneity of migraine headaches, see MGR1 (157300). Migraine is a complex and heterogeneous disorder characterized by recurrent attacks of headache associated with autonomic and neurologic symptoms. Two primary types of migraine can be distinguished: migraine without aura (MO) and migraine with aura. Soragna et al. (2003) studied a large 4-generation Italian family, originating from a restricted geographic area of northern Italy, in which migraine without aura appeared to segregate as an autosomal dominant trait. They excluded association between MO in this family and previously identified migraine loci, including the migraine with aura susceptibility locus on chromosome 4q24 (157300). Using a genomewide scan, they obtained significant evidence of linkage between the MO phenotype and marker D14S978 on 14q22.1 (maximum 2-point lod score of 3.70 at a recombination fraction of 0.01). Multipoint parametric analysis (maximum lod score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a 10-cM region flanked by markers D14S1027 and D14S980 on 14q21.2-q22.3. INHERITANCE \- Autosomal dominant ABDOMEN Gastrointestinal \- Nausea \- Vomiting NEUROLOGIC Central Nervous System \- Migraine without aura \- Photophobia \- Phonophobia \- Hyperreflexia MISCELLANEOUS \- Headache duration 4-72 hours \- Aggravated by physical activity \- Genetic heterogeneity, see MGR1, ( 157300 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MIGRAINE WITHOUT AURA, SUSCEPTIBILITY TO, 4	c1843773	6,908	omim	https://www.omim.org/entry/607501	2019-09-22T16:09:14	{"omim": ["607501"], "synonyms": ["Alternative titles", "MGR4", "MGOA"]}
A number sign (#) is used with this entry because of evidence that isolated pancreatic agenesis-2 (PAGEN2) is caused by homozygous or compound heterozygous mutation in a distal enhancer of the PTF1A gene (607194) on chromosome 10p12. Clinical Features Weedon et al. (2014) reported 14 affected individuals from 10 families with isolated pancreatic hypoplasia or agenesis. Patients were typically diagnosed with insulin-dependent diabetes mellitus at birth or in infancy, although 2 individuals were diagnosed at ages 8 and 10 years, respectively, and 1 at 22 years of age. All patients also had pancreatic exocrine insufficiency, with low or undetectable stool elastase in all who were tested. Pancreatic hypoplasia or agenesis was documented by ultrasound, CT, or MRI in the 9 patients studied. No neurologic features were reported, except for 1 patient who exhibited mild developmental delay, and no other abnormalities were reported, except for 1 patient who had fatal cholestatic liver failure. Mapping In 6 affected individuals and 1 unaffected family member from 3 unrelated consanguineous families with isolated pancreatic agenesis, Weedon et al. (2014) performed homozygosity mapping that revealed a single shared locus on chromosome 10p12.2-p12.1. Recombination events defined a 6.38-Mb minimal region at chr10:22,526,125-28,843,478 (GRCh37) containing 25 genes, including PTF1A; however, mutations in those genes were excluded by Sanger sequencing. Molecular Genetics By whole-genome sequencing of a Syrian and a Lebanese proband, both from multiplex consanguineous families with isolated pancreatic agenesis mapping to chromosome 10p12, Weedon et al. (2014) identified homozygosity for the same variant, a point mutation located about 25 kb downstream of the PTF1A gene within an approximately 400-bp evolutionarily conserved region. Sequencing of this putative pancreatic developmental enhancer in 19 additional probands with PAGEN revealed recessive mutations in 7 of 10 probands with isolated pancreatic agenesis as well as in 1 patient who also had fatal cholestatic liver failure. Overall, 9 affected individuals from 6 unrelated families of Syrian, Lebanese, Kurdish, and Turkish ancestry were homozygous for the same point mutation on chromosome 10, as part of a shared 1.2-Mb haplotype. In addition, a sporadic patient from Pakistan was homozygous and a sporadic patient from Germany compound heterozygous for point mutations in the same region, and 2 Arabian sibs were homozygous for a 7.6-kb deletion that included the entire putative enhancer. Finally, a sporadic Costa Rican patient who had pancreatic agenesis with fatal cholestatic liver failure was homozygous for another point mutation. Testing of parents and sibs demonstrated cosegregation of the mutations with diabetes and exocrine insufficiency, and none of the mutations were found in controls. Functional analysis demonstrated that the approximately 400-bp region acts as a developmental enhancer of PTF1A in human embryonic pancreatic progenitor cells and that the 6 mutations abolish enhancer activity. Amberger (2014) noted that the mutations identified by Weedon et al. (2014) are located within C10ORF115, a long noncoding RNA. INHERITANCE \- Autosomal recessive GROWTH Weight \- Low birth weight ABDOMEN Liver \- Cholestatic liver failure (rare) Pancreas \- Pancreatic hypoplasia or agenesis ENDOCRINE FEATURES \- Neonatal diabetes mellitus (in most patients) \- Pancreatic exocrine insufficiency \- Pancreatic hypoplasia or agenesis \- Stool elastase low or undetectable \- Steatorrhea MOLECULAR BASIS \- Caused by mutation in a downstream enhancer of the alpha subunit of the pancreas transcription factor 1 gene (PTF1A, 607194 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	PANCREATIC AGENESIS 2	c1850096	6,909	omim	https://www.omim.org/entry/615935	2019-09-22T15:50:32	{"mesh": ["C564908"], "omim": ["615935"], "orphanet": ["2805"], "synonyms": ["Alternative titles", "PANCREATIC HYPOPLASIA, CONGENITAL 2"]}
A rare, hereditary, hematologic disease characterized by an increase in hemoglobin, hematocrit and erythrocyte mass resulting in plethora or ruddy complexion, headache, dizziness, tinnitus and exertional dyspnea. In some cases, thrombophlebitis and arthralgia have also been 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Autosomal recessive secondary polycythemia not associated with VHL gene	None	6,910	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247378	2021-01-23T16:58:38	{"icd-10": ["D75.1"], "synonyms": ["Autosomal recessive secondary erythrocytosis not associated with VHL gene", "Autosomal recessive secondary erythrocytosis, non-Chuvash type", "Autosomal recessive secondary polycythemia, non-Chuvash type"]}
Cryopyrin-associated periodic syndrome Other namesCAPS[1] Cryopyrin-associated periodic syndrome is autosomal dominant in inheritance SpecialtyDermatology, medical genetics Cryopyrin-associated periodic syndrome is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold-induced urticaria), the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye. ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients with systemic involvement from 16 countries,[2] the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash; 97% of cases) especially after cold exposure, and musculoskeletal involvement (myalgia, arthralgia, and/or arthritis, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or osteolytic lesion; 86% of cases). Less common features included ophthalmological involvement (conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure, hydrocephalus or mental retardation; 40% of cases), and AA amyloidosis (4% of cases).[citation needed] In keratoendotheliitis fugax hereditaria, systemic symptoms are not reported whereas the patients suffer from periodical transient inflammation of the corneal endothelium and stroma, leading to short term blurring of vision and, after repeated attacks, to central corneal stromal opacities in some patients.[3] Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.[4][5] ## Pathogenesis[edit] Cryopyrin-associated periodic syndromes are associated with a gain-of-function missense mutation in exon 3 of NLRP3, the gene encoding cryopyrin, a major component of the interleukin 1 inflammasome.[2][6] In keratoendotheliitis fugax hereditaria, the mutation occurs in exon 1.[3] Intracellular formation of the interleukin 1 inflammasome leads to the activation of the potent pro-inflammatory cytokines interleukin 1β and interleukin-18 through a cascade involving caspase 1. The IL-1 inflammasome may also be released from activated macrophages, amplifying the cytokine production cascade.[7] The mutation in NLRP3 leads to aberrant formation of this inflammasome and subsequent unregulated production of interleukin 1β.[citation needed] Up to 170 heterogenous mutations in NLRP3 have been identified. Some reports suggest rare mutations are more frequently associated with a severe phenotype,[8] and some mutations are associated with distinct phenotypes, probably reflecting the differential impact of the mutation on the activity of the inflammasome in the context of individual genetic background.[2][3] Inheritance of these disorders is autosomal dominant with variable penetrance.[citation needed] ## Diagnosis[edit] Because CAPS is extremely rare and has a broad clinical presentation, it is difficult to diagnose, and a significant delay exists between symptom onset and definitive diagnosis.[9] There are currently no clinical or diagnostic criteria for CAPS based solely on clinical presentation. Instead, diagnosis is made by genetic testing for NLRP3 mutations. Acute phase reactants and white blood cell count are usually persistently elevated, but this is aspecific for CAPS.[citation needed] ## Treatment[edit] Since interleukin 1β plays a central role in the pathogenesis of the disease, therapy typically targets this cytokine in the form of monoclonal antibodies (such as canakinumab[10][11]), binding proteins/traps (such as rilonacept[12]), or interleukin 1 receptor antagonists (such as anakinra[13][14][15][16]). These therapies are generally effective in alleviating symptoms and substantially reducing levels of inflammatory indices. Case reports suggest that thalidomide[17] and the anti-IL-6 receptor antibody tocilizumab[18] may also be effective. ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Cryopyrin associated periodic syndrome". www.orpha.net. Retrieved 27 April 2019. 2. ^ a b c Levy, R.; Gérard, L.; Kuemmerle-Deschner, J.; Lachmann, H. J.; Koné-Paut, I.; Cantarini, L.; Woo, P.; Naselli, A.; Bader-Meunier, B. (2015-11-01). "Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry". Annals of the Rheumatic Diseases. 74 (11): 2043–2049. doi:10.1136/annrheumdis-2013-204991. ISSN 1468-2060. PMID 25038238. 3. ^ a b c Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184: 41–50. doi:10.1016/j.ajo.2018.01.017. PMID 29366613. 4. ^ Cuisset, L.; Drenth, J. P.; Berthelot, J. M.; Meyrier, A.; Vaudour, G.; Watts, R. A.; Scott, D. G.; Nicholls, A.; Pavek, S. (1999-10-01). "Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44". American Journal of Human Genetics. 65 (4): 1054–1059. doi:10.1086/302589. ISSN 0002-9297. PMC 1288238. PMID 10486324. 5. ^ Darisipudi, Murthy Narayana; Thomasova, Dana; Mulay, Shrikant R.; Brech, Dorothee; Noessner, Elfriede; Liapis, Helen; Anders, Hans-Joachim (2016-10-21). "Uromodulin Triggers IL-1β–Dependent Innate Immunity via the NLRP3 Inflammasome". Journal of the American Society of Nephrology. 23 (11): 1783–1789. doi:10.1681/ASN.2012040338. ISSN 1046-6673. PMC 3482735. PMID 22997256. 6. ^ Hoffman, H. M.; Mueller, J. L.; Broide, D. H.; Wanderer, A. A.; Kolodner, R. D. (2001-11-01). "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome". Nature Genetics. 29 (3): 301–305. doi:10.1038/ng756. ISSN 1061-4036. PMC 4322000. PMID 11687797. 7. ^ Neven, Bénédicte; Prieur, Anne-Marie; Quartier dit Maire, Pierre (2008-09-01). "Cryopyrinopathies: update on pathogenesis and treatment". Nature Clinical Practice Rheumatology. 4 (9): 481–489. doi:10.1038/ncprheum0874. ISSN 1745-8390. PMID 18665151. 8. ^ "Infevers". fmf.igh.cnrs.fr. Retrieved 2016-10-21. 9. ^ Toplak, Natasa; Frenkel, Joost; Ozen, Seza; Lachmann, Helen J.; Woo, Patricia; Koné-Paut, Isabelle; De Benedetti, Fabrizio; Neven, Benedicte; Hofer, Michael (2012-07-01). "An international registry on autoinflammatory diseases: the Eurofever experience". Annals of the Rheumatic Diseases. 71 (7): 1177–1182. doi:10.1136/annrheumdis-2011-200549. ISSN 1468-2060. PMID 22377804. 10. ^ Lachmann, Helen J.; Kone-Paut, Isabelle; Kuemmerle-Deschner, Jasmin B.; Leslie, Kieron S.; Hachulla, Eric; Quartier, Pierre; Gitton, Xavier; Widmer, Albert; Patel, Neha (2009-06-04). "Use of canakinumab in the cryopyrin-associated periodic syndrome". The New England Journal of Medicine. 360 (23): 2416–2425. doi:10.1056/NEJMoa0810787. ISSN 1533-4406. PMID 19494217. S2CID 28667263. 11. ^ Sibley, Cailin H.; Chioato, Andrea; Felix, Sandra; Colin, Laurence; Chakraborty, Abhijit; Plass, Nikki; Rodriguez-Smith, Jackeline; Brewer, Carmen; King, Kelly (2015-09-01). "A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease". Annals of the Rheumatic Diseases. 74 (9): 1714–1719. doi:10.1136/annrheumdis-2013-204877. ISSN 1468-2060. PMC 4258169. PMID 24906637. 12. ^ Hoffman, Hal M.; Throne, Martin L.; Amar, N. J.; Sebai, Mohamed; Kivitz, Alan J.; Kavanaugh, Arthur; Weinstein, Steven P.; Belomestnov, Pavel; Yancopoulos, George D. (2008-08-01). "Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies". Arthritis and Rheumatism. 58 (8): 2443–2452. doi:10.1002/art.23687. ISSN 0004-3591. PMID 18668535. 13. ^ Ross, J. Barrie; Finlayson, Laura A.; Klotz, P. Jennifer; Langley, Richard G.; Gaudet, Roxanne; Thompson, Kara; Churchman, Sarah M.; McDermott, Michael F.; Hawkins, Philip N. (2017-02-01). "Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up". Journal of Cutaneous Medicine and Surgery. 12 (1): 8–16. doi:10.2310/7750.2008.07050. ISSN 1203-4754. PMID 18258152. 14. ^ Hoffman, Hal M.; Rosengren, Sanna; Boyle, David L.; Cho, Jae Y.; Nayar, Jyothi; Mueller, James L.; Anderson, Justin P.; Wanderer, Alan A.; Firestein, Gary S. (2016-11-13). "Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist". Lancet. 364 (9447): 1779–1785. doi:10.1016/S0140-6736(04)17401-1. ISSN 1474-547X. PMC 4321997. PMID 15541451. 15. ^ Goldbach-Mansky, Raphaela; Dailey, Natalie J.; Canna, Scott W.; Gelabert, Ana; Jones, Janet; Rubin, Benjamin I.; Kim, H. Jeffrey; Brewer, Carmen; Zalewski, Christopher (2006-08-10). "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition". The New England Journal of Medicine. 355 (6): 581–592. doi:10.1056/NEJMoa055137. ISSN 1533-4406. PMC 4178954. PMID 16899778. 16. ^ Seitz, M.; Kamgang, R. K.; Simon, H. U.; Villiger, P. M. (2005-12-01). "Therapeutic interleukin (IL) 1 blockade normalises increased IL1 beta and decreased tumour necrosis factor alpha and IL10 production in blood mononuclear cells of a patient with CINCA syndrome". Annals of the Rheumatic Diseases. 64 (12): 1802–1803. doi:10.1136/ard.2005.036749. ISSN 0003-4967. PMC 1755296. PMID 16284353. 17. ^ Kallinich, T.; Hoffman, H. M.; Roth, J.; Keitzer, R. (2016-06-01). "The clinical course of a child with CINCA/NOMID syndrome improved during and after treatment with thalidomide". Scandinavian Journal of Rheumatology. 34 (3): 246–249. doi:10.1080/03009740410010236. ISSN 0300-9742. PMID 16134734. 18. ^ Matsubara, Tomoyo; Hasegawa, Masanari; Shiraishi, Masahiro; Hoffman, Hal M.; Ichiyama, Takashi; Tanaka, Takeo; Ueda, Haruo; Ishihara, Tokuhiro; Furukawa, Susumu (2006-07-01). "A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents". Arthritis and Rheumatism. 54 (7): 2314–2320. doi:10.1002/art.21965. ISSN 0004-3591. PMID 16802372. * Kubota T, Koike R. Cryopyrin-associated periodic syndromes: background and therapeutics. Mod Rheumatol. 2010 Jun;20(3):213-21 * Autoinflammatory Alliance CAPS Guidebook ## External links[edit] Classification D * ICD-10: E85.0 * MeSH: D056587 * SNOMED CT: 430079001 External resources * Orphanet: 208650 [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Cryopyrin-associated periodic syndrome	c2316212	6,911	wikipedia	https://en.wikipedia.org/wiki/Cryopyrin-associated_periodic_syndrome	2021-01-18T19:10:27	{"gard": ["10927"], "mesh": ["D056587"], "orphanet": ["208650"], "wikidata": ["Q1771331"]}
A number sign (#) is used with this entry because of evidence that Cowden syndrome-1 (CWS1) is caused by heterozygous germline mutation in the PTEN gene (601728) on chromosome 10q23. Description Cowden syndrome-1 is a hamartomatous disorder characterized by macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, and an increased risk for the development of breast, thyroid, and endometrial carcinoma. Bannayan-Riley-Ruvalcaba syndrome (BRRS), previously thought be distinct, shared clinical characteristics with Cowden syndrome, such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms, but had the additional features of developmental delay, macrocephaly, lipomas, hemangiomas, and pigmented speckled macules of the glans penis in males. Because features of BRRS and Cowden syndrome have been found in individuals within the same family with the same PTEN mutation, Cowden syndrome-1 and BRRS are considered to be the same disorder with variable expression and age-related penetrance (summary by Marsh et al., 1999, Lachlan et al., 2007, and Blumenthal and Dennis, 2008). Approximately 80% of patients reported with Cowden syndrome and 60% with BRSS have PTEN mutations (Blumenthal and Dennis, 2008). Some patients with Cowden syndrome may have immune system defects resulting in increased susceptibility to infections (summary by Browning et al., 2015). Nomenclature Marsh et al. (1999) suggested that the spectrum of disorders caused by mutation in the PTEN gene be referred to as PTEN hamartoma tumor syndrome (PHTS). Lachlan et al. (2007) concluded that the Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome represent a single condition with variable expression and age-related penetrance, which is common in tumor-suppressor disorders, and suggested that it is not helpful to split PTEN-related disorders into separate clinical syndromes. ### Genetic Heterogeneity of Cowden Syndrome Also see CWS4 (615107), caused by hypermethylation of the promoter of the KLLN gene (612105), which shares the same transcription site as the PTEN gene, on chromosome 10q23; CWS5 (615108), caused by mutation in the PIK3CA gene (171834) on chromosome 3q26; CWS6 (615109), caused by mutation in the AKT1 gene (164730) on chromosome 14q32; and CWS7 (616858), caused by mutation in the SEC23B gene (610512) on chromosome 20p11. Two previously designated forms of Cowden syndromes, CWS2 and CWS3, reported to be caused by mutations in the SDHB (185470) and SDHD (602690) genes, respectively, have been called into question based on the frequency of the reported variants in the ExAC and gnomAD databases; see Associations Pending Confirmation in the MOLECULAR GENETICS section. Clinical Features Riley and Smith (1960) described a mother and 2 of 7 children with macrocephaly, pseudopapilledema, and multiple hemangiomata. Two other sibs had macrocephaly and pseudopapilledema. Intellect and vision were unimpaired. Bannayan (1971) first described the triad of macrocephaly, lipomatosis, and angiomatosis in a single child observed at autopsy at the Johns Hopkins Hospital. Zonana et al. (1975, 1976) described the triad in a father and 2 sons, suggesting autosomal dominant inheritance. One son had overgrowth of the right index finger and involvement of the small bowel mesentery by hamartoma with angiomatous, lipomatous, and lymphangiomatous components. Miles et al. (1981) and Miles et al. (1984) documented Bannayan-Zonana syndrome in 11 persons in 4 additional families. Clinical features included high palate, scaphocephaly, lipomas of the anterior abdominal wall, thigh, perineum, scapula area, etc., hemangiomas of the anterior abdominal wall, wrist, knee, and foot, bleeding from intracranial hemangioma, and arteriovenous malformation leading to leg amputation. Some children had pectus excavatum. Most of the lipomas spontaneously regressed with age. In some patients, seizures resulted from intracranial hemorrhage. Despite macrocephaly, computerized axial tomography showed no enlargement of the cerebral ventricles, and there was no pseudopapilledema. Affected persons had increased birth weight and length, but growth leveled off at age 6 or 7 years. There was delayed motor development with incoordination, delayed speech development, and mild mental retardation. Drooling was a problem in children. The disorder appeared to be autosomal dominant, but the authors noted that about 80% of affected persons have been male. In 1 instance, the disorder was transmitted by a man with a head of normal size. Ruvalcaba et al. (1980) described 2 unrelated patients with macrocephaly, intestinal polyposis, and pigmented macules of the penis, and suggested that they had Sotos syndrome (117550). However, Smith (1982) subsequently suggested that these patients had a disorder different from Sotos syndrome. Higginbottom and Schultz (1982) described Bannayan syndrome in 3 generations of an American black kindred. They concluded that affected persons may have an increased risk of intracranial tumors: a woman in their family had meningothelial meningioma removed at age 28. DiLiberti et al. (1983) described a 7.5-year-old boy with macrocephaly, hamartomatous intestinal polyps, and cafe-au-lait spots on the penis, and referred to the disorder as 'Ruvalcaba-Myhre-Smith syndrome.' The patient's mother had macrocephaly, a facial appearance similar to the son's, and a hamartomatous intestinal polyp. DiLiberti et al. (1983) also identified prominent Schwalbe lines, which are a frequent normal finding but a consistent feature of 'anterior chamber cleavage syndromes,' prominent corneal nerves, and lipid storage myopathy as features of the disorder. DiLiberti et al. (1984) reported an association of a lipid storage myopathy with Ruvalcaba-Myhre-Smith syndrome, based on 4 patients with the disorder. The patients had delayed psychomotor development and/or hypotonia in childhood. Electromyography in 3 patients showed evidence of a myopathic process. Muscle biopsy in all 4 showed a lipid storage myopathy with increased numbers of neutral lipid droplets, predominantly in type 1 fibers. Type 2 fibers were consistently smaller than expected. In the sporadic cases of Bannayan (1971) and of Okumura et al. (1986), death occurred as a result of severe visceral lipomatosis at ages 3.5 years and 5.75 years, respectively. Dvir et al. (1988) reported a 4.5-year-old boy with macrocephaly, pseudopapilledema, enlarged penis, lipoangiomatosis, and spotted pigmentation of the glans penis. The patient's father and a brother had macrocephaly; the father had enlarged penis. Dvir et al. (1988) noted that the findings were consistent with features reported by Riley and Smith (1960), Bannayan (1971), and Ruvalcaba et al. (1980), and concluded that they all referred to the same syndrome. Dvir et al. (1988) proposed to unify the main features into 1 hereditary syndrome and name it 'macrocephaly-hamartomas-papilledema.' Gorlin (1988) also suggested that Ruvalcaba-Myhre-Smith syndrome was the same as the Bannayan-Zonana syndrome. He referred to the case of an 8-year-old male who had 50 or more hamartomas of the bowel through which he lost serum protein. The diagnosis of BZS had been made, but Gorlin found that the patient also had speckled penis, consistent with RMSS. In a 38-year-old man with macrocephaly, multiple lipomas, and vascular anomalies, Pyeritz (1988) observed 'unstable angina,' dilated aortic root, and ascending aorta. Halal and Silver (1989) described an 8.5-year-old boy with slowly progressive macrocephaly, psychomotor retardation, multiple subcutaneous angiolipomas, hypertelorism, exotropia, prolonged drooling to age 5 years, cutis marmorata, telangiectases over the shoulders, atrial septal defect repaired at age 4 years, broad thumbs and great toes, and muscle wasting. The angiolipomas were bluish subcutaneous nodules scattered all over his body. The parents were second cousins. The father was thought to have minor manifestations of the disorder, i.e., mild hypertelorism and broad thumbs and great toes, as well as mild cutis marmorata over the inner aspect of the forearms and a cluster of telangiectases and dilated vessels on the anterior aspect of both legs. Halal and Silver (1989) concluded that the proband and his father may have had the Bannayan-Zonana syndrome, with previously undescribed additional anomalies, overlapping with the syndrome of cutis marmorata telangiectatica congenita (CMTC; 219250). Alternatively, the disorder in the father and son may have represented a new syndrome of macrocephaly and hamartomas with overlapping manifestations with BZS and CMTC. Moretti-Ferreira et al. (1989) commented on the variability of severity in Bannayan-Zonana syndrome, which may represent different allelic mutations or genetic heterogeneity. DiLiberti (1992) examined the muscle biopsy results from 14 children with macrocephaly and hypotonia/weakness and correlated them with clinical findings. Of the 14, 13 had evidence of lipid storage myopathy, either generalized or focal. All 13 had examinations consistent with benign familial macrocephaly, Ruvalcaba-Myhre-Smith syndrome, or Bannayan-Zonana syndrome. Gorlin et al. (1992) reported a kindred in which 12 members had Bannayan-Riley-Ruvalcaba syndrome. The clinical features showed overlap between Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome. Seven of the patients had Hashimoto thyroiditis. Powell et al. (1993) reported 27 children, aged 14 months to 9 years, who had megalencephaly, hypotonia, proximal muscle weakness, speech and motor delay, and increased intracellular lipid (myoliposis) in needle muscle biopsy specimens. The patients had many features of the Ruvalcaba-Myhre-Smith syndrome, and in 17 families the authors confirmed the autosomal dominant inheritance pattern previously suggested. Muscle carnitine content was low in all 11 patients and all 4 affected relatives tested. All 27 probands were treated with oral L-carnitine; a clinical response was noted in 17. Powell et al. (1993) speculated that myoliposis may be found in other disorders with megalencephaly and muscle symptoms. Fryburg et al. (1994) suggested that a defect in long-chain fatty acid oxidation resulting from deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (LCHAD; 143450) may be responsible for the lipid myopathy in the Bannayan-Riley-Ruvalcaba syndrome. Their patient had macrocephaly with prominent frontal bossing and low-set ears, hypertelorism, and hemangiomas. Boccone et al. (2006) reported a Sardinian boy with BRRS confirmed by genetic analysis. In addition to the classic features of macrocephaly, downslanting palpebral fissures, joint hypermobility, and pigmented macules on the penis, the boy also had autism and reactive nodular lymphoid hyperplasia of the small and large intestinal mucosa. Boccone et al. (2006) recommended screening for lymphomas as well as other malignancies in patients with BRRS. In Cowden syndrome, multiple hamartomatous lesions, especially of the skin, mucous membranes, breast, and thyroid, are encountered. Verrucous skin lesions of the face and limbs, cobblestone-like papules of the gingiva and buccal mucosa, and multiple facial trichilemmomas are leading findings (Brownstein et al., 1977). Hamartomatous polyps of the colon and other intestines occur also. Only 1 case had been reported before the report of Weary et al. (1972). Weary et al. (1972) proposed the designation multiple hamartoma syndrome and identified an autosomal dominant pattern of inheritance in the family of Rachel Cowden, for whom Lloyd and Dennis (1963) had named the disorder. Affected brother and sister were observed by Gentry et al. (1974). Gentry et al. (1974) observed affected persons in 4 generations, with father-to-son transmission. Brownstein et al. (1979) reported on the dermatopathology in 19 patients with Cowden syndrome. Twenty-nine of 53 facial lesions biopsied were trichilemmomas. All oral mucosal lesions were fibromas. Biopsies from the hands and feet showed benign keratosis. Ruschak et al. (1981) described a patient who at the age of 18 years, after experiencing several years of recurrent diarrhea, underwent colectomy and ileostomy for multiple colonic polyposis. Several lipomas on the trunk were also removed. The patient was unique in having deficiency of T-lymphocyte function with recurrent cellulitis and abscess formation and the eventual development of acute myelogenous leukemia. Elston et al. (1986) described a 70-year-old woman in whom the diagnosis of Cowden syndrome had been made on the basis of facial trichilemmomas at age 63. Adenoid facies, high-arched palate, thickened, furrowed tongue, pectus excavatum, and scoliosis were described. Trichilemmomas were found in the sacral area. The need for close surveillance for malignancy was emphasized by the development of 3 different malignant neoplasms in this patient in a 16-year period. Starink et al. (1986) analyzed 21 cases of Cowden syndrome in 7 families, with multiple cases in 4 of the families. They reconfirmed autosomal dominant inheritance with high penetrance in both sexes and high frequency of breast cancer in females. Craniomegaly was the most frequent extracutaneous finding. About 60% of patients had gastrointestinal polyps and 76% had cutaneous fibromas. Breast cancer in CS is an indication for prophylactic mastectomy in the view of Walton et al. (1986). Williard et al. (1992) described the case of a woman who presented at age 32 with breast cancer. Her mother had died of breast cancer at age 42, and 2 maternal aunts had had premenopausal breast cancer. She had multiple soft, fleshy, 3- to 5-mm papillomatous lesions consistent with acrochordons in the axillae, inframammary folds, groins, and posterior neck. She also had nodular and papillomatous lesions of the tongue and frenulum. Schrager et al. (1998) analyzed the clinical and pathologic features of breast disease in 19 women with Cowden disease. The 19 women showed a spectrum of benign histopathologic findings, including ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic change. Features suggestive of a breast hamartoma were found in 17 (89%). Malignant disease, most of which was ductal carcinoma, was found in 14 women (74%): ductal carcinoma in situ in 12, and infiltrating ductal carcinoma in 12. A common benign breast lesion in CD is a densely fibrotic hyalinized nodule. Hanssen et al. (1993) described Cowden syndrome in a large 4-generation family. Anticipation was demonstrated with greater severity and earlier onset of signs and symptoms in successive generations. Macrocephaly was present in all affected individuals, was markedly progressive in 3 of 6 affected children in the fourth generation, and was associated with slight to moderate delay in psychomotor development. There was 1 instance of male-to-male transmission. In a survey of 87 reported patients, Hanssen et al. (1993) found a marked excess of affected females; the male-to-female ratio was 26 to 61. In 4 affected members in a 3-generation family with Cowden syndrome, Carlson et al. (1986) found that measurements of epidermal growth factor (EGF; 131530) in body fluids yielded normal findings. Haibach et al. (1992) reported renal cell adenocarcinoma and primary neuroendocrine carcinoma of the skin in association with Cowden syndrome. They searched for abnormalities in the EGFR gene (131550) in kidney, liver and thyroid as well as in the tissue of the primary neuroendocrine carcinoma, but found none. Primary neuroendocrine carcinoma of the skin (PNECS) is also known as trabecular carcinoma or Merkel cell carcinoma. First described by Tang and Toker (1978), it originates from the Merkel cell, a pluripotential basal epidermal cell. Lyons et al. (1993) observed meningioma in a 41-year-old woman known to have Cowden disease. In addition to many skin lesions, she had a history of follicular adenoma of the thyroid and breast carcinoma as well as a family history of carcinoma of the colon affecting 2 previous generations. Hanssen and Fryns (1995) indicated that progressive macrocephaly, scrotal tongue, and mild to moderate mental retardation are important signs of Cowden syndrome in young children. Trichilemmomas in the nasolabial folds and palmar and plantar hyperkeratotic pits usually become evident later in childhood. They are often accompanied by the appearance of subcutaneous lipomas and cutaneous hemangiomas. Omote et al. (1999) reported a patient with airway obstruction that occurred during induction of general anesthesia caused by the presence of extended multiple papillomas on the lingual tonsils, epiglottis, and the surrounding structure, in whom the diagnosis of Cowden disease was made postoperatively. The patient was a 55-year-old woman undergoing mastectomy for cancer of the right breast. At the age of 27 years, she had undergone partial thyroidectomy for benign adenomatous changes in the right lobe of the thyroid gland. Fackenthal et al. (2001) reported 2 males with Cowden syndrome and germline mutations in the PTEN gene who developed breast cancer. One developed breast cancer at the age of 41 years and the second at the age of 43 years. By a review of available imaging studies, Tan et al. (2007) identified vascular anomalies in 14 (54%) of 26 patients with BRRS or Cowden syndrome. The anomalies presented clinically as cutaneous discoloration, swelling, or pain. Eight (57%) of 14 patients had multiple lesions, and 11 (85%) of 13 with cross-sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12 (86%) of 14 were fast-flow vascular anomalies with focal segmental dilatation of draining veins. Excessive ectopic fat was present in 11 (92%) of 12 patients examined by MRI. Intracranial developmental venous anomalies were found in 8 (89%) of 9 patients who had brain MRI with contrast. Histology of some cases showed disordered growth of blood vessels, adipose, and fibrous tissue, with a low level of proliferation. Lachlan et al. (2007) were unable to find a genotype/phenotype correlation among 42 patients from 26 families with PTEN mutations and clinical features of either Cowden syndrome or BRRS. The earliest features of the PTEN-related phenotype were macrocephaly and hamartomas, with mucocutaneous features and sometimes malignancies developing over time in the same patients. Busch et al. (2013) studied 23 individuals with PTEN mutations and 2 with PTEN-negative Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, respectively. The mean IQ was in the average range and the range of intellectual functioning was very wide, from extremely low to very superior. However, in a large subset of patients, scores were lower than expected in motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. Busch et al. (2013) concluded that contrary to previous reports suggesting an association with intellectual disability, the mean intellectual intelligence quotient was average, with a broad range of function. They suggested that specific evidence of disrupted frontal circuits may have implications for treatment compliance and cancer surveillance. ### Lhermitte-Duclos Disease Padberg et al. (1991) suggested that the disorder previously referred to as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is merely part of the multiple hamartoma syndrome. Mental dullness and in some cases signs of increased intracranial pressure are features; the latter is the result of herniation of the cerebellar tonsils. The condition was first described by Lhermitte and Duclos (1920). Ambler et al. (1969), who described the disorder in mother and son, stated that a total of 35 cases had been reported. Padberg et al. (1991) observed 2 unrelated patients who had macrocephaly, seizures and mild cerebellar signs resulting from dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Both had autosomal dominant Cowden disease evidenced by facial, oral, and acral papules. In the 2 families, 9 sibs demonstrated the mucocutaneous lesions, thyroid disease, breast tumors, and ovarian tumors compatible with the diagnosis of Cowden disease. Some of them also showed various degrees of neurologic signs such as macrocephaly, mental retardation, seizures, tremors, and dysdiadochokinesia. Padberg et al. (1991) suggested that the combination of Lhermitte-Duclos disease and Cowden disease represents a new phakomatosis. Albrecht et al. (1992) described 2 patients who had both Cowden syndrome and Lhermitte-Duclos disease and concluded that these are the same entity, a hamartoma-neoplasia syndrome. The skin lesions were described as multiple trichilemmomas, a type of benign skin appendage tumor. Oral papillomatosis and cutaneous keratoses also occurred. Trichilemmomas covering the pinna and around the mouth were pictured as well as papillomatosis of the tongue and keratoses of the sole. Eng et al. (1994) described a 3-generation family with Cowden disease and Lhermitte-Duclos disease. Lhermitte-Duclos disease is believed to be a hamartomatous overgrowth of hypertrophic ganglion cells which replace the granular cell layer and Purkinje cells of the cerebellum. In the grandfather of the proband in the family reported by Eng et al. (1994), the diagnosis of Lhermitte-Duclos disease had been made by cerebellar biopsy. Eng et al. (1994) found no chromosomal abnormality in the peripheral lymphocytes of the proposita and her affected mother and by single-strand conformation polymorphism analysis found no evidence of mutation in the p53 gene. Wells et al. (1994) found reports of 7 cases of Lhermitte-Duclos syndrome occurring in adults with Cowden syndrome and reported this association in a 16-year-old girl with craniomegaly, choroidal hamartoma, right conjunctival papilloma, and a history of bilateral multinodular adenomatous goiter and cystic hygroma. Although Cowden syndrome has traditionally been defined by mucocutaneous criteria, it typically also involves hamartomas and neoplasms of internal organs, most commonly in the thyroid, breast, and female genitourinary tract. Because the mucocutaneous features may develop several decades after birth, the patient reported by Wells et al. (1994) highlighted the need for long-term follow-up of a pediatric patient with Lhermitte-Duclos syndrome because of the risk of malignancies associated with Cowden syndrome. The characteristic pathologic features of Lhermitte-Duclos syndrome are global hypertrophy of the cerebellum, coarse gyri, and the typical 'inverted cortex' pattern. Vinchon et al. (1994) described an affected woman who was first seen at the age of 16 for ataxia and symptoms of raised intracranial pressure. A ventriculoatrial shunting relieved the symptoms. A nodule in her left breast was removed at the age of 18. At the age of 24, the symptoms of raised intracranial pressure recurred, CT scan disclosed a trigonoseptal tumor, and partial resection of the lesion showed it to be a benign astrocytoma. Hypothalamic hyperprolactinemia and goiter due to microinvasive vesicular carcinoma were other complications. Dermatologic examinations showed several trichilemmomas over the nose, subclavian area, and right elbow. Vinchon et al. (1994) found 72 reported cases of Lhermitte-Duclos disease; 26 had conditions suggesting Cowden disease and 7 were definite cases of Cowden disease. ### Cowden Syndrome With Immunodeficiency Browning et al. (2015) reported 2 unrelated boys with genetically confirmed Cowden syndrome associated with primary immunodeficiency resulting in recurrent infections. However, the immune defect differed between the 2 patients: 1 had hypogammaglobulinemia with a functional antibody deficiency, whereas the other had persistent CD4+ T-cell lymphopenia with normal antibody production. T cells from the patient with hypogammaglobulinemia showed a reduced level of PTEN protein expression and an increase in Akt (164730) and S6 (see 608938) phosphorylation following stimulation. Driessen et al. (2016) studied peripheral B-cell development in 9 patients with heterozygous mutations in the PTEN gene. Only 3 of the patients had recurrent infections associated with hypogammaglobulinemia, fulfilling the diagnostic criteria for common variable immunodeficiency (CVID): a mother and daughter diagnosed with Cowden syndrome, and an unrelated boy with macrocephaly and hypogammaglobulinemia (case 2 in Cogulu et al., 2007). The remaining 6 patients did not have a clinically apparent antibody deficiency. Compared to controls, individuals with PTEN mutations had decreased absolute counts of class-switched memory B cells, with a more severe reduction observed in those with hypogammaglobulinemia. These findings suggested a T-cell-dependent B-cell defect. Those with PTEN mutations showed a decrease in class-switch recombination and in somatic hypermutation frequency. Driessen et al. (2016) hypothesized that increased PI3K (see 171834)/Akt signaling, resulting from PTEN defects, deregulates the humoral immune response, similar to the case in patients with IMD14 (615513), who have activating mutations in the PIK3CD gene (602839). Biochemical Features Hobert et al. (2012) evaluated plasma succinate levels in patients with mutations in PTEN, SDHB, and SDHD. Among 15 PTEN mutation-positive individuals who met Cowden syndrome criteria, 1 SDHB mutation-positive individual, and 5 SDHD mutation-positive individuals, elevated plasma succinate was observed in 13 of these 21 (62%) individuals as compared with 5 of 32 (16%) controls (p less than 0.001). Elevated plasma succinate in 10 of the 15 (67%) individuals with pathogenic germline PTEN mutations but in less than 20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%). Urine succinate was elevated in a smaller percentage of the patients. Hobert et al. (2012) concluded that their data suggested that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identified a common biochemical alteration in these 2 patient populations (PTEN and SDHx mutation-positive individuals) that provided a plausible link for the shared phenotypic findings across these groups. Diagnosis Pilarski and Eng (2004) reviewed the International Cowden Consortium operational criteria for the diagnosis of Cowden syndrome (2000 version) and the PTEN mutation spectrum in this and related disorders. Pilarski et al. (2011) reported the clinical features of 172 patients, including 90 females and 82 males, with PTEN mutations. These patients were identified from a larger cohort of 802 patients referred for PTEN analysis. However, only 79 (34%) of 230 patients who met the diagnostic criteria for Cowden syndrome were found to carry a PTEN mutation. Of those meeting criteria for BRRS, 23 (55%) of 42 patients had a mutation, and 7 (78%) of 9 patients with an overlap syndrome carried a mutation. Logistic regression analysis suggested that in women, the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal lesions predicted a mutation. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign gastrointestinal lesions, and benign thyroid disease. However, the incidence of benign breast disease and uterine fibroids were not higher in women with mutations than in the general population, and the rate of benign skin lesions in both sexes was less than commonly reported in association with PTEN mutations. Tan et al. (2011) developed a clinical scoring system for selection of patients for PTEN mutation testing based on a prospective study of 3,042 probands satisfying relaxed Cowden syndrome clinical criteria. For adults, a semiquantitative score resulted in a well-calibrated estimation of pretest probability of PTEN status. For pediatric individuals, macrocephaly (present in 100% of patients) was a necessary criterion for PTEN testing when present with one of the following: autism or developmental delay (present in 82%); dermatologic features, including lipomas, trichilemmomas, oral papillomas, and penile freckling (present in 60%); vascular features, such as arteriovenous malformations or hemangiomas (present in 29%); or gastrointestinal polyps (present in 14%). Tan et al. (2011) noted that in addition, pediatric-onset thyroid cancer and germ cell tumors (testicular cancer and dysgerminoma) are recognized associations of Cowden syndrome and should provoke consideration of PTEN testing. Population Genetics Nelen et al. (1999) estimated that the prevalence of Cowden disease is 1 in 200,000 to 250,000 in the Dutch population. Mapping To localize the gene for Cowden disease, Nelen et al. (1996) performed an autosomal genome scan using DNA markers. They examined a total of 12 families, and obtained a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on 10q22-q23. The authors stated that the neurologic and neoplastic features of Cowden disease are consistent with the possibility that the Cowden gene is a tumor suppressor gene. The high frequency of breast cancer in female Cowden patients (approximately 30%) made it a strong candidate for a breast cancer susceptibility gene. It should also be considered in connection with nonmedullary thyroid cancer. Cytogenetics Zigman et al. (1997) localized the gene for the Bannayan-Riley-Ruvalcaba syndrome to chromosome 10q23 by study of 2 patients with intestinal juvenile polyposis and karyotypic abnormalities involving 10q. Patient 1 was a boy who displayed cognitive and developmental delay, macrocephaly, subcutaneous hamartoma, and hypotonia, in addition to multiple intestinal juvenile polyps. He ultimately underwent a total abdominal colectomy for refractory anemia and failure to thrive. Patient 2 was a girl who had features consistent with Bannayan-Riley-Ruvalcaba syndrome, including hypotonia, cognitive and developmental delay, and multiple intestinal juvenile polyps. This patient also had additional features not typical of BRRS, including atrial and ventricular septal defects, dysplastic pulmonic valve, left superior vena cava draining into a dilated coronary sinus, and bilateral clubfoot. Patient 1 had an unbalanced translocation between chromosomes 10 and 9; patient 2 has an interstitial deletion of 10q23.1-q24.2. In each case, DNA markers allowed localization of the defect to 10q23. Three other unrelated patients with the diagnosis of BRRS but without karyotypic abnormalities were also studied; 2 of the 3 patients had pigmentary changes of the penis. Arch et al. (1997) described an 18-month-old patient originally thought to have BRRS. She had an interstitial deletion of chromosome 10q23.2-q24.1, the region to which Cowden disease and the PTEN gene had been mapped. Because of the considerable phenotypic overlap between the BRRS and Cowden disease and because of a demonstration in their patient that the PTEN gene was deleted on chromosome 10, Arch et al. (1997) suggested that these are allelic disorders. The 18-month-old patient had macrocephaly, facial dysmorphism with prominent forehead and hypertelorism, a lipoma on the right abdomen and on the right thumb, 2 small hemangiomas on the back and shoulder, and 2 skin tags at the base of the spine and in the groin area. Psychomotor development was delayed. Ophthalmologic examination showed pseudopapilledema bilaterally. Neither parent had any features of either Cowden disease or BRR syndrome. Hematochezia prompted upper and lower gastrointestinal endoscopy, which showed multiple sessile polyps throughout the duodenum and large intestine. Histology showed that these were hamartomatous. Tsuchiya et al. (1998) described a 6-year-old African American boy with mental retardation, dysmorphic features, and juvenile polyposis coli. A cytogenetically visible interstitial deletion of 10q23 was identified and characterized by fluorescence in situ hybridization. Five YACs that span an 11- to 15-cM region within the deletion were identified. The patient's deletion contained the putative locus for Cowden syndrome and the PTEN gene. The patient first had rectal bleeding at 2 years of age. Polyps were identified extending from the duodenum to the rectum. Dysmorphic features included macrocephaly with a head circumference of 53.6 cm, frontal bossing, hypertelorism, flat nasal bridge, hyperpigmentation at the corners of the mouth, thickened gingiva, bilateral preauricular pits, and a flat midface. He had a large penis with a hyperpigmented macule on the dorsal shaft. Multiple other hyperpigmented macules as well as a large area of hypopigmentation were identified. The distal phalanges of all fingers and toes were strikingly bulbous and nail clubbing was noted. Ahmed et al. (1999) reported a boy with features consistent with BRR who had a novel de novo balanced translocation, 46,XY, t(10;13)(q23.2;q33), and a malignant intracranial hCG-secreting tumor, resulting in precocious puberty. The pathology of such tumors can vary, but none had yet been associated with the Cowden disease or BRRS phenotype or with PTEN mutations. Although previous reports provided evidence that germline intragenic mutations and gross deletion of PTEN can lead to BRRS, the authors postulated that a germline balanced translocation incorporating PTEN could also lead to the BRRS phenotype. Molecular Genetics The chromosomal region containing the Cowden syndrome locus was known to contain the tumor suppressor gene PTEN, which had been found to be mutated in sporadic brain, breast, and prostate cancer. Liaw et al. (1997) found germline mutations in the PTEN gene in 4 of 5 families with Cowden syndrome. Missense (601728.0001) and nonsense mutations were predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of the protein. All affected individuals of the 5 families studied manifested trichilemmomas, regardless of whether their mutation was a missense or nonsense mutation. Nonsense mutations were associated with macrocephaly in 2 families. In 1 of these families, a premature stop codon at position 157 (601728.0003) was also associated with Lhermitte-Duclos disease (LDD), manifested by ataxia and dysplastic cerebellar gangliocytomatosis. In the other family, a stop codon at position 233 (601728.0002) was not associated with cerebellar manifestation. Liaw et al. (1997) speculated that the larger N-terminal truncation may be responsible for the more severe LDD phenotype. Their data indicated that PTEN is a tumor suppressor gene in the germline and that it plays a role in organizing the relationship of different cell types within an organ during development. Because germline mutations of PTEN predispose to a breast and thyroid cancer syndrome (Cowden syndrome) and somatic mutations are found in sporadic breast cancer, PTEN was an obvious candidate for predisposition to non-CS breast cancer. Nelen et al. (1997) confirmed that the PTEN gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN gene, and by mutation analysis in 8 unrelated familial and 11 sporadic patients with Cowden disease. They detected 8 different mutations in various regions of the PTEN gene (e.g., 601728.0005). One mutation was detected twice (601728.0007). All detected changes in the gene were predicted to have a deleterious effect on the putative protein. They found no indications of a correlation between genotype and phenotype. In 10 patients, no mutation could be detected. These were patients who showed linkage to the same region, 10q22-q23; no evidence emerged from the phenotype of these patients to suggest genetic heterogeneity. Nelen et al. (1999) identified PTEN mutations in an additional 13 patients with Cowden disease. The mutations were dispersed throughout the gene, with a clustering in exon 5. Arch et al. (1997) described an 18-month-old boy with macrocephaly, pseudopapilledema, 2 small lipomas, hamartomatous neoplasms, and polyps of the duodenum and colon who had an interstitial deletion of 10q23.2-q24.1. The initial diagnosis had been Bannayan-Riley-Ruvalcaba syndrome. Cowden disease is relatively poorly described in young children. The overlap of clinical features of Cowden disease and BBRS, the demonstration of an interstitial deletion of the region of chromosome 10 containing the Cowden disease locus, and the specific demonstration that the PTEN gene was missing from the deleted chromosome 10 in their patient led Arch et al. (1997) to suggest that these 2 disorders are allelic. Marsh et al. (1997) identified germline mutations in the PTEN gene in patients with Bannayan-Zonana syndrome. One of the mutations that Marsh et al. (1997) identified, R233X (601728.0002), had previously been reported in patients with Cowden disease. The identical mutation occurred in 2 unrelated families on 2 different 10q22-q23 haplotypes, arguing against a common ancestor or a founder effect. Marsh et al. (1998) carried out mutation analysis in the PTEN gene in 64 unrelated Cowden syndrome-like families. These families were defined as having some features of Cowden syndrome but did not meet the diagnostic criteria of the International Cowden Consortium. Minimally, these Cowden syndrome-like families contained at least 1 member with both nonmedullary thyroid cancer and at least 1 other related member with breast cancer diagnosed at any age. They could also comprise subjects with both breast cancer and nonmedullary thyroid cancer. Alternatively, families could be made up of either breast or nonmedullary thyroid cancer and other features of Cowden syndrome, such as trichilemmomas, without meeting diagnostic criteria. Mutation analysis identified only 1 mutation, leu70 to pro (601728.0012), in a male with follicular thyroid carcinoma. Marsh et al. (1998) concluded that germline PTEN mutations play a relatively minor role in Cowden syndrome-like families. Longy et al. (1998) identified 4 mutations in the PTEN gene in 6 patients from 4 unrelated families with Bannayan-Riley-Ruvalcaba syndrome. In 1 family, 1 individual had features more suggestive of Cowden disease, whereas the overall family phenotype was that of Bannayan-Riley-Ruvalcaba syndrome. Celebi et al. (1999) reported a further family with a single PTEN mutation (601728.0021) in which 2 female members had phenotypic findings of Cowden syndrome and 2 males had phenotypic findings of BZS. Olschwang et al. (1998) identified mutations in the PTEN gene (601728.0009-601728.0011) in 3 unrelated patients reported to have juvenile polyposis coli (174900). One of them was a 14-year-old boy who underwent colonoscopy that revealed juvenile polyposis; the second patient was a 74-year-old man with anemia and hypoalbuminemia in whom gastroscopy and colonoscopy showed polyps throughout the digestive tract; and the third patient was found to have juvenile polyps throughout the stomach, duodenum, and colon when gastroscopy and colonoscopy were performed at the age of 7 years, after a 3-year history of intermittent rectal bleeding. However, Eng and Peacocke (1998) and Eng and Ji (1998) questioned the role of PTEN mutations in the juvenile polyposis syndrome, and suggested further that the 3 patients found by Olschwang et al. (1998) had either Cowden disease or Bannayan-Zonana syndrome; the 74-year-old man had manifestations they interpreted as suggestive of Cowden disease, and the 2 children may not have yet demonstrated features of Cowden disease, which has a penetrance well below 10% under 15 years of age (Nelen et al., 1996). Similarly, Lynch et al. (1997) referred to germline PTEN mutations in individuals with juvenile polyposis, but it was obvious to Waite and Eng (2002), from the text, that all of the individuals had Cowden syndrome. Kurose et al. (1999) reported 1 individual with juvenile polyposis syndrome who had a germline PTEN mutation. However, on reexamination, classic cutaneous features of Cowden syndrome were found. Waite and Eng (2002) concluded that discovery of a germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect. Marsh et al. (1999) screened for PTEN mutations in constitutive DNA samples from 43 Bannayan-Riley-Ruvalcaba syndrome individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both Cowden disease and BRRS. Mutations were identified in 26 of 43 (60%) BRRS cases. Genotype-phenotype analyses within the BRRS group suggested a number of correlations, including the association of PTEN mutations and cancer or breast fibroadenoma in any given CS, BRRS, or BRRS/CS overlap family (p = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (p = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRRS patients (p = 0.028). In contrast to the report of Carethers et al. (1998), in which no PTEN mutations or deletions were found in sporadic cases of BRRS, Marsh et al. (1999) found that identification of germline PTEN mutations was equally likely in sporadic and familial BRRS (p = 0.113). Comparisons between BRRS and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRRS when compared with BRRS alone (p = 0.002). Among CS, BRRS, and BRRS/CS overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CS and BRRS may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance. Agrawal and Eng (2006) identified 8 novel naturally occurring PTEN splice variants that result in different downstream signaling effects. Sarquis et al. (2006) studied these and previously described naturally occurring splice variants in 85 (65 female and 20 male) patients with CS/BRRS (with or without PTEN mutations) compared with 27 controls. There appeared to be a splice variant genotype-phenotype correlation in which the splice variant expression profiles were distinct among CS, CS-like, and BRRS. Pal et al. (2012) measured insulin sensitivity and beta-cell function as well as anthropometric indices in 15 patients diagnosed with Cowden disease who carried mutations in the PTEN gene as well as 15 age-, sex-, and body mass index (BMI)-matched controls. Measures of insulin resistance were lower in patients with PTEN mutations than in controls (p = 0.001), which was confirmed by hyperinsulinemic euglycemic clamping studies. Increased AKT phosphorylation was observed in patients versus controls, suggesting that the patients' increased insulin sensitivity might be explained by enhanced insulin signaling through the PI3K/AKT pathway (see 164730). In addition, PTEN mutation carriers were obese compared to population-based controls (p less than 0.001); the increased body mass was due to augmented adiposity without corresponding changes in fat distribution. Pal et al. (2012) concluded that PTEN haploinsufficiency appears to result in an increased risk of obesity and cancer but a decreased risk of type 2 diabetes (125853), owing to enhanced insulin sensitivity. Mester and Eng (2012) studied 187 pathogenic PTEN-mutation positive families and confirmed 20 (10.7%) to be de novo mutations in the probands. De novo status was suspected based on family history in 36 (19.3%) probands. Inherited mutations showed no preference for maternal or paternal lineage. Mester and Eng (2012) concluded that the frequency of de novo PTEN mutation is at minimum 10.7% and at best 47.6%, and concluded that absence of PTEN hamartoma tumor syndrome features within a family history should not preclude consideration of this diagnosis for patients with relevant personal history. Orloff et al. (2013) reported that, while PTEN mutations are found in 85% of Cowden syndrome patients accrued from tertiary epidemic centers, prospective accrual from the community over the aforegoing 12 years revealed a 25% PTEN mutation frequency. ### 'Proteus-like' Syndrome Zhou et al. (2000) reported a boy with congenital hemihypertrophy, epidermoid nevi, macrocephaly, lipomas, arteriovenous malformations, and normal intellect. He was given the clinical diagnosis of 'Proteus-like' syndrome because of phenotypic similarities to Proteus syndrome (176920). Sequence analysis of DNA from peripheral blood revealed heterozygosity for a single base transversion resulting in an arg335-to-ter substitution in the PTEN gene product (601728.0021), whereas analysis of DNA from a nevus, lipoma, and arteriovenous mass also revealed heterozygosity for a somatic R130X (601728.0007) mutation. The former mutation had been reported in patients with Cowden syndrome, whereas the latter mutation had been reported in patients with Bannayan-Zonana syndrome. Zhou et al. (2000) postulated that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in 'Proteus-like' syndrome with its implications for cancer development in the future. Smith et al. (2002) described a 16-month-old male with a de novo 1-bp deletion in the cDNA of the PTEN gene, 507delC (601728.0032), and classic features of Proteus syndrome, including a left-sided epidermal nevus following the lines of Blaschko, widespread capillary venous malformation on his chest and abdomen, multiple lipoblastomata, disproportionate overgrowth of the right leg, and a progressive course. Cohen et al. (2003) disputed the diagnosis of Proteus syndrome in the cases reported by Zhou et al. (2000) and Smith et al. (2002). Cohen et al. (2003) noted that the patient reported by Zhou et al. (2000) had a 'Proteus-like' syndrome, an unhelpful and confounding term, and did not meet the classic diagnostic criteria, whereas 5 additional patients with classic Proteus syndrome had no PTEN mutations. An additional study by Zhou et al. (2001) failed to provide sufficient clinical data for a diagnosis of Proteus syndrome. Cohen et al. (2003) also stated that the patient reported by Smith et al. (2002) did not have classic clinical features of Proteus syndrome but rather had features more consistent with PTEN hamartoma-tumor syndrome. Based on a review of the literature and personal referrals, Cohen et al. (2003) concluded that many physicians misdiagnose Proteus syndrome and that no patient with a PTEN mutation has Proteus syndrome. Loffeld et al. (2006) reported a 3-year-old boy with a germline PTEN missense mutation inherited from his mother who had Cowden syndrome. The boy showed extensive epidermal nevus, macrocephaly, vascular malformations, asymmetric hypertrophy of 1 leg, localized macrodactyly, and abdominal lipoma. They identified loss of heterozygosity for the missense mutation in an epidermal nevus from the boy, suggesting wildtype PTEN allele loss. Caux et al. (2007) reported 2 unrelated families in which multiple members had typical Cowden syndrome confirmed by genetic analysis. The female proband of 1 family had an atypical phenotype of segmental overgrowth, lipomas, vascular malformations, and epidermal nevi, and molecular analysis revealed loss of the wildtype allele in several atypical lesions, including a cutaneous fibroma, an epidermal nevus, and a lipoma. The female proband of the other family also had an atypical presentation but lacked epidermal nevus, and molecular analysis of a single biopsy of her affected skin did not show loss of the wildtype PTEN allele. The findings suggested that heterozygous germline PTEN mutations associated with a mosaic inactivation of the wildtype allele may underlie multiple atypical dysmorphisms suggestive of other diseases, including Proteus syndrome (176920). These atypical lesions could be explained by biallelic inactivation and complete loss of PTEN function, resulting in segmental exacerbations of the disease. To clinically distinguish between Proteus syndrome and segmental exacerbation of Cowden disease, Caux et al. (2007) suggested 'SOLAMEN syndrome' as an acronym for segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus. ### Associations Pending Confirmation Ni et al. (2008) found that 74 (20%) of 375 individuals with a Cowden-like syndrome who were negative for PTEN mutations had increased manganese superoxide dismutase (MnSOD; 147460) expression, a manifestation of mitochondrial dysfunction. Among these 74 individuals, 3 had germline mutations or variants in the SDHB gene (185470.0014, 185470.0015) and 7 had germline or variants in the SDHD gene (602690.0011, 602690.0019, 602690.0028). In the absence of PTEN alteration, these SDH mutations/variants syndrome showed increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Ni et al. (2008) concluded that germline SDH mutations/variants occur in a subset of PTEN mutation-negative Cowden syndrome and Cowden-like syndrome individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. However, based on the high frequency of the variants identified by Ni et al. (2008) in the ExAC and gnomAD databases, these variants have been reclassified in OMIM as variants of unknown significance. Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. For discussion of a possible association of Cowden syndrome with variation in the USF3 gene, see 617568. Genotype/Phenotype Correlations Marsh et al. (1999) screened for PTEN mutations in constitutive DNA samples from 43 Bannayan-Riley-Ruvalcaba syndrome individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both Cowden disease and BRRS. Mutations were identified in 26 of 43 (60%) BRRS cases. Genotype-phenotype analyses within the BRRS group suggested a number of correlations, including the association of PTEN mutations and cancer or breast fibroadenoma in any given CS, BRRS, or BRRS/CS overlap family (p = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (p = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRRS patients (p = 0.028). In contrast to the report of Carethers et al. (1998), in which no PTEN mutations or deletions were found in sporadic cases of BRRS, Marsh et al. (1999) found that identification of germline PTEN mutations was equally likely in sporadic and familial BRRS (p = 0.113). Comparisons between BRRS and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRRS when compared with BRR alone (p = 0.002). Among CS, BRRS and BRRS/CS overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CS and BRRS may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance. Lachlan et al. (2007) were unable to find a genotype/phenotype correlation among 42 patients from 26 families with PTEN mutations and clinical features of either Cowden syndrome or BRRS. The earliest features of the PTEN-related phenotype were macrocephaly and hamartomas, with mucocutaneous features and sometimes malignancies developing over time in the same patients. Animal Model Backman et al. (2001) and Kwon et al. (2001) provided an explanation for the large neuronal soma size in Lhermitte-Duclos disease (LDD) in mice with selective inactivation of Pten in specific neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt (164730) and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of Lhermitte-Duclos disease. History Cohen (1990) suggested the designation 'Bannayan-Riley-Ruvalcaba syndrome' to unify 3 previously recognized syndromes (Bannayan, 1971; Riley and Smith, 1960; Ruvalcaba et al. (1980)) as a single entity. DiLiberti (1990) questioned the evidence that these syndromes were the same. However, DiLiberti (1992) later suggested that Ruvalcaba-Myhre-Smith syndrome and Bannayan-Zonana syndrome represent phenotypic variability resulting from mutation at a single genetic locus. DiLiberti (1998) proposed a new nomenclature reflecting the unification of multiple syndromes that are now known to be caused by mutations in the PTEN gene. He proposed that it be called the PTEN MATCHS syndrome; MATCHS was derived from macrocephaly, autosomal dominant, thyroid disease, cancer, hamartomata, and skin abnormalities. In a child with a Bannayan-Zonana phenotype, Israel et al. (1991) found a 19;Y translocation in circulating lymphocytes: 46X,t(Y;19)(q11;q13). They raised the possibility that a small deletion or position effect of chromosome 19q was responsible for this syndrome. Carethers et al. (1998) failed to find PTEN germline mutations in 3 sporadic cases of Bannayan-Riley-Ruvalcaba syndrome in males. One patient presented with macrocephaly, hypotonia, cognitive and developmental delays, cutaneous lipomas, and a 2-cm intestinal metaplastic polyp located in the ascending colon. The second patient presented with macrocephaly, multiple intestinal juvenile polyps, pigmentation of the genitalia, cutaneous and visceral lipomas, cutaneous hemangiomas, and hyporeflexia. The third patient presented with macrocephaly, multiple rectal juvenile polyps, pigmentary spotting of the penis, cutaneous lipomas, and cognitive and developmental delay. INHERITANCE \- Autosomal dominant GROWTH Weight \- Obesity, increased risk of HEAD & NECK Head \- Progressive macrocephaly Face \- 'Birdlike' facies (uncommon) \- Hypoplastic mandible (uncommon) \- Hypoplastic maxilla (uncommon) Ears \- Hearing loss Eyes \- Cataract \- Angioid streaks \- Myopia Mouth \- Microstomia \- High-arched palate \- Scrotal tongue \- Oral papillomas CARDIOVASCULAR Vascular \- Vascular anomalies (50% of patients) \- Intracranial developmental venous anomalies CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum Breasts \- Virginal hyperplasia \- Fibrocystic breast disease \- Gynecomastia in males \- Breast fibroadenomas ABDOMEN Gastrointestinal \- Hamartomatous polyps \- Colonic diverticula GENITOURINARY External Genitalia (Male) \- Hydrocele \- Varicocele External Genitalia (Female) \- Vaginal cysts \- Vulvar cysts Internal Genitalia (Female) \- Ovarian cysts \- Leiomyomas SKELETAL Spine \- Scoliosis \- Kyphosis SKIN, NAILS, & HAIR Skin \- Multiple facial papules \- Acral keratoses \- Palmoplantar keratoses \- Multiple skin tags \- Facial trichilemmomas \- Subcutaneous lipomas NEUROLOGIC Central Nervous System \- Seizure \- Intention tremor \- Lhermitte-Duclos disease \- Mental retardation, mild to moderate (in 12%) \- Psychomotor delay, mild to moderate \- Cerebellar gangliocytoma manifesting as seizure and tremor ENDOCRINE FEATURES \- Goiter \- Thyroid adenoma \- Hyperthyroidism \- Hypothyroidism \- Thyroiditis \- Enhanced insulin sensitivity IMMUNOLOGY \- Primary immunodeficiency (in some patients) \- Recurrent infections (in some patients) \- Opportunistic infections (in some patients) \- Hypogammaglobulinemia (in some patients) \- Lymphopenia (in some patients) \- Inverted CD4/CD8 T cell ratio (in some patients) \- Decreased memory B cells (in some patients) \- Decreased class-switched B cells (in some patients) NEOPLASIA \- Breast cancer \- Ovarian carcinoma \- Cervical carcinoma \- Uterine adenocarcinoma \- Thyroid cancer (follicular cell) \- Transitional cell carcinoma of the bladder \- Meningioma \- Mucosal neuromas MISCELLANEOUS \- Symptoms usually occur in adults \- Skin lesions are fully penetrant by second decade \- Skeletal abnormalities are variable \- Allelic to Bannayan-Riley-Ruvalcaba syndrome ( 153480 ), which has an earlier age at onset \- Approximately 80% of CS patients have PTEN mutations MOLECULAR BASIS \- Caused by mutation in the phosphatase and tensin homolog gene (PTEN, 601728.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	COWDEN SYNDROME 1	c1866398	6,912	omim	https://www.omim.org/entry/158350	2019-09-22T16:37:59	{"doid": ["0050657"], "mesh": ["D016715"], "omim": ["158350"], "orphanet": ["2969", "201", "65285", "109"], "synonyms": ["Alternative titles", "CS", "MULTIPLE HAMARTOMA SYNDROME", "PTEN HAMARTOMA TUMOR SYNDROME", "PTEN HAMARTOMA TUMOR SYNDROME WITH GRANULAR CELL TUMOR", "BANNAYAN-RILEY-RUVALCABA SYNDROME", "BANNAYAN-ZONANA SYNDROME", "RILEY-SMITH SYNDROME", "RUVALCABA-MYHRE-SMITH SYNDROME", "MACROCEPHALY, PSEUDOPAPILLEDEMA, AND MULTIPLE HEMANGIOMATA", "MACROCEPHALY, MULTIPLE LIPOMAS, AND HEMANGIOMATA"], "genereviews": ["NBK1488"]}
Late-onset localized jonctional epidermolysis bullosa-intellectual disability syndrome is a rare junctional epidermolysis bullosa subtype characterized by late-onset blistering surrounded by erythema and localized on the anterior aspect of the lower legs, associated with dystrophic toenails, tooth enamel defects and mild to severe intellectual disability. Lens subluxation and mild facial dysmorphism (with short midface, prognatism and thin upper lip vermilion) are additional reported features. There have been no further descriptions in the literature since 1992. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Late-onset localized junctional epidermolysis bullosa-intellectual disability syndrome	c1856969	6,913	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231556	2021-01-23T18:15:16	{"gard": ["299"], "mesh": ["C535492"], "omim": ["226440"], "umls": ["C1856969"], "icd-10": ["Q81.8"]}
## Summary ### Clinical characteristics. The TP63-related disorders comprise six overlapping phenotypes: * Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome) * Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome * Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) * Limb-mammary syndrome * Split-hand/foot malformation type 4 (SHFM4) * Isolated cleft lip/cleft palate (orofacial cleft 8) Individuals typically have varying combinations of ectodermal dysplasia (subjective hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring and alopecia, hypospadias, trismus, and excessive freckling. ### Diagnosis/testing. The diagnosis is based on clinical findings and molecular genetic testing of TP63. ### Management. Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry is recommended. Wigs can be used for sparse hair and alopecia; dentures may be considered in early childhood and dental implants in the teens or early adulthood. Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection. Cleft lip/palate is managed as per routine protocols with attention to feeding in infancy, recurrent otitis media, and speech therapy. Prevention of secondary complications: Infants with severe skin erosions need aggressive monitoring/treatment of dehydration, electrolyte imbalances, malnutrition, and secondary infection and sepsis. Surveillance: Regular evaluation with a multidisciplinary team with attention to dental needs and possible hearing loss. ### Genetic counseling. The TP63-related disorders are inherited in an autosomal dominant manner. Approximately 30% of individuals have an affected parent and approximately 70% have a de novo pathogenic variant. Each child of an individual with a TP63-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the TP63 pathogenic variant in the family is known. ## Diagnosis ### Suggestive Findings The TP63-related disorders include the following overlapping phenotypes (summarized in Table 1). Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome * Ankyloblepharon filiforme adnatum typically manifest as strands of tissue that completely or partially fuse the upper and lower eyelids. In the latter instance, they may be barely perceptible and lyse spontaneously. Although a definitive part of the syndrome, ankyloblepharon may not be present or detected in up to 50% of cases. * Ectodermal defects typically manifest as sparse wiry hair, skin erosions and unique pigmentary skin changes, nail changes, dental changes, and subjective decrease in sweating capacity. Note: (1) Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability. (2) Scalp erosions are characteristic of AEC syndrome and are NOT seen in other TP63-related disorders. * Cleft lip/palate presents in nearly 100%; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. In a series of 18 affected individuals: 44% had cleft lip (~1/3 bilateral); 100% had some form of palatal cleft (cleft hard palate: 56%; cleft soft palate: 89%; submucous cleft palate: 17%). * Craniofacial findings include the following: * Maxillary hypoplasia (reported in 94%) * Small mandible (reported in 65%) * Broad nasal bridge (76%) * Hypoplastic alae nasi (94%) * Thin vermilion border of the upper lip (82%) * Microstomia (94%) * Trismus (44%) * Hypospadias has been reported in 80% of males. Note: Rapp-Hodgkin syndrome (RHS), once thought to be a separate entity, is now considered to be part of the spectrum of the AEC syndrome because of the overlap of clinical manifestations and TP63 pathogenic variants observed in the two conditions [Cambiaghi et al 1994, Bertola et al 2004]. Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome * Acromelic malformation is present in the form of split hand and/or split foot with or without syndactyly. * Dermatologic abnormalities include sparse fine hair; dry skin, and unique pigmentary skin changes. * Excessive freckling in sun-exposed areas is common and progresses with age and sun exposure. It is unique to ADULT syndrome and not characteristic of other TP63–related disorders. * There may be subjective decrease in sweating capacity. Note: Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability. * Ungual defects manifest as hypoplastic, dysplastic, absent, and/or ridged nails. * Lacrimal puncta absence is seen in many affected individuals. * Tooth abnormalities include hypodontia or oligodontia. * Breast and/or nipple hypoplasia that may be symmetric or asymmetric is typically seen in ADULT syndrome and limb-mammary syndrome and not in other TP63-related disorders. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) * Ectrodactyly (now referred to as split-hand/foot malformation) with or without syndactyly is present in approximately 70% of all affected individuals and ranges widely in severity and location of the digital abnormalities [Rinne et al 2006a]. * Ectodermal defects typically manifest as silvery-blond, sparse fine hair; dry skin and unique pigmentary skin changes; nail changes; dental changes including oligodontia and enamel defects; and xerostomia and subjective decrease in sweating capacity. Note: Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability. * Cleft lip/palate is present in approximately 40% of affected individuals [Rinne et al 2006a]; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. * Other * Absent lacrimal puncta is seen in almost all affected individuals. * Blepharophimosis is seen occasionally. * Hypospadias has been reported often in males. Limb-mammary syndrome * Limb abnormalities can include split-hand/foot malformation, oligodactyly, and syndactyly. * Breast and/or nipple hypoplasia has been reported in 90% of individuals with limb-mammary syndrome [van Bokhoven et al 1999]. It may be symmetric or asymmetric, and is typical for ADULT syndrome and limb-mammary syndrome and rarely seen in other TP63-related disorders. * Less common findings * Absent lacrimal puncta and lacrimal duct atresia is seen in half of all affected individuals. * Cleft lip/palate is present in one quarter to one third of affected individuals; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. * Hypodontia and nail dysplasia is found in a small percentage of individuals; skin and hair abnormalities are NOT seen. Split-hand/foot malformation type 4 (SHFM4) * Split hand/foot with or without syndactyly is present in all affected individuals and ranges widely in severity and location. Aplasia or hypoplasia of phalanges and metacarpals is seen. * Ectodermal abnormalities and cleft lip/palate are very rarely seen. Isolated cleft lip/cleft palate (orofacial cleft 8). Cleft lip/palate includes a wide spectrum ranging from submucous cleft palate only to cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. ### Table 1. Clinical Features of TP63-Related Disorders View in own window FeatureTP63-Related Disorder AECADULTEEC3Limb- MammarySHFM4Isolated CL/P Ankyloblepharon filiforme adnatumX Ectodermal dysplasia:XXXRare * Hypohidrosis (mostly subjective) XXX * Nail dysplasia XXMildX * Sparse hair XXX * Tooth abnormalities XXXX Cleft lip/palateXXXX Split-hand/foot malformation/syndactylyXXXXX Lacrimal duct obstructionXXXX Dermal erosionsX HypopigmentationXXX HypospadiasXX TrismusX Excessive frecklingX Hypoplastic breastsXX Hypoplastic nipplesXX ADULT = acro-dermato-ungual-lacrimal-tooth; CL/P = cleft lip/cleft palate; EEC = ectrodactyly (split-hand/foot malformation), ectodermal dysplasia, clefting; SHFM4 = split-hand/foot malformation type 4 ### Establishing the Diagnosis The diagnosis of a TP63-related disorder is established by identification of a TP63 heterozygous pathogenic variant in a proband on molecular genetic testing (see Table 2). Molecular testing approaches can include single-gene testing and use of a multigene panel: * Single-gene testing. Sequence analysis of TP63 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes TP63 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. ### Table 2. Molecular Genetic Testing Used in TP63 Related Disorders View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method TP63Sequence analysis 375%-100% 4 Gene-targeted deletion/duplication analysis 5Rare 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\. van Bokhoven et al [2001], Rinne et al [2009] 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 gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. A single case report of a four-exon deletion of TP63 has been reported in an individual with EEC [Aradhya et al 2012]. ## Clinical Characteristics ### Clinical Description #### AEC Syndrome The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. Ankyloblepharon is present in 70% of neonates. While the upper- and lower-eyelid adhesions can be obvious, partial adhesion of the upper and lower eyelids can be subtle and these filiforme adhesions can spontaneously lyse before they are recognized as such. Lacrimal puncta are frequently absent, often leading to chronic conjunctivitis and blepharitis which is often not recognized in infancy but rather seen in early childhood [Sutton et al 2009]. Ectodermal defects * Skin. Nearly 100% of affected neonates have superficial skin erosions that vary from very limited to severe, life-threatening full-body involvement. The erosions most typically affect the scalp at birth and during infancy. Severe scalp erosions often lead to scarring alopecia and hypotrichosis. This is NOT seen in other TP63-related disorders. The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. Congenital erythroderma (i.e. diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [Siegfried et al 2005]. Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions which may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribiform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [Dishop et al 2009]. * Hair changes become more obvious with age. Hair is typically light-colored and coarse, wiry, and brittle with a spun glass/gold or “uncombable” appearance. Eyebrows and eyelashes are sparse. Light and scanning microscopy may reveal structural and pigmentary alterations of the hair including kinking, grooves, and discontinuous pigmentation. * Nail changes, present in all and more obvious with age, vary among individuals. Most affected individuals have nail dystrophy (abnormal nail plate texture) and hyperconvex nail plates. Micronychia (abnormally small nail plates), distal frayed edges with nail plate resorption, and absent nails are also frequent [Julapalli et al 2009]. * Dental anomalies. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence. Affected adults have an average of 4.75 secondary teeth [Farrington & Lausten 2009]. * Sweating. Subjective decreased sweat production is universal and is reported as heat intolerance; however, this does not lead to hyperthermia or fevers as seen in hypohidrotic ectodermal dysplasia. Clefting is present in all. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate [Cole et al 2009]. Other findings include the following: * Limb anomalies were initially not considered to be part of the syndrome, but syndactyly of fingers and toes and/or camptodactyly (permanent and irreducible flexion of the fingers) of hands have been seen. Split-hand/foot malformation was observed in 2/17 individuals (12%) with AEC syndrome [Sutton et al 2009]. * Hypospadias has been reported in 78% of males with AEC syndrome [Sutton et al 2009]. * Facial features become more distinctive with age. Findings commonly include maxillary hypoplasia, micrognathia, broad nasal root, underdeveloped alae nasi, thin vermilion of the upper lip, and short philtrum. * Trismus has been reported in 35% of individuals with AEC syndrome [Sutton et al 2009]. * Hearing loss. More than 90% of children have conductive hearing loss, often with secondary speech delay [Cole et al 2009]. * Growth. Poor weight gain and failure to thrive should be anticipated. When treated appropriately with nutritional supplementation poor weight gain improves with age. Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [Motil & Fete 2009]. * Psychological impact related to the phenotypic features of the disease can include a reduced quality of life with negative impact on both child and family. In one study, a variable degree of psychological functioning was noted with some families reporting few ill effects from the disease while others reported significant impact [Lane et al 2009]. #### ADULT Syndrome The manifestations of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are typically present at birth (although they may become more prominent with age), with the exception of skin freckling. Limb anomalies. Most commonly seen is syndactyly of fingers and toes. Ectodermal defects * Skin tends to be dry but erosions are not present. * Hair changes are more obvious with age. Hair is typically light-colored and fine. Eyebrows and eyelashes are sparse. * Nail dysplasia is commonly reported. * Dental anomalies. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence. * Sweating. Subjective decreased sweat production is universal and is reported as heat intolerance; however, this does not lead to hyperthermia or fevers as seen in hypohidrotic ectodermal dysplasia. Lacrimal duct atresia is frequent and often leads to chronic conjunctivitis and blepharitis, which are often not recognized until early childhood [Sutton et al 2009]. Breast and/or nipple hypoplasia is seen commonly and most notably in females. This feature is characteristic of ADULT and limb-mammary syndrome and NOT typically seen in other TP63-related disorders. Excessive freckling in sun exposed areas is seen in a subset of patients and progresses with age and sun exposure. This feature is NOT seen in other TP63-related disorders. #### EEC3 Syndrome The manifestations of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) are typically present at birth. Limb anomalies are seen in 68%-90% of individuals with 60% having tetramelic involvement. A wide variety of limb abnormalities are reported including syndactyly, oligodactyly, split-hand/foot malformation and digital duplication. A cohort of 152 EEC syndrome patients showed split-hand/foot malformation in 68% and syndactyly in 43% [Rinne et al 2006a]. Ectodermal defects * Skin tends to be dry but erosions are not present. * Hair changes become more obvious with age and are seen in 60%-80% of individuals with EEC syndrome [Rinne et al 2006a]. Hair is typically silvery-blond, coarse, and dry; 20% have sparse hair. Light microscopy has been reported to be normal in EEC syndrome [Pashayan et al 1974]. Eyebrows and eyelashes are sparse. * Nail dysplasia is commonly reported. * Dental anomalies. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence. * Sweating. Hypohidrosis is uncommon in EEC3 syndrome. Cleft lip with or without cleft palate is present in 60%-75% and is bilateral in half of cases. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate [Buss et al 1995]. Absent lacrimal puncta is reported in 90% of individuals and results in tearing, blepharitis, dacryocystitis, keratoconjunctivitis and photophobia and often lead to corneal ulceration and scaring [Buss et al 1995]. Genitourinary malformations are reported in 45% and may include hypospadias and developmental abnormalities of the kidneys and urinary collecting system. #### Limb-Mammary Syndrome The manifestations limb-mammary syndrome are typically present at birth. Limb anomalies, including split-hand/foot malformation and syndactyly are reported in 75%-85% of individuals. Breast and/or nipple hypoplasia is seen commonly with almost all individuals having nipple aplasia or hypoplasia and 90% of females having mammary gland aplasia or hypoplasia. This feature is characteristic of ADULT and limb-mammary syndrome and NOT typically seen in other TP63-related disorders. Lacrimal duct atresia is seen in about half leading to chronic conjunctivitis and blepharitis, which are often not recognized until early childhood [van Bokhoven et al 1999]. Ectodermal defects * Nail dysplasia is reported in 30% of individuals. * Dental anomalies. Hypodontia (reduced number of teeth) also become evident during childhood and adolescence and is seen in 10%-15%. Note: Skin and hair abnormalities are NOT typically seen, in contrast to other TP63-related disorders. Cleft lip with or without cleft palate is present in 25%-30% and can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate. #### SHFM4 The manifestations of split-hand/foot malformation-4 (SHFM4) are typically present at birth. Limb abnormalities include median clefts of the hands and feet; aplasia/hypoplasia of phalanges, metacarpals, and metatarsals; and some syndactyly. Ectodermal abnormalities and cleft lip/palate are considered to be exclusion criteria for making the diagnosis SHFM4. #### Orofacial Cleft 8 Leoyklang et al [2006] have investigated the occurrence of TP63 pathogenic variants in a cohort of 100 Thai patients with nonsyndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel nonsynonymous changes. No other features of TP63-related disorders were observed in these patients ### Genotype-Phenotype Correlations Note: Pathogenic variants have been described on two TP63 isoforms: the TAp63α isoform, encoded by NM_003722.4, and the ΔNp63α isoform, encoded by NM_001114982.1, which is 39 amino acids shorter and has an alternate N-terminal TA domain. See Molecular Genetics and Figure 1 for details. #### Figure 1. Typical and common TP63 pathogenic variants identified in various disorders as indicated by color key. Pathogenic variants indicated by * are specific for the ΔNp63α isoform and their numbering is based on the respective reference sequences (more...) AEC syndrome. All pathogenic variants associated with AEC syndrome occur in either the sterile alpha motif (SAM) domain (82%) or the ΔNp63-specific N-terminal domain (18%). Pathogenic variants in the N-terminal domain that introduce premature termination codons lead to the use of an alternative start codon [Rinne et al 2008] and to the consequent production of ΔNp63α isoforms lacking the N-terminal domain, which are specifically associated with AEC syndrome. This isoform of p63 is the predominant isoform in mature epidermis, and it has been shown to repress ZNF750, leading to impaired epidermal differentiation [Zarnegar et al 2012]. ADULT syndrome is typically associated with pathogenic variants in the DNA binding domain at p.Arg337 (TAp63α; formerly known as p.Arg298), such as c.1009C>G (p.Arg337Gly) and c.1010G>A (p.Arg337Gln). Other pathogenic variants have been reported in isolated patients with features reminiscent of ADULT syndrome, but also of other TP63-associated syndromes. Examples include c.16A>C (p.Asn6His in ΔNp63α), which is in an alternative TA domain and c.518G>T (p.Gly173Asp in TAp63α) which is between the TA and DNA binding domains [Rinne et al 2006b, Rinne et al 2007], and c.497C>T (p.Pro166Leu in TAp63α) [van Zelst-Stams & van Steensel 2009]. EEC3. All EEC pathogenic variants are missense variants in the DNA binding domain and have been demonstrated to disrupt DNA binding [Rinne et al 2006b]. Splice changes and frameshifts associated with EEC have been reported [Celli et al 1999, van Bokhoven et al 2001, Barrow et al 2002, Monti et al 2013]. Limb-mammary syndrome. Limb-mammary syndrome is caused by pathogenic missense variants that are located between the transactivation domain and the DNA binding domain (p.Gly115, p.Ser129, and p.Gly173 residues in TAp63α) or by truncating variants in the SAM domain of TP63 [van Bokhoven et al 2001, Rinne et al 2007]. SHFM4. Pathogenic missense variants in the TA and DNA binding domains have been associated with SHFM4 [Rinne et al 2007]. Isolated cleft lip/cleft palate (orofacial cleft 8) has been associated with TP63 variants in the DNA binding domain [Leoyklang et al 2006]. Of these variants, p.Arg352Gly in TAp63α was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. See Figure 1. ### Penetrance Reduced penetrance or possible germline mosaicism has been documented in a small number of individuals and families. Reduced penetrance for split-hand/foot malformation type 4 (SHFM4) [Spranger & Schapera 1988] and ADULT syndrome [Amiel et al 2001] has been reported. A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely caused by somatic and germline mosaicism in one parent. In one family, the TP63 pathogenic variant present in affected fraternal twins was seen in the phenotypically normal mother. The data suggested somatic mosaicism in the mother [van Bokhoven, unpublished data] with presumed germline mosaicism. ### Nomenclature Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is also known as Hay-Wells syndrome after the physicians who first described the condition in 1976. Rapp-Hodgkin syndrome (RHS), once considered a separate entity, is now considered to be part of the spectrum of the AEC syndrome because of the overlap of clinical manifestations and TP63 pathogenic variants in the two conditions [Cambiaghi et al 1994, McGrath et al 2001]. EEC3 is thought to be genetically unrelated to EEC1 (which has been mapped to chromosome 7q11q21). An entity called EEC2 was initially mapped to chromosome 19 [O’Quinn et al 1998]; however pathogenic variants in TP63 were ultimately identified [Celli et al 1999]. ### Prevalence TP63-related disorders are rare. The prevalence of disorders individually or collectively is unknown. ## Differential Diagnosis ### AEC Syndrome Epidermolysis bullosa. Because of the presence of skin erosions at birth, many affected individuals are misdiagnosed with epidermolysis bullosa; however, the erosions of AEC syndrome are typically more superficial and not associated with formation of bullae. In addition to the nondermatologic phenotypic differences, dermatopathology should distinguish epidermolysis bullosa from AEC syndrome. The presence of erythroderma with a collodion membrane can also lead to an initial misdiagnosis of ichthyosis in the newborn period [Siegfried et al 2005]. Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS) (OMIM 214350) has the overlapping features of ankyloblepharon and hair changes, but it does not typically include the significant facial/oral clefting or skin erosions that are virtually universal in AEC syndrome. ### EEC3 EEC1 (OMIM 129900) is suspected to be caused by pathogenic variants in a gene on chromosome 7q21q22 based on a series of individuals with various cytogenetically visible chromosomal abnormalities. Other EEC syndrome-like phenotypes that do not appear to involve the EEC1 and EEC3 loci have been described. ### SHFM4 SHFM1 (OMIM 183600) is caused by deletions of chromosome 7q21 involving DLX5 and DLX6 as well as homozygous pathogenic variants in DLX5 and is associated with a high incidence of hearing loss. Findings in this disorder are largely restricted to the limbs. Dental and lacrimal duct abnormalities are seen in fewer than 10% of individuals [Elliott & Evans 2006]. SHFM2 (OMIM 313350) has been mapped to Xq26 and while both males and females are affected, males tend to have a more severe phenotype. Cleft lip/palate and ectodermal defects are not seen in this condition. SHFM3 (OMIM 246560) is caused by a contiguous gene duplication on chromosome 10q24 and does not have lacrimal, dental, or ectodermal abnormalities (beyond nail abnormalities associated with developmental defects of the digits) [de Mollerat et al 2003, Elliott & Evans 2006]. SHFM5 (OMIM 606708) is caused by deletions of chromosome 2q31. Abnormally shaped teeth may be present, but neither oligodontia nor other ectodermal defects that may be seen in SHFM4 are reported. Dysmorphic facial features tend to be present [Elliott & Evans 2006]. SHFM6 (OMIM 225300) has been attributed to homozygous pathogenic variants in WNT10B. Interestingly, all but one of the affected individuals in the initial pedigree also had promoter polymorphism in TP63 [Ugur & Tolun 2008]. ### TP63-Related Disorders Generally Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). In HED the hypohidrosis is severe enough to impair body temperature regulation, a problem not seen in AEC syndrome. Orofacial clefting, universal in AEC syndrome, is not typically seen in HED. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a TP63 related disorder, the following evaluations are recommended: * Clinical genetics to aid in diagnosis, coordination of health surveillance, and genetic testing and counseling * Dermatology to evaluate and treat related skin issues, especially erosions * Gastroenterology for growth and nutrition issues * Dietary if there are concerns about failure to thrive * Ophthalmology for evaluation and treatment of ocular issues including ankyloblepharon, lacrimal duct atresia/obstruction, dry eyes, and blepharitis * Plastic surgery to evaluate and repair cleft lip and palate or breast/nipple assymetry * Otolaryngology for evaluation and treatment of recurrent otitis media and speech issues * Audiology to evaluate for hearing loss * Dental to evaluate and address issues of hypodontia * Prosthodontics to address potential need for dental implants * Psychology/psychiatry to address developmental issues and provide support for the individual and family by assisting in dealing with the impact of the phenotype on a normal life ### Treatment of Manifestations A multidisciplinary approach is recommended including regular evaluations with specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry. Ankyloblepharon filiforme adnatum. These strands of tissue between the upper and lower eyelids are often small and autolyse shortly after birth; larger ones may require surgical separation by an ophthalmologist. Ectodermal defects * Wigs can be used, if desired, for the sparse hair and alopecia. * There are no known therapies for the nail or skin pigment changes. * Dentures should be considered in early childhood and the possibility of dental implants should be considered in the teens or early adult years. * Sweating is not severely impaired and does not require special care. Skin erosions. The skin erosions are difficult to treat and prone to excessive ineffective granulation response; they are at increased risk for secondary infection and are not responsive to most standard wound care regimens or antibiotic therapy [Julapalli et al 2009]. Skin erosions should be treated with gentle wound care and periodic, dilute bleach soaks (Dakins solution) to prevent secondary infection. Occlusive dressings should not be used as they tend to stimulate granulation tissue. Secondary infections should be treated with topical or oral antibiotics or antifungal agents when appropriate. Empiric treatment (i.e., use of antibiotic without culture-proven infection) is not recommended. Cleft lip/palate. Clefting should be addressed as soon as developmentally possible. Typical feeding issues associated with clefting are seen and include: poor suck, difficulty coordinating feeding and breathing, and excessive air intake. A nurse, nutritionist, pediatrician, speech therapist, or other specialist familiar with the management of feeding issues in children with cleft lip/palate should be consulted. Early referral to a craniofacial surgeon for planning for surgical cleft repair is indicated. Other * Weight should be followed closely with assessment for signs of failure to thrive. If optimization of oral caloric intake fails to improve growth, gastrostomy tube placement may be considered. * Myringotomy is indicated as needed for conductive hearing loss resulting from chronic otitis media. * Significant breast asymmetry in women may be corrected through plastic surgery. * Psychological impact of the phenotypic features of the disorder on patient and family should also be considered and referrals made to psychiatry or psychology as appropriate. ### Prevention of Secondary Complications Infants with severe skin erosions should be monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition, and secondary infection and sepsis. ### Surveillance Regular evaluation with a multidisciplinary team is recommended for evaluation and prompt treatment of disease manifestations. In particular: * Dental findings over time may warrant use of dental prosthetics. * Periodic hearing evaluations should be performed as conductive hearing loss is common. ### Agents/Circumstances to Avoid Prolonged exposure to sunlight should be avoided to prevent sunburn of hypopigmented areas and to prevent increasing the contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome. Reduced sun exposure can minimize freckling of skin in individuals with ADULT syndrome. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing of the TP63 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation No specific trials for therapies are being conducted at this time. An investigational product developed to activate mutated p53 in cancer therapy has been tested for its ability to activate mutated p63 protein carrying EEC3-associated amino acid substitutions. This compound, denoted APR-246/PRIMA-1MET, showed a beneficial effect on skin differentiation [Shalom-Feuerstein et al 2013, Shen et al 2013]. 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. ### Other The National Foundation for Ectodermal Dysplasias (NFED) (www.nfed.org) is an excellent resource for affected individuals, their families, and clinicians who care for these individuals. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	TP63-Related Disorders	None	6,914	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK43797/	2021-01-18T20:53:16	{"synonyms": []}
Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, is a progressive condition that affects most tissues and organs. The severity of MPS VII varies widely among affected individuals. The most severe cases of MPS VII are characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Most babies with hydrops fetalis are stillborn or die soon after birth. Other people with MPS VII typically begin to show signs and symptoms of the condition during early childhood. The features of MPS VII include a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), distinctive-looking facial features that are described as "coarse," and a large tongue (macroglossia). Affected individuals also frequently develop an enlarged liver and spleen (hepatosplenomegaly), heart valve abnormalities, and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). The airway may become narrow in some people with MPS VII, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). The clear covering of the eye (cornea) becomes cloudy, which can cause significant vision loss. People with MPS VII may also have recurrent ear infections and hearing loss. Affected individuals may have developmental delay and progressive intellectual disability, although intelligence is unaffected in some people with this condition. MPS VII causes various skeletal abnormalities that become more pronounced with age, including short stature and joint deformities (contractures) that affect mobility. Individuals with this condition may also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Carpal tunnel syndrome develops in many children with MPS VII and is characterized by numbness, tingling, and weakness in the hands and fingers. People with MPS VII may develop a narrowing of the spinal canal (spinal stenosis) in the neck, which can compress and damage the spinal cord. The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood. Heart disease and airway obstruction are major causes of death in people with MPS VII. ## Frequency The exact incidence of MPS VII is unknown, although it is estimated to occur in 1 in 250,000 newborns. It is one of the rarest types of mucopolysaccharidosis. ## Causes Mutations in the GUSB gene cause MPS VII. This gene provides instructions for producing the beta-glucuronidase (β-glucuronidase) enzyme, which is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. Mutations in the GUSB gene reduce or completely eliminate the function of β-glucuronidase. The shortage (deficiency) of β-glucuronidase leads to the accumulation of GAGs within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions such as MPS VII that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. The accumulation of GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in this disorder. Researchers believe that the GAGs may also interfere with the functions of other proteins inside the lysosomes and disrupt many normal functions of cells. ### Learn more about the gene associated with Mucopolysaccharidosis type VII * GUSB ## 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Mucopolysaccharidosis type VII	c0085132	6,915	medlineplus	https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-vii/	2021-01-27T08:25:35	{"gard": ["7096"], "mesh": ["D016538"], "omim": ["253220"], "synonyms": []}
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Find sources: "Clouston's hidrotic ectodermal dysplasia" – news · newspapers · books · scholar · JSTOR (September 2015) (Learn how and when to remove this template message) Clouston's hidrotic ectodermal dysplasia Other namesAlopecia congenita with keratosis palmoplantaris, Clouston syndrome,[1]:571 Fischer–Jacobsen–Clouston syndrome, Hidrotic ectodermal dysplasia, Keratosis palmaris with drumstick fingers, Palmoplantar keratoderma and clubbing SpecialtyDermatology, medical genetics Clouston's hidrotic ectodermal dysplasia is caused by mutations in a connexin gene, GJB6 or connexin-30, characterized by scalp hair that is wiry, brittle, and pale, often associated with patchy alopecia.[2]:507,511,517–16 ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Screening * 5 Treatment * 6 See also * 7 References * 8 Further reading ## Presentation[edit] Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this entry) is characterized by partial or total alopecia, dystrophy of the nails, hyperpigmentation of the skin (especially over the joints), and clubbing of the fingers. Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is wiry, brittle, patchy, and pale; progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. The clinical manifestations are highly variable even within the same family. ## Genetics[edit] HED2 is inherited in an autosomal dominant manner. Most individuals with HED2 have an affected parent; de novo gene mutations have also been reported. Offspring of affected individuals have a 50% chance of inheriting the mutation and being affected. ## Diagnosis[edit] HED2 is suspected after infancy on the basis of physical features in most affected individuals. GJB6 is the only gene known to be associated with HED2. Targeted mutation analysis for the four most common GJB6 mutations is available on a clinical basis and detects mutations in approximately 100% of affected individuals. Sequence analysis is also available on a clinical basis for those in whom none of the four known mutations is identified. ## Screening[edit] Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in an affected family member is known; however, requests for prenatal testing for conditions such as HED2 are not common. ## Treatment[edit] Treatment of manifestations: special hair care products to help manage dry and sparse hair; wigs; artificial nails; emollients to relieve palmoplantar hyperkeratosis. ## See also[edit] * Palmoplantar keratoderma * List of cutaneous conditions * List of cutaneous neoplasms associated with systemic syndromes ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. ## Further reading[edit] * GeneReviews/NCBI/NIH/UW entry on Hidrotic Ectodermal Dysplasia 2 * OMIM entries on Hidrotic Ectodermal Dysplasia 2 Classification D * OMIM: 129500 * v * t * e Diseases of ion channels Calcium channel Voltage-gated * CACNA1A * Familial hemiplegic migraine 1 * Episodic ataxia 2 * Spinocerebellar ataxia type-6 * CACNA1C * Timothy syndrome * Brugada syndrome 3 * Long QT syndrome 8 * CACNA1F * Ocular albinism 2 * CSNB2A * CACNA1S * Hypokalemic periodic paralysis 1 * Thyrotoxic periodic paralysis 1 * CACNB2 * Brugada syndrome 4 Ligand gated * RYR1 * Malignant hyperthermia * Central core disease * RYR2 * CPVT1 * ARVD2 Sodium channel Voltage-gated * SCN1A * Familial hemiplegic migraine 3 * GEFS+ 2 * Febrile seizure 3A * SCN1B * Brugada syndrome 6 * GEFS+ 1 * SCN4A * Hypokalemic periodic paralysis 2 * Hyperkalemic periodic paralysis * Paramyotonia congenita * Potassium-aggravated myotonia * SCN4B * Long QT syndrome 10 * SCN5A * Brugada syndrome 1 * Long QT syndrome 3 * SCN9A * Erythromelalgia * Febrile seizure 3B * Paroxysmal extreme pain disorder * Congenital insensitivity to pain Constitutively active * SCNN1B/SCNN1G * Liddle's syndrome * SCNN1A/SCNN1B/SCNN1G * Pseudohypoaldosteronism 1AR Potassium channel Voltage-gated * KCNA1 * Episodic ataxia 1 * KCNA5 * Familial atrial fibrillation 7 * KCNC3 * Spinocerebellar ataxia type-13 * KCNE1 * Jervell and Lange-Nielsen syndrome * Long QT syndrome 5 * KCNE2 * Long QT syndrome 6 * KCNE3 * Brugada syndrome 5 * KCNH2 * Short QT syndrome * KCNQ1 * Jervell and Lange-Nielsen syndrome * Romano–Ward syndrome * Short QT syndrome * Long QT syndrome 1 * Familial atrial fibrillation 3 * KCNQ2 * BFNS1 Inward-rectifier * KCNJ1 * Bartter syndrome 2 * KCNJ2 * Andersen–Tawil syndrome * Long QT syndrome 7 * Short QT syndrome * KCNJ11 * TNDM3 * KCNJ18 * Thyrotoxic periodic paralysis 2 Chloride channel * CFTR * Cystic fibrosis * Congenital absence of the vas deferens * CLCN1 * Thomsen disease * Myotonia congenita * CLCN5 * Dent's disease * CLCN7 * Osteopetrosis A2, B4 * BEST1 * Vitelliform macular dystrophy * CLCNKB * Bartter syndrome 3 TRP channel * TRPC6 * FSGS2 * TRPML1 * Mucolipidosis type IV Connexin * GJA1 * Oculodentodigital dysplasia * Hallermann–Streiff syndrome * Hypoplastic left heart syndrome * GJB1 * Charcot–Marie–Tooth disease X1 * GJB2 * Keratitis–ichthyosis–deafness syndrome * Ichthyosis hystrix * Bart–Pumphrey syndrome * Vohwinkel syndrome) * GJB3/GJB4 * Erythrokeratodermia variabilis * Progressive symmetric erythrokeratodermia * GJB6 * Clouston's hidrotic ectodermal dysplasia Porin * AQP2 * Nephrogenic diabetes insipidus 2 See also: ion channels [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Clouston's hidrotic ectodermal dysplasia	c0162361	6,916	wikipedia	https://en.wikipedia.org/wiki/Clouston%27s_hidrotic_ectodermal_dysplasia	2021-01-18T19:02:06	{"gard": ["2056"], "mesh": ["D004476"], "umls": ["C0162361"], "orphanet": ["189"], "wikidata": ["Q5135822"]}
A number sign (#) is used with this entry because of evidence that it represents a contiguous gene deletion syndrome on chromosome 14q22.1-q22.3 (chr14:52.1-56.2 Mb). The deleted region contains at least 20 genes, including the BMP4 gene (112262). Description Frias syndrome is characterized by mild exophthalmia, palpebral ptosis, hypertelorism, short square hands with minimal proximal syndactyly between the second and third fingers, small broad great toes, and short stature. Some patients may exhibit bilateral pedunculated postminimi (summary by Martinez-Fernandez et al., 2014). Clinical Features Frias et al. (1975) reported a 6-year-old boy with a peculiar facies, characterized by downslanting palpebral fissures, epicanthic folds, hypertelorism, and ptosis. He was noted to have slightly slower psychomotor development than his unaffected sister and was reported to have 'low average intelligence.' His ears were cup-shaped and posteriorly rotated. Both hands were square in shape, with short stubby fingers, clinodactyly of the fifth fingers, and ulnar deviation of the index fingers. His toes were also short, and moderate hallux valgus was present. Radiographic studies revealed shortened middle phalanges of digits 2 to 5 of the hands and feet, and bone age was retarded. The patient's mother was similarly affected, with downslanting palpebral fissures, hypertelorism, ptosis, and poorly differentiated ears. Her hands were small and square, with evident brachydactyly and radial deviation of the fourth finger; her toes were small, and a moderate hallux valgus was present. X-ray showed shortened middle phalanges of digits 2 to 5 of her hands, and the middle phalanx of the second toe was short and wide. She was of average intelligence. Frias et al. (1975) suggested that this condition constituted a previously unrecognized autosomal dominant dysmorphic syndrome. Martinez-Frias et al. (2005) reported a 3-year-old girl with bilateral ptosis requiring surgical repair, mild exophthalmia, downslanting palpebral fissures, micrognathia, cup-shaped posteriorly rotated ears, bilateral pedunculated postminimi, and small, broad big toes. She had slow psychomotor development and delayed bone age. The patient's mother and maternal uncle had a similar facial appearance with bilateral ptosis requiring surgical repair, hypertelorism, mild exophthalmos, and downslanting palpebral fissures. The mother had short stature and short, square hands with small proximal syndactyly between fingers 2 and 3, and the uncle had very short hands with bowed fifth metacarpals. The proband's maternal grandmother had a similar facial appearance and hand anomalies, with ulnar deviation of the index fingers. Martinez-Frias et al. (2005) concluded that this family had the same condition as that described by Frias et al. (1975), with apparent complete penetrance and variable expressivity. Martinez-Frias et al. (2005) noted that X-linked inheritance could not be excluded. Martinez-Fernandez et al. (2014) provided follow-up on the family originally reported by Martinez-Frias et al. (2005), including a report of a newborn affected member of the family. The infant had mild exophthalmia, bilateral ptosis, downslanting palpebral fissures, and apparent hypertelorism. In addition, she had right diaphragmatic hernia, through which the liver had entered the thoracic cavity. She died of refractory hypoxemia 2 days after surgical repair of the diaphragmatic hernia; postmortem examination did not show any malformation of the brain or other organs. At 10 years of age, her older half sister, who was the proband reported by Martinez-Frias et al. (2005), had moderate psychomotor delay and mild right-sided hearing loss. Brain MRI showed segmental hypoplasia of the corpus callosum and mild increase in ventricular size. She also exhibited altered eruption of dentition, with absence of the upper and lower lateral incisors and a large upper right central incisor overlapping the left one. Martinez-Fernandez et al. (2014) noted that this anomaly appeared to be present in other affected family members, as suggested by clinical photographs. Molecular Genetics In 3 affected members of a family with Frias syndrome, originally reported by Martinez-Frias et al. (2005), Martinez-Fernandez et al. (2014) performed high resolution G-banded chromosome analysis, which was normal, and array-CGH, which revealed an identical 4.06-Mb interstitial deletion on chromosome 14q22.1-q22.3 (chr14:52,183,541-56,239,131, Genome Browser, 2009) in all 3 patients. The deleted area included at least 20 genes, including BMP4 (112262). Martinez-Fernandez et al. (2014) noted that the clinical manifestations in this family correlated with defects observed in patients with 14q22-q23 deletions or mutations of BMP4, although this family showed a milder phenotype; they concluded that haploinsufficiency of BMP4 was likely to be responsible for the clinical expression of Frias syndrome. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Face \- Micrognathia Ears \- Cup-shaped ears \- Posteriorly rotated ears \- Hearing loss, unilateral, mild Eyes \- Ptosis, bilateral \- Hypertelorism \- Exophthalmos, mild \- Downslanting palpebral fissures Teeth \- Absence of upper and lower lateral incisors \- Large upper right central incisor \- Overlapping left central incisor CHEST Diaphragm \- Right diaphragmatic hernia (rare) SKELETAL Hands \- Pedunculated postminimi, bilateral Feet \- Short broad halluces NEUROLOGIC Central Nervous System \- Psychomotor delay \- Segmental callosal hypoplasia, mild \- Ventricular enlargement, mild MISCELLANEOUS \- Contiguous gene deletion syndrome MOLECULAR BASIS \- Caused by deletion (4.06 Mb) of chromosome 14q22.1-q22.3 ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	FRIAS SYNDROME	c1864825	6,917	omim	https://www.omim.org/entry/609640	2019-09-22T16:05:44	{"mesh": ["C535639"], "omim": ["609640"], "orphanet": ["2055", "264200"], "synonyms": ["Alternative titles", "CHROMOSOME 14q22 DELETION SYNDROME", "GROWTH DEFICIENCY, FACIAL ANOMALIES, AND BRACHYDACTYLY"]}
A number sign (#) is used with this entry because Joubert syndrome-7 (JBTS7) is caused by homozygous or compound heterozygous mutation in the RPGRIP1L gene (610937) on chromosome 16q12. For general discussion of Joubert syndrome, see 213300. See also Meckel syndrome type 5 (MKS5; 611561), an allelic disorder with a more severe phenotype. Clinical Features Delous et al. (2007) reported 4 patients from 3 French families with Joubert syndrome and renal disease. Clinical features included the molar tooth sign on brain MRI, oculomotor apraxia, ptosis, nystagmus, cerebellar ataxia, and nephronophthisis. All children except 1 had mental retardation. All developed end-stage renal disease by age 10 years, except 1 patient who developed it at 18 years. Three patients had scoliosis, and 1 had genu valgum. Arts et al. (2007) reported 4 patients with JBTS7. Two were born of unrelated consanguineous Turkish families, and the other 2 were sibs born of unrelated European parents. The phenotype in all included the molar tooth sign, hypotonia, ataxia, developmental delay, and abnormal eye movements. One child had renal disease, and none had retinal disease. The 2 sibs had postaxial polydactyly, and 1 of them also had a small occipital encephalocele. Brancati et al. (2008) identified homozygous mutations in the RPGRIP1L gene in 2 (12%) of 16 families with the cerebello-renal type of Joubert syndrome. No pathogenic changes in this gene were found in 118 additional patients with other Joubert syndrome phenotypes, suggesting that RPGRIP1L mutations are more common in those with the cerebello-renal subgroup, although they overall represent a rare cause of Joubert syndrome (less than 2%). In the first family, a brother and sister presented with developmental delay, growth and mental retardation, nephronophthisis, and severe scoliosis. Visual acuity, fundus examination, and liver function were normal. There was clinical variability between the 2 sibs regarding some features, with the sister being more severely affected. She died at age 17.5 years from renal failure, while he was still alive at age 22 years after kidney transplant. Both had the molar tooth sign on MRI. Molecular analysis identified a homozygous mutation in the RPGRIP1L gene (610937.0002). The second proband was a Moroccan girl who was born of consanguineous parents and presented at birth with occipital meningoencephalocele, bilateral post-axial polydactyly of hands and feet, clubfoot, and right-sided inguinal hernia. She had several episodes of hyperpnea and apnea, and delayed milestones. At age 1 year, she developed renal dysfunction associated with small kidneys with increased echogenicity, loss of corticomedullary differentiation, and multiple cysts compatible with nephronophthisis. Ocular examination showed horizontal nystagmus and alternating internal strabismus, although funduscopy was negative. At age 4 years, she has chronic renal failure, marked growth retardation and severe psychomotor delay, with lack of head control and inability to speak any meaningful word. The molar tooth sign was present on MRI. Molecular analysis identified a homozygous 1-bp deletion in the RPGRIP1L gene (610937.0010). Mapping By genomewide linkage and haplotype analysis, Delous et al. (2007) identified a candidate disease locus on chromosome 16q in 2 families with Joubert syndrome and renal disease. Molecular Genetics In French patients with Joubert syndrome and renal disease, Delous et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0001-610937.0004). In patients with Joubert syndrome, Arts et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0008-610937.0009). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Abnormal eye movements \- Nystagmus \- Oculomotor apraxia \- Ptosis \- Retinal dystrophy (less common) RESPIRATORY \- Neonatal breathing dysregulation \- Hyperpnea, episodic \- Tachypnea, episodic \- Central apnea GENITOURINARY Kidneys \- Nephronophthisis \- Renal cysts \- Impaired renal function SKELETAL Spine \- Scoliosis Hands \- Polydactyly, postaxial NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Ataxia \- Hypotonia \- Encephalocele \- Dysgenesis or agenesis of the cerebellar vermis \- Hypoplasia of the brainstem \- Malformation of brainstem structures \- 'Molar tooth sign' on brain imaging' \- Deep posterior interpeduncular fossa \- Thick and elongated superior cerebellar peduncles \- Abnormal corpus callosum MISCELLANEOUS \- Variable phenotype \- Genetic heterogeneity \- Renal phenotype worsens with age \- See also Meckel syndrome type 5 ( 611561 ), an allelic disorder with a more severe phenotype MOLECULAR BASIS \- Caused by mutation in the RPGRIP1-like gene (RPGRIP1L, 610937.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	JOUBERT SYNDROME 7	c1969053	6,918	omim	https://www.omim.org/entry/611560	2019-09-22T16:03:07	{"doid": ["0111002"], "mesh": ["C566916"], "omim": ["611560", "609583"], "orphanet": ["220497"], "synonyms": ["JS-R"], "genereviews": ["NBK1325"]}
Radiation enteropathy Other namesRadiation enteritis, pelvic radiation disease SpecialtyGastroenterology, surgery, oncology SymptomsDiarrhea, abdominal pain, nausea, vomiting, anorexia and malaise ComplicationsStricture formation, malabsorption Usual onsetAcute: several weeks after radiation Chronic: 8-12 months after radiation Radiation enteropathy is a syndrome that may develop following abdominal or pelvic radiation therapy for cancer.[1][2] Many affected people are cancer survivors who had treatment for cervical cancer or prostate cancer; it has also been termed pelvic radiation disease with radiation proctitis being one of the principal features.[3] ## Contents * 1 Signs and symptoms * 1.1 Associated conditions * 2 Causes * 3 Pathology * 3.1 Acute intestinal injury * 3.2 Long-term effects of radiation * 4 Diagnosis * 5 Prevention * 6 Treatment * 7 Prevalence * 8 Research * 9 References * 10 External links ## Signs and symptoms[edit] People who have been treated with radiotherapy for pelvic and other abdominal cancers frequently develop gastrointestinal symptoms.[3][1][2] These include: * rectal bleeding * diarrhea and steatorrhea * other defecation disorders including fecal urgency and incontinence. * nutritional deficiencies and weight loss * abdominal pain and bloating * nausea, vomiting and fatigue Gastrointestinal symptoms are often found together with those in other systems including genitourinary disorders and sexual dysfunction. The burden of symptoms substantially impairs the patients' quality of life.[citation needed] Nausea, vomiting, fatigue, and diarrhea may happen early during the course of radiotherapy. Radiation enteropathy represents the longer-term, chronic effects that may be found after a latent period most commonly of 6 months to 3 years after the end of treatment. In some cases, it does not become a problem for 20–30 years after successful curative therapy.[1] ### Associated conditions[edit] * Small intestinal bacterial overgrowth[4] * Exocrine pancreatic insufficiency * Bile acid diarrhea * Urinary urgency * Sexual dysfunction ## Causes[edit] A large number of people receive abdominal and or pelvic radiotherapy as part of their cancer treatment with 60–80% experiencing gastrointestinal symptoms.[1] This is used in standard therapeutic regimens for cervical cancer, prostate cancer, rectal cancer, anal cancer, lymphoma and other abdominal malignancies. Symptoms can be made worse by the effects of surgery, chemotherapy or other drugs given to treat the cancer.[4] Improved methods of radiotherapy have reduced the exposure of non-involved tissues to radiation, concentrating the effects on the cancer. However, as the parts of the intestine such as the ileum and the rectum are immediately adjacent to the cancers, it is impossible to avoid some radiation effects.[1] Previous intestinal surgery, obesity, diabetes, tobacco smoking and vascular disorders increase the chances of developing enteropathy.[1] ## Pathology[edit] ### Acute intestinal injury[edit] See also: Acute radiation syndrome Early radiation enteropathy is very common during or immediately after the course of radiotherapy. This involves cell death, mucosal inflammation and epithelial barrier dysfunction. This injury is termed mucositis and results in symptoms of nausea, vomiting, fatigue, diarrhea and abdominal pain.[1][5] It recovers within a few weeks or months. ### Long-term effects of radiation[edit] The delayed effects, found 3 months or more after radiation therapy, produce pathology which includes intestinal epithelial mucosal atrophy, vascular sclerosis, and progressive fibrosis of the intestinal wall, among other changes in intestinal neuroendocrine and immune cells and in the gut microbiota.[1][5] These changes may produce dysmotility, strictures, malabsorption and bleeding. Problems in the terminal ileum and rectum predominate.[citation needed] ## Diagnosis[edit] Multiple disorders are found in patients with radiation enteropathy, so guidance including an algorithmic approach to their investigation has been developed.[4][6] This includes a holistic assessment with investigations including upper endoscopy, colonoscopy, breath tests and other nutritional and gastrointestinal tests. Full investigation is important as many cancer survivors of radiation therapy develop other causes for their symptoms such as colonic polyps, diverticular disease or hemorrhoids.[7] ## Prevention[edit] See also: Radiation therapy Prevention of radiation injury to the small bowel is a key aim of techniques such as brachytherapy, field size, multiple field arrangements, conformal radiotherapy techniques and intensity-modulated radiotherapy. Medications including ACE inhibitors, statins and probiotics have also been studied and reviewed.[2][8] ## Treatment[edit] In people presenting with symptoms compatible with radiation enteropathy, the initial step is to identify what is responsible for causing the symptoms. Management is best with a multidisciplinary team including gastroenterologists, nurses, dietitians, surgeons and others.[1] Medical treatments include the use of hyperbaric oxygen which has beneficial effects in radiation proctitis or anal damage.[9] Nutritional therapies include treatments directed at specific malabsorptive disorders such as low fat diets and vitamin B12 or vitamin D supplements, together with bile acid sequestrants for bile acid diarrhea and possibly antibiotics for small intestinal bacterial overgrowth.[2] Probiotics have all been suggested as another therapeutic avenue.[10] Endoscopic therapies including argon plasma coagulation have been used for bleeding telangiectasia in radiation proctitis and at other intestinal sites, although there is a rick of perforation.[2] Surgical treatment may be needed for intestinal obstruction, fistulae, or perforation, which can happen in more severe cases.[11] These can be fatal if patients present as an emergency, but with improved radiotherapy techniques are now less common.[citation needed] A systematic review has found there is some promising evidence for non-surgical interventions for late rectal damage, however due to low quality evidence no conclusions could be drawn.[12] Optimal treatment usually produces significant improvements in quality of life.[3] ## Prevalence[edit] An increasing number of people are now surviving cancer, with improved treatments producing cure of the malignancy (cancer survivors). There are now over 14 million such people in the US, and this figure is expected to increase to 18 million by 2022.[13] More than half are survivors of abdominal or pelvic cancers, with about 300,000 people receiving abdominal and pelvic radiation each year. It has been estimated there are 1.6 million people in the US with post-radiation intestinal dysfunction, a greater number than those with inflammatory bowel disease such as Crohn's disease or ulcerative colitis.[1] ## Research[edit] New agents have been identified in animal studies that may have effects on intestinal radiation injury.[1] The research approach in humans has been reviewed.[14] ## References[edit] 1. ^ a b c d e f g h i j k Hauer-Jensen M, Denham JW, Andreyev HJ (2014). "Radiation enteropathy--pathogenesis, treatment and prevention". Nat Rev Gastroenterol Hepatol. 11 (8): 470–9. doi:10.1038/nrgastro.2014.46. PMC 4346191. PMID 24686268. 2. ^ a b c d e Stacey R, Green JT (2014). "Radiation-induced small bowel disease: latest developments and clinical guidance". Ther Adv Chronic Dis. 5 (1): 15–29. doi:10.1177/2040622313510730. PMC 3871275. PMID 24381725. 3. ^ a b c Fuccio L, Guido A, Andreyev HJ (2012). "Management of intestinal complications in patients with pelvic radiation disease". Clin. Gastroenterol. Hepatol. 10 (12): 1326–1334.e4. doi:10.1016/j.cgh.2012.07.017. PMID 22858731. 4. ^ a b c Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E (2012). "Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer". Gut. 61 (2): 179–92. doi:10.1136/gutjnl-2011-300563. PMC 3245898. PMID 22057051. 5. ^ a b Carr KE (2001). "Effects of radiation damage on intestinal morphology". Int. Rev. Cytol. International Review of Cytology. 208: 1–119. doi:10.1016/s0074-7696(01)08002-0. ISBN 9780123646125. PMID 11510566. 6. ^ Andreyev HJ, Muls AC, Norton C, Ralph C, Watson L, Shaw C, Lindsay JO (2015). "Guidance: The practical management of the gastrointestinal symptoms of pelvic radiation disease". Frontline Gastroenterol. 6 (1): 53–72. doi:10.1136/flgastro-2014-100468. PMC 4283714. PMID 25580207. 7. ^ Min M, Chua B, Guttner Y, Abraham N, Aherne NJ, Hoffmann M, McKay MJ, Shakespeare TP (2014). "Is "pelvic radiation disease" always the cause of bowel symptoms following prostate cancer intensity-modulated radiotherapy?". Radiother Oncol. 110 (2): 278–83. doi:10.1016/j.radonc.2013.11.012. PMID 24412017. 8. ^ Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM (2013). "Systematic review of agents for the management of gastrointestinal mucositis in cancer patients". Support Care Cancer. 21 (1): 313–26. doi:10.1007/s00520-012-1644-z. PMID 23142924. 9. ^ Bennett, Michael H.; Feldmeier, John; Hampson, Neil B.; Smee, Robert; Milross, Christopher (2016-04-28). "Hyperbaric oxygen therapy for late radiation tissue injury". The Cochrane Database of Systematic Reviews. 4: CD005005. doi:10.1002/14651858.CD005005.pub4. ISSN 1469-493X. PMC 6457778. PMID 27123955. 10. ^ Hamad, Adeel; Fragkos, Konstantinos C.; Forbes, Alastair (2013). "A systematic review and meta-analysis of probiotics for the management of radiation induced bowel disease". Clinical Nutrition. 32 (3): 353–360. doi:10.1016/j.clnu.2013.02.004. PMID 23453637. 11. ^ Regimbeau JM, Panis Y, Gouzi JL, Fagniez PL (2001). "Operative and long term results after surgery for chronic radiation enteritis". Am. J. Surg. 182 (3): 237–42. doi:10.1016/s0002-9610(01)00705-x. PMID 11587684. 12. ^ van de Wetering, Fleur T; Verleye, Leen; Andreyev, H. Jervoise N; Maher, Jane; Vlayen, Joan; Pieters, Bradley R; van Tienhoven, Geertjan; Scholten, Rob JPM (2016-04-25). "Non-surgical interventions for late rectal problems (proctopathy) of radiotherapy in people who have received radiotherapy to the pelvis". Cochrane Database of Systematic Reviews. 2016 (4): CD003455. doi:10.1002/14651858.cd003455.pub2. ISSN 1465-1858. PMC 7173735. PMID 27111831. 13. ^ Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E (2012). "Cancer treatment and survivorship statistics, 2012". CA Cancer J Clin. 62 (4): 220–41. doi:10.3322/caac.21149. PMID 22700443. 14. ^ Movsas B, Vikram B, Hauer-Jensen M, Moulder JE, Basch E, Brown SL, Kachnic LA, Dicker AP, Coleman CN, Okunieff P (2011). "Decreasing the adverse effects of cancer therapy: National Cancer Institute guidance for the clinical development of radiation injury mitigators". Clin. Cancer Res. 17 (2): 222–8. doi:10.1158/1078-0432.CCR-10-1402. PMID 21047979. ## External links[edit] Classification D * ICD-10: K52.0, K62.7and K92.0 * ICD-9-CM: 558.1 [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Radiation enteropathy	c0259795	6,919	wikipedia	https://en.wikipedia.org/wiki/Radiation_enteropathy	2021-01-18T18:53:53	{"umls": ["C0259795"], "icd-10": ["K92.0", "K62.7", "K52.0"], "wikidata": ["Q7280350"]}
Primary intestinal lymphangiectasia is a digestive disorder in which the lymph vessels supplying the lining of the small intestine are enlarged. The cause of the condition is still unknown. The signs and symptoms include swelling of the legs and abdominal discomfort, loss of lymphatic fluid into the gastrointestinal tract, protein-losing enteropathy, too little albumin in the blood, reduced levels of antibodies, and immunodeficiency. Treatment involves a special long-term diet. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Primary intestinal lymphangiectasia	c2931241	6,920	gard	https://rarediseases.info.nih.gov/diseases/7873/primary-intestinal-lymphangiectasia	2021-01-18T17:58:11	{"mesh": ["C536567"], "omim": ["152800"], "umls": ["C2931241"], "orphanet": ["90362"], "synonyms": ["Waldmann's disease", "Primary intestinal lymphangiectasis", "Familial Waldmann's disease (type)", "Waldmann disease"]}
A rare, genetic, primary bone dysplasia disorder characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and hypoplasia/dysplasia of the third and fourth metatarsals, in the absence of ophthalmologic, cleft palate, and height anomalies. ## Epidemiology To date, fewer than 15 families have been reported worldwide. ## Clinical description The first clinical signs appearing in childhood are broad knees and flat nasal bridge, followed in late childhood and adolescence by short 3rd and 4th metatarsals (not always present), joint pain in knees and hips and later osteoarthritis of the spine, shoulder, hips, and knees. Shortening of the metacarpals may also be present. Vertebral abnormalities include mild platyspondyly, irregular end plates, and reduced intervertebral distances. Stature is within average range. Brachydactyly is restricted to metatarsals III, IV and, more variably, V. Progressive hearing loss may be associated and typically starts in early adulthood, although subclinical hearing impairment for high frequencies may be detected in children. ## Etiology The disorder is due to the R275C mutation in the geneCOL2A1 (12q13.11). ## Diagnostic methods Disorder is suspected based on family history and clinical presentation, but this may be difficult to detect in early childhood. Skeletal radiographs showing platyspondyly and shortened metatarsals and metacarpals may be helpful in the diagnosis work up. Diagnosis is confirmed by genetic testing for the R275C mutation in COL2A1. ## Differential diagnosis Disorders with early-onset osteoarthritis and polyarticular arthritis form the main differential diagnoses and include juvenile idiopathic osteoarthritis and mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis. Whilst COL2A1 mutations are involved in a spectrum of skeletal dysplasias, this specific disorder is typically distinguished by the absence of cleft palate, ophthalmologic pathology and short stature. ## Antenatal diagnosis Genetic prenatal diagnosis is possible when the mutation has been previously identified in a family member. ## Genetic counseling The pattern of inheritance is autosomal dominant. The risk of transmission to offspring is 50% and there is full disease penetrance. ## Management and treatment Treatment is symptomatic and frequently includes hip replacement (often by the age of 40), hearing aids for hearing loss, and anti-rheumatic medication for osteoarthritis. Appropriate surveillance of hearing loss and progression of osteoarthritis is required. ## Prognosis The disorder is associated with early-onset, progressive arthritis that is typically associated with significant joint pain and restricted mobility that can adversely impact quality of life. Early joint replacements are often recommended. Longevity does not appear to be different to that of the general population. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Spondyloepiphyseal dysplasia with metatarsal shortening	c1836683	6,921	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137678	2021-01-23T17:14:56	{"gard": ["10220"], "mesh": ["C535766"], "omim": ["609162"], "umls": ["C1836683"], "icd-10": ["Q77.7"], "synonyms": ["Czech dysplasia, metatarsal type", "SED with metatarsal shortening"]}
Camurati-Engelmann disease is a genetic condition that mainly affects the bones. People with this disease have increased bone density, particularly affecting the long bones of the arms and legs. In some cases, the skull and hip bones are also affected. The thickened bones can lead to pain in the arms and legs, a waddling walk, muscle weakness, and extreme tiredness. The age that symptoms begin varies greatly, but most people with this condition develop pain or weakness by adolescence. Camurati-Engelmann disease is caused by a mutation in the TGFB1 gene and inheritance is autosomal dominant. In some cases, people have the gene mutation that causes Camurati-Engelmann disease but they never develop symptoms. In others, symptoms are present, but a gene mutation cannot be found. These cases are referred to as Camurati-Engelmann disease type 2. Treatment for Camurati-Engelman disease depends on many factors including the signs and symptoms present in each person and the severity of the condition. Treatment options to control symptoms may include corticosteroid therapy, losartan as an adjuvant therapy to minimize the need for steroids, pain medications, and craniectomy to reduce intracranial pressure and headaches. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Camurati Engelmann disease, type 2	c2931683	6,922	gard	https://rarediseases.info.nih.gov/diseases/8748/camurati-engelmann-disease-type-2	2021-01-18T18:01:38	{"mesh": ["C537978"], "omim": ["606631"], "synonyms": ["CED2", "Progressive diaphyseal dysplasia with striations of the bones"]}
For other uses, see strangling. This article is about a disease in equines also known as "distemper". For other diseases known as "distemper", see Distemper. For "puppy strangles", see Juvenile cellulitis. 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: "Strangles" – news · newspapers · books · scholar · JSTOR (March 2012) (Learn how and when to remove this template message) Colonies of Streptococcus equi on a blood agar plate Strangles (equine distemper) is a contagious upper respiratory tract infection of horses and other equines caused by a Gram-positive bacterium, Streptococcus equi.[1] As a result, the lymph nodes swell, compressing the pharynx, larynx, and trachea, and can cause airway obstruction leading to death, hence the name strangles.[2] Strangles is enzootic in domesticated horses worldwide. The contagious nature of the infection has at times led to limitations on sporting events.[3] ## Contents * 1 Signs * 1.1 Complications * 2 Cause * 3 Prevention * 4 Treatment * 5 Outcomes * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs[edit] Two-year-old pony with week-old case of untreated strangles The swelling goes all the way down to the mouth A horse with strangles typically develops abscesses in the lymph nodes of the head and neck, causing coughing fits and difficulty swallowing. Clinical signs include fever up to 106°F and yellow-coloured nasal discharge from both the nose and eyes.[2] Abscesses may form in other areas of the body, such as the abdomen, lungs, and brain.[1] This is considered a chronic form of strangles called "bastard strangles", which can have serious implications if the abscesses rupture. Horses develop this form of strangles when their immune systems are compromised or if the bacteria rapidly invade the body.[2] ### Complications[edit] Possible complications include the horse becoming a chronic carrier of the disease, asphyxia due to enlarged lymph nodes compressing the larynx or windpipe, bastard strangles (spreading to other areas of the body), pneumonia, guttural pouch filled with pus, abscesses, purpura haemorrhagica, and heart disease. The average course of this disease is 23 days. ## Cause[edit] The disease is spread by an infected horse when nasal discharge or pus from the draining lymph nodes contaminate pastures, feed troughs, brushes, bedding, tack, etc.[2] ## Prevention[edit] Both intramuscular and intranasal vaccines are available. Isolation of new horses for 4 to 6 weeks, immediate isolation of infected horses, and disinfection of stalls, water buckets, feed troughs, and other equipment will help prevent the spread of strangles. As with any contagious disease, hand washing is a simple and effective tool. ## Treatment[edit] As with many streptococcal infections, beta-lactam antibiotics (e.g penicillins) are the most effective treatments. However, some authorities are of the opinion that use of antibiotics is contraindicated once abscesses have begun to form, as they predispose to lymphatic spread of the infection (bastard strangles), which has a much higher mortality rate. After an abscess has burst, keeping the wound clean is important. A diluted povidone-iodine solution has been used with good results to disinfect the open hole, flushing the inside with a syringe-tipped catheter or with a teat cannula, followed by gentle scrubbing to keep the surrounding area clean. Symptomatic therapy is an alternative treatment, and is where warm packs are used to mature the abscesses so making them less painful and more comfortable for the horse, but once the abscesses have been matured, they must be kept clean to prevent further infections. This treatment for S. equi only helps reduce pain for the horse rather than curing the infection. ## Outcomes[edit] Strangles has an 8.1% mortality rate.[2] Mortality is lower in cases without complications than it is in cases of bastard strangles. The disease is very contagious and morbidity is high. Precautions to limit the spread of the illness are necessary and those affected are normally isolated. An isolation period of 4–6 weeks is usually necessary to ensure that the disease is not still incubating before ending the quarantine. ## Epidemiology[edit] Equines of any age may contract the disease, although younger and elderly equines are more susceptible. Young equines may lack immunity to the disease because they have not had prior exposure. Geriatric equines may have a weaker immune system. ## See also[edit] * Pigeon fever ## References[edit] 1. ^ a b "Strangles in Horses". www.omafra.gov.on.ca. Retrieved 2016-11-24. 2. ^ a b c d e "Equine Strangles" (PDF). 2008. Retrieved November 23, 2016. 3. ^ "Race club downplays 'strangles' impact". ABC.au News. 1 May 2012. Retrieved 16 May 2012. ## External links[edit] Look up strangles or bastard strangles in Wiktionary, the free dictionary. * Strangles information sheet * American College of Veterinary Internal Medicine consensus statement on Strangles * Strangles in Horses, fact sheet, MSU Extension service * Strangles in Horses, Merck Vet Manual * Biology portal [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Strangles	c0275813	6,923	wikipedia	https://en.wikipedia.org/wiki/Strangles	2021-01-18T18:39:23	{"wikidata": ["Q1430934"]}
Rhinitis Other namesCoryza Pollen grains from a variety of common plants can cause hay fever. Pronunciation * * rhinitis /raɪˈnaɪtɪs/[1] * coryza /kəˈraɪzə/[2] SpecialtyInfectious disease, allergy and immunology Rhinitis, also known as coryza,[3] is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.[4] The inflammation is caused by viruses, bacteria, irritants or allergens. The most common kind of rhinitis is allergic rhinitis, [5] which is usually triggered by airborne allergens such as pollen and dander.[6] Allergic rhinitis may cause additional symptoms, such as sneezing and nasal itching, coughing, headache,[7] fatigue, malaise, and cognitive impairment.[8][9] The allergens may also affect the eyes, causing watery, reddened, or itchy eyes and puffiness around the eyes.[7] The inflammation results in the generation of large amounts of mucus, commonly producing a runny nose, as well as a stuffy nose and post-nasal drip. In the case of allergic rhinitis, the inflammation is caused by the degranulation of mast cells in the nose. When mast cells degranulate, they release histamine and other chemicals,[10] starting an inflammatory process that can cause symptoms outside the nose, such as fatigue and malaise.[11] In the case of infectious rhinitis, it may occasionally lead to pneumonia, either viral or bacterial. Sneezing also occurs in infectious rhinitis to expel bacteria and viruses from the respiratory tract. Rhinitis is very common. Allergic rhinitis is more common in some countries than others; in the United States, about 10–30% of adults are affected annually.[12] Mixed rhinitis (MR) refers to patients with nonallergic rhinitis and allergic rhinitis. MR is a specific rhinitis subtype. It may represent between 50 and 70% of all AR patients. However, true prevalence of MR has not been confirmed yet.[13] ## Contents * 1 Types * 1.1 Infectious * 1.2 Nonallergic rhinitis * 1.3 Allergic * 1.4 Rhinitis medicamentosa * 1.5 Chronic atrophic rhinitis * 1.6 Rhinitis sicca * 1.7 Polypous rhinitis * 2 Pathophysiology * 2.1 Association between rhinitis and asthma * 3 Diagnosis * 4 Prevention * 5 Management * 6 Pronunciation and etymology * 7 See also * 8 References * 9 External links ## Types[edit] Rhinitis is categorized into three types (although infectious rhinitis is typically regarded as a separate clinical entity due to its transient nature): (i) infectious rhinitis includes acute and chronic bacterial infections; (ii) nonallergic rhinitis[14] includes vasomotor, idiopathic, hormonal, atrophic, occupational, and gustatory rhinitis, as well as rhinitis medicamentosa (drug-induced); (iii) allergic rhinitis, triggered by pollen, mold, animal dander, dust, Balsam of Peru, and other inhaled allergens.[15] ### Infectious[edit] See also: Common cold and Sinusitis Rhinitis is commonly caused by a viral or bacterial infection, including the common cold, which is caused by Rhinoviruses, Coronaviruses, and influenza viruses, others caused by adenoviruses, human parainfluenza viruses, human respiratory syncytial virus, enteroviruses other than rhinoviruses, metapneumovirus, and measles virus, or bacterial sinusitis, which is commonly caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Symptoms of the common cold include rhinorrhea, sneezing, sore throat (pharyngitis), cough, congestion, and slight headache.[16][citation needed] ### Nonallergic rhinitis[edit] Main article: Nonallergic rhinitis Nonallergic rhinitis refers to rhinitis that is not due to an allergy. The category was formerly referred to as vasomotor rhinitis, as the first cause discovered was vasodilation due to an overactive parasympathetic nerve response. As additional causes were identified, additional types of nonallergic rhinitis were recognized. Vasomotor rhinitis is now included among these under the more general classification of nonallergic rhinitis.[17] The diagnosis is made upon excluding allergic causes.[18] It is an umbrella term of rhinitis of multiple causes, such as occupational (chemical), smoking, gustatory, hormonal, senile (rhinitis of the elderly), atrophic, medication-induced (including rhinitis medicamentosa), local allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome (NARES) and idiopathic (vasomotor or non-allergic, non-infectious perennial allergic rhinitis (NANIPER), or non-infectious non-allergic rhinitis (NINAR).[19] In vasomotor rhinitis,[20][21] certain nonspecific stimuli, including changes in environment (temperature, humidity, barometric pressure, or weather), airborne irritants (odors, fumes), dietary factors (spicy food, alcohol), sexual arousal, exercise,[22] and emotional factors trigger rhinitis.[23] There is still much to be learned about this, but it is thought that these non-allergic triggers cause dilation of the blood vessels in the lining of the nose, which results in swelling and drainage. Non-allergic rhinitis can co-exist with allergic rhinitis, and is referred to as "mixed rhinitis".[24] The pathology of vasomotor rhinitis appears to involve neurogenic inflammation[25] and is as yet not very well understood. The role of transient receptor potential ion channels on the non-neuronal nasal epithelial cells has also been suggested. Overexpression of these receptors have influence the nasal airway hyper-responsiveness to non-allergic irritant environmental stimuli (e.g., extremes of temperature, changes in osmotic or barometric pressure).[26] Vasomotor rhinitis appears to be significantly more common in women than men, leading some researchers to believe that hormone imbalance plays a role.[27][28] In general, age of onset occurs after 20 years of age, in contrast to allergic rhinitis which can be developed at any age. Individuals with vasomotor rhinitis typically experience symptoms year-round, though symptoms may be exacerbated in the spring and autumn when rapid weather changes are more common.[17] An estimated 17 million United States citizens have vasomotor rhinitis.[17] Drinking alcohol may cause rhinitis as well as worsen asthma (see alcohol-induced respiratory reactions). In certain populations, particularly those of East Asian countries such as Japan, these reactions have a nonallergic basis.[29] In other populations, particularly those of European descent, a genetic variant in the gene that metabolizes ethanol to acetaldehyde, ADH1B, is associated with alcohol-induced rhinitis. It is suggested that this variant metabolizes ethanol to acetaldehyde too quickly for further processing by ALDH2 and thereby leads to the accumulation of acetaldehyde and rhinitis symptoms.[30] In these cases, alcohol-induced rhinitis may be of the mixed rhinitis type and, it seems likely, most cases of alcohol-induced rhinitis in non-Asian populations reflect true allergic response to the non-ethanol and/or contaminants in alcoholic beverages, particularly when these beverages are wines or beers.[29] Alcohol-exacerbated rhinitis is more frequent in individuals with a history of rhinitis exacerbated by aspirin.[31] Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), particularly those that inhibit cyclooxygenase 1 (COX1), can worsen rhinitis and asthma symptoms in individuals with a history of either one of these diseases.[32] These exacerbations most often appear due to NSAID hypersensitivity reactions rather than NSAID-induced allergic reactions.[33] The antihistamine azelastine, applied as a nasal spray, may be effective for vasomotor rhinitis.[34] Fluticasone propionate or budesonide (both are steroids) in nostril spray form may also be used for symptomatic treatment. The antihistamine cyproheptadine is also effective, probably due to its antiserotonergic effects. A systematic review on non-allergic rhinitis reports improvement of overall function after treatment with capsaicin (the active component of chili peppers). The quality of evidence is low, however.[35] ### Allergic[edit] Main article: Allergic rhinitis Allergic rhinitis or hay fever may follow when an allergen such as pollen, dust, or Balsam of Peru[36] is inhaled by an individual with a sensitized immune system, triggering antibody production. These antibodies mostly bind to mast cells, which contain histamine. When the mast cells are stimulated by an allergen, histamine (and other chemicals) are released. This causes itching, swelling, and mucus production. Symptoms vary in severity between individuals. Very sensitive individuals can experience hives or other rashes. Particulate matter in polluted air and chemicals such as chlorine and detergents, which can normally be tolerated, can greatly aggravate the condition.[citation needed] Characteristic physical findings in individuals who have allergic rhinitis include conjunctival swelling and erythema, eyelid swelling, lower eyelid venous stasis, lateral crease on the nose, swollen nasal turbinates, and middle ear effusion.[37] Even if a person has negative skin-prick, intradermal and blood tests for allergies, they may still have allergic rhinitis, from a local allergy in the nose. This is called local allergic rhinitis.[38] Many people who were previously diagnosed with nonallergic rhinitis may actually have local allergic rhinitis.[39] A patch test may be used to determine if a particular substance is causing the rhinitis. ### Rhinitis medicamentosa[edit] Main article: Rhinitis medicamentosa Rhinitis medicamentosa is a form of drug-induced nonallergic rhinitis which is associated with nasal congestion brought on by the use of certain oral medications (primarily sympathomimetic amine and 2-imidazoline derivatives) and topical decongestants (e.g., oxymetazoline, phenylephrine, xylometazoline, and naphazoline nasal sprays) that constrict the blood vessels in the lining of the nose.[40] ### Chronic atrophic rhinitis[edit] Main article: Chronic atrophic rhinitis Chronic rhinitis is a form of atrophy of the mucous membrane and glands of the nose. ### Rhinitis sicca[edit] Chronic form of dryness of the mucous membranes. ### Polypous rhinitis[edit] Chronic rhinitis associated with polyps in the nasal cavity. ## Pathophysiology[edit] Pathological changes in non-allergic rhinitis[26] Mechanism of non-allergic rhinitis: Imbalance between sympathetic and parasympathetic components in the nasal mucous membrane[26] Most prominent pathological changes observed are nasal airway epithelial metaplasia in which goblet cells replace ciliated columnar epithelial cells in the nasal mucous membrane.[26] This results in mucin hypersecretion by goblet cells and decreased mucociliary activity. Nasal secretion are not adequately cleared with clinical manifestation of nasal congestion, sinus pressure, post-nasal dripping, and headache. Over-expression of transient receptor potential (TRP) ion channels, such as TRPA1 and TRPV1, may be involved in the pathogenesis of non-allergic rhinitis.[41] ### Association between rhinitis and asthma[edit] Neurogenic inflammation produced by neuropeptides released from sensory nerve endings to the airways is a proposed common mechanism of association between both allergic and non-allergic rhinitis with asthma. This may explain higher association of rhinitis with asthma developing later in life.[42] Environmental irritants acts as modulators of airway inflammation in these contiguous airways. Development of occupational asthma is often preceded by occupational rhinitis. Among the causative agents are flours, enzymes used in processing food, latex, isocyanates, welding fumes, epoxy resins, and formaldehyde. Accordingly, prognosis of occupational asthma is contingent on early diagnosis and the adoption of protective measures for rhinitis.[43] ## Diagnosis[edit] The different forms of rhinitis are essentially diagnosed clinically. Vasomotor rhinitis is differentiated from viral and bacterial infections by the lack of purulent exudate and crusting. It can be differentiated from allergic rhinitis because of the absence of an identifiable allergen.[44] ## Prevention[edit] In the case of infectious rhinitis, vaccination against influenza viruses, adenoviruses, measles, rubella, Streptococcus pneumoniae, Haemophilus influenzae, diphtheria, Bacillus anthracis, and Bordetella pertussis may help prevent it. ## Management[edit] The management of rhinitis depends on the underlying cause. For allergic rhinitis, intranasal corticosteroids are recommended.[45] For severe symptoms intranasal antihistamines may be added.[45] ## Pronunciation and etymology[edit] Rhinitis is pronounced /raɪˈnaɪtɪs/,[46] while coryza is pronounced /kəˈraɪzə/.[47] Rhinitis comes from the Ancient Greek ῥίς rhis, gen.: ῥινός rhinos "nose". Coryza has a dubious etymology. Robert Beekes rejected an Indo-European derivation and suggested a Pre-Greek reconstruction karutya.[48] According to physician Andrew Wylie, "we use the term [coryza] for a cold in the head, but the two are really synonymous. The ancient Romans advised their patients to clean their nostrils and thereby sharpen their wits."[49] ## See also[edit] Infectious coryza in chickens ## References[edit] 1. ^ "rhinitis \| Definition, meaning & more \| Collins Dictionary". www.collinsdictionary.com. Retrieved 4 January 2017. 2. ^ "coryza \| Definition, meaning & more \| Collins Dictionary". www.collinsdictionary.com. Retrieved 4 January 2017. 3. ^ Pfaltz CR, Becker W, Naumann HH (2009). Ear, nose, and throat diseases: with head and neck surgery (3rd ed.). Stuttgart: Thieme. p. 150. ISBN 978-3-13-671203-0. 4. ^ "Nonallergic rhinitis". Archived from the original on 2008-09-24. 5. ^ Settipane RA (2003). "Rhinitis: a dose of epidemiological reality". Allergy Asthma Proc. 24 (3): 147–54. PMID 12866316. 6. ^ Sullivan JB, Krieger GR (2001). Clinical environmental health and toxic exposures. p. 341. 7. ^ a b "Allergic rhinitis". 8. ^ Quillen DM, Feller DB (May 2006). "Diagnosing rhinitis: allergic vs. nonallergic". American Family Physician. 73 (9): 1583–90. PMID 16719251. 9. ^ Marshall PS, O'Hara C, Steinberg P (April 2000). "Effects of seasonal allergic rhinitis on selected cognitive abilities". Annals of Allergy, Asthma & Immunology. 84 (4): 403–10. doi:10.1016/S1081-1206(10)62273-9. PMID 10795648. 10. ^ "Inflammatory Nature of Allergic Rhinitis: Pathophysiology". 11. ^ "Immunopathogenesis of allergic rhinitis" (PDF). 12. ^ "Economic Impact and Quality-of-Life Burden of Allergic Rhinitis: Prevalence". 13. ^ Bernstein, Jonathan A. (September 2010). "Allergic and mixed rhinitis: Epidemiology and natural history". Allergy and Asthma Proceedings. 31 (5): 365–369. doi:10.2500/aap.2010.31.3380. ISSN 1539-6304. PMID 20929601. 14. ^ Kaliner, Michael A (2009-06-15). "Classification of Nonallergic Rhinitis Syndromes With a Focus on Vasomotor Rhinitis, Proposed to be Known henceforth as Nonallergic Rhinopathy". The World Allergy Organization Journal. 2 (6): 98–101. doi:10.1097/WOX.0b013e3181a9d55b. ISSN 1939-4551. PMC 3650985. PMID 24229372. 15. ^ "Allergic rhinitis". 2018-12-26. Cite journal requires `\|journal=` (help) 16. ^ Troullos E, Baird L, Jayawardena S (June 2014). "Common cold symptoms in children: results of an Internet-based surveillance program". Journal of Medical Internet Research. 16 (6): e144. doi:10.2196/jmir.2868. PMC 4090373. PMID 24945090. 17. ^ a b c Wheeler PW, Wheeler SF (September 2005). "Vasomotor rhinitis". American Family Physician. 72 (6): 1057–62. PMID 16190503. 18. ^ Brown KR, Bernstein JA (June 2015). "Clinically relevant outcome measures of novel pharmacotherapy for nonallergic rhinitis". Current Opinion in Allergy and Clinical Immunology. 15 (3): 204–12. doi:10.1097/ACI.0000000000000166. PMID 25899692. S2CID 22343815. 19. ^ Van Gerven L, Boeckxstaens G, Hellings P (September 2012). "Up-date on neuro-immune mechanisms involved in allergic and non-allergic rhinitis". Rhinology. 50 (3): 227–35. doi:10.4193/Rhino11.152. PMID 22888478. 20. ^ Wheeler, P. W.; Wheeler, S. F. (Sep 2005). "Vasomotor rhinitis". Am Fam Physician. 72 (6): 1057–62. PMID 16190503. 21. ^ "Vasomotor rhinitis Medline Plus". Nlm.nih.gov. Retrieved 2014-04-23. 22. ^ Silvers WS, Poole JA (February 2006). "Exercise-induced rhinitis: a common disorder that adversely affects allergic and nonallergic athletes". Annals of Allergy, Asthma & Immunology. 96 (2): 334–40. doi:10.1016/s1081-1206(10)61244-6. PMID 16498856. 23. ^ Adelman D (2002). Manual of Allergy and Immunology: Diagnosis and Therapy. Lippincott Williams & Wilkins. p. 66. ISBN 9780781730525. 24. ^ (Middleton's Allergy Principles and Practice, seventh edition.) 25. ^ Knipping S, Holzhausen HJ, Riederer A, Schrom T (August 2008). "[Ultrastructural changes in allergic rhinitis vs. idiopathic rhinitis]". Hno. 56 (8): 799–807. doi:10.1007/s00106-008-1764-4. PMID 18651116. S2CID 24135943. 26. ^ a b c d Bernstein JA, Singh U (April 2015). "Neural Abnormalities in Nonallergic Rhinitis". Current Allergy and Asthma Reports. 15 (4): 18. doi:10.1007/s11882-015-0511-7. PMID 26130469. S2CID 22195726. 27. ^ "What causes non-allergic rhinitis?". NHS. Gov.uk. 2018-09-07. Retrieved December 18, 2018. 28. ^ Hellings PW, Klimek L, Cingi C, Agache I, Akdis C, Bachert C, Bousquet J, Demoly P, Gevaert P, Hox V, Hupin C, Kalogjera L, Manole F, Mösges R, Mullol J, Muluk NB, Muraro A, Papadopoulos N, Pawankar R, Rondon C, Rundenko M, Seys SF, Toskala E, Van Gerven L, Zhang L, Zhang N, Fokkens WJ (November 2017). "Non-allergic rhinitis: Position paper of the European Academy of Allergy and Clinical Immunology". Allergy. 72 (11): 1657–1665. doi:10.1111/all.13200. PMID 28474799. 29. ^ a b Adams KE, Rans TS (December 2013). "Adverse reactions to alcohol and alcoholic beverages". Annals of Allergy, Asthma & Immunology. 111 (6): 439–45. doi:10.1016/j.anai.2013.09.016. PMID 24267355. 30. ^ Macgregor S, Lind PA, Bucholz KK, Hansell NK, Madden PA, Richter MM, Montgomery GW, Martin NG, Heath AC, Whitfield JB (February 2009). "Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis". Human Molecular Genetics. 18 (3): 580–93. doi:10.1093/hmg/ddn372. PMC 2722191. PMID 18996923. 31. ^ Cardet JC, White AA, Barrett NA, Feldweg AM, Wickner PG, Savage J, Bhattacharyya N, Laidlaw TM (2014). "Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology. In Practice. 2 (2): 208–13. doi:10.1016/j.jaip.2013.12.003. PMC 4018190. PMID 24607050. 32. ^ Rajan JP, Wineinger NE, Stevenson DD, White AA (March 2015). "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature". The Journal of Allergy and Clinical Immunology. 135 (3): 676–81.e1. doi:10.1016/j.jaci.2014.08.020. PMID 25282015. 33. ^ Choi JH, Kim MA, Park HS (February 2014). "An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease". Current Opinion in Allergy and Clinical Immunology. 14 (1): 1–6. doi:10.1097/aci.0000000000000021. PMID 24300420. S2CID 205433452. 34. ^ Bernstein JA (October 2007). "Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability". Current Medical Research and Opinion. 23 (10): 2441–52. doi:10.1185/030079907X226302. PMID 17723160. S2CID 25827650. 35. ^ Gevorgyan A, Segboer C, Gorissen R, van Drunen CM, Fokkens W (July 2015). "Capsaicin for non-allergic rhinitis". The Cochrane Database of Systematic Reviews. 7 (7): CD010591. doi:10.1002/14651858.CD010591.pub2. PMID 26171907. 36. ^ Brooks P (2012-10-25). The Daily Telegraph: Complete Guide to Allergies. ISBN 9781472103949. Retrieved 2014-04-23. 37. ^ Valet RS, Fahrenholz JM (2009). "Allergic rhinitis: update on diagnosis". Consultant. 49: 610–613. 38. ^ Rondón C, Canto G, Blanca M (February 2010). "Local allergic rhinitis: a new entity, characterization and further studies". Current Opinion in Allergy and Clinical Immunology. 10 (1): 1–7. doi:10.1097/ACI.0b013e328334f5fb. PMID 20010094. S2CID 3472235. 39. ^ Rondón C, Fernandez J, Canto G, Blanca M (2010). "Local allergic rhinitis: concept, clinical manifestations, and diagnostic approach". Journal of Investigational Allergology & Clinical Immunology. 20 (5): 364–71, quiz 2 p following 371. PMID 20945601. 40. ^ Ramey JT, Bailen E, Lockey RF (2006). "Rhinitis medicamentosa" (PDF). Journal of Investigational Allergology & Clinical Immunology. 16 (3): 148–55. PMID 16784007. 41. ^ Millqvist E (April 2015). "TRP channels and temperature in airway disease-clinical significance". Temperature. 2 (2): 172–7. doi:10.1080/23328940.2015.1012979. PMC 4843868. PMID 27227021. 42. ^ Eriksson J, Bjerg A, Lötvall J, Wennergren G, Rönmark E, Torén K, Lundbäck B (November 2011). "Rhinitis phenotypes correlate with different symptom presentation and risk factor patterns of asthma". Respiratory Medicine. 105 (11): 1611–21. doi:10.1016/j.rmed.2011.06.004. PMID 21764573. 43. ^ Scherer Hofmeier K, Bircher A, Tamm M, Miedinger D (April 2012). "[Occupational rhinitis and asthma]". Therapeutische Umschau. 69 (4): 261–7. doi:10.1024/0040-5930/a000283. PMID 22477666. 44. ^ "Nonallergic Rhinitis - Ear, Nose, and Throat Disorders". MSD Manual Professional Edition. Retrieved 2019-03-07. 45. ^ a b Wallace DV, Dykewicz MS, Oppenheimer J, Portnoy JM, Lang DM (December 2017). "Pharmacologic Treatment of Seasonal Allergic Rhinitis: Synopsis of Guidance From the 2017 Joint Task Force on Practice Parameters". Annals of Internal Medicine. 167 (12): 876–881. doi:10.7326/M17-2203. PMID 29181536. 46. ^ "rhinitis \| Definition, meaning & more \| Collins Dictionary". www.collinsdictionary.com. Retrieved 4 January 2017. 47. ^ "coryza \| Definition, meaning & more \| Collins Dictionary". www.collinsdictionary.com. Retrieved 4 January 2017. 48. ^ Beekes RS (2009). Etymological Dictionary of Greek. Brill. p. 756. 49. ^ Wylie A (1927). "Rhinology and laryngology in literature and Folk-Lore". The Journal of Laryngology & Otology. 42 (2): 81–87. doi:10.1017/S0022215100029959. ## External links[edit] Classification D * ICD-10: J00, J30, J31.0 * ICD-9-CM: 472.0, 477 * OMIM: 607154 * MeSH: D012220 * DiseasesDB: 26380 External resources * MedlinePlus: 000813 * eMedicine: ent/194 med/104, ped/2560 * Sinus Infection And Allergic Rhinitis * Specialist Library for ENT and Audiology Hay fever resources – online library of high quality research on hay fever and other ENT disorders * 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 * t * e Decongestants and other nasal preparations (R01) Topical Sympathomimetics, plain * Cyclopentamine * Ephedrine * Epinephrine * Fenoxazoline * Levomethamphetamine * Metizoline * Naphazoline * Oxymetazoline * Phenylephrine * Propylhexedrine * Tetryzoline * Tramazoline * Tuaminoheptane * Tymazoline * Xylometazoline Antiallergic agents, excluding corticosteroids * Spaglumic acid * histamine antagonists (Levocabastine * Antazoline * Thonzylamine) * mast cell stabilizer (some are also antihistamines) (Cromoglicic acid * Nedocromil * Azelastine * Olopatadine * Lodoxamide) Corticosteroids * Beclometasone dipropionate * Betamethasone# * Budesonide * Ciclesonide * Dexamethasone * Flunisolide * Fluticasone (Fluticasone furoate, Fluticasone propionate) * Mometasone furoate * Prednisolone# * Tixocortol * Triamcinolone * Triamcinolone acetonide Other nasal preparations * Cafaminol * Calcium hexamine thiocyanate * Eucalyptus oil * Framycetin * Hexamidine * Hyaluronan * Ipratropium bromide * Mupirocin * Retinol * Ritiometan * Saline water Combination products * Olopatadine/mometasone Systemic use: Sympathomimetics * Phenylephrine * Phenylpropanolamine * Pseudoephedrine (+loratadine) * #WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III * v * t * e Allergic conditions Respiratory system * Allergic rhinitis (hay fever) * Asthma * Hypersensitivity pneumonitis * Eosinophilic pneumonia * Eosinophilic granulomatosis with polyangiitis * Allergic bronchopulmonary aspergillosis * Farmer's lung * Laboratory animal allergy Skin * Angioedema * Urticaria * Atopic dermatitis * Allergic contact dermatitis * Hypersensitivity vasculitis Blood and immune system * Serum sickness Circulatory system * Anaphylaxis Digestive system * Coeliac disease * Eosinophilic gastroenteritis * Eosinophilic esophagitis * Food allergy * Egg allergy * Milk intolerance Nervous system * Eosinophilic meningitis Genitourinary system * Acute interstitial nephritis Other conditions * Drug allergy * Allergic conjunctivitis * Latex allergy * Medicine portal [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Rhinitis	c2718128	6,924	wikipedia	https://en.wikipedia.org/wiki/Rhinitis	2021-01-18T18:58:44	{"mesh": ["D012220"], "umls": ["C2718128", "C0035455"], "icd-9": ["472.0", "477"], "icd-10": ["J00", "J30", "J31.0"], "wikidata": ["Q114085"]}
MYH-associated polyposis is an inherited condition characterized by the development of multiple adenomatous colon polyps and an increased risk of colorectal cancer. This condition, a milder form of familial adenomatous polyposis (FAP), is sometimes called autosomal recessive familial adenomatous polyposis because it is inherited in an autosomal recessive manner. People with this condition have fewer polyps than those with the classic type of FAP; fewer than 100 polyps typically develop, rather than hundreds or thousands. They may also be at increased risk for upper gastrointestinal polyps. MYH-associated polyposis is caused by mutations in the MYH gene. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MYH-associated polyposis	c1837991	6,925	gard	https://rarediseases.info.nih.gov/diseases/10805/myh-associated-polyposis	2021-01-18T17:58:50	{"mesh": ["C563924"], "omim": ["608456"], "synonyms": ["MAP syndrome", "Autosomal recessive familial adenomatous polyposis", "Autosomal recessive multiple colorectal adenomas"]}
Remitting seronegative symmetrical synovitis with pitting edema Other namesRemitting seronegative symmetrical synovitis with pitting oedema[1] RS3PE SpecialtyRheumatology Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS3PE) is a rare syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema (swelling) of the back of the hands and/or feet, and a negative serum rheumatoid factor.[2] If no underlying disorder can be identified (idiopathic RS3PE), this entity has an excellent prognosis and responds well to treatment.[3] RS3PE typically involves the joints of the extremities, specifically the metacarpophalangeal and proximal interphalangeal joints, wrists, shoulders, elbows, knees and ankles.[4] It is more common in older adults, with the mean age between 70 and 80 years in most studies.[4][5] It occurs more often in men than in women with a 2:1 ratio.[4][6][7] It is unknown how common this condition is. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathogenesis * 4 Diagnosis * 5 Treatment * 6 History * 7 References ## Signs and symptoms[edit] Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs.[8] The arms and hands are more commonly affected than the legs and feet.[8] Both sides are usually involved though RS3PE can affect only one side in certain cases.[8] ## Causes[edit] RS3PE is a constellation of symptoms that can be caused by many other conditions. Since there is no definitive diagnostic test, other conditions have to be ruled out before this rare condition can be diagnosed. The main differential diagnosis is polymyalgia rheumatica (PMR), although pain, stiffness and weakness at the level of the shoulders and pelvic girdle with associated systemic symptoms (fever, malaise, fatigue, weight loss) is more typical of PMR. Prospective studies have found a subgroup of PMR patients with hand edema, as well as other similarities.[5] Thus, RS3PE has been proposed as a condition related to PMR or even that they are both part of the same disorder.[5] However, PMR typically requires protracted courses of steroids, whereas corticosteroids can be tapered more quickly with persisting remission in RS3PE.[5] Other rheumatological disorders that can cause the features typical for RS3PE include late onset (seronegative) rheumatoid arthritis, acute sarcoidosis, ankylosing spondylitis and other spondyloarthropathies such as psoriatic arthropathy, mixed connective tissue disease, chondrocalcinosis and arthropathy due to amyloidosis.[6][9] RS3PE has been documented in patients with cancers (Non-Hodgkin's lymphoma, gastric cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, prostate cancer and bladder cancer, among others), in whom it might represent a paraneoplastic manifestation.[10][11][12] Other underlying disorders include vasculitides such as polyarteritis nodosa.[8] Other causes of edema include heart failure, hypoalbuminemia, nephrotic syndrome and venous stasis. The key distinguishing feature is that these conditions don't tend to manifest with pitting edema at the back of the hands. ## Pathogenesis[edit] The disease mechanism (pathophysiology) of RS3PE remains unknown. One study suggested a possible role for vascular endothelial growth factor.[13] A study using magnetic resonance imaging found that tenosynovitis of the extensors of the hands and feet is the major contributor to edema.[14] ## Diagnosis[edit] Ultrasonography and magnetic resonance imaging of the hands and/or feet have been proposed as useful diagnostic investigations in RS3PE.[15] Some studies linked RS3PE to HLA-B27 whereas others have not. ## Treatment[edit] RS3PE responds excellently to low dose corticosteroids, with sustained and often complete remission. Non-steroidal anti-inflammatory drugs (NSAIDs) have also been used. Hydroxychloroquine has proven effective in some cases.[6] ## History[edit] In a 1985 paper published in the Journal of the American Medical Association, McCarty and colleagues first described a case series of patients with this disorder, for which they coined the abbreviation RS3PE.[16] RS3PE was initially thought to represent a form of seronegative rheumatoid arthritis but is now believed to be a separate syndrome.[8] ## References[edit] 1. ^ 'Oedema' is the standard form defined in the Concise Oxford English Dictionary (2011), with the precision that the spelling in the United States is 'edema'. 2. ^ Olivieri I, Salvarani C, Cantini F (2000). "RS3PE syndrome: an overview". Clin. Exp. Rheumatol. 18 (4 Suppl 20): S53–55. PMID 10948764. 3. ^ Queiro R (March 2004). "RS3PE syndrome: a clinical and immunogenetical study". Rheumatol. Int. 24 (2): 103–05. doi:10.1007/s00296-003-0330-3. PMID 12750942. S2CID 22516577. 4. ^ a b c Olivé A, del Blanco J, Pons M, Vaquero M, Tena X (February 1997). "The clinical spectrum of remitting seronegative symmetrical synovitis with pitting edema. The Catalán Group for the Study of RS3PE". J. Rheumatol. 24 (2): 333–36. PMID 9034993. 5. ^ a b c d Cantini F, Salvarani C, Olivieri I, et al. (April 1999). "Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study". Ann. Rheum. Dis. 58 (4): 230–36. doi:10.1136/ard.58.4.230. PMC 1752869. PMID 10364902. 6. ^ a b c Salam A, Henry R, Sheeran T (2008). "Acute onset polyarthritis in older people: Is it RS3PE syndrome?". Cases J. 1 (1): 132. doi:10.1186/1757-1626-1-132. PMC 2543002. PMID 18759976. 7. ^ Hartley AJ, Manson J, Jawad AS (2010). "Remitting seronegative symmetrical synovitis with pitting oedema". Grand Rounds. 10: 71–73. doi:10.1102/1470-5206.2010.0015 (inactive 2021-01-11). Archived from the original on 2011-07-11. Retrieved 2010-12-20.CS1 maint: DOI inactive as of January 2021 (link) 8. ^ a b c d e Kardes S, Karagulle M, Erdogan N (May 2015). "Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) associated with psoriatic arthritis". Scand J Rheumatol. 44 (4): 339–40. doi:10.3109/03009742.2015.1020069. PMID 25958968. S2CID 2298418. 9. ^ Díez-Porres L, Muñoz-Fernández S, Aguado P, Alonso M, Martín-Mola E (November 2002). "Remitting seronegative symmetrical synovitis with pitting oedema as the first manifestation of psoriatic arthropathy". Rheumatology (Oxford). 41 (11): 1333–35. doi:10.1093/rheumatology/41.11.1333-a. PMID 12422012. 10. ^ Russell EB (September 2005). "Remitting seronegative symmetrical synovitis with pitting edema syndrome: followup for neoplasia". J. Rheumatol. 32 (9): 1760–61. PMID 16142875. Archived from the original on 2009-04-29. Retrieved 2009-01-29. 11. ^ Fietta P, Manganelli P (November 2006). "Remitting seronegative symmetrical synovitis with pitting edema syndrome: followup for neoplasia". J. Rheumatol. 33 (11): 2365–66, author reply 2366. PMID 17086622.[dead link] 12. ^ Bucaloiu ID, Olenginski TP, Harrington TM (December 2007). "Remitting seronegative symmetrical synovitis with pitting edema syndrome in a rural tertiary care practice: a retrospective analysis". Mayo Clin. Proc. 82 (12): 1510–15. doi:10.4065/82.12.1510. PMID 18053459. Archived from the original on 2007-07-01. 13. ^ Arima K, Origuchi T, Tamai M, et al. (November 2005). "RS3PE syndrome presenting as vascular endothelial growth factor associated disorder". Ann. Rheum. Dis. 64 (11): 1653–55. doi:10.1136/ard.2004.032995. PMC 1755286. PMID 16227418. 14. ^ Olivieri I, Salvarani C, Cantini F (February 1997). "Remitting distal extremity swelling with pitting edema: a distinct syndrome or a clinical feature of different inflammatory rheumatic diseases?". J. Rheumatol. 24 (2): 249–52. PMID 9034979. 15. ^ Agarwal V, Dabra AK, Kaur R, Sachdev A, Singh R (September 2005). "Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome: ultrasonography as a diagnostic tool". Clin. Rheumatol. 24 (5): 476–79. doi:10.1007/s10067-004-1061-x. PMID 15856369. S2CID 20352825. 16. ^ McCarty DJ, O'Duffy JD, Pearson L, Hunter JB (November 1985). "Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome". JAMA. 254 (19): 2763–67. doi:10.1001/jama.254.19.2763. PMID 4057484. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Remitting seronegative symmetrical synovitis with pitting edema	c2919482	6,926	wikipedia	https://en.wikipedia.org/wiki/Remitting_seronegative_symmetrical_synovitis_with_pitting_edema	2021-01-18T19:00:39	{"gard": ["13640"], "umls": ["C2919482"], "wikidata": ["Q7311927"]}
Immune system response to a substance that most people tolerate well For the medical journal of this title, see Allergy (journal). Allergy Hives are a common allergic symptom SpecialtyImmunology SymptomsRed eyes, itchy rash, runny nose, shortness of breath, swelling, sneezing[1] TypesHay fever, food allergies, atopic dermatitis, allergic asthma, anaphylaxis[2] CausesGenetic and environmental factors[3] Diagnostic methodBased on symptoms, skin prick test, blood test[4] Differential diagnosisFood intolerances, food poisoning[5] PreventionEarly exposure to potential allergens[6] TreatmentAvoiding known allergens, medications, allergen immunotherapy[7] MedicationSteroids, antihistamines, epinephrine, mast cell stabilizers, antileukotrienes[7][8][9][10] FrequencyCommon[11] Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment.[12] These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis.[2] Symptoms may include red eyes, an itchy rash, sneezing, a runny nose, shortness of breath, or swelling.[1] Food intolerances and food poisoning are separate conditions.[4][5] Common allergens include pollen and certain foods.[12] Metals and other substances may also cause problems.[12] Food, insect stings, and medications are common causes of severe reactions.[3] Their development is due to both genetic and environmental factors.[3] The underlying mechanism involves immunoglobulin E antibodies (IgE), part of the body's immune system, binding to an allergen and then to a receptor on mast cells or basophils where it triggers the release of inflammatory chemicals such as histamine.[13] Diagnosis is typically based on a person's medical history.[4] Further testing of the skin or blood may be useful in certain cases.[4] Positive tests, however, may not mean there is a significant allergy to the substance in question.[14] Early exposure to potential allergens may be protective.[6] Treatments for allergies include the avoidance of known allergens and the use of medications such as steroids and antihistamines.[7] In severe reactions injectable adrenaline (epinephrine) is recommended.[8] Allergen immunotherapy, which gradually exposes people to larger and larger amounts of allergen, is useful for some types of allergies such as hay fever and reactions to insect bites.[7] Its use in food allergies is unclear.[7] Allergies are common.[11] In the developed world, about 20% of people are affected by allergic rhinitis,[15] about 6% of people have at least one food allergy,[4][6] and about 20% have atopic dermatitis at some point in time.[16] Depending on the country about 1–18% of people have asthma.[17][18] Anaphylaxis occurs in between 0.05–2% of people.[19] Rates of many allergic diseases appear to be increasing.[8][20][21] The word "allergy" was first used by Clemens von Pirquet in 1906.[3] ## Contents * 1 Signs and symptoms * 1.1 Skin * 2 Cause * 2.1 Foods * 2.2 Latex * 2.3 Medications * 2.4 Insect stings * 2.5 Toxins interacting with proteins * 2.6 Genetics * 2.7 Hygiene hypothesis * 2.8 Stress * 2.9 Other environmental factors * 3 Pathophysiology * 3.1 Acute response * 3.2 Late-phase response * 3.3 Allergic contact dermatitis * 4 Diagnosis * 4.1 Skin prick testing * 4.2 Patch testing * 4.3 Blood testing * 4.4 Other testing * 4.5 Differential diagnosis * 5 Prevention * 6 Management * 6.1 Medication * 6.2 Immunotherapy * 6.3 Alternative medicine * 7 Epidemiology * 7.1 Changing frequency * 8 History * 8.1 Diagnosis * 9 Medical specialty * 10 Research * 11 See also * 12 References * 13 External links ## Signs and symptoms[edit] Affected organ Common signs and symptoms Nose Swelling of the nasal mucosa (allergic rhinitis) runny nose, sneezing Sinuses Allergic sinusitis Eyes Redness and itching of the conjunctiva (allergic conjunctivitis, watery) Airways Sneezing, coughing, bronchoconstriction, wheezing and dyspnea, sometimes outright attacks of asthma, in severe cases the airway constricts due to swelling known as laryngeal edema Ears Feeling of fullness, possibly pain, and impaired hearing due to the lack of eustachian tube drainage. Skin Rashes, such as eczema and hives (urticaria) Gastrointestinal tract Abdominal pain, bloating, vomiting, diarrhea Many allergens such as dust or pollen are airborne particles. In these cases, symptoms arise in areas in contact with air, such as eyes, nose, and lungs. For instance, allergic rhinitis, also known as hay fever, causes irritation of the nose, sneezing, itching, and redness of the eyes.[22] Inhaled allergens can also lead to increased production of mucus in the lungs, shortness of breath, coughing, and wheezing.[23] Aside from these ambient allergens, allergic reactions can result from foods, insect stings, and reactions to medications like aspirin and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and swelling of the skin during hives. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis.[24] Insect stings, food, antibiotics, and certain medicines may produce a systemic allergic response that is also called anaphylaxis; multiple organ systems can be affected, including the digestive system, the respiratory system, and the circulatory system.[25][26][27] Depending on the rate of severity, anaphylaxis can include skin reactions, bronchoconstriction, swelling, low blood pressure, coma, and death. This type of reaction can be triggered suddenly, or the onset can be delayed. The nature of anaphylaxis is such that the reaction can seem to be subsiding, but may recur throughout a period of time.[27] ### Skin[edit] Substances that come into contact with the skin, such as latex, are also common causes of allergic reactions, known as contact dermatitis or eczema.[28] Skin allergies frequently cause rashes, or swelling and inflammation within the skin, in what is known as a "weal and flare" reaction characteristic of hives and angioedema.[29] With insect stings a large local reaction may occur (an area of skin redness greater than 10 cm in size).[30] It can last one to two days.[30] This reaction may also occur after immunotherapy.[31] ## Cause[edit] Risk factors for allergy can be placed in two general categories, namely host and environmental factors.[32] Host factors include heredity, sex, race, and age, with heredity being by far the most significant. However, there have been recent increases in the incidence of allergic disorders that cannot be explained by genetic factors alone. Four major environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[33] ### Foods[edit] Main article: Food allergy A wide variety of foods can cause allergic reactions, but 90% of allergic responses to foods are caused by cow's milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish.[34] Other food allergies, affecting less than 1 person per 10,000 population, may be considered "rare".[35] The use of hydrolysed milk baby formula versus standard milk baby formula does not appear to change the risk.[36] The most common food allergy in the US population is a sensitivity to crustacea.[35] Although peanut allergies are notorious for their severity, peanut allergies are not the most common food allergy in adults or children. Severe or life-threatening reactions may be triggered by other allergens, and are more common when combined with asthma.[34] Rates of allergies differ between adults and children. Peanut allergies can sometimes be outgrown by children. Egg allergies affect one to two percent of children but are outgrown by about two-thirds of children by the age of 5.[37] The sensitivity is usually to proteins in the white, rather than the yolk.[38] Milk-protein allergies are most common in children.[39] Approximately 60% of milk-protein reactions are immunoglobulin E-mediated, with the remaining usually attributable to inflammation of the colon.[40] Some people are unable to tolerate milk from goats or sheep as well as from cows, and many are also unable to tolerate dairy products such as cheese. Roughly 10% of children with a milk allergy will have a reaction to beef. Beef contains small amounts of proteins that are present in greater abundance in cow's milk.[41] Lactose intolerance, a common reaction to milk, is not a form of allergy at all, but rather due to the absence of an enzyme in the digestive tract. Those with tree nut allergies may be allergic to one or to many tree nuts, including pecans, pistachios, pine nuts, and walnuts.[38] Also seeds, including sesame seeds and poppy seeds, contain oils in which protein is present, which may elicit an allergic reaction.[38] Allergens can be transferred from one food to another through genetic engineering; however genetic modification can also remove allergens. Little research has been done on the natural variation of allergen concentrations in unmodified crops.[42][43] ### Latex[edit] Latex can trigger an IgE-mediated cutaneous, respiratory, and systemic reaction. The prevalence of latex allergy in the general population is believed to be less than one percent. In a hospital study, 1 in 800 surgical patients (0.125 percent) reported latex sensitivity, although the sensitivity among healthcare workers is higher, between seven and ten percent. Researchers attribute this higher level to the exposure of healthcare workers to areas with significant airborne latex allergens, such as operating rooms, intensive-care units, and dental suites. These latex-rich environments may sensitize healthcare workers who regularly inhale allergenic proteins.[44] The most prevalent response to latex is an allergic contact dermatitis, a delayed hypersensitive reaction appearing as dry, crusted lesions. This reaction usually lasts 48–96 hours. Sweating or rubbing the area under the glove aggravates the lesions, possibly leading to ulcerations.[44] Anaphylactic reactions occur most often in sensitive patients who have been exposed to a surgeon's latex gloves during abdominal surgery, but other mucosal exposures, such as dental procedures, can also produce systemic reactions.[44] Latex and banana sensitivity may cross-react. Furthermore, those with latex allergy may also have sensitivities to avocado, kiwifruit, and chestnut.[45] These people often have perioral itching and local urticaria. Only occasionally have these food-induced allergies induced systemic responses. Researchers suspect that the cross-reactivity of latex with banana, avocado, kiwifruit, and chestnut occurs because latex proteins are structurally homologous with some other plant proteins.[44] ### Medications[edit] Main article: Drug allergy See also: Adverse drug reaction and Drug eruption About 10% of people report that they are allergic to penicillin; however, 90% turn out not to be.[46] Serious allergies only occur in about 0.03%.[46] ### Insect stings[edit] Main article: Insect sting allergy Typically, insects which generate allergic responses are either stinging insects (wasps, bees, hornets and ants) or biting insects (mosquitoes, ticks). Stinging insects inject venom into their victims, whilst biting insects normally introduce anti-coagulants. ### Toxins interacting with proteins[edit] Another non-food protein reaction, urushiol-induced contact dermatitis, originates after contact with poison ivy, eastern poison oak, western poison oak, or poison sumac. Urushiol, which is not itself a protein, acts as a hapten and chemically reacts with, binds to, and changes the shape of integral membrane proteins on exposed skin cells. The immune system does not recognize the affected cells as normal parts of the body, causing a T-cell-mediated immune response.[47] Of these poisonous plants, sumac is the most virulent.[48] The resulting dermatological response to the reaction between urushiol and membrane proteins includes redness, swelling, papules, vesicles, blisters, and streaking.[49] Estimates vary on the percentage of the population that will have an immune system response. Approximately 25 percent of the population will have a strong allergic response to urushiol. In general, approximately 80 percent to 90 percent of adults will develop a rash if they are exposed to .0050 milligrams (7.7×10−5 gr) of purified urushiol, but some people are so sensitive that it takes only a molecular trace on the skin to initiate an allergic reaction.[50] ### Genetics[edit] Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[51] Allergic parents are more likely to have allergic children,[52] and those children's allergies are likely to be more severe than those in children of non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[52] The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[53] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[53] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[54] Overall, boys have a higher risk of developing allergies than girls,[52] although for some diseases, namely asthma in young adults, females are more likely to be affected.[55] These differences between the sexes tend to decrease in adulthood.[52] Ethnicity may play a role in some allergies; however, racial factors have been difficult to separate from environmental influences and changes due to migration.[52] It has been suggested that different genetic loci are responsible for asthma, to be specific, in people of European, Hispanic, Asian, and African origins.[56] ### Hygiene hypothesis[edit] Main article: Hygiene hypothesis Allergic diseases are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response. Many bacteria and viruses elicit a TH1-mediated immune response, which down-regulates TH2 responses. The first proposed mechanism of action of the hygiene hypothesis was that insufficient stimulation of the TH1 arm of the immune system leads to an overactive TH2 arm, which in turn leads to allergic disease.[57] In other words, individuals living in too sterile an environment are not exposed to enough pathogens to keep the immune system busy. Since our bodies evolved to deal with a certain level of such pathogens, when they are not exposed to this level, the immune system will attack harmless antigens and thus normally benign microbial objects—like pollen—will trigger an immune response.[58] The hygiene hypothesis was developed to explain the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were, it is presumed, exposed to more infectious agents through their siblings, than in children from families with only one child. The hygiene hypothesis has been extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of allergic disorders. It is used to explain the increase in allergic diseases that have been seen since industrialization, and the higher incidence of allergic diseases in more developed countries. The hygiene hypothesis has now expanded to include exposure to symbiotic bacteria and parasites as important modulators of immune system development, along with infectious agents. Epidemiological data support the hygiene hypothesis. Studies have shown that various immunological and autoimmune diseases are much less common in the developing world than the industrialized world and that immigrants to the industrialized world from the developing world increasingly develop immunological disorders in relation to the length of time since arrival in the industrialized world.[59] Longitudinal studies in the third world demonstrate an increase in immunological disorders as a country grows more affluent and, it is presumed, cleaner.[60] The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases.[61] The use of antibacterial cleaning products has also been associated with higher incidence of asthma, as has birth by Caesarean section rather than vaginal birth.[62][63] ### Stress[edit] Chronic stress can aggravate allergic conditions. This has been attributed to a T helper 2 (TH2)-predominant response driven by suppression of interleukin 12 by both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. Stress management in highly susceptible individuals may improve symptoms.[64] ### Other environmental factors[edit] There are differences between countries in the number of individuals within a population having allergies. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[65] Historically, the trees planted in urban areas were predominantly male to prevent litter from seeds and fruits, but the high ratio of male trees causes high pollen counts.[66] Alterations in exposure to microorganisms is another plausible explanation, at present, for the increase in atopic allergy.[33] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[67] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[68] Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[69] Recent research has shown that some common parasites, such as intestinal worms (e.g., hookworms), secrete chemicals into the gut wall (and, hence, the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[70] This gives rise to a new slant on the hygiene hypothesis theory—that co-evolution of humans and parasites has led to an immune system that functions correctly only in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[71] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[72] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[65] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[73] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[73] For more information on this topic, see Helminthic therapy. ## Pathophysiology[edit] A summary diagram that explains how allergy develops Tissues affected in allergic inflammation ### Acute response[edit] Degranulation process in allergy. Second exposure to allergen. 1 – antigen; 2 – IgE antibody; 3 – FcεRI receptor; 4 – preformed mediators (histamine, proteases, chemokines, heparin); 5 – granules; 6 – mast cell; 7 – newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF). In the early stages of allergy, a type I hypersensitivity reaction against an allergen encountered for the first time and presented by a professional antigen-presenting cell causes a response in a type of immune cell called a TH2 lymphocyte; a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage, are sensitized to the allergen.[33] If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[33] ### Late-phase response[edit] After the chemical mediators of the acute response subside, late-phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2–24 hours after the original reaction.[74] Cytokines from mast cells may play a role in the persistence of long-term effects. Late-phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils and are still dependent on activity of TH2 cells.[75] ### Allergic contact dermatitis[edit] Although allergic contact dermatitis is termed an "allergic" reaction (which usually refers to type I hypersensitivity), its pathophysiology actually involves a reaction that more correctly corresponds to a type IV hypersensitivity reaction.[76] In type IV hypersensitivity, there is activation of certain types of T cells (CD8+) that destroy target cells on contact, as well as activated macrophages that produce hydrolytic enzymes. ## Diagnosis[edit] An allergy testing machine being operated in a diagnostic immunology lab Effective management of allergic diseases relies on the ability to make an accurate diagnosis.[77] Allergy testing can help confirm or rule out allergies.[78][79] Correct diagnosis, counseling, and avoidance advice based on valid allergy test results reduces the incidence of symptoms and need for medications, and improves quality of life.[78] To assess the presence of allergen-specific IgE antibodies, two different methods can be used: a skin prick test, or an allergy blood test. Both methods are recommended, and they have similar diagnostic value.[79][80] Skin prick tests and blood tests are equally cost-effective, and health economic evidence shows that both tests were cost-effective compared with no test.[78] Also, early and more accurate diagnoses save cost due to reduced consultations, referrals to secondary care, misdiagnosis, and emergency admissions.[81] Allergy undergoes dynamic changes over time. Regular allergy testing of relevant allergens provides information on if and how patient management can be changed, in order to improve health and quality of life. Annual testing is often the practice for determining whether allergy to milk, egg, soy, and wheat have been outgrown, and the testing interval is extended to 2–3 years for allergy to peanut, tree nuts, fish, and crustacean shellfish.[79] Results of follow-up testing can guide decision-making regarding whether and when it is safe to introduce or re-introduce allergenic food into the diet.[82] ### Skin prick testing[edit] Skin testing on arm Skin testing on back Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny punctures or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (e.g., pollen, grass, mite proteins, peanut extract) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients similar to a mosquito bite. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/− meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[83] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[84] If a serious life-threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease, or has taken antihistamines in the last several days. ### Patch testing[edit] Main article: Patch test Patch test Patch testing is a method used to determine if a specific substance causes allergic inflammation of the skin. It tests for delayed reactions. It is used to help ascertain the cause of skin contact allergy, or contact dermatitis. Adhesive patches, usually treated with a number of common allergic chemicals or skin sensitizers, are applied to the back. The skin is then examined for possible local reactions at least twice, usually at 48 hours after application of the patch, and again two or three days later. ### Blood testing[edit] An allergy blood test is quick and simple, and can be ordered by a licensed health care provider (e.g., an allergy specialist) or general practitioner. Unlike skin-prick testing, a blood test can be performed irrespective of age, skin condition, medication, symptom, disease activity, and pregnancy. Adults and children of any age can get an allergy blood test. For babies and very young children, a single needle stick for allergy blood testing is often more gentle than several skin pricks. An allergy blood test is available through most laboratories. A sample of the patient's blood is sent to a laboratory for analysis, and the results are sent back a few days later. Multiple allergens can be detected with a single blood sample. Allergy blood tests are very safe, since the person is not exposed to any allergens during the testing procedure. The test measures the concentration of specific IgE antibodies in the blood. Quantitative IgE test results increase the possibility of ranking how different substances may affect symptoms. A rule of thumb is that the higher the IgE antibody value, the greater the likelihood of symptoms. Allergens found at low levels that today do not result in symptoms can not help predict future symptom development. The quantitative allergy blood result can help determine what a patient is allergic to, help predict and follow the disease development, estimate the risk of a severe reaction, and explain cross-reactivity.[85][86] A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens.[87] Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with allergy tests for specific IgE antibodies for a carefully chosen of allergens is often warranted. Laboratory methods to measure specific IgE antibodies for allergy testing include enzyme-linked immunosorbent assay (ELISA, or EIA),[88] radioallergosorbent test (RAST)[88] and fluorescent enzyme immunoassay (FEIA).[89] ### Other testing[edit] Challenge testing: Challenge testing is when small amounts of a suspected allergen are introduced to the body orally, through inhalation, or via other routes. Except for testing food and medication allergies, challenges are rarely performed. When this type of testing is chosen, it must be closely supervised by an allergist. Elimination/challenge tests: This testing method is used most often with foods or medicines. A patient with a suspected allergen is instructed to modify his diet to totally avoid that allergen for a set time. If the patient experiences significant improvement, he may then be "challenged" by reintroducing the allergen, to see if symptoms are reproduced. Unreliable tests: There are other types of allergy testing methods that are unreliable, including applied kinesiology (allergy testing through muscle relaxation), cytotoxicity testing, urine autoinjection, skin titration (Rinkel method), and provocative and neutralization (subcutaneous) testing or sublingual provocation.[90] ### Differential diagnosis[edit] Before a diagnosis of allergic disease can be confirmed, other possible causes of the presenting symptoms should be considered.[91] Vasomotor rhinitis, for example, is one of many illnesses that share symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[92] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy. ## Prevention[edit] Further information: Allergy prevention in children Giving peanut products early may decrease the risk allergies while only breastfeeding during at least the first few months of life may decrease the risk of dermatitis.[93][94] There is no good evidence that a mother's diet during pregnancy or breastfeeding affects the risk.[93] Nor is there evidence that delayed introduction of certain foods is useful.[93] Early exposure to potential allergens may actually be protective.[6] Fish oil supplementation during pregnancy is associated with a lower risk.[94] Probiotic supplements during pregnancy or infancy may help to prevent atopic dermatitis.[95][96] ## Management[edit] Management of allergies typically involves avoiding what triggers the allergy and medications to improve the symptoms.[7] Allergen immunotherapy may be useful for some types of allergies.[7] ### Medication[edit] Several medications may be used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, and antileukotriene agents are common treatments of allergic diseases.[97] Anti-cholinergics, decongestants, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. Although rare, the severity of anaphylaxis often requires epinephrine injection, and where medical care is unavailable, a device known as an epinephrine autoinjector may be used.[27] ### Immunotherapy[edit] Main article: Allergen immunotherapy Anti-allergy immunotherapy Allergen immunotherapy is useful for environmental allergies, allergies to insect bites, and asthma.[7][98] Its benefit for food allergies is unclear and thus not recommended.[7] Immunotherapy involves exposing people to larger and larger amounts of allergen in an effort to change the immune system's response.[7] Meta-analyses have found that injections of allergens under the skin is effective in the treatment in allergic rhinitis in children[99][100] and in asthma.[98] The benefits may last for years after treatment is stopped.[101] It is generally safe and effective for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insects.[102] The evidence also supports the use of sublingual immunotherapy for rhinitis and asthma but it is less strong.[101] For seasonal allergies the benefit is small.[103] In this form the allergen is given under the tongue and people often prefer it to injections.[101] Immunotherapy is not recommended as a stand-alone treatment for asthma.[101] ### Alternative medicine[edit] An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[104] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favoring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but evidence does not show effectiveness.[104] A review found no effectiveness of homeopathic treatments and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of homeopathic treatments.[105] According to the National Center for Complementary and Integrative Health, U.S, the evidence is relatively strong that saline nasal irrigation and butterbur are effective, when compared to other alternative medicine treatments, for which the scientific evidence is weak, negative, or nonexistent, such as honey, acupuncture, omega 3's, probiotics, astragalus, capsaicin, grape seed extract, Pycnogenol, quercetin, spirulina, stinging nettle, tinospora or guduchi. [106][107] ## Epidemiology[edit] The allergic diseases—hay fever and asthma—have increased in the Western world over the past 2–3 decades.[108] Increases in allergic asthma and other atopic disorders in industrialized nations, it is estimated, began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[109] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[110] The number of new cases per year of atopy in developing countries has, in general, remained much lower.[109] Allergic conditions: Statistics and epidemiology Allergy type United States United Kingdom[111] Allergic rhinitis 35.9 million[112] (about 11% of the population[113]) 3.3 million (about 5.5% of the population[114]) Asthma 10 million have allergic asthma (about 3% of the population). The prevalence of asthma increased 75% from 1980 to 1994. Asthma prevalence is 39% higher in African Americans than in Europeans.[115] 5.7 million (about 9.4%). In six- and seven-year-olds asthma increased from 18.4% to 20.9% over five years, during the same time the rate decreased from 31% to 24.7% in 13- to 14-year-olds. Atopic eczema About 9% of the population. Between 1960 and 1990, prevalence has increased from 3% to 10% in children.[116] 5.8 million (about 1% severe). Anaphylaxis At least 40 deaths per year due to insect venom. About 400 deaths due to penicillin anaphylaxis. About 220 cases of anaphylaxis and 3 deaths per year are due to latex allergy.[117] An estimated 150 people die annually from anaphylaxis due to food allergy.[118] Between 1999 and 2006, 48 deaths occurred in people ranging from five months to 85 years old. Insect venom Around 15% of adults have mild, localized allergic reactions. Systemic reactions occur in 3% of adults and less than 1% of children.[119] Unknown Drug allergies Anaphylactic reactions to penicillin cause 400 deaths per year. Unknown Food allergies About 6% of US children under age 3 and 3.5–4% of the overall US population.[citation needed] Peanut and/or tree nut (e.g. walnut) allergy affects about three million Americans, or 1.1% of the population.[118] 5–7% of infants and 1–2% of adults. A 117.3% increase in peanut allergies was observed from 2001 to 2005, an estimated 25,700 people in England are affected. Multiple allergies (Asthma, eczema and allergic rhinitis together) Unknown 2.3 million (about 3.7%), prevalence has increased by 48.9% between 2001 and 2005.[120] ### Changing frequency[edit] Although genetic factors govern susceptibility to atopic disease, increases in atopy have occurred within too short a time frame to be explained by a genetic change in the population, thus pointing to environmental or lifestyle changes.[109] Several hypotheses have been identified to explain this increased rate; increased exposure to perennial allergens due to housing changes and increasing time spent indoors, and changes in cleanliness or hygiene that have resulted in the decreased activation of a common immune control mechanism, coupled with dietary changes, obesity and decline in physical exercise.[108] The hygiene hypothesis maintains[121] that high living standards and hygienic conditions exposes children to fewer infections. It is thought that reduced bacterial and viral infections early in life direct the maturing immune system away from TH1 type responses, leading to unrestrained TH2 responses that allow for an increase in allergy.[71][122] Changes in rates and types of infection alone however, have been unable to explain the observed increase in allergic disease, and recent evidence has focused attention on the importance of the gastrointestinal microbial environment. Evidence has shown that exposure to food and fecal-oral pathogens, such as hepatitis A, Toxoplasma gondii, and Helicobacter pylori (which also tend to be more prevalent in developing countries), can reduce the overall risk of atopy by more than 60%,[123] and an increased rate of parasitic infections has been associated with a decreased prevalence of asthma.[124] It is speculated that these infections exert their effect by critically altering TH1/TH2 regulation.[125] Important elements of newer hygiene hypotheses also include exposure to endotoxins, exposure to pets and growing up on a farm.[125] ## History[edit] Some symptoms attributable to allergic diseases are mentioned in ancient sources.[126] Particularly, three members of the Roman Julio-Claudian dynasty (Augustus, Claudius and Britannicus) are suspected to have a family history of atopy.[126][127] The concept of "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noticed that patients who had received injections of horse serum or smallpox vaccine usually had quicker, more severe reactions to second injections.[128] Pirquet called this phenomenon "allergy" from the Ancient Greek words ἄλλος allos meaning "other" and ἔργον ergon meaning "work".[129] All forms of hypersensitivity used to be classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[130] With this new classification, the word allergy, sometimes clarified as a true allergy, was restricted to type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions involving IgE antibodies.[131] A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE). IgE was simultaneously discovered in 1966–67 by two independent groups:[132] Ishizaka's team at the Children's Asthma Research Institute and Hospital in Denver, Colorado,[133] and by Gunnar Johansson and Hans Bennich in Uppsala, Sweden.[134] Their joint paper was published in April 1969.[135] ### Diagnosis[edit] Radiometric assays include the radioallergosorbent test (RAST test) method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[136] Other newer methods use colorimetric or fluorescence-labeled technology in the place of radioactive isotopes.[citation needed] The RAST methodology was invented and marketed in 1974 by Pharmacia Diagnostics AB, Uppsala, Sweden, and the acronym RAST is actually a brand name. In 1989, Pharmacia Diagnostics AB replaced it with a superior test named the ImmunoCAP Specific IgE blood test, which uses the newer fluorescence-labeled technology.[citation needed] American College of Allergy Asthma and Immunology (ACAAI) and the American Academy of Allergy Asthma and Immunology (AAAAI) issued the Joint Task Force Report "Pearls and pitfalls of allergy diagnostic testing" in 2008, and is firm in its statement that the term RAST is now obsolete: > The term RAST became a colloquialism for all varieties of (in vitro allergy) tests. This is unfortunate because it is well recognized that there are well-performing tests and some that do not perform so well, yet they are all called RASTs, making it difficult to distinguish which is which. For these reasons, it is now recommended that use of RAST as a generic descriptor of these tests be abandoned.[14] The new version, the ImmunoCAP Specific IgE blood test, is the only specific IgE assay to receive Food and Drug Administration approval to quantitatively report to its detection limit of 0.1kU/l.[citation needed] ## Medical specialty[edit] Allergist/ImmunologistOccupation Names * Physician Occupation type Specialty Activity sectors Medicine Specialtyimmunology Description Education required * Doctor of Medicine (M.D.) * Doctor of Osteopathic medicine (D.O.) * Bachelor of Medicine, Bachelor of Surgery (M.B.B.S.) * Bachelor of Medicine, Bachelor of Surgery (MBChB) Fields of employment Hospitals, Clinics An allergist is a physician specially trained to manage and treat allergies, asthma and the other allergic diseases. In the United States physicians holding certification by the American Board of Allergy and Immunology (ABAI) have successfully completed an accredited educational program and evaluation process, including a proctored examination to demonstrate knowledge, skills, and experience in patient care in allergy and immunology.[137] Becoming an allergist/immunologist requires completion of at least nine years of training. After completing medical school and graduating with a medical degree, a physician will undergo three years of training in internal medicine (to become an internist) or pediatrics (to become a pediatrician). Once physicians have finished training in one of these specialties, they must pass the exam of either the American Board of Pediatrics (ABP), the American Osteopathic Board of Pediatrics (AOBP), the American Board of Internal Medicine (ABIM), or the American Osteopathic Board of Internal Medicine (AOBIM). Internists or pediatricians wishing to focus on the sub-specialty of allergy-immunology then complete at least an additional two years of study, called a fellowship, in an allergy/immunology training program. Allergist/immunologists listed as ABAI-certified have successfully passed the certifying examination of the ABAI following their fellowship.[138] In the United Kingdom, allergy is a subspecialty of general medicine or pediatrics. After obtaining postgraduate exams (MRCP or MRCPCH), a doctor works for several years as a specialist registrar before qualifying for the General Medical Council specialist register. Allergy services may also be delivered by immunologists. A 2003 Royal College of Physicians report presented a case for improvement of what were felt to be inadequate allergy services in the UK.[139] In 2006, the House of Lords convened a subcommittee. It concluded likewise in 2007 that allergy services were insufficient to deal with what the Lords referred to as an "allergy epidemic" and its social cost; it made several recommendations.[140] ## Research[edit] Low-allergen foods are being developed, as are improvements in skin prick test predictions; evaluation of the atopy patch test; in wasp sting outcomes predictions and a rapidly disintegrating epinephrine tablet, and anti-IL-5 for eosinophilic diseases.[141] Aerobiology is the study of the biological particles passively dispersed through the air. One aim is the prevention of allergies due to pollen.[142][143] ## See also[edit] * List of allergens * Allergic shiner * Histamine intolerance * Oral allergy syndrome ## References[edit] 1. ^ a b "Environmental Allergies: Symptoms". NIAID. 22 April 2015. Archived from the original on 18 June 2015. Retrieved 19 June 2015. 2. ^ a b "Types of Allergic Diseases". NIAID. 29 May 2015. Archived from the original on 17 June 2015. 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PMID 2513902. 122. ^ Renz H, Blümer N, Virna S, Sel S, Garn H (2006). "The immunological basis of the hygiene hypothesis". Allergy and Asthma in Modern Society: A Scientific Approach. Chemical Immunology and Allergy. 91. pp. 30–48. doi:10.1159/000090228. ISBN 978-3-8055-8000-7. PMID 16354947. 123. ^ Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M, Bonini S (February 2000). "Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study". BMJ. 320 (7232): 412–17. doi:10.1136/bmj.320.7232.412. PMC 27285. PMID 10669445. 124. ^ Masters S, Barrett-Connor E (1985). "Parasites and asthma--predictive or protective?". Epidemiologic Reviews. 7: 49–58. doi:10.1093/oxfordjournals.epirev.a036285. PMID 4054238. 125. ^ a b Sheikh A, Strachan DP (June 2004). "The hygiene theory: fact or fiction?". Current Opinion in Otolaryngology & Head and Neck Surgery. 12 (3): 232–36. doi:10.1097/01.moo.0000122311.13359.30. PMID 15167035. S2CID 37297207. 126. ^ a b Kürşat Epöztürk; Şefik Görkey (2018). "Were Allergic Diseases Prevalent in Antiquity?". Asthma Allergy Immunol. doi:10.21911/aai.406. Retrieved 22 September 2018. 127. ^ Ring J. (August 1985). "1st description of an "atopic family anamnesis" in the Julio-Claudian imperial house: Augustus, Claudius, Britannicus". Hautarzt. 36 (8): 470–71. PMID 3899999. 128. ^ Clemens Peter Pirquet von Cesenatico at Who Named It? 129. ^ Von Pirquet C (1906). "Allergie". Munch Med Wochenschr. 53 (5): 388–90. PMID 20273584. Reprinted in Von Pirquet C (1946). "Allergie". Annals of Allergy. 4 (5): 388–90. PMID 20273584. 130. ^ Gell PG, Coombs RR (1963). Clinical Aspects of Immunology. London: Blackwell. 131. ^ Szebeni, Janos (8 May 2007). The Complement System: Novel Roles in Health and Disease. Springer Science & Business Media. p. 361. ISBN 978-1-4020-8056-2. 132. ^ Stanworth DR (1993). "The discovery of IgE". Allergy. 48 (2): 67–71. doi:10.1111/j.1398-9995.1993.tb00687.x. PMID 8457034. S2CID 36262710. 133. ^ Ishizaka K, Ishizaka T, Hornbrook MM (July 1966). "Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity". Journal of Immunology. 97 (1): 75–85. PMID 4162440. 134. ^ Johansson SG, Bennich H. Immunological studies of an atypical (myeloma) immunoglobulin" Immunology 1967; 13:381–94. 135. ^ Ishizaka, Teruko; Ishizaka, Kimishige; Johansson, S. Gunnar O.; Bennich, Hans (1 April 1969). "Histamine Release from Human Leukocytes by Anti-λE Antibodies". Journal of Immunology. 102 (4): 884–92. Retrieved 29 February 2016. 136. ^ Ten RM, Klein JS, Frigas E (August 1995). "Allergy skin testing". Mayo Clinic Proceedings. 70 (8): 783–84. doi:10.4065/70.8.783. PMID 7630219. 137. ^ "ABAI: American Board of Allergy and Immunology". Archived from the original on 20 July 2011. Retrieved 5 August 2007. 138. ^ "AAAAI – What is an Allergist?". Archived from the original on 30 November 2010. Retrieved 5 August 2007. 139. ^ Royal College of Physicians (2003). Allergy: the unmet need. London: Royal College of Physicians. ISBN 978-1-86016-183-4. PDF version Archived 28 November 2007 at the Wayback Machine (1.03 MB) 140. ^ House of Lords – Science and Technology Committee (2007). Allergy – HL 166-I, 6th Report of Session 2006–07 – Volume 1: Report. London: TSO (The Stationery Office). ISBN 978-0-10-401149-2. Archived from the original on 29 March 2017. 141. ^ Sicherer SH, Leung DY (June 2007). "Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects". The Journal of Allergy and Clinical Immunology. 119 (6): 1462–69. doi:10.1016/j.jaci.2007.02.013. PMID 17412401. 142. ^ Galán, C., Smith, M., Thibaudon, M., Frenguelli, G., Oteros, J., Gehrig, R., ... & EAS QC Working Group. (2014). Pollen monitoring: minimum requirements and reproducibility of analysis. Aerobiologia, 30(4), 385–395. 143. ^ Oteros J, Galán C, Alcázar P, Domínguez-Vilches E (January 2013). "Quality control in bio-monitoring networks, Spanish Aerobiology Network". The Science of the Total Environment. 443: 559–65. Bibcode:2013ScTEn.443..559O. doi:10.1016/j.scitotenv.2012.11.040. PMID 23220389. ## External links[edit] Classification D * ICD-10: T78.4 * ICD-9-CM: 995.3 * MeSH: D006967 * DiseasesDB: 33481 External resources * MedlinePlus: 000812 * eMedicine: med/1101 Wikimedia Commons has media related to Allergies. Wikivoyage has travel information for Allergies. * Allergy at Curlie * "Allergy". MedlinePlus. U.S. National Library of Medicine. * v * t * e Allergic conditions Respiratory system * Allergic rhinitis (hay fever) * Asthma * Hypersensitivity pneumonitis * Eosinophilic pneumonia * Eosinophilic granulomatosis with polyangiitis * Allergic bronchopulmonary aspergillosis * Farmer's lung * Laboratory animal allergy Skin * Angioedema * Urticaria * Atopic dermatitis * Allergic contact dermatitis * Hypersensitivity vasculitis Blood and immune system * Serum sickness Circulatory system * Anaphylaxis Digestive system * Coeliac disease * Eosinophilic gastroenteritis * Eosinophilic esophagitis * Food allergy * Egg allergy * Milk intolerance Nervous system * Eosinophilic meningitis Genitourinary system * Acute interstitial nephritis Other conditions * Drug allergy * Allergic conjunctivitis * Latex allergy * v * t * e Consequences of external causes Temperature Elevated Hyperthermia Heat syncope Reduced Hypothermia Immersion foot syndromes Trench foot Tropical immersion foot Warm water immersion foot Chilblains Frostbite Aerosol burn Cold intolerance Acrocyanosis Erythrocyanosis crurum Radiation Radiation poisoning Radiation burn Chronic radiation keratosis Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Radiation acne Radiation-induced cancer Radiation recall reaction Radiation-induced erythema multiforme Radiation-induced hypertrophic scar Radiation-induced keloid Radiation-induced morphea Air * Hypoxia/Asphyxia * Barotrauma * Aerosinusitis * Decompression sickness * High altitude * Altitude sickness * Chronic mountain sickness * Death zone * HAPE * HACE Food * Starvation Maltreatment * Physical abuse * Sexual abuse * Psychological abuse Travel * Motion sickness * Seasickness * Airsickness * Space adaptation syndrome Adverse effect * Hypersensitivity * Anaphylaxis * Angioedema * Allergy * Arthus reaction * Adverse drug reaction Other * Electrical injury * Drowning * Lightning injuries Ungrouped skin conditions resulting from physical factors * Dermatosis neglecta * Pinch mark * Pseudoverrucous papules and nodules * Sclerosing lymphangitis * Tropical anhidrotic asthenia * UV-sensitive syndrome environmental skin conditions Electrical burn frictional/traumatic/sports Black heel and palm Equestrian perniosis Jogger's nipple Pulling boat hands Runner's rump Surfer's knots Tennis toe Vibration white finger Weathering nodule of ear Wrestler's ear Coral cut Painful fat herniation Uranium dermatosis iv use Skin pop scar Skin track Slap mark Pseudoacanthosis nigricans Narcotic dermopathy * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex 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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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Allergy	c0020517	6,927	wikipedia	https://en.wikipedia.org/wiki/Allergy	2021-01-18T19:01:20	{"mesh": ["D006967"], "umls": ["C0020517"], "icd-9": ["995.3"], "wikidata": ["Q42982"]}
Marshall syndrome Other namesDeafness, myopia, cataract, saddle nose-Marshall type [1] Marshall syndrome and Stickler syndrome is inherited in an autosomal dominant pattern. Marshall syndrome is a genetic disorder of the connective tissue[2] which can cause hearing loss. The three most common areas to be affected are the eyes which are uncommonly large, joints and the mouth and facial structures. Marshall syndrome and Stickler syndrome closely resemble each other; in fact they are so similar, some say they are the same.[3][4] ## Contents * 1 Presentation * 1.1 Eyes * 1.2 Joints * 1.3 Orofacial Structure * 1.4 Hearing loss * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Presentation[edit] ### Eyes[edit] Myopia is the most common eye problem in Marshall syndrome. Cataracts also occur more frequently and detached retina less frequently than in Stickler syndrome. Myopia also is the most common problem with the eyes in Stickler syndrome. In the latter syndrome, extreme myopia may lead to severe eye problems such as detached retina more frequently than in Marshall syndrome.[citation needed] ### Joints[edit] The joint changes include hyperextensibility (double-jointedness) and arthritis. Babies and young children with Stickler syndrome usually have very hyperextensible joints. As an affected child gets older, they may experience pain and stiffness from overuse of a joint. Osteoarthritis of the large joints often develops during the third or fourth decade. The joint changes in Marshall syndrome are of the same type but to a lesser degree. There also may be changes in the bones that show up on X-ray but generally are not a problem.[citation needed] ### Orofacial Structure[edit] Main article: Pierre Robin syndrome The most severe problem associated with Stickler syndrome is Pierre Robin syndrome. This refers to a cleft palate resulting from a very small lower jaw. During early fetal life, the roof of the mouth is normally open and the sides of the palate have to come together to close. If the jaw is too small, there is not enough room for the tongue which is then pushed up and gets in the way of the closing palate. Sometimes the chin is so small the baby has problems with eating and breathing if the tongue blocks the back of the throat. Cleft palate is found less frequently in Marshall Syndrome than in Stickler syndrome but still more frequently than in the general population.[citation needed] The facial features of Marshall Syndrome include a flat midface, the appearance of large eyes, short upturned nose, and a round face. The facial features of Stickler syndrome are less prominent but include a rather long flat face, and depressed nasal bridge.[citation needed] ### Hearing loss[edit] The hearing loss associated with Stickler syndrome can be progressive and usually involves the high frequencies. Sensorineural hearing loss has been reported in as many as 100% and as low as 20% of affected individuals. A conductive loss due to otitis can magnify an existing sensorineural loss and is a frequent problem for children with Stickler or Marshall Syndrome.[citation needed] ## Genetics[edit] Stickler syndrome and Marshall syndrome have an autosomal dominant pattern of inheritance. However, there is a great deal of variation within and among families with regard to gene expression. Some may be more severely affected and others may be very mildly affected. Often these syndromes are not recognized in a family until a baby is born with Pierre Robin syndrome or some members have detached retinas or cataracts at a young age.[5] Both syndromes where correlated with mutations in the COL11A1 gene.[6] ## Diagnosis[edit] Diagnosis is made based on features as well as by the very early onset of serious eye and ear disease. Because Marshall syndrome is an autosomal dominant hereditary disease, physicians can also note the characteristic appearance of the biological parent of the child. There are no tests for Stickler syndrome or Marshall syndrome. Some families with Stickler syndrome have been shown to have mutations in the Type II collagen gene on chromosome 1. However, other families do not show the linkage to the collagen gene. It is an area of active research, also the genetic testing being expensive supports that the diagnosis is made depending on the features.[citation needed] ## Treatment[edit] There is no medical treatment for either syndrome but there are some recommendations that can help with prevention or early identification of some of the problems. Children with either syndrome should have their hearing tested, and adults should be aware that the hearing loss may not develop until the adult years. Yearly visits to an ophthalmologist or other eye care professional who has been informed of the diagnosis of Stickler or Marshall syndrome is important for all affected individuals. Children should have the opportunity to have myopia corrected as early as possible, and treatment for cataracts or detached retinas may be more effective with early identification. Support for the joints is especially important during sports, and some recommend that contact sports should be avoided by those who have very loose joints.[citation needed] ## References[edit] 1. ^ "Marshall syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 20 June 2019. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. pp. 146–7. ISBN 0-7216-2921-0. 3. ^ Annunen S, Körkkö J, Czarny M, et al. (October 1999). "Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes". Am. J. Hum. Genet. 65 (4): 974–83. doi:10.1086/302585. PMC 1288268. PMID 10486316. 4. ^ Griffith AJ, Sprunger LK, Sirko-Osadsa DA, Tiller GE, Meisler MH, Warman ML (April 1998). "Marshall syndrome associated with a splicing defect at the COL11A1 locus". Am. J. Hum. Genet. 62 (4): 816–23. doi:10.1086/301789. PMC 1377029. PMID 9529347. 5. ^ Annunen S, Korkko J, Czarny M, Warman ML, Brunner HG, Kaariainen H, Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, Curtis MA, Davenport SL, Friedrich CA, Kaitila I, Krawczynski MR, Latos-Bielenska A, Mukai S, Olsen BR, Shinno N, Somer M, Vikkula M, Zlotogora J, Prockop DJ, Ala-Kokko L (1999). "Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes". Am J Hum Genet. 65 (4): 974–83. doi:10.1086/302585. PMC 1288268. PMID 10486316. 6. ^ Majava, Marja (2007). Molecular genetics of Stickler and Marshall syndromes, and the role of collagen II and other candidate proteins in high myopia and impaired hearing. Oulu: Oulun yliopisto. ISBN 978-951-42-8362-8. ## External links[edit] Classification D * OMIM: 154780 * MeSH: C536025 * DiseasesDB: 31965 External resources * Orphanet: 560 * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Marshall syndrome	c0265235	6,928	wikipedia	https://en.wikipedia.org/wiki/Marshall_syndrome	2021-01-18T19:03:04	{"gard": ["6984"], "mesh": ["C536025"], "umls": ["C0265235"], "orphanet": ["560"], "wikidata": ["Q6773846"]}
The eye, like any other optical system, suffers from a number of specific optical aberrations. The optical quality of the eye is limited by optical aberrations, diffraction and scatter.[1] Correction of spherocylindrical refractive errors has been possible for nearly two centuries following Airy's development of methods to measure and correct ocular astigmatism. It has only recently become possible to measure the aberrations of the eye and with the advent of refractive surgery it might be possible to correct certain types of irregular astigmatism. The appearance of visual complaints such as halos, glare and monocular diplopia after corneal refractive surgery has long been correlated with the induction of optical aberrations. Several mechanisms may explain the increase in the amount of higher-order aberrations with conventional eximer laser refractive procedures: a change in corneal shape toward oblateness or prolateness (after myopic and hyperopic ablations respectively), insufficient optical zone size and imperfect centration. These adverse effects are particularly noticeable when the pupil is large.[2] ## Contents * 1 Wavefront approach to aberrations of the eye * 2 Aberration of normal eyes * 3 Low order aberrations * 4 High order aberrations * 5 Assessment and quantitative expression of ocular aberrations * 5.1 Assessment * 5.2 Quantitative expression * 5.2.1 RMS * 5.2.2 Zernike polynomials * 6 Management * 7 See also * 8 References ## Wavefront approach to aberrations of the eye[edit] The flat wavefronts change to spherical wavefronts as they pass through a pinhole A wavefront is a surface over which an optical disturbance has a constant phase. Rays and wavefronts are two mutually complementary approaches to light propagation. Wavefronts are always normal (perpendicular) to the rays. For light to converge to a perfect point, the wavefront emerging from the optical system must be a perfect sphere centered on the image point. The distance in micrometers between the actual wavefront and the ideal wavefront is the wavefront aberration, which is the standard method of showing the aberrations of the eye. Therefore, aberrations of the eye are the difference between two surfaces: the ideal and the actual wavefront. ## Aberration of normal eyes[edit] In normal population the dominant aberrations are the ordinary second-order spherocylindrical focus errors, which are called refractive errors. Higher order aberrations are a relatively small component, comprising about 10% of the eye's total aberrations.[3] High order aberrations increase with age and mirror symmetry exists between the right and the left eyes.[4] Several studies have reported a compensation of the aberration of the cornea by the aberration of the crystalline lens. The spherical aberration of the cornea is usually positive whereas the young crystalline lens exhibits a negative spherical aberration. Besides, there is strong evidence of compensation for aberrations between the cornea and intraocular optics in cases of astigmatism (horizontal/vertical) and horizontal coma. The balance of corneal and internal aberrations is a typical example of creating two coupling optical systems.[5] The accommodative response of the eye results in changes to the lens shape and substantially affects the wavefront aberration pattern. Most eyes show positive spherical aberration when unaccomodated with a trend toward negative spherical aberration on accommodation.[1] ## Low order aberrations[edit] Low order aberrations include Myopia (positive defocus), hyperopia (negative defocus), and regular astigmatism. Other lower-order aberrations are non- visually significant aberrations known as first order aberrations, such as prisms and zero-order aberrations (piston). Low order aberrations account for approximately 90% of the overall wave aberration in the eye.[5][6] ## High order aberrations[edit] This section appears to contradict itself on spherical aberration dependence on pupil size - is it to the second or fourth power?. Please see the talk page for more information. (June 2019) Spherical aberration. A perfect lens (top) focuses all incoming rays to a point on the Optical axis. In spherical aberration (Bottom) peripheral rays are focused more tightly than central rays. There are numerous higher-order aberrations, of which only spherical aberration, coma and trefoil are of clinical interest. Spherical aberration is the cause of night myopia and is commonly increased after myopic LASIK and surface ablation. It results in halos around point images. Spherical aberration exacerbates myopia in low light (night myopia). In brighter conditions, the pupil constricts, blocking the more peripheral rays and minimizing the effect of spherical aberration. As the pupil enlarges, more peripheral rays enter the eye and the focus shifts anteriorly, making the patient slightly more myopic in low-light conditions. In general, the increase in overall wave aberration with pupil size has been reported to increase to approximately the second power of the pupil radius. This is because of the fact that most wave aberration is due to 2nd order aberrations, which have a square radius dependency.[5] The effect of spherical aberration increases as the fourth power of the pupil diameter. Doubling pupil diameter increases spherical aberration 16 times.[7] Thus, a small change in pupil size can cause a significant change in refraction. This possibility should be considered in patients who have fluctuating vision despite well-healed corneas following keratorefractive surgery. Coma is common in patients with decentred corneal grafts, keratoconus, and decentred laser ablations. Trefoil produces less degradation in image quality compared with coma of similar RMS magnitude.[6] ## Assessment and quantitative expression of ocular aberrations[edit] ### Assessment[edit] Illustration of Shack-Hartmann system Many techniques for measuring the eye's aberrations have been described, The most common technique is Shack-Hartmann aberrometry. Other methods include Tscherning systems, ray tracing and Skiascopy methods.[2][8] ### Quantitative expression[edit] #### RMS[edit] Quantitative comparisons between different eyes and conditions are usually made using RMS (root mean square). To measure RMS for each type of aberration involves squaring the difference between the aberration and mean value and averaging it across the pupil area. Different kinds of aberrations may have equal RMS across the pupil but have different effects on vision, therefore, RMS error is unrelated to visual performance. The majority of eyes have total RMS values less than 0.3 µm.[6] #### Zernike polynomials[edit] The most common method of classifying the shapes of aberration maps is to consider each map as the sum of fundamental shapes or basis functions. One popular set of basis functions are the Zernike polynomials.[2] Each aberration may be positive or negative in value and induces predictable alterations in the image quality.[9] Because there is no limit to the number of terms that may be used by Zernike polynomials, vision scientists use the first 15 polynomials, based on the fact that they are enough to obtain a highly accurate description of the most common aberrations found in human eye.[10] Among these the most important Zernike coefficients affecting visual quality are coma, spherical aberration, and trefoil.[6] Zernike polynomials are usually expressed in terms of polar coordinates (ρ,θ), where ρ is radial coordinate and θ is the angle. The advantage of expressing the aberrations in terms of these polynomials includes the fact that the polynomials are independent of one another. For each polynomial the mean value of the aberration across the pupil is zero and the value of the coefficient gives the RMS error for that particular aberration (i.e. the coefficients show the relative contribution of each Zernike mode to the total wavefront error in the eye).[4] However these polynomials have the disadvantage that their coefficients are only valid for the particular pupil diameter they are determined for. In each Zernike polynomial Z n m {\displaystyle Z_{n}^{m}} , the subscript n is the order of aberration, all the Zernike polynomials in which n=3 are called third-order aberrations and all the polynomials with n=4, fourth order aberrations and so on. Z 4 2 {\displaystyle Z_{4}^{2}} and Z 4 − 2 {\displaystyle Z_{4}^{-2}} are usually called secondary Astigmatism and should not cause confusion. The superscript m is called the angular frequency and denotes the number of times the Wavefront pattern repeats itself.[4] List of Zernike modes and their common names:[11] Plots of Zernike polynomials in the unit disk Zernike Term Name Z 0 0 {\displaystyle Z_{0}^{0}} Piston Z 1 1 {\displaystyle Z_{1}^{1}} , Z 1 − 1 {\displaystyle Z_{1}^{-1}} Tilt (Prism) Z 2 0 {\displaystyle Z_{2}^{0}} Defocus Z 2 2 {\displaystyle Z_{2}^{2}} , Z 2 − 2 {\displaystyle Z_{2}^{-2}} Astigmatism Z 4 2 {\displaystyle Z_{4}^{2}} , Z 4 − 2 {\displaystyle Z_{4}^{-2}} Secondary Astigmatism Z 4 0 {\displaystyle Z_{4}^{0}} Spherical aberration Z 3 1 {\displaystyle Z_{3}^{1}} , Z 3 − 1 {\displaystyle Z_{3}^{-1}} Coma Z 3 3 {\displaystyle Z_{3}^{3}} , Z 3 − 3 {\displaystyle Z_{3}^{-3}} Trefoil Z 4 4 {\displaystyle Z_{4}^{4}} , Z 4 − 4 {\displaystyle Z_{4}^{-4}} Quadrafoil ## Management[edit] Low order aberrations (hyperopia, Myopia and regular astigmatism), are correctable by eyeglasses, soft contact lenses and refractive surgery. Neither spectacles nor soft contact lenses nor routine keratorefractive surgery adequately corrects high order aberrations. Significant high order aberration usually requires a rigid gas-permeable contact lens for optimal visual rehabilitation.[6] Customized Wavefront-guided refractive corneal laser treatments are designed to reduce existing aberrations and to help prevent the creation of new aberrations.[6] The wavefront map of the eye may be transferred to a Lasik system and enable the surgeon to treat the aberration. Perfect alignment of the treatment and the pupil on which the Wavefront is measured is required, which is usually achieved through iris feature detection. An efficient eye tracking system and small spot size laser is necessary for treatment . Wavefront customization of ablation increases the depth of ablation because additional corneal tissue must be ablated to compensate for the high order aberrations.[2] Actual results with Wavefront guided LASIK showed that not only it cannot remove HOA but also the optical aberrations are increased. However, the amount of increase in aberrations are less than conventional Lasik.[12] Corneal optical aberrations after photorefractive keratectomy with a larger ablation zone and a transition zone are less pronounced and more physiologic than those associated with first-generation (5 mm) ablations with no transition zone.[13] An upcoming systematic review will seek to compare the safety and effectiveness of wavefront excimer laser refractive surgery with conventional excimer laser refractive surgery, and will measure differences in residual higher order aberrations between the two procedures.[14] Aspherical intraocular lenses (IOLs) have been used clinically to compensate for positive corneal spherical aberrations. Although Aspherical IOLs may give better contrast sensitivity, it is doubtful, whether they have a beneficial effect on distance visual acuity. Conventional (not Aspherical) IOLs give better depth of focus and better near vision. The reason for improved depth of focus in conventional lenses is linked to residual spherical aberration. The small improvement in depth of focus with the conventional IOLs enhances uncorrected near vision and contribute to reading ability.[15] Wavefront customized lenses can be used in eyeglasses. Based on Wavefront map of the eye and with the use of laser a lens is shaped to compensate for the aberrations of the eye and then put in the eyeglasses. Ultraviolet Laser can alter the refractive index of curtain lens materials such as epoxy polymer on a point by point basis in order to generate the desired refractive profile.[1] Wavefront customized contact lenses can theoretically correct HOA. The rotation and decentration reduces the predictability of this method.[1] ## See also[edit] * Optical aberrations * Wavefront * Zernike polynomials ## References[edit] 1. ^ a b c d Cerviño, A; Hosking, SL; Montes-Mico, R; Bates, K (Jun 2007). "Clinical ocular wavefront analyzers". Journal of Refractive Surgery. 23 (6): 603–16. doi:10.3928/1081-597X-20070601-12. PMID 17598581. 2. ^ a b c d Dimitri T. Azar; Damien Gatinel; Thang Hoang-Xuan (2007). Refractive surgery (2nd ed.). Philadelphia: Mosby Elsevier. ISBN 978-0-323-03599-6. 3. ^ Lawless, MA; Hodge, C (Apr 2005). "Wavefront's role in corneal refractive surgery". Clinical & Experimental Ophthalmology. 33 (2): 199–209. doi:10.1111/j.1442-9071.2005.00994.x. PMID 15807834. S2CID 39844061. 4. ^ a b c Charman, WN (Jun 2005). "Wavefront technology: past, present and future". Contact Lens & Anterior Eye : The Journal of the British Contact Lens Association. 28 (2): 75–92. doi:10.1016/j.clae.2005.02.003. PMID 16318838. 5. ^ a b c Lombardo, M; Lombardo, G (Feb 2010). "Wave aberration of human eyes and new descriptors of image optical quality and visual performance". Journal of Cataract and Refractive Surgery. 36 (2): 313–31. doi:10.1016/j.jcrs.2009.09.026. PMID 20152616. 6. ^ a b c d e f Basic and Clinical Science Course, Section 13: Refractive Surgery (2011-2012. ed.). American Academy of Ophthalmology. 2011–2012. pp. 7–9. ISBN 978-1615251209. 7. ^ Basic and Clinical Science Course, Section 3: Clinical Optics (2011-2012 last major rev. 2010-2012. ed.). American Academy of Ophthalmology. 2011–2012. p. 100. ISBN 978-1615251100. 8. ^ Myron Yanoff; Jay S. Duker (2009). Ophthalmology (3rd ed.). Mosby Elsevier. p. 104. ISBN 978-0-323-04332-8. 9. ^ Applegate, RA; Thibos, LN; Hilmantel, G (Jul 2001). "Optics of aberroscopy and super vision". Journal of Cataract and Refractive Surgery. 27 (7): 1093–107. CiteSeerX 10.1.1.597.7451. doi:10.1016/s0886-3350(01)00856-2. PMID 11489582. S2CID 29323497. 10. ^ Thibos, LN; Applegate, RA; Schwiegerling, JT; Webb, R (Sep–Oct 2000). "Report from the VSIA taskforce on standards for reporting optical aberrations of the eye". Journal of Refractive Surgery. 16 (5): S654–5. PMID 11019893. 11. ^ Wyant, James C. "Zernike Polynomials". 12. ^ Kohnen, T; Bühren, J; Kühne, C; Mirshahi, A (Dec 2004). "Wavefront-guided LASIK with the Zyoptix 3.1 system for the correction of myopia and compound myopic astigmatism with 1-year follow-up: clinical outcome and change in higher order aberrations". Ophthalmology. 111 (12): 2175–85. doi:10.1016/j.ophtha.2004.06.027. PMID 15582071. 13. ^ Endl, MJ; Martinez, CE; Klyce, SD; McDonald, MB; Coorpender, SJ; Applegate, RA; Howland, HC (Aug 2001). "Effect of larger ablation zone and transition zone on corneal optical aberrations after photorefractive keratectomy". Archives of Ophthalmology. 119 (8): 1159–64. doi:10.1001/archopht.119.8.1159. PMID 11483083. 14. ^ Li SM, Kang MT, Zhou Y, Wang NL, Lindsley K (2017). "Wavefront excimer laser refractive surgery for adults with refractive errors". Cochrane Database Syst Rev. 6: CD012687. doi:10.1002/14651858.CD012687. PMC 6481747. 15. ^ Nanavaty, MA; Spalton, DJ; Boyce, J; Saha, S; Marshall, J (Apr 2009). "Wavefront aberrations, depth of focus, and contrast sensitivity with aspheric and spherical intraocular lenses: fellow-eye study". Journal of Cataract and Refractive Surgery. 35 (4): 663–71. doi:10.1016/j.jcrs.2008.12.011. PMID 19304086. S2CID 10016253. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Aberrations of the eye	c2717990	6,929	wikipedia	https://en.wikipedia.org/wiki/Aberrations_of_the_eye	2021-01-18T18:58:47	{"mesh": ["D057108"], "umls": ["C2717990"], "wikidata": ["Q16001403"]}
Severe neonatal-onset encephalopathy with microcephaly is a rare monogenic disease with epilepsy characterized by neonatal-onset encephalopathy, microcephaly, severe developmental delay or absent development, breathing abnormalities (including central hypoventilation and/or respiratory insufficiency), intractable seizures, abnormal muscle tone and involuntary movements. Early death is usual. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Severe neonatal-onset encephalopathy with microcephaly	c1968556	6,930	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=209370	2021-01-23T17:11:29	{"mesh": ["C566878"], "omim": ["300673"], "icd-10": ["Q02"], "synonyms": ["Severe congenital encephalopathy due to MECP2 mutation"]}
A rare inflammatory optic neuropathy characterized by isolated episodes (either single or recurrent) of optic neuritis not associated with other neurological or systemic disease. Patients typically present with subacute unilateral loss of vision progressing over several days to two weeks, periocular pain and pain on eye movement (which may precede the onset of visual symptoms), light flashes on eye movement, abnormal color vision, reduced contrast sensitivity, and relative afferent pupillary defect. The optic disc appears swollen in many patients, and uveitis may be associated and can be present for years before the onset of optic neuritis. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Isolated optic neuritis	None	6,931	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=499096	2021-01-23T17:31:19	{"synonyms": ["ION"]}
Parkinsonism with dementia of Guadeloupe is characterised by symmetrical bradykinesia, predominantly axial rigidity, postural instability with early falls and cognitive decline with prominent features of frontal lobe dysfunction. ## Epidemiology Prevalence is unknown, but a higher number of cases have been described in the French West Indies. ## Etiology This form of atypical parkinsonism may be related to exposure to tropical plants containing mitochondrial complex I inhibitors. ## Differential diagnosis Guadelupian parkinsonism may actually be a tauopathy identical or closely related to progressive supranuclear palsy (see this term). ## Management and treatment Most patients are L-dopa unresponsive. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Caribbean parkinsonism	None	6,932	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97355	2021-01-23T18:49:34	{"icd-10": ["F02.3*", "G20+"], "synonyms": ["Atypical parkinsonism in the Caribbean"]}
Postarthroscopic glenohumeral chondrolysis Human shoulder(joint) SpecialtyOrthopedic Risk factorsComplication of arthroscopic surgery Postarthroscopic glenohumeral chondrolysis (PAGCL) is a rare complication of arthroscopic surgery and involves chondrolysis wherein the articular cartilage of the shoulder undergoes rapid, degenerative changes shortly after arthroscopic surgery.[1] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 References ## Causes[edit] Bupivacaine, lidocaine, ropivacaine and levobupivacaine are all toxic to cartilage and their intra-articular infusions can lead to this toxic effect.[2] Intra-articular pain pumps with local anesthetics have been implicated as a potential cause.[3] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] Total Joint Arthroplasty or reverse total joint arthroplasty (shoulder replacement surgery)[citation needed] ## References[edit] 1. ^ Yeh, PC; Kharrazi, FD (February 2012). "Postarthroscopic glenohumeral chondrolysis". The Journal of the American Academy of Orthopaedic Surgeons. 20 (2): 102–12. doi:10.5435/JAAOS-20-02-102. PMID 22302448. S2CID 11304366. 2. ^ Gulihar, Abhinav; Robati, Shibby; Twaij, Haider; Salih, Alan; Taylor, Grahame J.S. (December 2015). "Articular cartilage and local anaesthetic: A systematic review of the current literature". Journal of Orthopaedics. 12 (Suppl 2): S200–S210. doi:10.1016/j.jor.2015.10.005. PMC 4796530. PMID 27047224. 3. ^ Busfield, Benjamin T.; Romero, Denise M.; Korshad, Daniel; Kharrazi, F. Daniel (June 2014). "Subacromial pain pump use is safe after arthroscopic rotator cuff repair". Journal of Orthopaedics. 11 (2): 64–67. doi:10.1016/j.jor.2014.04.012. PMC 4118566. PMID 25104887. * v * t * e Bone and joint disease Bone Inflammation endocrine: * Osteitis fibrosa cystica * Brown tumor infection: * Osteomyelitis * Sequestrum * Involucrum * Sesamoiditis * Brodie abscess * Periostitis * Vertebral osteomyelitis Metabolic * Bone density * Osteoporosis * Juvenile * Osteopenia * Osteomalacia * Paget's disease of bone * Hypophosphatasia Bone resorption * Osteolysis * Hajdu–Cheney syndrome * Ainhum * Gorham's disease Other * Ischaemia * Avascular necrosis * Osteonecrosis of the jaw * Complex regional pain syndrome * Hypertrophic pulmonary osteoarthropathy * Nonossifying fibroma * Pseudarthrosis * Stress fracture * Fibrous dysplasia * Monostotic * Polyostotic * Skeletal fluorosis * bone cyst * Aneurysmal bone cyst * Hyperostosis * Infantile cortical hyperostosis * Osteosclerosis * Melorheostosis * Pycnodysostosis Joint Chondritis * Relapsing polychondritis Other * Tietze's syndrome Combined Osteochondritis * Osteochondritis dissecans Child leg: * hip * Legg–Calvé–Perthes syndrome * tibia * Osgood–Schlatter disease * Blount's disease * foot * Köhler disease * Sever's disease spine * * Scheuermann's_disease arm: * wrist * Kienböck's disease * elbow * Panner disease * v * t * e Inflammation Symptoms * Flushing (Rubor) * Fever (Calor) * Swelling (Tumor) * Pain (Dolor) * Malaise Mechanism Acute Plasma-derived mediators * Bradykinin * complement * C3 * C5a * MAC * coagulation * Factor XII * Plasmin * Thrombin Cell-derived mediators preformed: * Lysosome granules * biogenic amines * Histamine * Serotonin synthesized on demand: * cytokines * IFN-γ * IL-8 * TNF-α * IL-1 * eicosanoids * Leukotriene B4 * Prostaglandins * Nitric oxide * Kinins Chronic * Macrophage * Epithelioid cell * Giant cell * Granuloma Other * Acute-phase reaction * Vasodilation * Increased vascular permeability * Exudate * Leukocyte extravasation * Chemotaxis Tests * Full blood count * Leukocytosis * C-reactive protein * Erythrocyte sedimentation rate General * Lymphadenopathy * List of inflammed body part states This article about a disease of musculoskeletal and connective tissue 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Postarthroscopic glenohumeral chondrolysis	None	6,933	wikipedia	https://en.wikipedia.org/wiki/Postarthroscopic_glenohumeral_chondrolysis	2021-01-18T18:45:25	{"umls": ["CL468858"], "wikidata": ["Q30314857"]}
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: "Ochronosis" – news · newspapers · books · scholar · JSTOR (December 2007) (Learn how and when to remove this template message) Ochronosis Homogentisic acid SpecialtyEndocrinology Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the affected tissues appear bluish-grey because of a light-scattering phenomenon known as the Tyndall effect. The condition is most often associated with alkaptonuria, but can occur from exogenous administration of phenol complexes such as hydroquinone. It was first described by Rudolf Virchow in 1865.[1] ## Contents * 1 Types * 2 Signs and symptoms * 3 Causes * 4 Pathophysiology * 5 Diagnosis * 6 Treatment * 7 See also * 8 References * 9 External links ## Types[edit] The two types of ochronosis are endogenous and exogenous. The endogenous variety is an autosomal-recessive disease, known as alkaptonuria, that is caused by a lack of homogentisate oxidase enzyme.[2] Exogenous ochronosis is an avoidable dermatitis that can be caused by the topical application of compounds such as hydroquinone or phenols.[2] It was first seen in 1912, when a patient who used phenol on a leg ulcer was found by Beddard and Plumtre to have this condition.[3] Hydroquinone-induced exogenous ochronosis was found in 1975 by Findlay, who observed the condition in patients who used skin lightening creams containing the compound.[4] The three clinical stages of exogenous ochronosis are:[5] 1. Erythema and mild hyperpigmentation 2. Hyperpigmentation and "caviar-like" lesions 3. Papulonodular lesions ## Signs and symptoms[edit] * Skin: The pigment is deposited throughout the skin, but only becomes apparent in certain locations, where the concentration is great enough to be seen clinically. This usually occurs in areas where connective tissue is thick (joints, tympanic membrane) or close to the surface of the skin (thenar and hypothenar eminences and the sides of the fingers). In exogenous ochronosis, the hyperpigmentation is localized to the area where the inciting agent is applied. Intradermal nevi can appear like blue nevi. * Eye: Ocular manifestations are frequent in patients with ochronosis; most commonly hyperpigmentation of the sclera, primarily observed symmetrically to both sides of the cornea within the palpebral fissure. Furthermore, brown pigment spots in the limbus are generally considered pathognomonic. These ocular signs generally occur early in the development of the disease and can serve as a valuable diagnostic feature of the disease.[6] * Cartilage: Darkening and hardening of ear cartilage is a prominent feature of ochronosis. Nasal cartilage is also frequently involved. The voice can be affected by hardening of the laryngeal cartilage. Stiffening of the ribs with decreased lung function has also been reported. The intervertebral cartilage is also more prone to herniation. * Connective tissue: Hardening of tendons and ligaments can predispose them to rupture. Color changes in the joints can be observed clinically. Arthropathy is common due to chronic inflammation and microruptures. * Heart valves: Stenosis can results from the increased rigidity of the connective tissue as well as chronic inflammation.[1] Symptoms of exogenous ochronosis include:[7] 1. Yellow-brown, banana-shaped fibers 2. Caviar-like papules 3. Brown-grey or blue-black hyperpigmentation Most of the lesions are seen on areas of the body that get the most sun.[2] ## Causes[edit] Exogenous ochronosis can be caused from long-term use of certain "skin-lightening" products, even if the hydroquinone is in amounts as small as 2%.[2] Skin-lightening products are still prevalent in many parts of the world.[8] This may be due to aesthetic or social-standing reasons, in areas where a lighter skin tone is considered to be a sign of wealth or beauty.[8] Also, skin-lightening creams containing compounds such as hydroquinone are commonly used to help with hyperpigmentation disorders such as melasma.[9] Hydroquinone is the compound most frequently used in skin-whitening products. Due to concerns about its side effects, it was almost banned by the FDA in 2006, as medical issues of carcinogenicity and reports of disfiguring ochronosis existed.[10] In the European Union hydroquinone has been banned in cosmetic creams since 2000.[11] Long-term use of creams containing this compound may lead to exogenous ochronotic lesions. The duration of use is directly proportional to the risk of developing the condition, with most cases occurring after years of use.[2] Around 10–15 million skin lightening products are sold annually, with Japan being the major buyer.[12] ## Pathophysiology[edit] Ochronosis occurs because of deposition of phenols (such as homogentisic acid and hydroquinone) as plaques in the matrix of cartilage. The pigments can also be incorporated into collagen and elastin fibers. In the skin, the pigment alters the structure of the fibers, causing enlargement and curling. The embedded pigments also form crosslinks with pigment depositions in adjacent fibers, stabilizing and reducing the elastic recoil of the fibers. This results in hardening of elastic structures, increasing their rigidity and brittleness. Once ruptured, the exposed pigments cause a foreign body reaction and inflammation. This pigment deposition also invokes deposition of hydroxyapatite, the mineral responsible for bone calcification, further hardening the connective tissue. The pigment can also be excreted by glandular cells in apocrine and ceruminous sweat glands, as well as breast and prostate tissue. This results in darkly pigmented sweat and breast milk. Excretion of the pigment is only found in endogenous ochronosis and should not occur from topical phenols. Pathophysiology of alcaptonuria is due to the absence of functional homogentisate dioxygenase in the liver. ## Diagnosis[edit] This section is empty. You can help by adding to it. (April 2018) The diagnosis is often made as an incidental finding intraoperatively. Cartilage exposed to the air turns dark gray or black within minutes. ## Treatment[edit] Treatment is predominantly preventive. Avoidance of topical phenols and diets low in tyrosine may help.[citation needed] Replacement and repair of damaged tissue is also possible. Hydroquinone-induced exogenous ochronosis is an avoidable dermatosis that is exceedingly difficult to treat. However, some studies show that treatment may be possible with a Q-switched alexandrite (755 nm) laser.[13] Individuals with this disorder are recommended to stop using hydroquinone-containing compounds.[2] Awareness of this is important, as dermatologists may think the symptoms a patient is exhibiting are a melasma, and prescribe a hydroquinone-containing cream.[13] ## See also[edit] * Alkaptonuria * Tyrosinemia * Phenylketonuria * List of cutaneous conditions ## References[edit] 1. ^ a b Findlay GH, et al. Ochronosis. Clinics in Dermatology 1989;7:28-35 2. ^ a b c d e f Charlín, R., Barcaui, C. B., Kac, B. K., Soares, D. B., Rabello-Fonseca, R. and Azulay-Abulafia, L. (2008), Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. International Journal of Dermatology, 47: 19–23. doi:10.1111/j.1365-4632.2007.03351.x 3. ^ Beddard AP, Plumtre CM. "A further note on ochronosis associated with carboluria". Q S Med 1912; 5: 505–507. 4. ^ FINDLAY, G., MORRISON, J. and SIMSON, I. (1975), Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams. British Journal of Dermatology, 93: 613–622. doi:10.1111/j.1365-2133.1975.tb05110.x 5. ^ Dogliotte M, Leibowitz M. "Granulomatous ochronosis – a cosmetic- induced skin disorder in blacks". S Afr Med J 1979; 56: 757–760. 6. ^ Linder, Moritz; Bertelmann, Thomas (2014). "On the ocular findings in ochronosis: a systematic review of the literature". BMC Ophthalmology. 14: 12–19. doi:10.1186/1471-2415-14-12. PMC 3915032. PMID 24479547. 7. ^ Olumide, Y. M., Akinkugbe, A. O., Altraide, D., Mohammed, T., Ahamefule, N., Ayanlowo, S., Onyekonwu, C. and Essen, N. (2008), Complications of chronic use of skin lightening cosmetics. International Journal of Dermatology, 47: 344–353. doi:10.1111/j.1365-4632.2008.02719.x 8. ^ a b Joan Baxter (18 April 2000). "BBC News - AFRICA - The heavy cost of light skin". BBC.co.uk. Retrieved 9 January 2017. 9. ^ Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for melasma. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD003583. doi:10.1002/14651858.CD003583.pub2. 10. ^ Toombs, E. L. (2007), Hydroquinone – what is it's [sic] future?. Dermatologic Therapy, 20: 149–156. doi:10.1111/j.1529-8019.2007.00128.x 11. ^ "Skin lightening products - The Facts About - CTPA". TheFactsAbout.co.uk. Retrieved 9 January 2017. 12. ^ Leah Armstrong. "Global skin lightening market predicted to reach $10 billion by 2015 – WHITERskin". WhiterSkin.info. Archived from the original on 26 January 2017. Retrieved 9 January 2017. 13. ^ a b Bellew, S. G. and Alster, T. S. (2004), Treatment of Exogenous Ochronosis With a Q-Switched Alexandrite (755 nm) Laser. Dermatologic Surgery, 30: 555–558. doi:10.1111/j.1524-4725.2004.30177.x ## External links[edit] Classification D * ICD-10: E70.2 (ILDS E70.230) * ICD-9-CM: 270.2 * MeSH: D009794 * DiseasesDB: 409 External resources * eMedicine: derm/476 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Ochronosis	c0028817	6,934	wikipedia	https://en.wikipedia.org/wiki/Ochronosis	2021-01-18T19:07:51	{"gard": ["7231"], "mesh": ["D009794"], "umls": ["C0028817"], "icd-9": ["270.2"], "wikidata": ["Q1507609"]}
Wolff et al. (1994) described 2 severely retarded brothers, the only children of consanguineous Italian parents, with severe mental retardation, striking and very similar facial features, and other anomalies. The faces were characterized by a broad nasal bridge, bulbous nose, upward slanting palpebral fissures, microretrognathia, low anterior hairline, and large ears with an incompletely developed upper helix. In addition, both brothers had type II hypospadias, limb contractures, and delayed bone age. Pictures of the patients as infants and as young adults were presented. One brother had a bilateral cleft lip with cleft palate and cryptorchidism, and developed scoliosis during adolescence. The other had bilateral inguinal hernias and strabismus. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	WOLFF MENTAL RETARDATION SYNDROME	c1848439	6,935	omim	https://www.omim.org/entry/277990	2019-09-22T16:21:10	{"mesh": ["C537448"], "omim": ["277990"], "orphanet": ["3080"]}
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: "Tick-borne encephalitis" – news · newspapers · books · scholar · JSTOR (January 2010) (Learn how and when to remove this template message) Tick-borne meningoencephalitis Infected countries/areas in Eurasia SpecialtyInfectious disease Tick-borne encephalitis (TBE) is a viral infectious disease involving the central nervous system. The disease most often manifests as meningitis, encephalitis, or meningoencephalitis. Long-lasting or permanent neuropsychiatric consequences are observed in 10 to 20% of infected patients. The number of reported cases has been increasing in most countries.[1] TBE is posing a concerning health challenge to Europe, as the number of reported human cases of TBE in all endemic regions of Europe have increased by almost 400% within the last three decades.[2] The tick-borne encephalitis virus is known to infect a range of hosts including ruminants, birds, rodents, carnivores, horses, and humans. The disease can also be spread from animals to humans, with ruminants and dogs providing the principal source of infection for humans.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Transmission * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Symptoms of TBE-infection The disease typically follows a biphasic pattern in 72–87% of patients and the median incubation period is 8 days (range, 4–28 days) after tick bite. Non-speciﬁc symptoms of mild fever, malaise, headache, nausea, vomiting and myalgias may be present as ﬁrst manifestation of the disease and spontaneously resolve within 1 week. After another week the patient may develop neurological symptoms.[4] The virus can result in long neurological symptoms, infecting the brain (encephalitis), the meninges (meningitis) or both (meningoencephalitis).[5] In general, mortality is 1% to 2%, with deaths occurring 5 to 7 days after the onset of neurologic signs. In dogs, the disease also manifests as a neurological disorder with signs varying from tremors to seizures and death.[3] In ruminants, neurological disease is also present, and animals may refuse to eat, appear lethargic, and also develop respiratory signs.[3] ## Cause[edit] TBE is caused by tick-borne encephalitis virus, a member of the genus Flavivirus in the family Flaviviridae. It was first isolated in 1937. Three virus sub-types also exist: European or Western tick-borne encephalitis virus (transmitted by Ixodes ricinus), Siberian tick-borne encephalitis virus (transmitted by I. persulcatus), and Far-Eastern tick-borne encephalitis virus, formerly known as Russian spring summer encephalitis virus (transmitted by I. persulcatus).[2][6] Russia and Europe report about 5,000–7,000 human cases annually.[1][7] The former Soviet Union conducted research on tick-borne diseases, including the TBE viruses. ### Transmission[edit] Sheep ticks (Ixodes ricinus), such as this engorged female, transmit the disease It is transmitted by the bite of several species of infected woodland ticks, including Ixodes scapularis, I. ricinus and I. persulcatus,[8] or (rarely) through the non-pasteurized milk of infected cows.[9] Infection acquired through goat milk consumed as raw milk or raw cheese (Frischkäse) has been documented in 2016 and 2017 in the German state of Baden-Württemberg. None of the infected had neurological disease.[10] ## Diagnosis[edit] Detection of specific IgM and IgG antibodies in patients sera combined with typical clinical signs, is the principal method for diagnosis. In more complicated situations, e.g. after vaccination, testing for presence of antibodies in cerebrospinal fluid may be necessary.[11] PCR (Polymerase Chain Reaction) method is rarely used, since TBE virus RNA is most often not present in patient sera or cerebrospinal fluid at the time of clinical symptoms. ## Prevention[edit] A sign in Lithuanian forest, warning about a high probability to be infected by tick-borne encephalitis Prevention includes non-specific (tick-bite prevention, tick checks) and specific prophylaxis in the form of a vaccination. Tick-borne encephalitis vaccines are very effective and available in many disease endemic areas and in travel clinics.[12] Trade names are Encepur N[13] and FSME-Immun CC.[14] ## Treatment[edit] There is no specific antiviral treatment for TBE. Symptomatic brain damage requires hospitalization and supportive care based on syndrome severity. Anti-inflammatory drugs, such as corticosteroids, may be considered under specific circumstances for symptomatic relief. Tracheal intubation and respiratory support may be necessary. ## Epidemiology[edit] As of 2011, the disease was most common in Central and Eastern Europe, and Northern Asia. About ten to twelve thousand cases are documented a year but the rates vary widely from one region to another.[15] Most of the variation has been the result of variation in host population, particularly that of deer. In Austria, an extensive free vaccination program since the 1960s reduced the incidence in 2013 by roughly 85%.[16] In Germany, during the 2010s, there have been a minimum of 95 (2012) and a maximum of 584 cases (2018) of TBE (or FSME as it is known in German). More than half of the reported cases from 2019 had meningitis, encephalitis or myelitis. The risk of infection was noted to be increasing with age, especially in people older than 40 years and it was greater in men than women. Most cases were acquired in Bavaria (46%) and Baden-Württemberg (37%), much less in Saxonia, Hesse, Niedersachsen and other states. Altogether 164 Landkreise are designated FSME-risk areas, including all of Baden-Württemberg except for the city of Heilbronn.[10] In Sweden, most cases of TBE occur in a band running from Stockholm to the west, especially around lakes and the nearby region of the Baltic sea.[17][18] It reflects the greater population involved in outdoor activities in these areas. Overall, for Europe, the estimated risk is roughly 1 case per 10,000 human-months of woodland activity. Although in some regions of Russia and Slovenia, the prevalence of cases can be as high as 70 cases per 100,000 people per year.[16][19] Travelers to endemic regions do not often become cases, with only 5 cases reported among U.S. travelers returning from Eurasia between 2000 and 2011, a rate so low that as of 2016 the U.S. Centers for Disease Control and Prevention recommended vaccination only for those who will be extensively exposed in high risk areas.[20] ## References[edit] 1. ^ a b Suss J (June 2008). "Tick-borne encephalitis in Europe and beyond--the epidemiological situation as of 2007". Euro Surveill. 13 (26). PMID 18761916. 2. ^ a b "Factsheet about tick-borne encephalitis (TBE)". European Centre for Disease Prevention and Control. Retrieved 15 January 2019. 3. ^ a b c Tickborne Encephalitis Virus reviewed and published by WikiVet, accessed 12 October 2011. 4. ^ Riccardi N (22 January 2019). "Tick-borne encephalitis in Europe: a brief update on epidemiology, diagnosis, prevention, and treatment". Eur J Intern Med. 62: 1–6. doi:10.1016/j.ejim.2019.01.004. PMID 30678880. 5. ^ Kaiser R (September 2008). "Tick-borne encephalitis". Infect. Dis. Clin. North Am. 22 (3): 561–75, x. doi:10.1016/j.idc.2008.03.013. PMID 18755391. 6. ^ "Tick-borne Encephalitis (TBE)". Centers for Disease Control and Prevention. Retrieved 15 January 2019. 7. ^ Salisbury, Dr David; Noakes, Dr Karen (2006). Immunisation against infectious disease (Third ed.). TSO (The Stationery Office - UK Department Of Health). pp. 385–390. ISBN 978-0-11-322528-6. 8. ^ Dumpis U, Crook D, Oksi J (April 1999). "Tick-borne encephalitis". Clin. Infect. Dis. 28 (4): 882–90. doi:10.1086/515195. PMID 10825054. 9. ^ CDC Yellow Book, accessed 5 October 2013. 10. ^ a b "FSME: Risikogebiete in Deutschland" (PDF). Epidemiologisches Bulletin, RKI (in German). Berlin. 8. 2020. 11. ^ "Factsheet about tick-borne encephalitis (TBE)". European Centre for Disease Prevention and Control. Retrieved 2018-10-18. 12. ^ Demicheli V, Debalini MG, Rivetti A (2009). Demicheli V (ed.). "Vaccines for preventing tick-borne encephalitis". Cochrane Database Syst Rev (1): CD000977. doi:10.1002/14651858.CD000977.pub2. PMC 6532705. PMID 19160184. 13. ^ "Encepur® N". compendium.ch. 2016-04-28. Retrieved 2018-01-21. 14. ^ "FSME-Immun® CC". compendium.ch. 2017-08-11. Retrieved 2018-01-21. 15. ^ "Vaccines against tick-borne encephalitis: WHO position paper" (PDF). Relevé Épidémiologique Hebdomadaire. 86 (24): 241–56. 10 June 2011. PMID 21661276. 16. ^ a b Amicizia, Daniela; Domnich, Alexander; Panatto, Donatella; Lai, Piero Luigi; Cristina, Maria Luisa; Avio, Ulderico; Gasparini, Roberto (2013-05-14). "Epidemiology of tick-borne encephalitis (TBE) in Europe and its prevention by available vaccines". Human Vaccines & Immunotherapeutics. 9 (5): 1163–1171. doi:10.4161/hv.23802. ISSN 2164-5515. PMC 3899155. PMID 23377671. 17. ^ Pettersson, John H.-O.; Golovljova, Irina; Vene, Sirkka; Jaenson, Thomas G. T. (2014-01-01). "Prevalence of tick-borne encephalitis virus in Ixodes ricinus ticks in northern Europe with particular reference to Southern Sweden". Parasites & Vectors. 7: 102. doi:10.1186/1756-3305-7-102. ISSN 1756-3305. PMC 4007564. PMID 24618209. 18. ^ team, European Centre for Disease Prevention and Control (ECDC)-Health Communication Unit- Eurosurveillance editorial (2011). "Tick-borne encephalitis increasing in Sweden, 2011". Eurosurveillance. 16 (39). doi:10.2807/ese.16.39.19981-en. PMID 21968422. 19. ^ team, European Centre for Disease Prevention and Control (ECDC)-Health Communication Unit- Eurosurveillance editorial (2011-03-11). "Case report: Tick-borne encephalitis in two Dutch travellers returning from Austria, Netherlands, July and August 2011". Eurosurveillance. 16 (44): 20003. doi:10.2807/ese.16.44.20003-en (inactive 2021-01-14). PMID 22085619. Retrieved 2016-06-04.CS1 maint: DOI inactive as of January 2021 (link) 20. ^ "Tickborne Encephalitis - Chapter 3 - 2016 Yellow Book \| Travelers' Health \| CDC". wwwnc.cdc.gov. 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Neurological disease Leukoencephalopathy with vanishing white matter Other namesChildhood ataxia with central nervous system hypomyelinization, Vanishing white matter leukodystrophy, Cree leukoencephalopathy, Vanishing white matter leukodystrophy with ovarian failure, included, Myelinopathia centralis diffusa This condition is inherited in an autosomal recessive manner Leukoencephalopathy with vanishing white matter (VWM disease) is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies. ## Contents * 1 Symptoms and signs * 2 Causes * 2.1 eIF2B's role * 3 Neuropathology * 4 Diagnosis * 4.1 Case report on diagnosis of adult-onset VWM * 4.2 MRI * 4.3 Common misdiagnosis * 5 Treatment * 6 Epidemiology * 7 History * 8 See also * 9 References * 10 External links ## Symptoms and signs[edit] Onset usually occurs in childhood, however some adult cases have been found. Generally, physicians look for the symptoms in children. Symptoms include cerebellar ataxia, spasticity, optic atrophy, epilepsy,[1] loss of motor functions, irritability, vomiting, coma,[2] and even fever has been tied to VWM.[3] The neurological disorders and symptoms which occur with VWM are not specific to countries; they are the same all over the world.[4] Neurological abnormalities may not always be present in those who experience onset as adults. Symptoms generally appear in young children or infants who were previously developing fairly normally.[citation needed] ## Causes[edit] VWM is a leukodystrophy which has unique biochemical abnormalities.[3] A unique characteristic of VWM is that only oligodendrocytes and astrocytes are negatively affected while other glial cells and neurons seem to be unaffected. This is the central question behind VWM. The real reasons behind this behavior are unknown since the cells are in the brain and have been rarely studied. However, there is a theory which is generally accepted by most experts in the field. The main characteristic of these cells is the fact that they synthesize a lot of proteins. These cells produce a large amount of proteins from a small amount of precursors and so are constantly working and under a reasonable amount of stress. So with a mutation in eIF2B, slight increases in the amount of stress these cells encounter occur, making them more susceptible to failure due to stress.[4] The large amount of oligodendrocytes which display apoptotic characteristics and express apoptotic proteins suggests cell number reduction in the early stages of the disease.[1] Premature ovarian failure has also been associated with diminishing white matter. However through an intensive survey, it was determined that even if an individual has premature ovarian failure, she does not necessarily have VWM.[5] ### eIF2B's role[edit] Overview of eIF2 and eIF2B's purpose in cells eIF2B is the guanine nucleotide-exchange factor for eIF2, and is composed of 5 subunits. The largest subunit, eIF2B5 contains the most mutations for VWM. eIF2B is a complex which is very involved with the regulation of in the translation of mRNA into proteins.[6] eIF2B is essential for the exchange of guanosine diphosphate(GDP) for guanosine-5'-triphosphate(GTP) in the initiation of translation via eIF2, because eIF2 is regenerated through this exchange. A decrease in eIF2B activity has been correlated with the onset of VWM.[7] A common factor among VWM patients is mutations in the five subunits of eIF2B (21 discovered thus far),[6] expressed in over 60% of the patients. These mutations lead to the decreased activity of eIF2B. The most common mutation is R113H, which is the mutation of histidine to arginine. The homozygous form of the mutation is the least severe form.[4] This mutation has also been documented in rodents, but they do not acquire VWM, while humans do.[6] Another common mutation is G584A found in the eIF2B5 subunit.[8] A correlation with stress has also been made, as eIF2B plays a central role in stress management – it is essential in down regulation protein synthesis in different stress conditions – and VWM patients are highly sensitive to stress.[7] Protein eIF2B exists in all cells, and if this protein is reduced enough the cell will be negatively affected, and if it is reduced to zero, the cell will die. In affected cells, the protein is reduced to about 50%, which is acceptable for functionality in most cells, but not in glial cells since they synthesize a large amount of proteins constantly and need as many functioning proteins within them as possible. This would lower the baseline of the amount of stress a cell can handle, and thus in a stressed environment, it would have detrimental effects on these cells.[4] Mutations in three of the subunits of eIF2B (2,4,&5) has been seen in both VWM and premature ovarian failure.[5] The North American Cree population has also been found to have a distinctive mutation, R195H, which can lead to VWM.[6] All patients who have been studied only have one mutation present in the gene, causing the eIF2B to still be active, which leads to VWM. If two mutations occurred, then eIF2B activity would be stopped by the body.[9] ## Neuropathology[edit] Upon autopsy, the full effect of VWM has been documented. The gray matter remains normal in all characteristics while the white matter changes texture, becoming soft and gelatinous. Rarefaction of the white matter is seen through light microscopy and the small number of axons and U-fibers that were affected can also be seen. Numerous small cavities in the white matter are also apparent. The key characteristic that sets VWM apart from the other leukodystrophies is the presence of foamy oligodendrocytes. These foamy oligodendrocytes tend to have increased cytoplasmic structures, a greater number of irregular mitochondria and a higher rate of apoptosis. Abnormally shaped astrocytes with fibrile infections are very prevalent throughout the capillaries in the brain. Strangely, astrocytes are affected more than oligodendrocytes; there is even a reduction in the astrocyte progenitors, yet axons remain relatively unharmed.[10] ## Diagnosis[edit] Most diagnosis occurs in the early years of life around 2 to 6 years old.[2] There have been cases in which onset and diagnosis have occurred late into adulthood. Those with onset at this time have different signs, particularly the lack of cognitive deterioration. Overall, detection of adult forms of VWM is difficult as MRI was not a common tool when they were diagnosed.[3] Common signs to look for include chronic progressive neurological deterioration with cerebellar ataxia, spasticity, mental decline, decline of vision, mild epilepsy, hand tremor, the ability to chew and swallow food becomes difficult, rapid deterioration and fibrile infections following head trauma or fright, loss of motor functions, irritability, behavioural changes, vomiting, and even coma. Those who go into coma, if they do come out usually die within a few years.[2] The diagnosis can be difficult if the physician does not take an MRI.[4] ### Case report on diagnosis of adult-onset VWM[edit] The individual was examined at age 32, but he stated that he started noting differences 5 years before. He noticed sexual impotency, social isolation, unexplained aggression and sadness, loss of motivation, inert laughs, auditory hallucinations, thought insertion, delusions, and imperative commenting. He showed very minimal physical impairments, commonly seen in child-onsets. However, his MRI showed characteristic signs of VWM disease.[11] ### MRI[edit] The MRI of patients with VWM shows a well defined leukodystrophy. These MRIs display reversal of signal intensity of the white matter in the brain. Recovery sequences and holes in the white matter are also visible.[4] Over time, the MRI is excellent at showing rarefaction and cystic degeneration of the white matter as it is replaced by fluid. To show this change, displaying white matter as a high signal (T2-weighted), proton density, and Fluid attenuated inversion recovery (FLAIR) images are the best approach. T2-weighted images also displaying cerebrospinal fluid and rarefied/cystic white matter. To view the remaining tissue, and get perspective on the damage done (also helpful in determining the rate of deterioration) (T1-weighted), proton density, and FLAIR images are ideal as they show radiating stripe patterns in the degenerating white matter. A failure of MRI images is their ineffectiveness and difficulty in interpretation in infants since the brain has not fully developed yet. Though some patterns and signs may be visible, it is still difficult to conclusively diagnose. This often leads to misdiagnosis in infants particularly if the MRI results in equivocal patterns or because of the high water content in infants' brains. The easiest way to fix this problem is a follow-up MRI in the following weeks. A potentially similar appearance of MRI with white matter abnormalities and cystic changes may be seen in some patients with hypomelanosis of Ito, some forms of Lowe's (oculocerebrorenal) disease, or some of the mucopolysaccharidoses.[2] ### Common misdiagnosis[edit] Often with VWM, the lack of knowledge of the disease causes a misdiagnosis among physicians. As VWM is a member of the large group of leukodystrophy syndromes, it is often misdiagnosed as another type such as metachromatic leukodystrophy. More often than not, it is simply classified as a non-specific leukodystrophy.[4] The characteristics of the brain upon autopsy are often very similar to atypical diffuse sclerosis, such as the presence of fibrillary astrocytes and scant sudanophilic lipids.[2] Adult-onset VWM disease can present with psychosis and may be hard to differentiate from schizophrenia.[11] Common misdiagnosis from misinterpreting the MRI include asphyxia, congential infections, metabolic diseases.[2] Multiple sclerosis is often a misdiagnosis, but only in children due to its neurological characteristics, onset in early years, and MRI abnormalities.[1] However, there are many differences between the two diseases. The glial cells express a loss of myelin. This loss of myelin is different from that seen in other diseases where hypomyelination occurs. In VWM, the cells never produce the normal amounts, whereas with diseases like MS, the cells' normal amounts are deteriorated. Also, with MS, the demyelination occurs due to inflammation, which is not the case in VWM.[4] Cell differences include a lower penetration of the macrophages and microglia, as well as the lack of T cells and B cells in VWM.[1] Finally, patients with MS have widespread demyelination, but those with VWM only express demyelination in a localized area.[4] Some atypical forms of multiple sclerosis (multiple sclerosis with cavitary lesions) can be specially difficult to differentiate but there are some clues in MRI imaging that can help.[12] ## Treatment[edit] There are no treatments, only precautions which can be taken, mainly to reduce trauma to the head and avoiding physiological stress.[2] Melatonin has been shown to provide cytoprotective traits to glial cells exposed to stressors such as excitotoxicity and oxidative stress. These stressors would be detrimental to cells with a genetically reduced activity of protein eIF2B. However, research connecting these ideas have not been conducted yet.[4] ## Epidemiology[edit] Extensive pathological and biochemical tests were performed, however the cause was found by studying a small population in which mutations in the eIF2B gene were found.[10] No effective systemic studies have been conducted to determine the incidence around the world, but through the studies conducted thus far, it appears to be more prevalent in the white populations.[2] VWM appears to have a lower number of cases in the Middle East, and Turkey has not yet had a reported case. Its prevalence is limited by the physician’s ability to identify the disease.[4] As of 2006, more than 200 people have been identified with VWM, many of whom were originally diagnosed with an unclassified leukodystrophy.[10] ## History[edit] The first time this disease was documented was in 1962 when Eickle studied a 36-year-old woman. Her first symptoms, gait difficulties and secondary amenorrhoea, occurred when she was 31 years old. Throughout the duration of her life, she experienced chronic episodes with extensive deterioration of her brain following minor physical trauma. Upon death, autopsy was performed in which the cerebral white matter displayed dispersed cystic areas. These areas were surrounded by a dense net of oligodendrocytes in which only mild fibrillary astrocytes and scant sudanophilic lipids were found.[2] As the years progressed, more accounts of similar patients with similar symptoms were documented; however no one classified all the accounts as the same disease. It was not until 1993-94 when Dr. Hanefeld and Dr. Schiffmann and their colleagues identified the disease as childhood-onset progressive leukoencephalopathy. They determined it was autosomal recessive. They too saw that head trauma was a trigger for the onset of VWM. The key factor which allowed them to connect these patients together was the results of the magnetic-resonance spectroscopy in which the normal white matter signals were gone and often replaced with resonances indicative of lactate and glucose. They determined the cause was hypomyelination. in 1997-98, Dr. Marjo S. van der Knaap and colleagues saw the same characteristics in another set of patients, but these patients also expressed febrile infections. Dr. van der Knaap used MRI as well as magnetic-resonance spectroscopy and determined that ongoing cystic degeneration of the cerebral white matter[2] and matter rarefaction[7] was more descriptive of the disease rather than hypomyelination and proposed the name vanishing white matter.[2] The name proposed by Dr. Schiffmann in 1994, childhood ataxia with central hypomyelination (CACH) is another commonly accepted name.[7] ## See also[edit] * The Stennis Foundation * CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) * Progressive multifocal leukoencephalopathy * Metachromatic leukodystrophy * general leukoencephalopathies ## References[edit] 1. ^ a b c d Kuhlmann, T.; Lassmann, H.; Bruck, W (2008). "Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach". Acta Neuropathol. 115 (3): 275–287. doi:10.1007/s00401-007-0320-8. PMC 2668559. PMID 18175128. 2. ^ a b c d e f g h i j k van der Knaap, M.S.; Pronk, J.C.; Scheper, G.C. (2006). "Vanishing White Matter Disease". Lancet Neurology. 5 (5): 413–423. doi:10.1016/S1474-4422(06)70440-9. PMID 16632312. S2CID 44301370. 3. ^ a b c Baumann, N.; Turpin, J-C (2000). "Adult-onset leukodystrophies". Journal of Neurology. 247 (10): 751–9. doi:10.1007/s004150070088. PMID 11127529. S2CID 6817046. 4. ^ a b c d e f g h i j k Dr. Raphael Schiffmann (Director of Baylor Research Institute at Dallas, Texas). Telephone Interview 2008-11-08. 5. ^ a b Goswami, D.; Conway, G.S. (2005). "Premature ovarian failure". Human Reproduction Update. 11 (4): 391–410. doi:10.1093/humupd/dmi012. PMID 15919682. S2CID 23396413. 6. ^ a b c d Abbott, C.M.; Proud, C.G. (2004). "Translation factors: in sickness and in health". Trends in Biochemical Sciences. 29 (1): 25–31. doi:10.1016/j.tibs.2003.11.006. PMID 14729329. 7. ^ a b c d Pronk, J.C.; van Kollenburg, B.; Scheper, G.C.; van der Knaap, M.S. (2006). "Vanishing White Matter Disease: A Review with Focus on Its Genetics". Mental Retardation and Developmental Disabilities Research Reviews. 12 (2): 123–8. doi:10.1002/mrdd.20104. PMID 16807905. 8. ^ Laberge, A-M.; Michaud, J.; Richter, A.; Lambert, M.; Brais, B.; Mitchell G.A. (2005). "Population history and its impact on medical genetics in Quebec". Clinical Genetics. 68 (4): 287–301. doi:10.1111/j.1399-0004.2005.00497.x. PMID 16143014. S2CID 26368522. 9. ^ Scheper, G.C.; Proud, C.G.; van der Knaap, M.S. (2006). "Defective translation initiation causes vanishing of cerebral white matter". Trends in Molecular Medicine. 12 (4): 159–166. doi:10.1016/j.molmed.2006.02.006. PMID 16545608. 10. ^ a b c Schiffmann, R.; Elroy-Stein, O. (2006). "Childhood ataxia with CNS hypomyelination/vanishing white matter disease – A common leukodystrophy caused by abnormal control of protein synthesis". Molecular Genetics and Metabolism. 88 (1): 7–15. doi:10.1016/j.ymgme.2005.10.019. PMID 16378743. 11. ^ a b Denier C, Orgibet A, Roffi F, Jouvent E, Buhl C, Niel F, Boespflug-Tanguy O, Said G, Ducreux D (2007). "Adult-onset vanishing white matter leukoencephalopathy presenting as psychosis". Neurology. 68 (18): 1538–9. doi:10.1212/01.wnl.0000260701.76868.44. PMID 17470759. S2CID 28752485. 12. ^ Ayrignac et al. Brain magnetic resonance imaging helps to differentiate atypical multiple sclerosis with cavitary lesions and vanishing white matter disease, European Journal of Neurology Volume 23, Issue 6, 04 January 2016, doi=https://doi.org/10.1111/ene.12931 ## External links[edit] * "Leukoencephalopathy with vanishing white matter". Neurographics. 2 (1). March 2012. Classification D * OMIM: 603896 603945 606273 606454 606686 606687 603896 603945 606273 606454 606686 606687 (CACH/VWM) CARASIL: 610149 600142 602194 600142 602194CADASIL: 125310 600276 125310 600276 External resources * GeneReviews: CARASIL Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, Maeda Syndrome * Orphanet: 135 * v * t * e Multiple sclerosis and other demyelinating diseases of the central nervous system Signs and symptoms * Ataxia * Depression * Diplopia * Dysarthria * Dysphagia * Fatigue * Incontinence * Nystagmus * Optic neuritis * Pain * Uhthoff's phenomenon Investigations and diagnosis * Multiple sclerosis diagnosis * McDonald criteria * Poser criteria * Clinical * Clinically isolated syndrome * Expanded Disability Status Scale * Serological and CSF * Oligoclonal bands * Radiological * Radiologically isolated syndrome * Lesional demyelinations of the central nervous system * Dawson's fingers Approved[by whom?] treatment * Management of multiple sclerosis * Alemtuzumab * Cladribine * Dimethyl fumarate * Fingolimod * Glatiramer acetate * Interferon beta-1a * Interferon beta-1b * Mitoxantrone * Natalizumab * Ocrelizumab * Ozanimod * Siponimod * Teriflunomide Other treatments * Former * Daclizumab * Multiple sclerosis research Demyleinating diseases Autoimmune * Multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis Inflammatory * Acute disseminated encephalomyelitis * MOG antibody disease * Balo concentric sclerosis * Marburg acute multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis * Tumefactive multiple sclerosis * Experimental autoimmune encephalomyelitis Hereditary * Adrenoleukodystrophy * Alexander disease * Canavan disease * Krabbe disease * Metachromatic leukodystrophy * Pelizaeus–Merzbacher disease * Leukoencephalopathy with vanishing white matter * Megalencephalic leukoencephalopathy with subcortical cysts * CAMFAK syndrome Other * Central pontine myelinolysis * Marchiafava–Bignami disease * Mitochondrial DNA depletion syndrome Other * List of multiple sclerosis organizations * List of people with multiple sclerosis * Multiple sclerosis drug pipeline * Pathophysiology * v * t * e Disorders of translation and posttranslational modification Translation * Ribosome: Diamond–Blackfan anemia * FMR1 * Fragile X syndrome * Fragile X-associated tremor/ataxia syndrome * Premature ovarian failure 1 * Initiation factor: Leukoencephalopathy with vanishing white matter * snRNP: Retinitis pigmentosa 33 Posttranslational modification Protein folding * Alzheimer's disease * Huntington's disease * Creutzfeldt–Jakob disease * chaperonins: 3-Methylglutaconic aciduria 5 Protein targeting * I-cell disease Ubiquitin * E1: X-linked spinal muscular atrophy 2 * E3: Johanson–Blizzard syndrome * Von Hippel–Lindau disease * 3-M syndrome * Angelman syndrome * Deubiquitinating enzyme: Machado–Joseph disease * Aneurysmal bone cyst * Multiple familial trichoepithelioma 1 SUMO * OFC10 Other * Multiple sulfatase deficiency * Hyperproinsulinemia * Ehlers–Danlos syndrome 6 [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Leukoencephalopathy with vanishing white matter	c1858991	6,937	wikipedia	https://en.wikipedia.org/wiki/Leukoencephalopathy_with_vanishing_white_matter	2021-01-18T18:28:21	{"gard": ["231"], "mesh": ["D056784"], "umls": ["C1858991"], "orphanet": ["135", "99854"], "wikidata": ["Q3508563"]}
Prevalence of vitamin A deficiency, 1995. Clinical Severe subclinical Moderate subclinical Mild subclinical VAD under control No data available Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues.[1] It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries.[1] Nyctalopia (night blindness) is one of the first signs of VAD. Xerophthalmia, keratomalacia, and complete blindness can also occur since vitamin A has a major role in phototransduction.[1] The three forms of vitamin A include retinols, beta-carotenes, and provitamin A carotenoids.[2] Vitamin A deficiency is the world’s leading cause of preventable childhood blindness,[1] and is critical to achieving Millennium Development Goal 4 to reduce child mortality. About 250,000 to 500,000 malnourished children in the developing world go blind each year from a deficiency of vitamin A, around half of whom die within a year of becoming blind.[3] The United Nations Special Session on Children in 2002 set a goal of the elimination of VAD by 2010.[4] The prevalence of night blindness due to VAD is also high among pregnant women in many developing countries. VAD also contributes to maternal mortality and other poor outcomes in pregnancy and lactation.[5][6][7][8] VAD also diminishes the ability to fight infections.[1] In countries where children are not immunized, infectious diseases such as measles have higher fatality rates.[1] As elucidated by Alfred Sommer, even mild, subclinical deficiency can also be a problem, as it may increase children's risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness. VAD is estimated to affect about one-third of children under the age of five around the world.[9] It is estimated to claim the lives of 670,000 children under five annually.[10] Around 250,000–500,000 children in developing countries become blind each year owing to VAD, with the highest prevalence in Southeast Asia and Africa. According to the World Health Organization (WHO), VAD is under control in the United States, but in developing countries, VAD is a significant concern. Globally, 65% of all children aged 6 to 59 months received two doses of vitamin A in 2013, fully protecting them against VAD (80% in the least developed countries).[11] ## Contents * 1 Signs and symptoms * 1.1 Night blindness * 1.2 Infection * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Global initiatives * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] The most common cause of blindness in developing countries is Vitamin A deficiency (VAD). The WHO estimated in 1995 that 13.8 million children had some degree of visual loss related to VAD.[12] Night blindness and its worsened condition, xerophthalmia, are markers of Vitamin A deficiency (VAD), collections of keratin in the conjunctiva, known as Bitot's spots, and ulceration and necrosis of cornea keratomalacia can be seen. Nyctalopia is the earliest ocular sign of VAD. Conjunctival epithelial defects occur around lateral aspect of the limbus in the subclinical stage of VAD. These conjunctival epithelial defects are not visible on a biomicroscope, but they take up black stain and become readily visible after instillation of kajal (surma); this is called "Imtiaz's sign".[13] VAD can also lead to impaired immune function, cancer, and birth defects. Vitamin A deficiency is one of several hypovitaminoses implicated in follicular hyperkeratosis. ### Night blindness[edit] Main article: Nyctalopia Night blindness is the difficulty for the eyes to adjust to dim light. Affected individuals are unable to distinguish images in low levels of illumination. People with night blindness have poor vision in the darkness but see normally when adequate light is present. VAD affects vision by inhibiting the production of rhodopsin, the eye pigment responsible for sensing low-light situations. Rhodopsin is found in the retina and is composed of retinal (an active form of vitamin A) and opsin (a protein). Because the body cannot create retinal in sufficient amounts, a diet low in vitamin A leads to a decreased amount of rhodopsin in the eye, as the retinal is inadequate to bind with opsin. Night blindness results. Night blindness caused by VAD has been associated with the loss of goblet cells in the conjunctiva, a membrane covering the outer surface of the eye. Goblet cells are responsible for secretion of mucus, and their absence results in xerophthalmia, a condition where the eyes fail to produce tears. Dead epithelial and microbial cells accumulate on the conjunctiva and form debris that can lead to infection and possibly blindness.[14] Decreasing night blindness requires the improvement of vitamin A status in at-risk populations. Supplements and fortification of food have been shown to be effective interventions. Supplement treatment for night blindness includes massive doses of vitamin A (200,000 IU) in the form of retinyl palmitate to be taken by mouth, which is administered two to four times a year.[15] Intramuscular injections are poorly absorbed and are ineffective in delivering sufficient bioavailable vitamin A. Fortification of food with vitamin A is costly, but can be done in wheat, sugar, and milk.[16] Households may circumvent expensive fortified food by altering dietary habits. Consumption of yellow-orange fruits and vegetables rich in carotenoids, specifically beta-carotene, provides provitamin A precursors that can prevent VAD-related night blindness. However, the conversion of carotene to retinol varies from person to person and bioavailability of carotene in food varies.[17][18] ### Infection[edit] Along with poor diet, infection and disease are common in many developing communities.[1] Infection depletes vitamin A reserves which in turn make the affected individual more susceptible to further infection.[1] Increased incidence of xerophthalmia has been observed after an outbreak of measles, with mortality correlated with severity of eye disease.[1] In longitudinal studies of preschool children, susceptibility to disease increased substantially when severe VAD was present.[1] The reason for the increased infection rate in vitamin A deficient individuals is that T-killer cells require the retinol metabolite retinoic acid to proliferate correctly.[1] Retinoic acid is a ligand for nuclear retinoic acid receptors that bind the promoter regions of specific genes,[19] thus activating transcription and stimulating T cell replication.[1] Vitamin A deficiency will often entail deficient retinol intake, resulting in a reduced number of T-cells and lymphocytes, leading to an inadequate immune response and consequently a greater susceptibility to infections.[1] In the presence of dietary deficiency of vitamin A, VAD and infections reciprocally aggravate each other.[1] ## Causes[edit] In addition to dietary problems, other causes of VAD are known. Iron deficiency can affect vitamin A uptake; other causes include fibrosis, pancreatic insufficiency, inflammatory bowel disease, and small-bowel bypass surgery.[20] Protein energy malnutrition is often seen in VAD; suppressed synthesis of retinol binding protein (RBP) due to protein deficiency leads to reduced retinol uptake.[21] Excess alcohol consumption can deplete vitamin A, and a stressed liver may be more susceptible to vitamin A toxicity. People who consume large amounts of alcohol should seek medical advice before taking vitamin A supplements. In general, people should also seek medical advice before taking vitamin A supplements if they have any condition associated with fat malabsorption such as pancreatitis, cystic fibrosis, tropical sprue, and biliary obstruction. Other causes of vitamin A deficiency are inadequate intake, fat malabsorption, or liver disorders. Deficiency impairs immunity and hematopoiesis and causes rashes and typical ocular effects (e.g., xerophthalmia, night blindness).[22] ## Diagnosis[edit] Initial assessment may be made based on clinical signs of VAD.[23] Conjunctival impression cytology can be used to assess the presence of xerophthalmia which is strongly correlated with VAD status (and can be used to monitor recovery progress).[23][24] Several methods of assessing bodily vitamin A levels are available, with HPLC the most reliable.[24] Measurement of plasma retinol levels is a common laboratory assay used to diagnose VAD. Other biochemical assessments include measuring plasma retinyl ester levels, plasma and urinary retonioic acid levels, and vitamin A in breast milk.[23] ## Treatment[edit] Treatment of VAD can be undertaken with both oral vitamin A and injectable forms, generally as vitamin A palmitate. * As an oral form, the supplementation of vitamin A is effective for lowering the risk of morbidity, especially from severe diarrhea, and reducing mortality from measles and all-cause mortality. Vitamin A supplementation of children under five who are at risk of VAD can reduce all‐cause mortality by 23%.[25] Some countries where VAD is a public-health problem address its elimination by including vitamin A supplements available in capsule form with national immunization days (NIDs) for polio eradication or measles. Additionally, the delivery of vitamin A supplements, during integrated child health events such as child health days, have helped ensure high coverage of vitamin A supplementation in a large number of least developed countries. Child health events enable many countries in West and Central Africa to achieve over 80% coverage of vitamin A supplementation.[11] According to UNICEF data, in 2013 worldwide, 65% of children between the ages of 6 and 59 months were fully protected with two high-dose vitamin A supplements. Vitamin A capsules cost about US$0.02. The capsules are easy to handle; they do not need to be stored in a refrigerator or vaccine carrier. When the correct dosage is given, vitamin A is safe and has no negative effect on seroconversion rates for oral polio or measles vaccines. However, because the benefit of vitamin A supplements is transient, children need them regularly every four to six months. Since NIDs provide only one dose per year, NIDs-linked vitamin A distribution must be complemented by other programs to maintain vitamin A in children[26][27] Maternal high supplementation benefits both mother and breast-fed infant: high-dose vitamin A supplementation of the lactating mother in the first month postpartum can provide the breast-fed infant with an appropriate amount of vitamin A through breast milk. However, high-dose supplementation of pregnant women should be avoided because it can cause miscarriage and birth defects.[28] * Food fortification is also useful for improving VAD. A variety of oily and dry forms of the retinol esters, retinyl acetates, and retinyl palmitate are available for food fortification of vitamin A. Margarine and oil are the ideal food vehicles for vitamin A fortification. They protect vitamin A from oxidation during storage and prompt absorption of vitamin A. Beta-carotene and retinyl acetate or retinyl palmitate are used as a form of vitamin A for vitamin A fortification of fat-based foods. Fortification of sugar with retinyl palmitate as a form of vitamin A has been used extensively throughout Central America. Cereal flours, milk powder, and liquid milk are also used as food vehicles for vitamin A fortification.[29][30] Genetic engineering is another method that could be used to fortify food, and golden rice[31][32] is a genetic engineering project designed to fortify rice with beta-carotene (which humans can convert into vitamin A) and thereby prevent and/or treat VAD. Although opposition to genetically modified foods resulted in the destruction of a field trial of golden rice prototypes in 2013, development of golden rice has proceeded and developers are currently (as of September 2018) awaiting regulatory approval to publicly release golden rice in the Philippines. * Dietary diversification can also control VAD. Nonanimal sources of vitamin A like fruits and vegetables contain preformed vitamin A and account for greater than 80% of intake for most individuals in the developing world. The increase in consumption of vitamin A-rich foods of animal origin has beneficial effects on VAD.[33] The richest animal sources of vitamin A (retinol) are livers (beef liver – 100 grams provides around 32,000 IUs,[34] and cod liver oil – 10 g provides around 10,000 IUs [35]). Researchers at the U. S. Agricultural Research Service have been able to identify genetic sequences in corn that are associated with higher levels of beta-carotene, the precursor to vitamin A. They found that breeders can cross certain variations of corn to produce a crop with an 18-fold increase in beta-carotene. Such advancements in nutritional plant breeding could one day aid in the illnesses related to VAD in developing countries.[36] ## Global initiatives[edit] Global efforts to support national governments in addressing VAD are led by the Global Alliance for Vitamin A (GAVA), which is an informal partnership between Nutrition International, Helen Keller International, UNICEF, WHO, and CDC. About 75% of the vitamin A required for supplementation of preschool-aged children in low- and middle-income countries is supplied through a partnership between Nutrition International and UNICEF, with support from Global Affairs Canada.[3] An estimated 1.25 million deaths due to vitamin A deficiency have been averted in 40 countries since 1998.[3] In 2013, the prevalence of vitamin A deficiency was 29% in low-income and middle-income countries, remaining highest in sub-Saharan Africa and South Asia.[37] A 2017 review found that vitamin A supplementation in children 5 years old and younger in 70 countries was associated with a 12% reduction in mortality rate.[38][needs update] The review reported that synthetic vitamin A supplementation may not be the best long‐term solution for vitamin A deficiency, but rather food fortification, improved food distribution programs, and crop improvement, such as for fortified rice or vitamin A-rich sweet potato, may be more effective in eradicating vitamin A deficiency.[38] ## Epidemiology[edit] Disability-adjusted life year for vitamin A deficiency per 100,000 inhabitants in 2002.[39] no data less than 35 35–70 70–105 105–140 140–175 175–210 210–245 245–280 280–315 315–350 350–400 more than 400 ## See also[edit] * St. Jerome's description of vitamin A deficiency ## References[edit] 1. ^ a b c d e f g h i j k l m n "Vitamin A". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. January 2015. Retrieved 1 November 2019. 2. ^ "Vitamin A Deficiency: Background, Pathophysiology, Epidemiology". 17 May 2018 – via eMedicine. Cite journal requires `\|journal=` (help) 3. ^ a b c "Micronutrient Deficiencies: Vitamin A". World Health Organization. Retrieved 12 September 2019. 4. ^ "In Preventing Vitamin A Deficiency, a Little Friendly Bacteria Might Go a Long Way". Rutgers Today. 2011-12-19. Retrieved 2019-10-27. 5. ^ "WHO Vitamin A deficiency \| Micronutrient deficiencies". Retrieved 2008-03-03. 6. ^ Latham, Michael E. (1997). Human Nutrition in the Developing World (Fao Food and Nutrition Paper). Food & Agriculture Organization of the United. ISBN 92-5-103818-X. 7. ^ Sommer, Alfred (1995). Vitamin a Deficiency and Its Consequences: A Field Guide to Detection and Control. Geneva: World Health Organization. ISBN 92-4-154478-3. 8. ^ "A world fit for children" (PDF). Retrieved 2008-03-03. 9. ^ World Health Organization, Global prevalence of vitamin A deficiency in populations at risk 1995–2005, WHO global database on vitamin A deficiency. 10. ^ Black RE et al., Maternal and child undernutrition: global and regional exposures and health consequences, The Lancet, 2008, 371(9608), p. 253. 11. ^ a b "Vitamin A Deficiency and Supplementation UNICEF Data". Retrieved 2015-04-07. 12. ^ Rahi J S, Sripathi S, Gilbert C E, Foster A (1995). "Childhood blindness due to VAD in India: regional variations". Archives of Disease in Childhood. 72 (4): 330–333. doi:10.1136/adc.72.4.330. PMC 1511233. PMID 7763066.CS1 maint: multiple names: authors list (link) 13. ^ http://www.paramountbooks.com.pk/LoginIndex.asp?title=Concise-Ophthalmology-(pb)-2014&Isbn=9789696370017&opt=3&sUBcAT=06 14. ^ Underwood, Barbara A. Vitamin A Deficiency Disorders: International Efforts to Control A Preventable “Pox.” J. Nutr. 134: 231S–236S, 2004. 15. ^ Sommer A, Muhilal Tarwotjo I, Djunaedi E, Glover J (1980b). "Oral versus intramuscular vitamin A in the treatment of xerophthalmia". Lancet. 1 (8168 Pt 1): 557–559. doi:10.1016/S0140-6736(80)91053-3. PMID 6102284. S2CID 35416519.CS1 maint: multiple names: authors list (link) 16. ^ Arroyave G, Mejia LA, Aguilar JR (1981). "The effect of vitamin A fortification of sugar on the serum vitamin A levels of preschool Guatemalan children: a longitudinal evaluation". J. Nutr. 34 (1): 41–49. doi:10.1093/ajcn/34.1.41. PMID 7446457.CS1 maint: multiple names: authors list (link) 17. ^ Borel P, Drai J, Faure H, Fayol V, Galabert C, Laromiguière M, Le Moël G (2005). "Recent knowledge about intestinal absorption and cleavage of carotenoids". Annales de Biologie Clinique (in French). 63 (2): 165–177. PMID 15771974. 18. ^ Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA (2005). "Spinach or carrots can supply significant amounts of vitamin A as assessed by feeding with intrinsically deuterated vegetables". The American Journal of Clinical Nutrition. 82 (4): 821–828. doi:10.1093/ajcn/82.4.821. PMID 16210712. 19. ^ Cunningham, T.J.; Duester, G. (2015). "Mechanisms of retinoic acid signalling and its roles in organ and limb development". Nat. Rev. Mol. Cell Biol. 16 (2): 110–123. doi:10.1038/nrm3932. PMC 4636111. PMID 25560970. 20. ^ "Vitamin A Deficiency Clinical Presentation: History, Physical, Causes". emedicine.medscape.com. 21. ^ (Combs, 1991). 22. ^ Merck Manuals Professional Edition. "Vitamin A – Nutritional Disorders". merckmanuals.com. 23. ^ a b c Bates, C J (1999-01-01). "Diagnosis and detection of vitamin deficiencies". British Medical Bulletin. 55 (3): 643–657. doi:10.1258/0007142991902529. ISSN 0007-1420. PMID 10746353. 24. ^ a b "Diagnosis and Treatment of Vitamin A Deficiency: Workup". Retrieved 2019-11-01. 25. ^ Beaton GH et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. United Nations Administrative Committee on Coordination, Sub-committee on Nutrition State-of-the-Art Series: Nutrition Policy Discussion Paper No. 13. Geneva, 1993. 26. ^ "Distribution of vitamin A during national immunization days" (PDF). Retrieved 2008-03-03. 27. ^ "WHO Vitamin A supplementation". Archived from the original on 2013-01-25. Retrieved 2008-03-03. 28. ^ Stoltzfus RJ, Hakimi M, Miller KW, et al. (1993). "High dose vitamin A supplementation of breast-feeding Indonesian mothers: effects on the vitamin A status of mother and infant". J. Nutr. 123 (4): 666–675. doi:10.1093/jn/123.4.666. PMID 8463867. 29. ^ edited by Lindsay Allen ... (2006). Guidelines on Food Fortification With Micronutrients. Geneva: World Health Organization. ISBN 92-4-159401-2.CS1 maint: extra text: authors list (link) 30. ^ Food and Agriculture Organization of the United Nations (1996). Food Fortification: Tech & Quality Control (Food & Nutrition Papers). Bernan Assoc. ISBN 92-5-103884-8. 31. ^ Ye, X; Al-Babili, S; Klöti, A; Zhang, J; Lucca, P; Beyer, P; Potrykus, I (2000). "Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm". Science. 287 (5451): 303–305. Bibcode:2000Sci...287..303Y. doi:10.1126/science.287.5451.303. PMID 10634784. S2CID 40258379. 32. ^ One existing crop, genetically engineered "golden rice" that produces vitamin A, already holds enormous promise for reducing blindness and dwarfism that result from a vitamin-A deficient diet. – Bill Frist, physician and politician, in a Washington Times commentary – November 21, 2006 [1] 33. ^ "childinfo.org: Vitamin A Deficiency". Archived from the original on 2008-02-18. Retrieved 2008-03-14. 34. ^ "Beef, variety meats and by-products, liver, cooked, braised Nutrition Facts & Calories". nutritiondata.self.com. 35. ^ "Fish oil, cod liver Nutrition Facts & Calories". nutritiondata.self.com. 36. ^ "A New Approach that Saves Eyesight and Lives in the Developing World". USDA Agricultural Research Service. May 3, 2010. 37. ^ Stevens, Gretchen A; Bennett, James E; Hennocq, Quentin; Lu, Yuan; De-Regil, Luz Maria; Rogers, Lisa; Danaei, Goodarz; Li, Guangquan; White, Richard A; Flaxman, Seth R; Oehrle, Sean-Patrick; Finucane, Mariel M; Guerrero, Ramiro; Bhutta, Zulfiqar A; Then-Paulino, Amarilis; Fawzi, Wafaie; Black, Robert E; Ezzati, Majid (2015). "Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: a pooled analysis of population-based surveys". The Lancet Global Health. 3 (9): e528–e536. doi:10.1016/s2214-109x(15)00039-x. ISSN 2214-109X. PMID 26275329. 38. ^ a b Imdad, Aamer; Mayo-Wilson, Evan; Herzer, Kurt; Bhutta, Zulfiqar A (2017-03-11). "Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age". Cochrane Database of Systematic Reviews. 3: CD008524. doi:10.1002/14651858.cd008524.pub3. ISSN 1465-1858. PMC 6464706. PMID 28282701. 39. ^ "Mortality and Burden of Disease Estimates for WHO Member States in 2002" (xls). World Health Organization. 2002. ## Further reading[edit] * UNICEF, Vitamin A Supplementation: A Decade of Progress, UNICEF, New York, 2007. * Flour Fortification Initiative, GAIN, Micronutrient Initiative, USAID, The World Bank, UNICEF, Investing in the Future: A United Call to Action on Vitamin and Mineral Deficiencies, 2009. * UNICEF, Improving Child Nutrition: The achievable imperative for global progress, UNICEF, New York, 2013. ## External links[edit] * Micronutrient Initiative * UNICEF Data on Vitamin A Deficiency and Supplementation * Helen Keller International * A2Z * World Health Organization Database on Vitamin A Deficiency * Vitamin A Deficiency on IAPB * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Vitamin A deficiency	c0042842	6,938	wikipedia	https://en.wikipedia.org/wiki/Vitamin_A_deficiency	2021-01-18T18:28:28	{"mesh": ["D014802"], "umls": ["C0042842"], "icd-9": ["264.8", "264.9"], "icd-10": ["E50"], "wikidata": ["Q2655893"]}
A rare, non-syndromic cerebral malformation due to abnormal neuronal migration characterized by variable clinical manifestation depending on the location, size and thickness of subcortical bands. Clinical presentation ranges from mild cognitive deficit to developmental delay with severe intellectual disability, seizures and behavioral problems. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Subcortical band heterotopia	c1848201	6,939	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99796	2021-01-23T16:55:49	{"gard": ["1904"], "mesh": ["D054221"], "omim": ["300067", "600348", "607432"], "umls": ["C1848201"], "icd-10": ["Q04.3"], "synonyms": ["Subcortical laminar heterotopia"]}
Congenital cutaneous candidiasis Other namesBeck-Ibrahim disease[1] SpecialtyDermatology Congenital cutaneous candidiasis is a skin condition in newborn babies caused by premature rupture of membranes together with a birth canal infected with Candida albicans.[2]:309 Congenital cutaneous candidiasis can occur with candidemia that can lead to neonatal sepsis.[3] ## See also[edit] * Candidiasis * Skin lesion ## References[edit] 1. ^ Strous, Rael D.; Edelman, Morris C. (2007). "Eponyms and the Nazi Era: Time to Remember and Time for Change". Israel Medical Association Journal. 9: 207–214. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 3. ^ Skoczylas, MM; Walat, A; Kordek, A; Loniewska, B; Rudnicki, J; Maleszka, R; Torbé, A (2014). "Congenital candidiasis as a subject of research in medicine and human ecology". Annals of Parasitology. 60 (3): 179–89. PMID 25281815. This infection-related 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Congenital cutaneous candidiasis	None	6,940	wikipedia	https://en.wikipedia.org/wiki/Congenital_cutaneous_candidiasis	2021-01-18T18:50:28	{"wikidata": ["Q5160415"]}
Ichthyoallyeinotoxism, or hallucinogenic fish inebriation, comes from eating certain species of fish found in several parts of the tropics, the effects of which are reputed to be similar in some aspects to LSD. Experiences may include vivid auditory and visual hallucinations. This has given rise to the collective common name "dream fish" for ichthyoallyeinotoxic fish. The species most commonly claimed to be capable of producing this kind of toxicity include several species from the genus Kyphosus, including Kyphosus fuscus, K. cinerascens and K. vaigiensis.[citation needed] It is unclear whether the toxins are produced by the fish themselves or by marine algae in their diet, but a dietary origin may be more likely.[citation needed] Sarpa salpa, a species of bream, can induce LSD-like hallucinations if it is eaten.[1] These widely distributed coastal fish[2] are called "the fish that make dreams" in Arabic. In 2006, two men who ate fish, apparently the Sarpa salpa caught in the Mediterranean, were affected by ichthyoallyeinotoxism and experienced hallucinations lasting for several days.[3][4] Other hallucinogenic fish are Siganus spinus,[5] called "the fish that inebriates" in Reunion Island, and Mulloides flavolineatus (formerly Mulloidichthys samoensis),[6] called "the chief of ghosts" in Hawaii.[7] ## See also[edit] * 5-Bromo-DMT * Entheogen * Venomous fish ## References[edit] 1. ^ Sarpa Salpa Mahalo 2. ^ Froese, Rainer and Pauly, Daniel, eds. (2009). "Sarpa salpa" in FishBase. October 2009 version. 3. ^ de Haro, L.; Pommier, P. (2006). "Hallucinatory fish poisoning (ichthyoallyeinotoxism): two case reports from the Western Mediterranean and literature review". Clinical Toxicology. 44 (2): 185–8. doi:10.1080/15563650500514590. PMID 16615678. S2CID 41191477. 4. ^ Clarke, Matt (2006-04-19). "Men hallucinate after eating fish". Practical Fishkeeping. Archived from the original on 2011-06-05. Retrieved 2010-03-31. 5. ^ Froese, Rainer and Pauly, Daniel, eds. (2009). "Siganus spinus" in FishBase. October 2009 version. 6. ^ Froese, Rainer and Pauly, Daniel, eds. (2009). "Mulloidichthys samoensis" in FishBase. October 2009 version. 7. ^ Thomas, Craig, M.D. and, Susan Scott (Jun 1, 1997). All Stings Considered: First Aid and Medical Treatment of Hawai'i's Marine Injuries. Hawaii: University of Hawai'i Press. p. 120. ISBN 9780824819002.CS1 maint: multiple names: authors list (link) * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Ichthyoallyeinotoxism	c1562426	6,941	wikipedia	https://en.wikipedia.org/wiki/Ichthyoallyeinotoxism	2021-01-18T19:08:52	{"wikidata": ["Q5986402"]}
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. (July 2011) Presbyphagia refers to characteristic changes in the swallowing mechanism of otherwise healthy older adults.[1] Although age-related changes place older adults at risk swallowing disorders, an older adult’s swallow is not necessarily an impaired swallow. Clinicians are becoming more aware of the need to distinguish among swallowing disorders, presbyphagia (an old yet healthy swallow) and other related diagnoses in order to avoid over diagnosing and over treating presbyphagia. Older adults are more vulnerable and with the increased threat of acute illnesses, medications and any number of age-related conditions, they can cross the line from having a healthy older swallow to being dysphagic. Work focused primarily on the anatomy and physiology of the oropharyngeal swallowing mechanism indicates a progression of change that may put the older population at increased risk for swallowing disorders.[1][2][3][4][5][6][7] Such changes combined with naturally diminished functional reserve, the resilient ability to adapt to physiological stress, make the older population more susceptible to dysphagia. ## Contents * 1 Age-Associated Changes in Swallowing * 1.1 Age-Associated Changes in Oropharyngeal Swallowing * 1.2 Age-related Change in Lingual Pressure Generation * 2 See also * 3 References ## Age-Associated Changes in Swallowing[edit] ### Age-Associated Changes in Oropharyngeal Swallowing[edit] A major characteristic of older healthy swallowing is that it occurs more slowly.[1][2][3][4] The longer duration is found to occur largely before the more automatic pharyngeal phase of the swallow is initiated. In those over age 65, the initiation of laryngeal and pharyngeal events, including laryngeal vestibule closure, are delayed significantly longer than in adults younger than 45 years of age.[2] Although the specific neural underpinning is not confirmed it might be hypothesized that oral events become “uncoupled” from the pharyngeal response, which includes airway protection. Thus, in older healthy adults it is not uncommon for the bolus to be adjacent to an open airway by pooling or pocketing in the pharyngeal recesses, for more time than in younger adults. Whereas older adults demonstrate a delay in the onset of specific pharyngeal events, such as opening of the upper esophageal sphincter (UES) to permit bolus passage from the pharynx into the esophagus, an equally critical finding is that the range of UES opening is diminished. A scintigraphic study revealed increased pharyngeal residue with age, possibly related to the limited UES opening.[4] Again, these findings indicate exposure of an open airway to material retained in the pharynx, increasing the risk for aspiration in older individuals. Aspiration (defined as entry of material into the airway [trachea] thus passing below the vocal folds) and airway penetration (defined as entry of material into the laryngeal vestibule but not below the level of the vocal folds) (Figure 2) are believed to be the most significant adverse clinical outcomes of misdirected bolus flow. In older adults, penetration of the bolus into the airway occurs more often and to a deeper and more severe level than in younger adults.[5] When the swallowing mechanism is functionally altered or perturbed in older people, such as with the placement of a nasogastric tube, airway penetration can be even more pronounced. A study examining this issue found that liquid penetrated the airway significantly more frequently when a nasogastric tube was in place in men and women older than 70 years.[1] That study and additional evidence indicates that under stressful conditions or system perturbations, older individuals are less able to compensate due to the age-related reduction in reserve capacity (add Pendergast reference) and are more at risk to experience airway penetration or aspiration. ### Age-related Change in Lingual Pressure Generation[edit] The tongue is the primary propulsive agent for pumping food through the mouth, into the pharynx while bypassing the airway and through to the esophagus. Recent findings clearly reveal that an age-related change in lingual pressures is another contributing factor to presbyphagia. Healthy older individuals demonstrate significantly reduced isometric (i.e., static) tongue pressures compared with younger counterparts. In contrast, maximal tongue pressures generated during swallowing (i.e., dynamic) remain normal in magnitude.[6][7] because, fortunately, swallowing is a submaximal pressure-demanding activity. In general, swallowing is considered a submaximal pressure task such that peak tongue pressures used in swallowing are lower than those generated isometrically. Although older individuals manage to achieve pressures necessary to affect a successful swallow, despite a reduction in overall maximum tongue strength, they achieve these pressures more slowly than young swallowers. It has been suggested that the slowness that characterizes senescent swallowing may reflect the increased time necessary to recruit sufficient motor units to generate pressures necessary to operate an effective, safe swallow. ## See also[edit] * Dysphagia * Swallowing ## References[edit] 1. ^ a b c d Robbins JA, Hamilton JW, Lof GL, Kempster G. Oropharyngeal swallowing in normal adults of different ages. Gastroenterology 1992;103:823-9. 2. ^ a b c Tracy F, Logemann JA, Kahrilas PJ, Jacob P, Kobara M, Krugla C. Preliminary observations on the effects of age on oropharyngeal deglutition. Dysphagia 1989;4:90-4. 3. ^ a b Shaw DW, Cook IJ, Dent J et al. Age influences oropharyngeal and upper esophageal sphincter function during swallowing. Gastroenterology 1990;98:A390. 4. ^ a b c Shaw DW, Cook IJ, Gabb M et al. Influence of normal aging on oropharyngeal and upper esophageal sphincter function during swallow. Am J Physiol 1995;L68:G389-G390. 5. ^ a b Robbins J, Coyle J, Roecker E, Rosenbek J, Wood J. Differentiation of normal and abnormal airway protection during swallowing using the penetration-aspiration scale. Dysphagia 1999;14:228-32. 6. ^ a b Robbins J, Levine R, Wood J, Roecker E, Luschei E. Age effects on lingual pressure generation as a risk factor for dysphagia. J Gerontol Med Sci 1995;50:M257-M262. 7. ^ a b Nicosia MA, Hind JA, Roecker EB, Carnes M, Robbins JA. Age effects on the temporal evolution of isometric and swallowing pressure. J Gerontol Med Sci 2000;55A:M634-M640. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Presbyphagia	c3532351	6,942	wikipedia	https://en.wikipedia.org/wiki/Presbyphagia	2021-01-18T19:00:09	{"umls": ["C3532351"], "wikidata": ["Q7240714"]}
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. (October 2013) 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: "Idiopathic childhood occipital epilepsy of Gastaut" – news · newspapers · books · scholar · JSTOR (October 2015) (Learn how and when to remove this template message) Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a pure but rare form of idiopathic occipital epilepsy that affects otherwise normal children and adolescents.[1] It is classified amongst benign idiopathic childhood focal epilepsies such as rolandic epilepsy and Panayiotopoulos syndrome.[2] ## Contents * 1 Presentation * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 4.1 Brain Magnetic Resonance Imaging * 4.2 Electroencephalography * 4.3 Differential diagnosis * 5 Management * 6 Prognosis * 7 Epidemiology * 8 References ## Presentation[edit] Seizures are purely occipital and primarily manifest with elementary visual hallucinations, blindness or both.[3][4] They are usually frequent and diurnal, develop rapidly within seconds and are brief, lasting from a few seconds to 1–3 min, and, rarely, longer.[citation needed] Elementary visual hallucinations are the most common and characteristic ictal symptoms, and are most likely to be the first and often the only clinical manifestation. They consist mainly of small multicoloured circular patterns that often appear in the periphery of a visual field, becoming larger and multiplying during the course of the seizure, frequently moving horizontally towards the other side. Other occipital symptoms, such as sensory illusions of ocular movements and ocular pain, tonic deviation of the eyes, eyelid fluttering or repetitive eye closures, may occur at the onset of the seizures or appear after the elementary visual hallucinations.[5] Deviation of the eyes, often associated with ipsilateral turning of the head, is the most common (in about 70% of cases) nonvisual ictal symptom. It is often associated with ipsilateral turning of the head and usually starts after visual hallucinations, although it may also occur while the hallucinations still persist. It may be mild, but more often it is severe and progresses to hemiconvulsions and secondarily generalised tonic clonic seizures (GTCS). Some children may have seizures of eye deviation from the start without visual hallucinations. Forced eyelid closure and eyelid blinking occur in about 10% of patients, usually at a stage at which consciousness is impaired. They signal an impending secondarily GTCS. Ictal blindness, appearing from the start or, less commonly, after other manifestations of occipital seizures, usually lasts for 3–5 min. It can occur alone and be the only ictal event in patients who could, at other times, have visual hallucinations without blindness. Complex visual hallucinations, visual illusions and other symptoms resulting from more anterior ictal spreading rarely occur from the start. They may terminate in hemiconvulsions or generalised convulsions. Ictal headache, or mainly orbital pain, may occur and often precedes visual or other ictal occipital symptoms in a small number of patients. Consciousness is not impaired during the visual symptoms (simple focal seizures), but may be disturbed or lost in the course of the seizure, usually before eye deviation or convulsions. Occipital seizures of ICOE-G may rarely progress to extra-occipital manifestations, such as hemiparaesthesia. Spread to produce symptoms of temporal lobe involvement is exceptional and may indicate a symptomatic cause. Post-ictal headache, mainly diffuse, but also severe, unilateral and pulsating, or indistinguishable from migraine headache, occurs in half the patients, in 10% of whom it may be associated with nausea and vomiting. Circadian distribution: Visual seizures are predominantly diurnal and can occur at any time of the day. Longer seizures, with or without hemi or generalised convulsions, tend to occur either during sleep, causing the patient to wake up, or after awakening. Thus, some children may have numerous diurnal visual seizures and only a few seizures that are exclusively nocturnal or occur on awakening. Frequency of seizures: If untreated, patients experience frequent and brief visual seizures (often several every day or weekly). However, propagation to other seizure manifestations, such as focal or generalised convulsions, is much less frequent. ## Cause[edit] There may be an increased family history of epilepsies (37% of cases) or migraine (16% of cases) but a family history of similar seizures is exceptional. ## Pathophysiology[edit] The seizures are of a purely occipital lobe origin. The mechanisms for postictal headache, which is a common event after minor idiopathic or symptomatic visual seizures, with or without a predisposition to migraine, are unknown. It is likely that the occipital seizure discharge triggers a genuine migraine headache through trigeminovascular or brainstem mechanisms. ## Diagnosis[edit] ### Brain Magnetic Resonance Imaging[edit] By definition of an idiopathic epilepsy, all tests other than the EEG are normal. However, high resolution brain magnetic resonance imaging is probably mandatory because of the high incidence of symptomatic occipital epilepsies with the same clinico-EEG manifestations. ### Electroencephalography[edit] The inter-ictal EEG shows occipital paroxysms, often demonstrating fixation-off sensitivity. However, some patients may only have random occipital spikes, whereas others may have occipital spikes only in the sleep EEG, and a few may have a consistently normal EEG. Photoparoxysmal abnormalities occur in patients whose seizures are triggered by lights.[6] Ictal EEG, preceded by regression of occipital paroxysms, is characterised by the sudden appearance of an occipital discharge that consists of fast rhythms, fast spikes or both. Ictal EEG during blindness show pseudo-periodic slow waves and spikes, which differ from those seen in ictal visual hallucinations. There are usually no postictal abnormalities. ### Differential diagnosis[edit] The differential diagnosis of ICOE-G is mainly from symptomatic occipital epilepsy and migraine where misdiagnosis is high. The differential diagnosis from migraine should be easy because elementary visual hallucinations of occipital seizures develop rapidly within seconds, are brief in duration (2–3 minutes) are usually colored and circular. These are fundamentally different from the visual aura of migraine which develops slowly in minutes, is longer lasting ≥5 minutes and mainly achromatic with linear patterns. Symptomatic occipital epilepsy often imitates ICOE-G; neuroophthalmological examination and brain imaging may be normal. Thus, high resolution MRI is required to detect subtle lesions. The differentiation of ICOE-G from Panayiotopoulos syndrome is straightforward. The seizures of ICOE-G are purely occipital, brief, frequent and diurnal. Conversely seizures in Panayiotopoulos syndrome manifest with autonomic manifestations, they are lengthy and infrequent; visual symptoms are rare and not the sole manifestation of a seizure. ## Management[edit] Patients with ICOE-G need prophylactic treatment mainly with carbamazepine or other antiepileptic drugs licensed for focal seizures. A slow reduction in the dose of medication 2 or 3 years after the last visual or other minor or major seizure should be advised, but if visual seizures reappear, treatment should be restored. ## Prognosis[edit] The prognosis of ICOE-G is unclear, although available data indicate that remission occurs in 50–60% of patients within 2–4 years of onset. Seizures show a dramatically good response to carbamazepine in more than 90% of patients. However, 40–50% of patients may continue to have visual seizures and infrequent secondarily generalized convulsions, particularly if they have not been appropriately treated with antiepileptic drugs. ## Epidemiology[edit] Onset is between 3 and 15 years of age with a mean of around 8. Both sexes are equally affected. The disorder accounts for about 2–7% of benign childhood focal seizures. ## References[edit] 1. ^ Caraballo, Roberto; Koutroumanidis, Michael; Panayiotopoulos, Chrysostomos P.; Fejerman, Natalio (2 December 2009). "Idiopathic Childhood Occipital Epilepsy of Gastaut: A Review and Differentiation From Migraine and Other Epilepsies". Journal of Child Neurology. 24 (12): 1536–1542. doi:10.1177/0883073809332395. PMID 19955346. S2CID 206547729. 2. ^ Panayiotopoulos, C. P.; Michael, M.; Sanders, S.; Valeta, T.; Koutroumanidis, M. (21 August 2008). "Benign childhood focal epilepsies: assessment of established and newly recognized syndromes". Brain. 131 (9): 2264–2286. doi:10.1093/brain/awn162. PMID 18718967. 3. ^ Gastaut H, Zifkin BG. Benign epilepsy of childhood with occipital spike and wave complexes. In: Andermann F, Lugaresi E, editors. Migraine and epilepsy. Boston: Butterworths; 1987. 47-81. 4. ^ Panayiotopoulos, C P (1 April 1999). "Elementary visual hallucinations, blindness, and headache in idiopathic occipital epilepsy: differentiation from migraine". Journal of Neurology, Neurosurgery & Psychiatry. 66 (4): 536–540. doi:10.1136/jnnp.66.4.536. PMC 1736305. PMID 10201433. 5. ^ "A Brief Treatment Of Ocular Migraine". 2016-08-01. Retrieved 2017-04-19. 6. ^ Parmeggiani L, Guerrini R. Idiopathic photosensitive occipital lobe epilepsy. In: Panayiotopoulos CP, editor. Atlas of epilepsies. London: Springer; 2010. 1077-1080. doi:10.1007/978-1-84882-128-6_158 [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Idiopathic childhood occipital epilepsy of Gastaut	None	6,943	wikipedia	https://en.wikipedia.org/wiki/Idiopathic_childhood_occipital_epilepsy_of_Gastaut	2021-01-18T18:57:47	{"orphanet": ["98816"], "synonyms": ["Late-onset benign childhood occipital epilepsy"], "wikidata": ["Q5988868"]}
Potocki-Lupski syndrome is a condition that results from having an extra copy (duplication) of a small piece of chromosome 17 in each cell. The duplication occurs on the short (p) arm of the chromosome at a position designated p11.2. This condition is also known as 17p11.2 duplication syndrome. Infants with Potocki-Lupski syndrome may have weak muscle tone (hypotonia) and swallowing difficulties (dysphagia) that lead to feeding problems. Some affected babies do not grow and gain weight at the expected rate (described as failure to thrive), and children with this condition tend to be shorter and weigh less than their peers. About 40 percent of babies with Potocki-Lupski syndrome are born with a heart defect, which in some cases is life-threatening. Babies and children with Potocki-Lupski syndrome have delayed development, including delayed speech and language skills and gross motor skills such sitting, standing, and walking. As they get older, affected individuals have intellectual disability, which is usually mild to moderate, and ongoing difficulties with speech. Potocki-Lupski syndrome is also associated with behavioral problems, which can include attention problems, hyperactivity, compulsive or impulsive behaviors, and anxiety. Many people with this condition have features of autism spectrum disorder, which affects social interaction and communication. Other signs and symptoms of Potocki-Lupski syndrome can include vision and hearing problems, dental and skeletal abnormalities, and abnormal kidney development and function. Many affected individuals have problems with sleep, including short pauses in breathing during sleep (sleep apnea) and trouble falling asleep and staying asleep. The condition can also have subtle differences in facial features, including outside corners of the eyes that point downward (down-slanting palpebral fissures), a triangular face with a broad forehead and a small jaw (micrognathia), and widely spaced eyes (hypertelorism). ## Frequency Potocki-Lupski syndrome affects an estimated 1 in 25,000 people worldwide. More than 50 affected individuals have been described in the medical literature. ## Causes Potocki-Lupski syndrome results from a duplication of genetic material at 17p11.2. In about two-thirds of affected individuals, the duplicated segment includes approximately 3.7 million DNA building blocks (base pairs), also written as 3.7 megabases (Mb). (A deletion of this segment causes a related condition called Smith-Magenis syndrome.) In the remaining one-third of cases, the duplication is larger or smaller, ranging from less than 1 Mb to almost 20 Mb. All of these duplications affect one of the two copies of chromosome 17 in each cell. Although the duplicated region contains multiple genes, researchers believe that having an extra copy of one particular gene, RAI1, underlies many of the characteristic features of Potocki-Lupski syndrome. All of the duplications known to cause the condition contain this gene. The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, this protein appears to control the expression of several genes involved in daily (circadian) rhythms, such as the sleep-wake cycle. Studies suggest that the duplication increases the amount of RAI1 protein, which disrupts the expression of genes that influence circadian rhythms. These changes may account for the sleep disturbances that occur with Potocki-Lupski syndrome. It is unclear how an extra copy of the RAI1 gene leads to intellectual disability and the other signs and symptoms of this condition. Extra copies of other genes at 17p11.2 likely also contribute to the features of this disorder; the role of these genes is under study. ### Learn more about the gene and chromosome associated with Potocki-Lupski syndrome * RAI1 * chromosome 17 ## Inheritance Pattern This condition has an autosomal dominant pattern of inheritance, which means one copy of a 17p11.2 duplication in each cell is sufficient to cause the disorder. Most cases of Potocki-Lupski syndrome result from a new (de novo) chromosomal duplication and occur in people with no history of the disorder in their families. Less commonly, an affected person inherits the duplication from one affected parent. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Potocki-Lupski syndrome	c2931246	6,944	medlineplus	https://medlineplus.gov/genetics/condition/potocki-lupski-syndrome/	2021-01-27T08:25:47	{"gard": ["10145"], "mesh": ["C538355"], "omim": ["610883"], "synonyms": []}
Prader-Willi-like syndrome is a rare, genetic, endocrine disease characterized by manifestations of a Prader-Willi syndrome phenotype (including obesity, hyperphagia, hypotonia, psychomotor delay, intellectual disability, small hands/feet, hypogonadism, growth hormone deficiency and characteristic facial features) ocurring in the absence of 15q11-q13 genomic abnormalities. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Prader-Willi-like syndrome	c3809877	6,945	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=398073	2021-01-23T17:01:15	{"icd-10": ["Q87.1"], "synonyms": ["PWS-like"]}
Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome is characterised by ichthyosis, hepatosplenomegaly and late-onset cerebellar ataxia. It has been described in two brothers. Transmission is either autosomal recessive or X-linked. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome	c1275088	6,946	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2274	2021-01-23T18:25:29	{"gard": ["1993"], "mesh": ["C535727"], "omim": ["242520"], "umls": ["C1275088"], "icd-10": ["Q87.8"], "synonyms": ["Dykes-Marks-Harper syndrome"]}
Pincer nail Other namesOmega nails,and Trumpet nails[1] SpecialtyDermatology Pincer nails are a toenail disorder in which the lateral edges of the nail slowly approach one another, compressing the nailbed and underlying dermis. It occurs less often in the fingernails than toenails, and there usually are no symptoms.[1][2]:788–9 Hereditary pincer nails have been described although the genes or mutations causing the hereditary form seem to be unknown.[3] ## See also[edit] * Nail anatomy * List of cutaneous conditions ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1032. ISBN 978-1-4160-2999-1. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Mimouni, D.; Ben-Amitai, D. (2002). "Hereditary pincer nail". Cutis; Cutaneous Medicine for the Practitioner. 69 (1): 51–53. PMID 11829181. * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Pincer nail	c0423806	6,947	wikipedia	https://en.wikipedia.org/wiki/Pincer_nail	2021-01-18T18:30:21	{"umls": ["C0423806"], "wikidata": ["Q7194880"]}
A number sign (#) is used with this entry because X-linked recessive hypophosphatemic rickets is caused by mutation in the CLCN5 gene (300008) on chromosome Xp11.22. For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see 193100. Description X-linked recessive hypophosphatemic rickets is a form of X-linked hypercalciuric nephrolithiasis, which comprises a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009. Clinical Features Bolino et al. (1993) reported an Italian family with X-linked recessive hypophosphatemic rickets. Five males presented with rickets or osteomalacia, hypophosphatemia, hypercalciuria, and proteinuria. The patients developed nephrocalcinosis with progressive renal failure in adulthood. Oudet et al. (1997) reported a French family with X-linked recessive hypophosphatemic rickets. Mapping In an Italian family with X-linked recessive hypophosphatemic rickets, Bolino et al. (1993) identified a putative disease locus on chromosome Xp11.2 at 0% recombination with DXS1039. Molecular Genetics In affected members of an Italian family with X-linked recessive hypophosphatemic rickets reported by Bolino et al. (1993), Lloyd et al. (1996) identified a mutation in the CLCN5 gene (S244L; 300008.0007). Oudet et al. (1997) reported a second family with the S244L mutation but with a milder phenotype than that in the family reported by Lloyd et al. (1996). The family reported by Oudet et al. (1997) had neither nephrocalcinosis nor nephrolithiasis. The affected individuals were, however, significantly younger than those of the family reported by Lloyd et al. (1996). INHERITANCE \- X-linked recessive GROWTH Height \- Short stature Other \- Poor growth GENITOURINARY Kidneys \- Proximal renal tubule defect \- Decreased renal tubular phosphate reabsorption \- Nephrocalcinosis \- Nephrolithiasis \- Renal insufficiency, progressive \- Renal failure in adulthood SKELETAL \- Rickets \- Osteomalacia \- Increased fractures \- Bone pain \- Sparse bone trabeculae \- Thin bony cortex Limbs \- Delayed opacification of the epiphyses \- Widened, distorted epiphyses \- 'Bulging' epiphyses \- Frayed, irregular metaphyses \- Lower limb deformities \- Bowing of the legs \- Curvatures of the femur, tibia, fibula \- Enlargement of the wrists \- Enlargement of the ankles LABORATORY ABNORMALITIES \- Hypophosphatemia \- Hypercalciuria \- Low-molecular-weight proteinuria \- Appropriately increased serum 1,25-dihydroxyvitamin D3 MISCELLANEOUS \- Variable phenotypic severity \- Female carriers may have asymptomatic hypercalciuria or hypophosphatemia only \- Part of 'Dent disease complex' (see 300009 ) MOLECULAR BASIS \- Caused by mutation in the chloride channel 5 gene (CLCN5, 300008.0007 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HYPOPHOSPHATEMIC RICKETS, X-LINKED RECESSIVE	c1839874	6,948	omim	https://www.omim.org/entry/300554	2019-09-22T16:20:07	{"doid": ["0080353"], "mesh": ["C545036"], "omim": ["300554"], "orphanet": ["1652", "93622"]}
A number sign (#) is used with this entry because Tangier disease (TGD) is caused by homozygous or compound heterozygous mutation in the ABCA1 gene (600046) on chromosome 9q31. A more common form of genetic HDL deficiency, familial HDL deficiency (604091), is allelic to Tangier disease. Description Tangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999). Clinical Features Tangier disease was originally described and named on the basis of a kindred living in Tangier Island in the Chesapeake Bay (Fredrickson et al., 1961), most of whom were descendants of first settlers of 1686. Other affected families have been discovered in Missouri and Kentucky. The 2 hallmarks of the disease, enlarged lipid-laden tonsils and low serum HDL, were based on the initial description of the original kindred. Engel et al. (1967) observed that patients with Tangier disease had recurrent peripheral neuropathy, intestinal lipid storage, and decreased serum alpha-lipoproteins. Obligate heterozygotes also had decreased serum alpha-lipoproteins. Kocen et al. (1967) described a 37-year-old British air force corporal with Tangier disease who showed widespread loss of pain and temperature sensation and progressive muscle wasting and weakness. They commented that, whereas the characteristic pharyngeal appearance had been the presenting feature in children, adolescents tended to present with relapsing peripheral neuropathy, and adults with hypersplenism or precocious coronary artery disease. Hypocholesterolemia was a tip-off to the diagnosis in a 38-year-old patient with Tangier disease described by Brook et al. (1977). Assmann et al. (1977) reported cases in Germany. Pietrini et al. (1985) reported a case they alleged to be the thirty-third in the 'world literature' and the second in Italy. A complete tabulation of the 33 cases was given. Age at diagnosis varied from 2 years to 67 years. The patient of Pietrini et al. (1985) had widespread neuropathy with facial diplegia, bilateral wasting of the hand muscles, and dissociated loss of pain and temperature sensation sparing the distal parts of the limbs, known as a 'syringomyelia-like' syndrome. First neurologic symptoms appeared at age 37; he burned the base of the neck by application of an excessively hot heating pad and noted induced sensation to heat and pain in some areas of the shoulder and later in the hand and arm. Levels of apoA-I (107680) and HDL cholesterol were very low and triglycerides were high. Pressly et al. (1987) described a 66-year-old man with Tangier disease and discussed the ocular complications, including corneal clouding, decreased corneal sensation, cicatricial ectropion, and slowly progressive visual impairment. The authors noted that ectropion and incomplete eyelid closure may precede corneal clouding. The combination of exposure keratopathy and corneal infiltration was responsible for the visual impairment in their patient. Dyck et al. (1978) studied a 67-year-old woman with typical biochemical features of Tangier disease and a syringomyelia-like syndrome that has been observed in other patients with adult onset. Over a period of 17 years, she had developed progressive facial diplegia, bilateral wasting of hand muscles, and loss of sensation over cranial, cervical, and brachial dermatomes. Schaefer et al. (1980) presented data consistent with increased risk for premature vascular disease in Tangier disease. However, the strikingly accelerated atherosclerosis of familial hypercholesterolemia (143890) was not seen, possibly because of the normal or reduced LDL cholesterol levels. Cheung et al. (1993) described a 48-year-old Caucasian female of central European origin with very low apoprotein A-I and A-II (107670) and low HDL cholesterol. She had most of the clinical features typical of Tangier disease, including early corneal opacities, yellow-streaked tonsils, hepatomegaly, and variable degrees of peripheral neuropathy, but no splenomegaly. She had a myocardial infarction at the age of 46. Schippling et al. (2008) reported a 49-year-old Afghan Caucasian patient with Tangier syndrome who presented with a 15-year history of a progressive syringomyelia-like syndrome with episodes of appendicular stabbing pain. He had tonsillectomy at age 14. Physical examination revealed marked distal atrophic weakness with absent tendon reflexes, loss of pain and temperature sensation, trophic changes of nails and skin, distal loss of facial hair, and mild splenomegaly. He had proximal internal carotid artery stenosis (60% left, 50% right) on color coded duplex sonography, left ventricular hypertrophy with reduced left ventricular function on echocardiography, and severe coronary artery disease with proximal LAD stenosis on coronary angiography. Laboratory studies showed undetectable serum HDL and decreased total cholesterol and apoA-I. Electrophysiologic studies demonstrated a predominantly axonal sensorimotor polyneuropathy with signs of chronic and active denervation and mild to moderate demyelination. Sural nerve biopsy showed de- and remyelination, endoneurial fibrosis, and deposition of fat droplets in axons and Schwann cells. Relatively low levels of HDL were also found in the patient's mother and the 2 daughters, consistent with heterozygosity. Genetic analysis identified a homozygous truncating mutation in the ABCA1 gene, consistent with complete loss of protein function. Pathogenesis Schmitz et al. (1985) showed that in macrophages, subsequent to receptor-mediated binding, HDL is internalized and then resecreted. Studying human monocytes from normal subjects and from patients with Tangier disease, Schmitz et al. (1985) found that HDL was internalized but only a minor amount, most of which was degraded, was resecreted from Tangier monocytes. They postulated that Tangier disease is a disorder of intracellular membrane traffic in which HDL is diverted into the lysosomal compartment and degraded instead of being secreted through its regular transcellular route. In contrast to 2 other monogenic HDL deficiencies in which defects in the plasma proteins APOA1 and LCAT (606967) interfere primarily with the formation of HDL, Tangier disease shows a defect in cell signaling and the mobilization of cellular lipids (Rust et al., 1998). Studies of cultured cells from the original Tangier kindred and others were pivotal in confirming the importance of the apolipoprotein-mediated pathway in cholesterol and phospholipid cellular efflux in the reverse cholesterol transport pathway (Remaley et al., 1999). Mapping Rust et al. (1998) mapped the Tangier disease phenotype to chromosome 9q31 using a genomewide graphical linkage exclusion strategy in 1 large pedigree complemented by classic lod score calculations at that region in a total of 3 pedigrees. The results yielded a combined lod score of 10.05 at D9S1784. The studies of a mentally retarded boy with a heterozygous de novo deletion of 9q22-q32 showed an HDL cholesterol level below the 2.5 percentile. The HDL cholesterol in the parents of the boy was normal. The findings in this boy were taken to support assignment of the Tangier disease locus, and suggested that the disorder results from a loss-of-function defect. Molecular Genetics In 2 probands with Tangier disease, Brooks-Wilson et al. (1999) identified compound heterozygous or homozygous mutations in the ABCA1 gene (600046.0001-600046.0003). One of the patients had presented with acute myocardial infarction at 38 years of age; the second patient was born of consanguineous parents and had been reported by Frohlich et al. (1987). Bodzioch et al. (1999) analyzed 5 kindreds with Tangier disease and identified 7 different mutations in the ABCA1 gene, including 3 that were predicted to impair the function of the gene product (see, e.g., 600046.0005-600046.0008). Rust et al. (1999) likewise identified mutations in the ABCA1 gene in Tangier disease (600046.0009-600046.0010). Remaley et al. (1999) demonstrated that in the original Tangier disease family (Fredrickson et al., 1961) the disorder was caused by homozygosity for a dinucleotide deletion in exon 22 of the ABCA1 gene (600046.0011). ### Exclusion of a Defect in the Apolipoprotein A-I Gene HDL is the designation of lipoproteins derived from density properties revealed by ultracentrifugation; alphalipoprotein is the designation based on mobility in an electrophoretic system. The apoproteins of the lipoproteins are named by their C-terminal amino acid (Schaefer et al., 1978). Lux et al. (1972) demonstrated a marked reduction in 1 of the 2 major apoproteins of high density lipoprotein, 'Apo-Gln-I' (Apo-I). Because no immunochemical difference could be demonstrated between this apoprotein of Tangier disease and that of normals, they concluded that Tangier disease could be caused by a mutation in a gene that regulates the synthesis of Apo-Gln-I. Schaefer et al. (1978, 1981) presented evidence suggesting that the deficiency of apolipoproteins in Tangier disease was largely due to increased rapid catabolism. Heterozygotes showed normal catabolism. Kay et al. (1982) concluded that apoA-I in Tangier disease is abnormal in amino acid composition, electrophoretic mobility, apparent molecular weight on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and heterogeneity of isoforms on isoelectric focusing. Schmitz et al. (1983) suggested that the underlying defect in Tangier disease is a faulty conversion of pro-apoA-I to mature apoA-I, either because of a defect in the converting enzyme activity or a specific structural defect in Tangier apoA-I. Thus, the failure of Tangier pro-apoA-I to associate with HDL may be at least partially responsible for the HDL deficiency in Tangier subjects. Bojanovski et al. (1987) found that both proapolipoprotein A-I and the mature protein are metabolized abnormally rapidly in Tangier disease. By restriction enzyme analysis, Rees et al. (1984) could demonstrate no major deletion or insertion in the apoA-I gene in a patient with Tangier disease. Law and Brewer (1985) derived the complete amino acid sequence from the nucleic acid sequence of a cloned apoA-I cDNA from liver of a patient with Tangier disease. The structure of Tangier preproapoA-I was identical to the normal preproapoA-I except for a single base substitution (G-to-T) that resulted in the isosteric substitution of aspartic acid for glutamic acid at position 120. These results were interpreted as indicating that there is no major structural defect in Tangier apoA-I and that the rapid rate of catabolism must be from a posttranslational defect in apoA-I metabolism. Specifically, a structural defect at the propeptide cleavage site, as suggested by Zannis et al. (1982), was excluded. Makrides et al. (1988) likewise concluded that the APOA1 gene is structurally normal in patients with Tangier disease. They isolated and characterized the gene from a lambda-L47.1 genomic library constructed with DNA from lymphocytes of a Tangier disease patient. The DNA-derived protein sequence of Tangier apoA-I was found to be identical to normal apoA-I. Transfection into mouse cells resulted in synthesis of a protein that was indistinguishable from the apoA-I secreted by cultured normal human cells. Population Genetics Young and Fielding (1999) stated that the inhabitants of Tangier Island in the Chesapeake Bay 'still speak a unique Elizabethan dialect, and three-quarters of them bear one of four surnames from the original group of founders.' History By identifying heterozygotes for Tangier disease, Suarez et al. (1982) excluded close linkage to RH, MN, GPT, and GLO. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial diplegia due to peripheral neuropathy Eyes \- Corneal opacities \- Decreased corneal sensation due to peripheral neuropathy \- Cicatricial ectropion \- Incomplete eyelid closure \- Exposure keratopathy \- Visual impairment Mouth \- Enlarged, yellow-orange tonsils CARDIOVASCULAR Heart \- Heart disease, premature \- Myocardial infarction \- Left ventricular hypertrophy Vascular \- Coronary artery disease, premature \- Atherosclerosis ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Dry skin Nails \- Dystrophic nails Hair \- Distal loss of facial hair MUSCLE, SOFT TISSUES \- Distal muscle atrophy due to peripheral neuropathy NEUROLOGIC \- Syringomyelia-like syndrome Peripheral Nervous System \- Peripheral axonal neuropathy \- Pain and temperature sensation loss \- Hyporeflexia \- Nerve biopsy showed demyelination, remyelination, and deposition of fat droplets in axons LABORATORY ABNORMALITIES \- Decreased serum HDL cholesterol \- Decreased or absent apolipoprotein A-I \- Accumulation of cholesterol esters in various tissues \- Deficient efflux of intracellular cholesterol MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily A, member 1 gene (ABCA1, 600046.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	TANGIER DISEASE	c0039292	6,949	omim	https://www.omim.org/entry/205400	2019-09-22T16:31:04	{"doid": ["1388"], "mesh": ["D013631"], "omim": ["205400"], "icd-10": ["E78.6"], "orphanet": ["31150"], "synonyms": ["Alternative titles", "HIGH DENSITY LIPOPROTEIN DEFICIENCY, TYPE 1", "HIGH DENSITY LIPOPROTEIN DEFICIENCY, TANGIER TYPE", "ANALPHALIPOPROTEINEMIA"]}
Prevalence of HIV/AIDS in adult (ages 15–49) populations (1999–2002) As of 2012[update], approximately 1,100,000 people in Malawi are HIV-positive, which represents 10.8% of the country's population.[1] Because the Malawian government was initially slow to respond to the epidemic under the leadership of Hastings Banda (1966–1994), the prevalence of HIV/AIDS increased drastically between 1985, when the disease was first identified in Malawi, and 1993, when HIV prevalence rates were estimated to be as high as 30% among pregnant women.[1] The Malawian food crisis in 2002 resulted, at least in part, from a loss of agricultural productivity due to the prevalence of HIV/AIDS.[1] Various degrees of government involvement under the leadership of Bakili Muluzi (1994–2004) and Bingu wa Mutharika (2004–2012) resulted in a gradual decline in HIV prevalence, and, in 2003, many people living in Malawi gained access to antiretroviral therapy.[1] Condoms have become more widely available to the public through non-governmental organizations, and more Malawians are taking advantage of HIV testing services.[1] Due to several successful television and radio campaigns by the Malawian government and non-governmental organizations in Malawi, levels of awareness regarding HIV/AIDS are high among the general population.[2] However, many men have adopted fatalistic attitudes in response to the epidemic, convincing themselves that death from AIDS is inevitable; on the other hand, some have implemented preventive techniques such as partner selection to try to reduce their risk of infection.[3] Although many women have developed strategies to protect themselves from HIV, women are more likely to be HIV-positive than men in Malawi.[1] The epidemic has affected sexual relationships between partners, who must cooperate to protect themselves from the disease.[4] In addition, many teachers exclude HIV/AIDS from their curricula because they are uncomfortable discussing the topic or because they do not feel knowledgeable about the issue, and, therefore, many children are not exposed to information about HIV/AIDS at school.[5] Finally, the epidemic has produced significant numbers of orphans in Malawi, leaving children vulnerable to abuse and exploitation.[6] ## Contents * 1 History * 2 Awareness and risk perception * 3 Education * 4 Affected groups * 4.1 Men * 4.2 Women * 4.3 Children * 5 Marriage and relationships * 6 Economic impact * 7 Impact on health services * 8 Interventions * 8.1 Antiretroviral therapy * 8.2 Condom distribution * 8.3 Voluntary counseling and testing * 9 See also * 10 References ## History[edit] Bingu wa Mutharika, third President of Malawi (2004–2012) The first case of HIV/AIDS in Malawi was reported at Lilongwe's Kamuzu Central Hospital in 1985.[7] President Hastings Banda, who was in power at the time, responded with several small-scale prevention initiatives and created the National AIDS Control Programme, a division of the Ministry of Health, to manage the growing epidemic.[1] Banda believed that issues relating to sex, including HIV transmission, should not be addressed in the public sphere; during this time, it was illegal for Malawian citizens to discuss the epidemic openly.[8] In 1989, Banda introduced a five-year World Bank Medium Term Plan to combat the epidemic, but HIV prevalence had already increased drastically at this point.[1] In 1994, when Bakili Muluzi became president, he addressed the nation's need for a coordinated response to the HIV/AIDS epidemic.[1] In 2000, Muluzi introduced another five-year policy known as the National Strategic Framework, but, like Banda's five-year World Bank Medium Term Plan, this plan was largely ineffective.[1] In 2001, in response to problems within the National AIDS Control Programme established by Banda, Muluzi created the National AIDS Commission.[1] Unlike Banda, who prevented the public from accessing information about the epidemic, Muluzi ensured that information about HIV/AIDS was available on the radio and television, in newspapers, and on billboards.[8] However, despite Muluzi's efforts, HIV prevalence was already significantly influencing national agricultural productivity during this period, and Malawi experienced an AIDS-related nationwide famine in 2002.[1] Malawians gained access to antiretroviral drugs in 2003, and, with a donation from the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the election of new President Bingu wa Mutharika in 2004, government interventions increased substantially.[1] However, soon after his election, Mutharika experienced tensions with Muluzi after implementing an anti-corruption program, which distracted the government from addressing the nation's food and HIV/AIDS-related crises.[9] Despite these obstacles, Mutharika successfully developed a National AIDS Policy and appointed a Principal Secretary for HIV/AIDS during his presidency.[1] ## Awareness and risk perception[edit] Partners in Health worker with disease treatment literature in Malawi Despite Malawi's limited health and educational infrastructure, knowledge regarding HIV/AIDS is high among many people living in both urban and rural Malawi.[2] According to a 2004 study by Barden-O'Fallon et al. involving 100 households, women in Malawi are most likely to learn about HIV/AIDS through radio and television, health workers at local clinics, and female members of their social networks.[2] Men are also likely to access information about HIV/AIDS through radio and television; however, unlike women, they are not likely to gain information about HIV/AIDS from their male friends.[2] When 57 Malawian men were interviewed in 2003, 100% of them said they had heard about the HIV/AIDS epidemic on the radio, and 84.2% of them said they had learned about HIV/AIDS during their visits to local health facilities; this supports the fact that many people in Malawi have access to information about the epidemic, both through the radio and other sources.[8] Personal traits such as age, gender, location, and education correlate, either positively or negatively, with HIV/AIDS awareness levels. For example, older women have demonstrated higher levels of knowledge regarding HIV/AIDS than younger women in Malawi.[2] Because men typically have greater access to education and other social resources, they are often more knowledgeable about HIV prevention and transmission than women.[2] While men are, on average, able to list 2.2 ways to prevent HIV transmission, women are only able to list 1.5 ways.[2] Only 38% of women surveyed in 2003-2004 understood that their husbands would be less likely to contract HIV if they used condoms during intercourse with prostitutes and other women from high-risk groups.[9] In addition, men who are raised in urban environments are, on average, more informed about HIV/AIDS than men who are raised in rural environments, presumably because urban children typically have greater access to educational resources than rural children.[2] Among both men and women, higher levels of education correspond to increased knowledge about HIV/AIDS: men and women who have received secondary school educations are significantly more likely to understand complex aspects of the disease, such as the fact that people who appear healthy can still be HIV-positive, than those who have not.[2] Finally, people who have lost friends or family members to the disease are likely to have greater knowledge about HIV/AIDS due to their personal, firsthand exposure to the problem.[2] The aforementioned study by Barden-O'Fallon et al., which surveyed 940 women and 661 men, indicated that, despite their knowledge and awareness, many people in Malawi do not feel personally susceptible to HIV infection.[2] On average, only 23% of the adults who were surveyed during this study, both male and female, believed that they were likely to contract HIV and die of AIDS.[2] Greater HIV/AIDS awareness among men does not seem to correspond with increased perceived risk; on the other hand, increased levels of knowledge about HIV/AIDS do correlate positively to perceived risk among women.[2] Another study conducted in rural Malawi between 1998 and 2001 by Kirsten P. Smith et al. indicated that concerns about personal vulnerability to HIV/AIDS declined during this four-year time frame, probably because the increased use of preventive strategies gave people a sense of control.[10] In fact, many participants in this study claimed that they were "not at all worried" about HIV/AIDS; unless they had simply adopted a fatalistic standpoint towards the epidemic, these respondents probably felt that they had successfully reduced their risk of exposure through personal behavioral changes.[10] ## Education[edit] Health Education Center in Blantyre, Malawi Students in Malawi have expressed high levels of dissatisfaction regarding the HIV/AIDS-related education and support they receive at school.[6] According to a survey of students in Malawi, most secondary students do not believe that the HIV/AIDS curricula at their schools provide them with an adequate understanding of the disease.[6] Although the Malawian government and non-governmental organizations have conducted many campaigns to improve awareness about HIV/AIDS in schools, there is still a significant shortage of age-appropriate audio and visual educational materials relating to HIV/AIDS available to instructors, particularly in rural areas.[6] In addition, most teachers cannot identify the students in their classes who have been personally affected by the epidemic, either through friends or relatives, which suggests that school-based support for HIV/AIDS is minimal.[6] However, despite this lack of support, surveys indicate that children who have been affected by the epidemic do not usually experience HIV/AIDS-based discrimination at school.[6] Most teachers are required to address HIV/AIDS in their curricula; although instructors are, for the most part, committed to helping their students understand and avoid the disease, they face many obstacles that prevent them from informing their students about HIV/AIDS in productive ways.[5] For example, some teachers cannot advise their students to remain faithful to their sexual partners without seeming hypocritical because they engage in extramarital sexual relations themselves.[5] Others feel uncomfortable discussing sexual matters with their students, and some believe that, due to their limited training, they are not knowledgeable enough about HIV/AIDS to direct classroom discussions about the disease.[5] In addition, many teachers feel unsupported by community members, who often either deny the extent of the epidemic or believe that HIV/AIDS should not be addressed in the classroom.[5] ## Affected groups[edit] Although the HIV/AIDS epidemic has affected men, women, and children in Malawi, certain factors such as sexual orientation, gender, and age influence infection patterns. In Malawi, HIV/AIDS is usually transmitted through heterosexual sex, but the epidemic has also significantly impacted the homosexual male population in Malawi.[1] In addition, women in Malawi are more likely to be HIV-positive than men, suggesting that women are particularly vulnerable to HIV/AIDS.[1] Finally, the disease has affected children and young adults both directly and indirectly; 170,000 Malawian children were HIV-positive in 2011, and the number of orphans in Malawi has increased dramatically since the epidemic began in 1985.[1] ### Men[edit] Due to the vast scope of the HIV/AIDS epidemic, many Malawian men believe that HIV contraction and death from AIDS are inevitable.[3] Older men in particular often claim that the HIV/AIDS epidemic is a punishment issued by God or other supernatural forces.[3] Other men refer to their own irresponsible sexual behaviors when explaining why they believe that death from AIDS is inevitable.[3] These men sometimes claim that unprotected sex is natural (and therefore necessary and good) when justifying their lack of condom use during sex with extramarital partners.[3] Finally, some men identify as HIV-positive without having undergone testing for HIV, preferring to believe that they have already been infected so they can avoid adopting undesirable preventive measures such as condom use or strict fidelity.[3] Because of these fatalistic beliefs, many men continue engaging in extramarital sexual relations despite the prevalence of HIV/AIDS in Malawi.[8] However, despite these widespread feelings of fatalism, some men believe that they can avoid HIV contraction by modifying their personal behaviors.[3] Men who decide to change their behaviors to reduce their risk of infection are unlikely to use condoms consistently, particularly during marital intercourse; instead, they usually continue engaging in extramarital sexual relations, but alter the ways in which they choose their sexual partners.[3] For example, before selecting extramarital sexual partners, men sometimes survey their peers to determine whether their potential partners are likely to have exposed themselves to the virus.[10] Men who choose their sexual partners based on external appearances and peer recommendations often believe that women who violate traditional gender norms by, for example, wearing modern clothing are more likely to carry HIV, while young girls, who are perceived as sexually inexperienced, are considered "pure."[3] Because of this perception, many people are concerned that schoolchildren in Malawi, particularly girls, are becoming exposed to the virus through sexual harassment or abuse by their instructors.[6] ### Women[edit] According to traditional gender roles in Malawi, men operate primarily in the formal work sector and are responsible for supporting their families through paid labor, whereas women, who are valued for their domestic skills, are responsible for agricultural labor and care work; this gender-based division of labor decreases women's autonomy, thereby increasing their vulnerability to HIV/AIDS.[9] Even within the home, women often lack bargaining power because they have limited access to education, formal employment, and other resources that could give them a sense of financial and personal independence.[9] Women who are able to work in the formal sector typically earn significantly less money than men, even when they are completing the same tasks, making it difficult for them to elevate their status.[9] Many women are convinced that their husbands are putting their lives at risk by engaging in extramarital sexual relations without using protection; however, because of their secondary status, they are often unwilling to initiate discussions about HIV/AIDS in the home.[9] Most women in Malawi do not view divorce as a viable option, even when their husbands are HIV-positive and refuse to protect them from the virus by wearing condoms during marital intercourse.[9] Because they lack the education and training needed to seek gainful employment, women are not usually able to support themselves and their children outside of marriage without resorting to commercial sex work for money.[9] However, despite their vulnerability, some women in rural Malawi believe that they do, to a certain extent, have control over their own health and well-being.[11] They tell their husbands that the HIV/AIDS epidemic has made sexual infidelity extremely dangerous and encourage them to refrain from engaging in extramarital sexual contact.[11] In addition, many women are convinced that, by appealing to the vulnerability of their children (who will probably be orphaned if their parents contract HIV), they can convince their husbands to use condoms consistently during extramarital sexual encounters.[11] Other women seek support from their friends and family members when they believe that their husbands' unsafe behaviors are putting their lives at risk.[11] Finally, as a last resort, women might warn their husbands that they will visit the ankhoswe, or traditional marriage counselor, and demand divorce if their husbands refuse to remain faithful and actively prevent the transmission of the disease.[11] ### Children[edit] AIDS orphans in Lilongwe, Malawi The number of orphaned children in Malawi has increased dramatically since the HIV/AIDS epidemic began in 1985, with certain surveys indicating that more than 35% of schoolchildren have experienced the death of at least one parent due to HIV/AIDS.[6] Because HIV is transmitted sexually, married couples who engage in unprotected sexual relations put their children at increased risk of becoming double orphans, or children who have lost both parents to HIV/AIDS.[6] Older children who have lost both parents to HIV/AIDS often become responsible for the care of their younger siblings, and many double orphans drop out of school or migrate to urban areas to try to support themselves and their siblings.[6] Girls who have been orphaned by HIV/AIDS have unusually high rates of school absenteeism in Malawi.[6] When parents die of HIV/AIDS, extended family members usually become the children's primary caregivers: in Malawi, 44% of double orphans are adopted by grandparents or other close relatives.[6] Extended family members often provide crucial support to HIV/AIDS orphans;[12] however, some sources indicate that extended family members mistreat orphans whose parents have died from HIV/AIDS.[6] For example, family members who are unable to support adopted children often arrange early marriages for female orphans, who may then become victims of domestic violence and sexual abuse.[6] Evidence suggests that schoolchildren in Malawi are at risk of being exposed to HIV by their teachers, who sometimes value them as sexual partners because they believe that children have not yet been exposed to the virus.[6] Children are particularly vulnerable to exploitation by adults who offer them money in exchange for sex; because they are often unable to afford basic necessities, they might feel compelled to accept gifts in exchange for sex out of desperation.[6] Interviews indicate that teachers and school administrators in Malawi often misinterpret the definition of sexual assault, as some believe that sexual relations between teachers and students are appropriate as long as the children have consented.[6] Although most schools have strict policies against sexual abuse, children are often hesitant to accuse adults of wrongdoing, and many administrators are unwilling or unable to investigate the truth behind the accusations.[6] ## Marriage and relationships[edit] Although couples are starting to use condoms during extramarital intercourse more frequently, condom use during marital sex is still viewed as inappropriate by many Malawians; in 2000, only 2.3% of people reported using condoms regularly during sexual intercourse with their spouses.[4] Some people believe that condoms are only necessary during sex with high-risk partners such as sex workers, and that condom use during marital sex implies infidelity.[4] Others believe that marital condom use violates the religious purposes of marriage: sexual pleasure and reproduction.[4] In a study published in 2007 by Agnes M. Chimbiri, men claimed that they use condoms with their wives for the sake of avoiding unwanted pregnancies; on the other hand, they were more concerned about sexually transmitted infections when discussing condom use with extramarital sexual partners.[4] Many different sources of information can motivate discussion about HIV/AIDS among married couples.[13] After hearing information about HIV/AIDS at local health facilities or during conversations with friends or family members, people are more likely to address the risk of HIV contraction with their spouses.[13] In addition, women are more likely than men to mention the dangers of HIV/AIDS when they suspect that their spouses are engaging in extramarital sexual relations. According to a 2003 study by Eliya Msiyaphazi Zulu and Gloria Chepngeno, although higher levels of education do correspond to greater knowledge about HIV/AIDS, education levels do not significantly impact the likelihood that couples will discuss HIV-related prevention strategies.[13] ## Economic impact[edit] Farmers with composting materials in Malawi A 2002 study conducted by CARE International across three districts in the Central Region of Malawi considers how HIV/AIDS has affected economic well-being in rural Malawi.[14] When skilled laborers are infected with HIV, they are usually unable to work; therefore, they often shift agricultural production on their land to less labor-intensive crops, sacrificing the opportunity to grow more profitable, labor-intensive crops such as tobacco.[15] When family members fall ill with HIV/AIDS, their relatives invest time in their treatment and care, further reducing household productivity.[14] In addition, when family members are infected with HIV, households often use the money they would normally invest in agriculture to cover medical expenses, further decreasing economic stability at the household level.[14] Finally, when adults contract HIV, their children often remain home from school to work in the fields, threatening long-term productivity and economic advancement in Malawi.[15] CARE International proposes several strategies that might reduce the destructive economic impact of HIV/AIDS on rural households.[14] They recommend introducing new technologies that improve productivity to allow households affected by HIV/AIDS to continue supporting themselves through agriculture.[14] Women in patrilineal/patrilocal villages are often unable to support themselves and their children when their husbands die of HIV/AIDS; therefore, helping women acquire traditionally masculine agricultural skills might decrease their vulnerability while improving agricultural productivity at the household and community levels.[14] CARE International recommends increasing cooperation at the community level by establishing labor and food banks in areas that have been devastated by the HIV/AIDS epidemic.[14] Finally, CARE International highlights the importance of increasing access to information about HIV/AIDS in Malawi to help families prepare for and cope with the economic burdens associated with the epidemic.[14] ## Impact on health services[edit] The HIV/AIDS epidemic in Malawi has been characterized by drastic declines in the number of health workers available to provide treatment and care and increasing strain on health services: more than half of all hospital admissions in Malawi are related to HIV/AIDS.[16] However, Malawi currently faces a significant deficit in human resources: only 159 doctors were practicing in Malawi in 2007.[17] The World Health Organization's Essential Health Package recommends placing at least three health workers at every health facility in the country, but the vast majority of Malawi's health facilities fail to meet this standard.[17] While migration to more developed countries in search of better opportunities, also known as "brain drain," is partially responsible for the shortage of health care workers in Malawi, many health care workers have been personally affected by the HIV/AIDS epidemic; in fact, an average of 48 nurses die of HIV/AIDS in Malawi every year.[1] The HIV/AIDS epidemic has resulted in high levels of absenteeism among health workers in Malawi, who often leave work to spend time with HIV-positive friends or relatives, and the Malawian government has failed to respond to the declining number of full-time employees working in the health sector.[16] Health workers who are not chronically absent frequently abandon their jobs because they are unable to cope with the heavy patient loads or because they are afraid that working in a medical environment will increase their risk of becoming infected with HIV.[16] Malawi has adopted task shifting strategies to overcome the shortage of workers available for HIV/AIDS treatment and care.[17] Task shifting, which has been successful in many other regions, involves training less specialized health workers to perform health-related tasks that do not require professional training, such as the initiation of antiretroviral therapy.[17] For example, at Thyolo District Hospital, health workers spend one week learning how to initiate antiretroviral therapy in a classroom setting and an additional two weeks practicing their knowledge in a supervised clinical setting; after completing this course, they are legally (under Ministry of Health guidelines) allowed to initiate antiretroviral therapy.[17] Another form of task shifting involves training health-oriented counselors in HIV testing and counseling, which relieves nurses of this additional task.[17] ## Interventions[edit] Malawi has taken many steps towards slowing the spread of HIV/AIDS, such as increasing access to condoms and improving testing services and treatment options.[1] Many of these efforts have been funded by international donors including the World Bank, the Global Fund, the World Health Organization, the President's Emergency Plan for AIDS Relief (PEPFAR), and the Joint United Nations Programme on HIV and AIDS (UNAIDS).[1] The World Bank has lent $407.9 million to Malawi, the Global Fund has agreed to give $390 million, and PEPFAR has donated $25 million for prevention and treatment campaigns.[1] ### Antiretroviral therapy[edit] The number of people using antiretroviral therapy in Malawi has increased dramatically in the past decade: between 2004 and 2011, an estimated 300,000 people gained access to antiretroviral treatment.[1] In addition to improving access to antiretroviral therapy, in 2008, Malawi introduced the World Health Organization's treatment guidelines for antiretroviral therapy, which improved the quality of treatment available to Malawians.[1] However, Malawi's proposal for a new antiretroviral treatment plan in 2011, which would have cost $105 million per year, was rejected by the Global Fund, threatening Malawi's ability to continue expanding access to antiretroviral treatment.[1] In 2000, Malawi's Ministry of Health and Population began developing a plan to distribute antiretroviral drugs to the population, and, as of 2003, there were several sites providing antiretroviral drugs in Malawi.[16] The Lighthouse, a trust in Lilongwe that fights HIV/AIDS, provides antiretroviral drugs at a cost of 2,500 kwacha per month.[16] Queen Elizabeth Central Hospital in Blantyre provides antiretroviral therapy through its outpatient department, and Médecins Sans Frontières distributes antiretroviral drugs to patients for free in the Chiradzulu and Thyolo Districts.[16] Many different private providers sell antiretroviral drugs, particularly in cities; however, very few patients can afford to receive drugs from the private sector in Malawi.[16] In addition, private providers are not currently required to obtain certification before selling antiretroviral drugs, and, therefore, this practice is not closely monitored.[16] Finally, some employees receive access to antiretroviral drugs through the health insurance policies provided by their employers, but this practice is not widespread.[16] Due to the advent of antiretroviral drugs, HIV/AIDS has become a manageable disease for people who can access and afford treatment; however, antiretroviral therapy remains largely unaffordable and inaccessible to most people in Malawi.[16] For example, the South East region of Malawi has disproportionately low access to antiretroviral drugs.[1] In many rural areas, poor health infrastructure combined with widespread famine have made sustained, high-quality antiretroviral therapy difficult or impossible.[1] In addition, donations from the Global Fund to Fight AIDS, Tuberculosis, and Malaria were used to fund antiretroviral therapy programs that distributed medication on a "first-come, first-served" basis, making the drugs more accessible to the male, urban, educated population.[16] Because there are no explicit policies regarding the fair distribution of antiretroviral drugs in Malawi, individual health care workers often become responsible for deciding who will receive treatment, which inevitably leads to inequitable distribution.[16] ### Condom distribution[edit] Although condoms effectively prevent the sexual transmission of HIV, several factors have limited widespread condom distribution and uptake in Malawi.[1] People living in non-urban areas often have difficulty accessing condoms, and condoms are not typically available at bars and other social locations where they could have a significant impact on HIV prevention.[1] Many people oppose condoms because they believe that condoms make sex less enjoyable or because they question their ability to prevent the transmission of HIV.[1] However, despite these factors, many unmarried couples have started using condoms more consistently as concern and fear about the HIV/AIDS epidemic have increased.[4] Non-governmental organizations such as Population Services International (Malawi), an organization that strives to improve the health of Malawians, and Banja La Mtsogolo, an organization that distributes information and resources related to family planning, have conducted campaigns advertising condom use as an effective form of protection against HIV/AIDS.[1] Banja La Mtsogolo provides condoms to both men and women, and has significantly improved the availability of condoms for women in particular.[1] Because of efforts by Population Services International, Banja La Mtsogolo, and many other organizations, condoms have become more widely available to many people in Malawi.[1] ### Voluntary counseling and testing[edit] People living in areas with high rates of HIV/AIDS face several psychological barriers when deciding whether to undergo testing for HIV.[1] For example, people may prefer not to know if they are HIV-positive because, due to the obstacles they often face in gaining access to antiretroviral drugs, many view HIV/AIDS diagnoses as death sentences.[1] Others may simply believe that they are HIV-negative, either because they practice strict monogamy and consistently use condoms during sexual intercourse or because they are in denial about the prevalence of the disease.[1] However, despite these barriers, both mobile and static testing services have become more widely available in Malawi recently: 1,392 testing and counseling sites existed in 2011.[1] Certain non-governmental organization such as the Malawi AIDS Counseling and Resource Organisation (MACRO) provide door-to-door counseling and testing services, which have drastically improved the accessibility of HIV testing.[7] ## See also[edit] * Malawi portal * Viruses portal * Sub-Saharan Africa * HIV/AIDS in Africa * Diseases of poverty * Epidemiology of HIV/AIDS * Misconceptions about HIV and AIDS * AIDS orphan * Healthcare in Malawi * Sex for Fish ## References[edit] 1. ^ 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 ag ah ai aj "HIV & AIDS in Malawi". AVERT. Retrieved 14 March 2014. 2. ^ a b c d e f g h i j k l m Barden-O'Fallon, Janine; Joseph Degraft-Johnson (2004). "Factors Associated with HIV/AIDS Knowledge and Risk Perception in Rural Malawi". AIDS and Behavior. 8 (2): 131–40. doi:10.1023/b:aibe.0000030244.92791.63. PMID 15187475. S2CID 9024663. 3. ^ a b c d e f g h i Kaler, Amy (2004). "AIDS-talk in Everyday Life: The Presence of HIV/AIDS in Men's Informal Conversation in Southern Malawi". Social Science & Medicine. 59 (2): 285–97. doi:10.1016/j.socscimed.2003.10.023. PMID 15110420. 4. ^ a b c d e f Chimbiri, Agnes (2007). "The condom is an 'intruder' in marriage: Evidence from rural Malawi". Social Science & Medicine. 64 (5): 1102–1115. doi:10.1016/j.socscimed.2006.10.012. PMID 17240504. 5. ^ a b c d e Kachingwe, Sitingawawo (2005). "Preparing Teachers as HIV/AIDS Prevention Leaders in Malawi: Evidence from Focus Groups". International Electronic Journal of Health Education. 8: 193–204. 6. ^ a b c d e f g h i j k l m n o p q r Mitchell, Claudia (2004). "The Impact of the HIV/AIDS Epidemic on the Education Sector in Sub-Saharan Africa: A Synthesis of the Findings and Recommendations of Three Country Studies (review)". Transformation: Critical Perspectives on Southern Africa. 54 (1): 160–63. doi:10.1353/trn.2004.0024. S2CID 154783763. 7. ^ a b Government of Malawi (2012). GLOBAL AIDS RESPONSE PROGRESS REPORT: Malawi Country Report for 2010 and 2011 (PDF) (Report). Retrieved 14 April 2014. 8. ^ a b c d Kalipeni, Ezekiel; Jayati Ghosh (2007). "Concern and practice among men about HIV/AIDS in low socioeconomic income areas of Lilongwe, Malawi". Social Science & Medicine. 64 (5): 1116–1127. doi:10.1016/j.socscimed.2006.10.013. PMID 17110008. 9. ^ a b c d e f g h Ghosh, Jayati; Ezekiel Kalipeni (2005). "Women in Chinsapo, Malawi: Vulnerability and Risk to HIV/AIDS". Journal of Social Aspects of HIV/AIDS. 2 (3): 320–32. doi:10.1080/17290376.2005.9724857. PMID 17600974. 10. ^ a b c Smith, Kirsten; Susan Watkins (2005). "Perceptions of Risk and Strategies for Prevention: Responses to HIV/AIDS in Rural Malawi". Social Science & Medicine. 60 (3): 649–660. doi:10.1016/j.socscimed.2004.06.009. PMID 15550312. 11. ^ a b c d e Schatz, Enid (2005). "'Take Your Mat and Go!': Rural Malawian Women's Strategies in the HIV/AIDS Era". Culture, Health & Sexuality. 7 (5): 479–92. doi:10.1080/13691050500151255. PMID 16864217. S2CID 11483329. 12. ^ Crampin, Amelia (2003). "The Long-term Impact of HIV and Orphanhood on the Mortality and Physical Well-being of Children in Rural Malawi". AIDS. 17 (3): 389–97. doi:10.1097/00002030-200302140-00013. PMID 12556693. S2CID 27946968. 13. ^ a b c Zulu, Eliya Msiyaphazi; Gloria Chepngeno (2003). "Spousal Communication about the Risk of Contracting HIV/AIDS in Rural Malawi". Demographic Research. 1: 247–78. doi:10.4054/demres.2003.s1.8. 14. ^ a b c d e f g h Impact of HIV/AIDS on agricultural productivity and rural livelihoods in the central region of Malawi. Malawi: CARE International. January 2002. pp. 5–10. 15. ^ a b Dorward, Andrew; Idrissa Mwale; Rosalba Tuseo (2006). "Labor Market and Wage Impacts of HIV/AIDS in Rural Malawi". Review of Agricultural Economics. 28 (3): 429–39. doi:10.1111/j.1467-9353.2006.00309.x. 16. ^ a b c d e f g h i j k l Kemp, Julia; Jean Marion Aitken; Sarah LeGrand; Biziwick Mwale (2003). "Equity in health sector responses to HIV/AIDS in Malawi". Regional Network for Equity in Health in Southern Africa (EQUINET). 17. ^ a b c d e f Bemelmans, Marielle; Thomas van den Akker; Nathan Ford; Mit Philips; Rony Zachariah; Anthony Harries; Erik Schouten; Katharina Hermann; Beatrice Mwagomba; Moses Massaquoi (2010). "Providing Universal Access to Antiretroviral Therapy in Thyolo, Malawi through Task Shifting and Decentralization of HIV/AIDS Care". Tropical Medicine & International Health. 15 (12): 1413–420. doi:10.1111/j.1365-3156.2010.02649.x. hdl:10144/116359. PMID 20958897. S2CID 33739153. * v * t * e HIV/AIDS in Africa Sovereign states * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde (Cabo Verde) * Central African Republic * Chad * Comoros * Democratic Republic of the Congo * Republic of the Congo * Djibouti * Egypt * Equatorial Guinea * Eritrea * Eswatini (Swaziland) * Ethiopia * Gabon * The Gambia * Ghana * Guinea * Guinea-Bissau * Ivory Coast (Côte d'Ivoire) * Kenya * Lesotho * Liberia * Libya * Madagascar * Malawi * Mali * Mauritania * Mauritius * Morocco * Mozambique * Namibia * Niger * Nigeria * Rwanda * São Tomé and Príncipe * Senegal * Seychelles * Sierra Leone * Somalia * South Africa * South Sudan * Sudan * Tanzania * Togo * Tunisia * Uganda * Zambia * Zimbabwe States with limited recognition * Sahrawi Arab Democratic Republic * Somaliland Dependencies and other territories * Canary Islands / Ceuta / Melilla (Spain) * Madeira (Portugal) * Mayotte / Réunion (France) * Saint Helena / Ascension Island / Tristan da Cunha (United Kingdom) * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HIV/AIDS in Malawi	None	6,950	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Malawi	2021-01-18T18:38:12	{"wikidata": ["Q5629863"]}
Ramsay Hunt (1921) described the association of generalized myoclonus and signs of cerebellar dysfunction, especially intention tremor, under the designation of dyssynergia cerebellaris myoclonica. Autopsy in 1 case confirmed his impression of a lesion in the dentate nucleus of the cerebellum. His cases were nonfamilial. Gilbert et al. (1963) described 2 females and 2 males in 3 sibships of a family with the combination of myoclonus and ataxia. Cerebrospinal fluid uric acid was elevated in 2. Autosomal dominant inheritance with reduced penetrance was suggested. Takahata et al. (1978) described an extensively affected family. The main lesion affected the cerebellar dentate nuclei. Neumann (1959) described combined degeneration of the globus pallidus and the dentate nucleus, and reports of autosomal dominant inheritance of the combination were referred to by Takahata et al. (1978). Berkovic et al. (1986) concluded that the Ramsay Hunt syndrome 'does not represent a specific disease, and its use should now be abandoned.' Berkovic et al. (1987) described 11 cases previously diagnosed as having the Ramsay Hunt syndrome (among more than 70 patients with progressive myoclonus epilepsy). Two had died; the remaining 9 patients included 3 sporadic cases and a family with 6 affected members. Reevaluation of these 9 living patients showed evidence of mitochondrial abnormalities in all: ragged-red fibers on muscle biopsy in 8 and abnormal mitochondria in a skin biopsy in the remaining case. From a study 'supported by a traveling grant from the University of Navarra and under the inspiration of the products of that region,' Marsden and Obeso (1989), 2 neurologists specializing particularly in movement disorders, argued for the usefulness of the designation 'Ramsay Hunt syndrome.' They concluded that many patients with progressive myoclonus and ataxia have no tonic-chronic seizures, although most have abnormal EEGs. Andermann et al. (1989) again argued that the Ramsay Hunt syndrome is no longer a useful diagnostic category. Harding (1989) took a middle-of-the-road position, insisting that 'the concept of the Ramsay Hunt syndrome is clinically useful as long as those using it remember that it is a syndrome, not a disease.' In the view of Harding (1989), there are undoubtedly cases of myoclonus, occasional tonic-chronic seizures, and ataxia in which no underlying cause such as mitochondrial myopathy, sialidosis, or ceroid lipofuscinosis can be demonstrated. Neuro \- Myoclonus \- Cerebellar ataxia \- Intention tremor \- Occasional tonic-clonic seizures Lab \- Lesion of cerebellar dentate nucleus \- Degeneration of globus pallidus \- Elevated cerebrospinal fluid uric acid \- Mitochondrial abnormalities \- Ragged-red fibers on muscle biopsy Inheritance \- Autosomal dominant \- heterogeneous ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MYOCLONUS AND ATAXIA	c1834580	6,951	omim	https://www.omim.org/entry/159700	2019-09-22T16:37:50	{"mesh": ["C535287"], "omim": ["159700"], "synonyms": ["Alternative titles", "RAMSAY HUNT SYNDROME"]}
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the persistence of thromboemboli in the form of organized tissue obstructing the pulmonary arteries. The consequence is an increase in pulmonary vascular resistance (PVR) resulting in pulmonary hypertension (PH) and progressive right heart failure. ## Epidemiology The true prevalence is unknown: CTEPH is a rare disease but recent reports suggest that it is underdiagnosed. ## Clinical description Patients commonly present with progressive dyspnea on exertion with or without signs of right heart dysfunction including fatigue, palpitations, syncope, or edema. A period between the initial event (acute embolism) and the development of clinical signs is common and may last from a few months to many years. However, up to 60% of patients have no history of acute pulmonary embolism. ## Etiology The pathophysiology of CTEPH is assumed to be associated with restricted flow through the pulmonary arteries, initially related to vascular obliteration caused by unresolved thromboemboli and subsequently to progressive vascular remodeling in unobstructed vessels. The underlying causes of the disease remain unknown. ## Diagnostic methods Diagnosis is suspected on the presence of mismatched segmental perfusion defects on ventilation-perfusion scanning. When CTEPH is suspected, pulmonary angiography and high-resolution CT scan are required to confirm the diagnosis and to assess operability. Pulmonary angiography is always performed in conjunction with diagnostic right heart catheterization, which is mandatory to confirm the diagnosis of PH and to determine the degree of hemodynamic impairment. ## Management and treatment If there is a good correlation between the PVR and the anatomical obstruction (evaluated by pulmonary angiography), pulmonary endarterectomy (PEA) must be proposed. Indeed, PEA is the treatment of choice whenever possible as it can restore near-normal cardiorespiratory function. In other cases, vasodilator and antiproliferative treatments, and lung or heart-lung transplantation represent treatment alternatives. However, further randomized trials are needed to assess the efficacy of medical therapies for some patients: 1) those with inoperable CTEPH due to distal lesions, 2) before PEA (therapeutic bridge) in patients considered as ``high risk'' due to extremely poor hemodynamics, and 3) in patients with persistent pulmonary hypertension after surgery. Indeed, several medical agents including bosentan, sildenafil, iloprost, treprostinil and epoprostenol have been evaluated in CTEPH, but none of them is approved for the treatment of CTEPH. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Chronic thromboembolic pulmonary hypertension	c2363973	6,952	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70591	2021-01-23T17:48:04	{"omim": ["612862"], "umls": ["C2363973"], "synonyms": ["CTEPH"]}
A rare neurologic disease characterized by global developmental delay, intellectual disability, multiple ischemic lesions in brain MRI, behavioral abnormalities, dystonia, choreic movements and pyramidal syndrome, facial dysmorphism (hypertelorism, arched palate, macroglossia), retinitis pigmentosa, scoliosis, seizures. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome	None	6,953	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314572	2021-01-23T17:00:18	{}
A number sign (#) is used with this entry because of evidence that childhood-onset epileptic encephalopathy (EEOC) is caused by heterozygous mutation in the CHD2 gene (602119) on chromosome 15q26. Description Childhood-onset epileptic encephalopathy (EEOC) is a severe form of epilepsy characterized by onset of multiple seizure types in the first few years of life and associated with poor prognosis. Affected individuals have cognitive regression and intellectual disability (summary by Carvill et al., 2013). Clinical Features Rauch et al. (2012) reported a German girl (MS134) with childhood-onset epileptic encephalopathy. She had delayed psychomotor development with an IQ of 50-69 and onset of absence seizures at age 5 years. Carvill et al. (2013) reported 6 unrelated patients with childhood-onset epileptic encephalopathy. The median age of seizure onset was 18 months (range, 1-3 years). All patients had myoclonic seizures in addition to variable seizure types, including absence, atonic, tonic, tonic-clonic, febrile, and status epilepticus. EEG studies showed multiple abnormalities. Four patients had developmental delay before the onset of seizures, 5 showed developmental regression after the onset of seizures, 3 had photosensitivity, and all had moderate to severe intellectual disability. One patient was diagnosed with autism spectrum disorder. The patients ranged in age from 2.5 to 29 years. Suls et al. (2013) reported 3 unrelated patients with onset of seizures associated with fever between the ages of 14 months and 3.5 years. All subsequently developed multiple seizure types, including myoclonic, atypical absence, generalized tonic-clonic, and status epilepticus, that were mostly therapy-resistant. EEG studies showed generalized polyspike-wave discharges. Two patients had normal development before the onset of seizures, whereas 1 patient had mildly delayed development before seizure onset. All had mild but persistent intellectual and neurologic impairment, including autism spectrum disorder in 1 patient. Petersen et al. (2018) reported a 5-year-old girl with global developmental delay, microcephaly, and seizures. Developmental delay was first noted at age 12 months, with delays in cognitive adaptive, clinical linguistic and auditory, and gross motor areas. Seizures began at at age 13 months in the context of a febrile illness and developed into medical refractory cryptogenic generalized epilepsy by age 2 years. She also had a diagnosis of attention deficit-hyperactivity disorder (ADHD). Her mother had a history of infantile meningitis, bipolar disorder, ADHD, language delays, and dyslexia. She had seizures that started at age 5 years and were well controlled. Her development was reportedly normal, and she completed high school in mainstream classes without difficulty. Molecular Genetics In a German girl (MS134) with childhood-onset epileptic encephalopathy, Rauch et al. (2012) identified a de novo heterozygous truncating mutation in the CHD2 gene (602119.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in either parent. The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism. In 6 unrelated patients with childhood-onset epileptic encephalopathy, Carvill et al. (2013) identified 6 different de novo heterozygous mutations in the CHD2 gene (see, e.g., 602119.0002-602119.0006). Four of the mutations were truncating, and 2 were missense substitutions at highly conserved residues. The mutations were found by targeted sequencing of known or candidate genes in 500 individuals with epileptic encephalopathies and thus accounted for 1.2% of cases. Carvill et al. (2013) postulated haploinsufficiency as the disease mechanism. They noted that mutations in the related CHD7 gene (608892) cause developmental abnormalities. In 3 unrelated patients with childhood-onset epileptic encephalopathy, Suls et al. (2013) identified 3 different de novo heterozygous mutations in the CHD2 gene (602119.0007-602119.0009). The mutations in the first 2 patients were found by whole-exome sequencing of 9 probands with a similar disorder. The third patient was identified by sequencing of the CHD2 gene in 150 probands with epileptic encephalopathy. Suls et al. (2013) postulated that haploinsufficiency for CHD2 was responsible for the phenotype, and suggested that helicase dysfunction in humans may result in neuronal hyperexcitability in the absence of dysmorphic features. In a 5-year-old proband with EEOC and her mildly affected mother, Petersen et al. (2018) identified a heterozygous nonsense mutation in the CHD2 gene (E210X; 602119.0010). The authors noted that this was the first known case of an inherited autosomal dominant pathogenic CHD2 variant in a clinically affected mother and daughter, and emphasized the importance of parental testing before providing recurrence risk estimates. Animal Model Suls et al. (2013) found that morpholino knockdown of Chd2 in zebrafish resulted in multiple developmental abnormalities, including pericardial edema, microcephaly, body curvature, absent swim bladder, and stunted growth. Mutant zebrafish larvae also showed abnormal movement patterns, such as twitching and trembling, associated with epileptiform discharges. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Photosensitivity (in some patients) NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Delayed psychomotor development \- Seizures \- Myoclonic seizures \- Atonic seizures \- Febrile seizures \- Absence seizures \- Tonic-clonic seizures \- Status epilepticus \- Psychomotor regression \- Mental retardation \- Abnormal EEG Behavioral Psychiatric Manifestations \- Autism spectrum disorder (rare) MISCELLANEOUS \- Onset between ages 1 to 3 years \- Patients can have multiple seizure types \- All reported cases have occurred de novo MOLECULAR BASIS \- Caused by mutation in the chromodomain helicase DNA-binding protein 2 gene (CHD2, 602119.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	EPILEPTIC ENCEPHALOPATHY, CHILDHOOD-ONSET	c0393702	6,954	omim	https://www.omim.org/entry/615369	2019-09-22T15:52:26	{"doid": ["0060475"], "mesh": ["D004831"], "omim": ["615369"], "orphanet": ["1942", "2382"], "genereviews": ["NBK333201"]}
Hyperosmia Pronunciation * /ˌhaɪpəˈrɒzmiə/[1] Hyperosmia is an increased olfactory acuity (heightened sense of smell), usually caused by a lower threshold for odor.[2] This perceptual disorder arises when there is an abnormally increased signal at any point between the olfactory receptors and the olfactory cortex. The causes of hyperosmia may be genetic, hormonal, environmental or the result of benzodiazepine withdrawal syndrome. When odorants enter the nasal cavity, they bind to odorant receptors at the base of the olfactory epithelium. These receptors are bipolar neurons that connect to the glomerular layer of the olfactory bulb, traveling through the cribriform plate.[3] At the glomerular layer, axons from the olfactory receptor neurons intermingle with dendrites from intrinsic olfactory bulb neurons: mitrial/tufted cells and dopaminergic periglomerular cells. From the olfactory bulb, mitral/tufted cells send axons via the lateral olfactory tract (the cranial nerve I) to the olfactory cortex, which includes the piriform cortex, entorhinal cortex, and parts of the amygdala.[3] From the entorhinal cortex, axons extend to the medial dorsal nucleus of the thalamus, which then proceed to the orbitofrontal cortex.[3] ## Contents * 1 Causes * 1.1 Genetics * 1.2 Environmental * 2 Treatment * 3 See also * 4 References * 5 External links ## Causes[edit] ### Genetics[edit] A study by Menashe et al. has found that individuals with a single nucleotide polymorphism variant in the OR11H7P pseudogene have a lower receptor activation threshold for isovaleric acid.[4] These individuals are hyperosmic for this single odorant. Another study by Keller et al. has found that people with the intact human odorant receptor OR7D4 are more sensitive to androstenone and androstadienone and thus find them unpleasant (individuals with the semi-functional OR7D4 have two non-synonymous single nucleotide polymorphisms in the OR7D4 pseudogene, resulting in two amino acid substitutions).[5] There has not yet been extensive research into the genetic background of those with general hyperosmia, rather than for just a single odorant. ### Environmental[edit] There has not been extensive research into environmental causes of hyperosmia, but there are some theories of some possible causes. In a study by Atianjoh et al., it has been found that amphetamines decrease levels of dopamine in the olfactory bulbs of rodents.[6] On this basis, it has been hypothesized that amphetamine use may cause hyperosmia in rodents and humans, but further research is still needed. Anecdotal support for the belief that amphetamines may cause hyperosmia comes from Oliver Sacks's account of a patient (who he later revealed to be himself) with a heightened sense of smell after taking amphetamines.[7] It has been observed that the inhalation of hydrocarbons can cause hyperosmia, most likely due to the destruction of dopaminergic neurons in the olfactory bulb.[8] Methotrexate, administered in the treatment of psoriasis, has been known to cause hyperosmia, and may be more likely to do so in patients with a history of migraines.[9] However, this is only an observation and not part of a study; therefore, it is yet to be verified. ## Treatment[edit] Normal olfactory acuity will usually return over time if the cause is environmental, even if it is untreated.[7][8] The hyperosmic person may need to be removed from strong odorants for a period of time if the sensation becomes unbearable.[8] Before they had been discontinued due to undesirable side effects, butyrophenones or thioridazine hydrochloride, both of which are dopamine antagonists, have been used to treat hyperosmia.[8] ## See also[edit] * Phantosmia * Hyposmia * Multiple chemical sensitivity, a condition that some believe is caused by a very acute sense of smell * Olfaction * Oliver Sacks * Benzodiazepine withdrawal syndrome * Parosmia ## References[edit] 1. ^ "hyperosmia". Merriam-Webster Dictionary. Retrieved 13 April 2020. 2. ^ Walker, HK (1990). Clinical Methods: The History, Physical, and Laboratory Examinations. Boston: Butterworths. pp. Ch 59. 3. ^ a b c Bear, Mark (2007). Neuroscience: Exploring the Brain. New York: Lippincott Williams and Wilkins. pp. 265–274. ISBN 978-0-7817-6003-4. 4. ^ Menashe, I; Abaffy, T; Hasin, Y; Goshen, S; Yahalom, V; Luetje, CW; Lancet, D (2007-10-30). "Genetic elucidation of human hyperosmia to isovaleric acid". PLoS Biology. 5 (11): e284. doi:10.1371/journal.pbio.0050284. PMC 2043052. PMID 17973576. 5. ^ Keller, A; Zhuang, H; Chi, Q; Vosshall, LB; Matsunami, H (2007-09-27). "Genetic variation in a human odorant receptor alters odour perception". Nature. 449 (7161): 468–72. doi:10.1038/nature06162. PMID 17873857. 6. ^ Atianjoh, FE; Ladenheim, B; Krasnova, IN; Cadet, JL (2008-07-28). "Amphetamine causes dopamine depletion and cell death in the mouse olfactory bulb". European Journal of Pharmacology. 589 (1–3): 94–7. doi:10.1016/j.ejphar.2008.05.001. PMC 2536718. PMID 18544452. 7. ^ a b Sacks, Oliver (1985). The Man Who Mistook His Wife for a Hat. New York: Simon & Schuster. pp. 156–160. ISBN 978-0-684-85394-9. 8. ^ a b c d Henkin, RI (1990-12-05). "Hyperosmia and depression following exposure to toxic vapors". JAMA: The Journal of the American Medical Association. 264 (21): 2803. doi:10.1001/jama.264.21.2803. PMID 2232068. 9. ^ Zargari, O (2006-12-10). "Methotrexate, hyperosmia, and migraine". Dermatology Online Journal. 12 (7): 28. PMID 17459314. Abstract. ## External links[edit] Classification D * ICD-9-CM: 781.1 * v * t * e Symptoms and signs relating to perception, emotion and behaviour Cognition * Confusion * Delirium * Psychosis * Delusion * Amnesia * Anterograde amnesia * Retrograde amnesia * Convulsion * Dizziness * Disequilibrium * Presyncope/Lightheadedness * Vertigo Emotion * Anger * Anxiety * Depression * Fear * Paranoia * Hostility * Irritability * Suicidal ideation Behavior * Verbosity * Russell's sign Perception * Sensory processing disorder * Hallucination (Auditory hallucination) * Smell * Anosmia * Hyposmia * Dysosmia * Parosmia * Phantosmia * Hyperosmia * Synesthesia * Taste * Ageusia * Hypogeusia * Dysgeusia * Hypergeusia [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hyperosmia	c0234259	6,955	wikipedia	https://en.wikipedia.org/wiki/Hyperosmia	2021-01-18T18:37:45	{"icd-9": ["781.1"], "wikidata": ["Q3144185"]}
Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome is an inherited epidermal disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules on the flexural side of large joints (cord-like distribution around wrists, in antecubital and popliteal folds), hyperkeratotic plaques (on neck, axillae, elbows, wrists, and knees), mild ichthyosiform scaling, and sclerotic constrictions around fingers that present flexural 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome	c1866029	6,956	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=281201	2021-01-23T18:34:38	{"mesh": ["C566600"], "omim": ["601952"], "umls": ["C1866029"], "icd-10": ["Q82.8"], "synonyms": ["KLICK syndrome"]}
A number sign (#) is used with this entry because of evidence that encephalopathy due to defective mitochondrial and peroxisomal fission-2 (EMPF2) is caused by homozygous or compound heterozygous mutation in the MFF gene (614785) on chromosome 2q36. Description Encephalopathy due to defective mitochondrial and peroxisomal fission-2 is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (summary by Koch et al., 2016). For a discussion of genetic heterogeneity of EMPF, see EMPF1 (614388). Clinical Features Shamseldin et al. (2012) reported 2 brothers, born of consanguineous Saudi Arabian parents, with EMPF2. The proband was a 4.5-year-old boy with delayed psychomotor development. He was unable to walk, but could stand supported and say a few words. He had borderline microcephaly, pale optic discs, and mild hypertonia with brisk reflexes, but no clonus. Brain MRI showed abnormal intensity of the globus pallidus. Lactate levels and mitochondrial respiratory chain complex profiles on skin fibroblasts were normal. He had a younger brother who showed similar developmental delay. Patient fibroblasts showed an abnormal tubular appearance of mitochondria and peroxisomes, suggesting a defect in the balance of fission and fusion in these organelles. Koch et al. (2016) reported 3 patients, including an Austrian boy and 2 sibs born of consanguineous Turkish parents, with EMPF2. All had onset of severe seizures within the first year of life, and EEG showed hypsarrhythmia, consistent with an epileptic encephalopathy. The patients had severely delayed psychomotor development or regression of milestones after onset of seizures. Other features included microcephaly, severe hypotonia with inability to sit, spasticity, hyperreflexia, visual impairment, external ophthalmoparesis, and lack of verbal communication. More variable features included pale optic discs, loss of vision, swallowing difficulties necessitating gastric tube feeding, and electrophysiologic evidence of a peripheral neuropathy. Brain imaging performed between 14 and 24 months of age showed signal abnormalities in the basal ganglia and thalamus, reminiscent of Leigh syndrome (256000), as well as progressive cerebellar atrophy. One patient developed abnormal signals in the optic radiations. One patient died of respiratory failure at age 3 years; he had never acquired trunk control. The other 2 patients were severely hypotonic without trunk control at ages 7 and 4 years, respectively. Plasma lactate tended to be normal, but was sometimes increased. Mitochondrial respiratory chain activities were normal in skeletal muscle, and laboratory studies did not show evidence of peroxisomal dysfunction. However, patient fibroblasts showed abnormally elongated peroxisomes and mitochondria compared to controls, suggestive of a fission defect. Inheritance The transmission pattern of EMPF2 in the families reported by Koch et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 brothers, born of consanguineous Saudi Arabian parents, with EMPF2, Shamseldin et al. (2012) identified a homozygous nonsense mutation in the MFF gene (Q64X; 614785.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. In 3 patients from 2 unrelated families with EMPF2, Koch et al. (2016) identified homozygous or compound heterozygous truncating mutations in the MFF gene (614785.0002-614785.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed normal levels of DRP1 (DNM1L; 603850), but there was abnormal diffuse intracellular localization of DRP1, suggesting that it was not properly recruited to mitochondrial fission nodes. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Eyes \- Optic atrophy \- Poor or absent fixation \- Visual impairment \- External ophthalmoplegia ABDOMEN Gastrointestinal \- Dysphagia MUSCLE, SOFT TISSUES \- Hypotonia, severe NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Regression of developmental skills \- Inability to walk \- Poor head and trunk control \- Absent speech \- Seizures \- Hypsarrhythmia \- Spasticity \- Hyperreflexia \- Lesions in the basal ganglia \- Cerebellar atrophy Peripheral Nervous System \- Peripheral neuropathy LABORATORY ABNORMALITIES \- Serum lactate may be normal of increased \- Fibroblasts show elongated peroxisomes \- Fibroblasts show elongated mitochondria \- Defect in mitochondrial fission \- Defect in peroxisomal fission MISCELLANEOUS \- Onset in infancy \- Progressive disorder \- Death in childhood may occur MOLECULAR BASIS \- Caused by mutation in the mitochondrial fission factor gene (MFF, 614785.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	ENCEPHALOPATHY DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL FISSION 2	c4310726	6,957	omim	https://www.omim.org/entry/617086	2019-09-22T15:46:56	{"omim": ["617086"], "orphanet": ["485421"], "synonyms": ["Leigh-like basal ganglia disease-optic atrophy-peripheral neuropathy syndrome", "Leigh-like encephalopathy-optic atrophy-peripheral neuropathy syndrome"]}
Weismann-Netter syndrome is a rare, genetic, primary, bent bone dysplasia characterized by anterior diaphyseal bowing of the tibia and fibula, broadening of the fibula, posterior cortical thickening of both bones and short stature. Additional skeletal abnormalities include scoliosis with marked lumbar lordosis, horizontal sacrum and square iliac wings and/or, less frequently, vertebral malformations, abnormal shape of the clavicles and ribs, calvarial hyperostosis and delayed eruption of permanent teeth. Delayed ambulation is also frequently 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Weismann-Netter syndrome	c1862172	6,958	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3344	2021-01-23T17:29:41	{"gard": ["5232"], "mesh": ["C537082"], "omim": ["112350"], "umls": ["C1862172"], "icd-10": ["Q77.8"], "synonyms": ["Anterior bowing of legs with dwarfism", "WNS", "Weismann-Netter-Stuhl syndrome"]}
Mild hemophilia B is a form of hemophilia B (see this term) characterized by a small deficiency of factor IX leading to abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction. ## Epidemiology Mild hemophilia B accounts for around 30% of all cases of hemophilia B. ## Clinical description The biological activity of factor IX is between 5 and 40%. Spontaneous hemorrhages do not occur. ## Etiology The disorder is caused by mutations in the F9 gene (Xq28) encoding coagulation factor IX. ## Genetic counseling Transmission is X-linked 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Mild hemophilia B	c0008533	6,959	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=169799	2021-01-23T17:23:51	{"mesh": ["D002836"], "omim": ["306900"], "icd-10": ["D67"], "synonyms": ["Mild factor IX deficiency"]}
A number sign (#) is used with this entry because episodic ataxia-1 (EA1) is caused by heterozygous mutation in the potassium channel gene KCNA1 (176260) on chromosome 12p13. Description Episodic ataxia is a neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia (Jen et al., 2007). ### Genetic Heterogeneity of Episodic Ataxia Episodic ataxia is a genetically heterogeneous disorder. See also EA2 (108500), caused by mutation in the CACNA1A gene (601011) on chromosome 19p13; EA3 (606554), which maps to chromosome 1q42; EA4 (606552); EA5, caused by mutation in the CACNB4 gene (601949) on chromosome 2q22-q23; EA6 (612656), caused by mutation in the SLC1A3 gene (600111) on chromosome 5p13; EA7 (611907), which maps to chromosome 19q13; and EA8 (616055), which maps to chromosome 1p36-p34. Isolated myokymia-2 (see 121200) is associated with mutation in the KCNQ2 gene (602235). Clinical Features VanDyke et al. (1975) described a kindred in which 11 persons in 3 consecutive generations had continuous muscle movement (myokymia) and periodic ataxia. Only 2 of the 11 affected were male and no male-to-male transmission was noted. Indeed, neither affected male had children. The disorder presented in early childhood with attacks of ataxia of 1 to 2 minutes in duration, with associated jerking movements of the head, arms, and legs. Attacks were provoked by abrupt postural change, emotional stimulus, and caloric-vestibular stimulation. Myokymia of the face and limbs began at about age 12 years. Physical findings included large calves, normal muscle strength, and widespread myokymia of face, hands, arms, and legs, with a hand posture resembling carpopedal spasm. EMG at rest showed continuous spontaneous activity. Gastrocnemius biopsy showed changes consistent with denervation, as well as enlargement of muscle fibers. The same disorder was reported in 2 other families (Hanson et al., 1977; Gancher and Nutt, 1986). Brunt and van Weerden (1990) described a large family with paroxysmal ataxia and continuous myokymic discharges. There was at least 1 instance of male-to-male transmission. Often a postural tremor of the head and hands and fine twitching in the face and hand muscles were present. The attacks, which usually lasted a few minutes, might occur several times a day. They first appeared in childhood and tended to abate after early adulthood. The attacks were frequently precipitated by kinesigenic stimuli similar to the phenomenon observed in paroxysmal kinesigenic choreoathetosis (128200). In about half the adults, fine rippling myokymia could be detected on close inspection; in a few, it was obvious. Brunt and van Weerden (1990) concluded that the myokymic activity resulted from multiple impulse generation in peripheral nerves. Vaamonde et al. (1991) described the disorder in a 26-year-old woman who had had episodic unsteadiness lasting for a few minutes since the age of 6 years. The mother and 1 sister were identically affected. Electromyographic studies revealed myokymia (neuromyotonia). Phenytoin produced good control of the symptoms but acetazolamide was ineffective. Lubbers et al. (1995) studied 6 affected individuals in a 4-generation pedigree in which paroxysmal ataxia and myokymia were linked to markers on chromosome 12p in affected individuals who demonstrated kinesigenic provocation, attacks being brought on by repeat knee bends or sudden rising from a chair. Myokymic discharges were invariably demonstrable electromyographically, although not all affected members showed clinical myokymia. One affected family member also had attacks of paroxysmal kinesigenic choreoathetosis (see 601042 for kinesigenic choreoathetosis that has been mapped to chromosome 1p). Members of Lubbers' kindred responded to low doses of acetazolamide, although there was some loss of efficacy after prolonged treatment. Graves et al. (2010) reported 2 unrelated sets of monozygotic twins with genetically confirmed EA1 who showed remarkably different phenotypes. In the first family, twin sisters had onset of symptoms at ages 14 and 16 years, respectively. One sister had daily episodes lasting from 10 to 15 minutes and required maintenance on carbamazepine, whereas her twin had a less severe phenotype with weekly episodes lasting 5 to 10 minutes and did not require medication. Both had dizziness, slurred speech, and incoordination of the hands during attacks, but the more severely affected sister also had unsteady gait, weakness, and myokymia. In the second family, 1 twin brother had onset at age 1 year of weekly episodes lasting seconds to 10 minutes; medication was not required. His twin brother had onset at age 6 years of daily episodes lasting seconds to 3 minutes; carbamazepine was not effective. The attacks in both brothers were characterized by imbalance, weakness, blurred vision, slurred speech, myokymia, and incoordination of the hands. These symptoms were less severe in the first brother, although he had associated vertigo, headache, and nausea. Their affected mother had a progressive interictal cerebellar syndrome with ataxia and dysarthria. The report indicated that nongenetic factors play a role in the severity of EA1. ### Isolated Myokymia Isolated spontaneous muscle twitches occur in many persons and have no grave significance. Wieczorek and Greger (1962) described a dominant pedigree with myokymia. Sheaff (1952) observed myokymia in a man and his 4 sons. In a portion of muscle removed for biopsy, fasciculations persisted for 8 minutes. Affected persons probably have an increased frequency of muscle cramps ('night cramps'). A syndrome of continuous muscle fiber activity was described by Ashizawa et al. (1983). Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid were increased in the proband. Referred to as continuous motor neuron discharge, the disorder was present in 7 members of 3 generations. McGuire et al. (1984) described the syndrome of continuous muscle fiber activity in a 3-year-old boy and his 28-year-old mother. The boy had shown persistent fisting from the age of 4 months. Previously the family had observed diminished spontaneous motor activity with flexion contractures of the lower limbs. Cardiopulmonary studies, prompted by recurrent episodes of peripheral cyanosis, showed eventration of both diaphragms with poor motion. Increased muscle tone and stiffness persisted during sleep. EMG showed continuous motor unit activity which continued despite peripheral nerve blockade or general anesthesia. Phenytoin sodium effected 'considerable improvement.' The cyanotic episodes disappeared after plication of the diaphragms and phenytoin therapy. The mother had demonstrated persistent stiffness and fisting in early childhood. No form of medication was beneficial until phenytoin was given at age 8 for suspected seizures. She was still taking phenytoin at age 28 and showed toxic effects with a serum level of 36 mg/L. With decreased dosage, serpentine movements of the fingers and lower eyelids appeared. After discontinuation of phenytoin, myokymia continued in sleep and transient stiffness developed after initiation of movements. Chen et al. (2007) reported a family in which a mother and 3 sons had isolated myokymia without epilepsy or episodic ataxia. The proband was a 13-year-old boy who was diagnosed with cerebral palsy due to leg stiffness and showed delayed walking at age 18 months. At age 4 years, he was hospitalized with increasing leg pain, stiffness, and inability to walk during a flu-like illness. Serum creatine kinase was elevated during the acute attack. Examination showed periorbital myokymia, spastic gait, hyperreflexia, and extensor plantar responses. EMG studies showed continuous motor unit discharges. His mother and 2 affected brothers showed a similar phenotype; 3 of the patients also had esotropia. The 3 brothers were asymptomatic with carbamazepine treatment. Genetic studies identified a heterozygous mutation in the KCNA1 gene (176260.0014) that segregated with the disorder. Chen et al. (2007) noted that patients in this family showed unusual features, such as extensor plantar responses suggestive of corticospinal tract involvement and worsening of symptoms with febrile illness or anesthesia. ### Association With Hypomagnesemia Glaudemans et al. (2009) studied a large 5-generation Brazilian family segregating autosomal dominant hypomagnesemia, in which 21 of 46 family members were affected. Beginning in infancy, the proband had recurrent muscle cramps, tetanic episodes, tremor, and muscle weakness, especially in the distal limbs. The proband reported several episodes during which she was 'not able to walk straight,' but no objective clinical signs of cerebellar dysfunction were apparent on examination; cerebral MRI showed slight atrophy of the cerebellar vermis. A younger brother had died in infancy from a severe attack of cramps and tetany, during which time his serum magnesium was as low as 0.28 mmol/l. Serum electrolyte levels measured during severe episodes of cramps and tetany in 2 affected family members revealed low serum magnesium with normal calcium and potassium concentrations; urinary magnesium excretion was normal, suggesting impaired tubular magnesium reabsorption, and urinary calcium excretion was normal. During the course of the study, the proband was hospitalized due to a sudden episode of facial myokymia, tremor, severe muscle spasms, muscular pain, cramps, muscular weakness, and intermittent tetanic contraction, all of which improved shortly after intravenous magnesium administration. Electromyographs of some affected family members showed myokymic discharge. Mapping Using a group of Genethon markers from a region of 12p carrying the potassium channel genes, Litt et al. (1993, 1994) demonstrated linkage in 4 AEMK kindreds. A maximum combined lod score of 13.6 was obtained with the marker D12S99 at theta = 0. They were prompted to study linkage to this region because potassium channel genes, e.g., KCNA1 and KCNA2 (176262), mapped there. The KCNA5 gene (176267) also maps to that region but was ruled out as the site of the defect by the observation of a single crossover between the disease gene and a (CA)n repeat marker in the KCNA5 cosmid. Studies of a large episodic ataxia family with a clinical phenotype that lacks myokymia but is associated with nystagmus (108500) excluded the gene causing that disease from the chromosome 12p region. In a 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia, Glaudemans et al. (2009) performed SNP-based linkage analysis that identified a 14.3-cM locus on chromosome 12q. Fine mapping with microsatellite markers narrowed the region of interest to an 11.6-cM interval between D12S1626 and D12S1623, with a maximum multipoint lod score of 3.0. Molecular Genetics Browne et al. (1994) demonstrated mutations in the KCNA1 gene in 4 families with AEMK (176260.0001-176260.0004). A different missense point mutation was present in heterozygous state in each. All affected individuals are heterozygous. In 2 families with myokymia without ataxic episodes, Eunson et al. (2000) identified mutations in the KCNA1 gene (176260.0010-176260.0011). One of these families also segregated seizures. In a 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia mapping to chromosome 12q, Glaudemans et al. (2009) identified a heterozygous missense mutation in the KCNA1 gene (N255D; 176250.0015) that segregated with the disease and was not found in 100 control chromosomes. ### Reviews For a comprehensive review of episodic ataxia type 1 and its causative mutations, see Brandt and Strupp (1997). Jen et al. (2007) provided a detailed review of the pathophysiology and molecular genetics of known episodic ataxia syndromes. Animal Model Using homologous recombination, Herson et al. (2003) introduced the Kcna1 val408-to-ala mutation (V408A; 176260.0001) into mice. In contrast to Kcna1 null mice, homozygous V408A mice died after embryonic day 3, consistent with V408A being a homozygous lethal allele. V408A heterozygous mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, similar to patients with EA1. Cerebellar Purkinje cells from V408A heterozygous mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents than did wildtype. The authors noted that Kcna1 is localized to GABAergic interneurons in the cerebellum, suggesting that it may be important for regulating GABA release, and that mutations in the gene may alter excitability in the cerebellum, leading to clinical symptoms. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Vertigo, episodic Eyes \- Blurred vision, episodic SKELETAL Hands \- Hand posture resembling carpopedal spasm, episodic MUSCLE, SOFT TISSUES \- Calf muscle enlargement \- EMG shows polyphasic continuous motor unit discharges \- Muscle biopsy shows enlargement of type I muscle fibers, consistent with denervation NEUROLOGIC Central Nervous System \- Ataxia, episodic \- Dysarthria \- Slurred speech \- Dizziness \- Incoordination of the hands \- Leg stiffness \- Spastic gait \- Coarse tremor \- Headache \- Hyperreflexia \- Extensor plantar responses (reported in 1 family) Peripheral Nervous System \- Myokymia, interictal \- Jerking movements of face and limbs LABORATORY ABNORMALITIES \- Increased serum creatine kinase during episodes MISCELLANEOUS \- Onset in childhood \- Highly variable severity \- Symptoms precipitated by sudden movement, stress, exertion, fatigue, illness \- Typical attacks last from seconds to minutes, but longer occurrences have been reported \- Aura may occur \- Some patients may develop interictal progressive ataxia \- Variable response to acetazolamide and carbamazepine MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, shaker-related subfamily, member 1 gene (KCNA1, 176260.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	EPISODIC ATAXIA, TYPE 1	c1834559	6,960	omim	https://www.omim.org/entry/160120	2019-09-22T16:37:50	{"doid": ["0050989"], "mesh": ["C563545"], "omim": ["160120"], "orphanet": ["972", "37612"], "synonyms": ["Alternative titles", "EPISODIC ATAXIA WITH MYOKYMIA", "ATAXIA, EPISODIC, WITH MYOKYMIA", "PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY", "MYOKYMIA WITH PERIODIC ATAXIA"], "genereviews": ["NBK25442"]}
A papulopustular condition is a condition composed of both papule and pustules.[1] Examples of papulopustular conditions include: * Papulopustular rosacea * Papulopustular acne * Sycosis ## References[edit] 1. ^ thefreedictionary.com > papulopustular citing: * The American Heritage® Medical Dictionary Copyright © 2007 * Mosby's Medical Dictionary, 8th edition. © 2009 * Miller-Keane Encyclopedia & Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. 2003 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Papulopustular	c2609319	6,961	wikipedia	https://en.wikipedia.org/wiki/Papulopustular	2021-01-18T18:52:58	{"umls": ["C2609319"], "wikidata": ["Q7133233"]}
Cono-spondylar dysplasia is a rare genetic primary bone dysplasia disorder characterized by early-onset severe lumbar kyphosis, marked brachydactyly and irregular, pronounced cone epiphyses of the metacarpals and phalanges. Additional reported features include developmental delay, intellectual disability, hypotonia, epileptic seizures and mild facial dysmorphism (incl. long and thin or square-shaped face, slight mid-face hypoplasia, hypertelorism, epicanthic folds, low-set ears, anteverted nostrils). Radiographic findings also reveal hypoplasia of iliac wings and anterior defect of vertebral bodies. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Cono-spondylar dysplasia	c4707860	6,962	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=420794	2021-01-23T17:07:08	{"icd-10": ["Q77.7"], "synonyms": ["Short stature-kyphosis-hypoplasia of basal ilia-cone epiphyses-facial dysmorphism syndrome"]}
Fumaric aciduria (FA), an autosomal recessive metabolic disorder, is most often characterized by early onset but non-specific clinical signs: hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies. Some patients present with only moderate intellectual impairment. ## Epidemiology FA is very rare, fewer than 100 cases have been reported to date. ## Clinical description Newborns are frequently microcephalic and may present with facial dysmorphisms. Severe encephalopathy manifests with poor feeding, failure to thrive, hypotonia, lethargy and epileptic seizures. In the most severe cases APGAR scores are low immediately following birth, and bradycardia and respiratory failure may follow. Most children do not achieve visual fixation and are unable to speak or walk. Less severely affected individuals survive beyond childhood, most nonetheless displaying moderate cognitive impairment. Some patients have been reported to present with only moderate cognitive deficits. An increased risk of certain tumors has also been reported, in particular familial leiomyomatosis (see this term). ## Etiology FA is caused by mutations in the FH gene (1q42.1) encoding fumarate hydratase, an enzyme that catalyzes the transformation of fumarate into malate in the Krebs cycle. Complete deletions of FH have been reported to be fatal, whereas more mildly affected individuals retain some residual enzymatic activity. ## Diagnostic methods Chromatography of organic acids provides evidence of excreted fumaric acid, often associated with succinic acid and alphacetoglutaric acid. Hyperlactacidemia and moderate hyperammonemia are other common findings. Diagnosis can be confirmed by measuring fumarate hydratase activity in leukocytes or cultured fibroblasts. Brain MRI reveals a variety of anomalies including cerebral atrophy, enlarged ventricles and enlarged extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum and an abnormally small brain stem. Developmental malformations including bilateral polymicrogyria and absence of the corpus callosum may also be observed. ## Differential diagnosis An elevated level of fumaric acid in urine may be caused by metabolic stress; therefore testing for fumaric aciduria must be repeated after the patient has been stabilized. Differential diagnoses include polymicrogyria and Leigh syndrome (see these terms). ## Antenatal diagnosis Polyhydramnios, intrauterine growth delay and premature birth occur in over one third of cases. Fetal ultrasound reveals enlarged cerebral ventricles and other brain abnormalities. ## Genetic counseling FA is transmitted as an autosomal recessive trait. ## Management and treatment Only symptomatic treatment is available to FA patients. Gastrostomy may be necessary to facilitate feeding in newborns. Therapies to control seizures should not include a ketogenic diet, which is contraindicated for this family of enzymatic defects. Physical therapy to reduce scoliosis and improve mobility may be helpful in some cases. Special education and occupational therapy are required to attempt to improve motor skills and language development in less severely affected cases. For patients that survive long-term, regular tumor testing is required. ## Prognosis Prognosis is poor, except for those patients with only moderate cognitive impairment. Complete losses of enzymatic activity are fatal during childhood with severe psychomotor handicap: verbal communication and independent mobility remain limited. Some milder cases have been reported to survive longer, a diagnosis that is most likely underestimated. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Fumaric aciduria	c0342770	6,963	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=24	2021-01-23T17:55:35	{"gard": ["6476"], "mesh": ["C538191"], "omim": ["606812"], "umls": ["C0342770", "C2936826"], "icd-10": ["E88.8"], "synonyms": ["Fumarase deficiency"]}
Say et al. (1986) reported 2 brothers with microcephaly, dysmorphic facies, developmental delay, and hypoglobulinemia. Their facial similarity was striking, with sloping forehead, beaked nose, large and protruding ears, micrognathia, and high-arched palate. One brother had craniosynostosis. Both brothers had hypogonadism, flexion contractures, hypoplastic patellae, and scoliosis. They also showed low levels of serum gammaglobulins in infancy reaching normal levels by 3.5 years and 15 months, respectively. Defective chemotaxis and recurrent infections were present from the beginning and persisted to age of report, age 7 in the older brother. Carpenter et al. (1996) provided a brief follow-up of the patients reported by Say et al. (1986) at ages 18 and 19 years. Both boys had recurrent infections since birth, and they also developed skeletal changes consistent with multiple epiphyseal dysplasia and the autoimmune phenomena of recurrent panniculitis and erythema nodosum. Treatment with gammaglobulin every 3 weeks improved their condition. Linkage analysis showed that the brothers both inherited the same maternal alleles at Xp22.2-p21.2, suggesting X-linked inheritance. Perandones et al. (1996) reported a 13-year-old boy with severe microcephaly, mental retardation, short stature, and recurrent infections. Dysmorphic features included a sloping forehead, metopic suture synostosis, abnormal hairlines, sparse eyebrows, hypertelorism, upslanting palpebral fissures, prominent nasal bridge, high-arched palate, irregular dental implantation, multiple caries, micrognathia, and low-set, posteriorly rotated ears. He also had flexion contractures of the limbs, ulnar deviation of the fingers with clinodactyly of the fifth fingers, dislocated hips, hypoplastic and displaced patellae, scoliosis, hypogonadism, cryptorchidism, and eczematous skin. Laboratory studies showed defective neutrophil chemotaxis. Perandones et al. (1996) suggested that this patient had the same syndrome as that described by Say et al. (1986). Carpenter et al. (2000) stated that the 2 brothers reported by Say et al. (1986) developed macular degeneration and pigmented retinal lesions resembling retinitis pigmentosa. Laboratory studies showed normal IgG levels but IgG subclass deficiencies and decreased cellular immunity. Nijmegen syndrome (NBS; 251260), ADA deficiency (102700), cartilage-hair hypoplasia (CHH; 250250), and Lowry-Wood syndrome (226960) were excluded. Carpenter et al. (2000) suggested that their patients had the disorder reported by Roifman (1999) (300258). In a reply, however, Roifman (2000) noted several phenotypic differences and differences in specific immunodeficiencies between the 2 disorders and disputed that the 2 disorders were the same entity. HEENT \- Microcephaly \- Sloping forehead \- Beaked nose \- Large ears \- Protruding ears \- Micrognathia GU \- Hypogonadism Inheritance \- Autosomal recessive Immunology \- Newborn gammaglobulin deficiency \- Defective chemotaxis \- Recurrent infections Skel \- Flexion contractures \- Hypoplastic patellae \- Scoliosis ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MICROCEPHALY WITH CHEMOTACTIC DEFECT AND TRANSIENT HYPOGAMMAGLOBULINEMIA	c2931267	6,964	omim	https://www.omim.org/entry/251240	2019-09-22T16:25:12	{"mesh": ["C536618"], "omim": ["251240"], "orphanet": ["3132"]}
Inherited thyroxine-binding globulin deficiency is a genetic condition that typically does not cause any health problems. Thyroxine-binding globulin is a protein that carries hormones made or used by the thyroid gland, which is a butterfly-shaped tissue in the lower neck. Thyroid hormones play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). Most of the time, these hormones circulate in the bloodstream attached to thyroxine-binding globulin and similar proteins. If there is a shortage (deficiency) of thyroxine-binding globulin, the amount of circulating thyroid hormones is reduced. Researchers have identified two forms of inherited thyroxine-binding globulin deficiency: the complete form (TBG-CD), which results in a total loss of thyroxine-binding globulin, and the partial form (TBG-PD), which reduces the amount of this protein or alters its structure. Neither of these conditions causes any problems with thyroid function. They are usually identified during routine blood tests that measure thyroid hormones. Although inherited thyroxine-binding globulin deficiency does not cause any health problems, it can be mistaken for more serious thyroid disorders (such as hypothyroidism). Therefore, it is important to diagnose inherited thyroxine-binding globulin deficiency to avoid unnecessary treatments. ## Frequency The complete form of inherited thyroxine-binding globulin deficiency, TBG-CD, affects about 1 in 15,000 newborns worldwide. The partial form, TBG-PD, affects about 1 in 4,000 newborns. These conditions appear to be more common in the Indigenous (native) population of Australia and in the Bedouin population of southern Israel. ## Causes Inherited thyroxine-binding globulin deficiency results from mutations in the SERPINA7 gene. This gene provides instructions for making thyroxine-binding globulin. Some mutations in the SERPINA7 gene prevent the production of a functional protein, causing TBG-CD. Other mutations reduce the amount of this protein or alter its structure, resulting in TBG-PD. Researchers have also described non-inherited forms of thyroxine-binding globulin deficiency, which are more common than the inherited form. Non-inherited thyroxine-binding globulin deficiency can occur with a variety of illnesses and is a side effect of some medications. ### Learn more about the gene associated with Inherited thyroxine-binding globulin deficiency * SERPINA7 ## Inheritance Pattern Inherited thyroxine-binding globulin deficiency has an X-linked pattern of inheritance. The SERPINA7 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes partial or complete inherited thyroxine-binding globulin deficiency. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell reduces the amount of thyroxine-binding globulin. However, their levels of this protein are usually within the normal range. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Inherited thyroxine-binding globulin deficiency	c4016583	6,965	medlineplus	https://medlineplus.gov/genetics/condition/inherited-thyroxine-binding-globulin-deficiency/	2021-01-27T08:25:03	{"omim": ["314200"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that EBS with mottled pigmentation is caused by heterozygous mutation in the keratin-5 gene (KRT5; 148040) on chromosome 12q13. Mutation in the same gene causes several other forms of epidermolysis bullosa simplex, including EBS Dowling-Meara type (131760), EBS Koebner type (131900), and EBS Weber-Cockayne type (131800). Similar disorders may also be caused by mutation in the keratin-14 gene (148066). Clinical Features Fischer and Gedde-Dahl (1979) reported a Swedish family in which 11 members presented with epidermolysis bullosa simplex with some unusual features, 10 of whom (1 male and 9 females) had a congenital mottled appearance of the skin. Both anomalies were inherited together in an autosomal dominant pattern. Recurrent blistering from birth resembled that of EBS Koebner, but in addition the patients showed 2- to 5-mm hyper- and hypopigmented spots giving the skin, especially of the limbs, a mottled 'dirty' appearance. 'Premature aging of the skin,' mild bruisability of the legs, and longitudinally curved nails were other features. The pigmentary anomaly was delayed in some individuals. Linkage with GPT (138200) on chromosome 8q was excluded. The epidermolysis without dyspigmentation in the eleventh individual suggested to the authors that the syndrome in the other 10 members may be due to genetic linkage of 2 independent genes and not to pleiotropism of a single mutant gene. Matthews and Peachey (1977) reported a father and daughter with EBS with pigmentation and palmar and plantar keratosis; pigmentation was delayed. Reports of other families (Sparrow et al., 1976; Verbov, 1980; Boss et al., 1981) suggested pleiotropism. Histologically and ultrastructurally, the blistering in EBS with mottled pigmentation closely resembles that found in other EBS subtypes. This is consistent with a disorder of the basal keratinocyte cytoskeleton in which disease-causing mutations have been found within the central rod domains of keratins 5 and 14 (KRT14; 148066) (Irvine et al., 1997). Glasz-Bona et al. (2010) reported a large 4-generation Hungarian pedigree with EBSMP. There were 10 affected members, 5 of whom were deceased. All had localized blistering and skin fragility in childhood, followed by the development of brownish, lentigo-like mottled pigmentation and hypopigmentation on the trunk and/or extremities during adolescence and adulthood. Two patients also had nail dystrophy. Molecular Genetics In 2 unrelated families with EBSMP, Uttam et al. (1996) identified a mutation in the KRT5 gene (P25L; 148040.0009). The same mutation was found in a sporadic case (Irvine et al., 1997) and in 2 additional families (Irvine et al., 2001), increasing the total number of EBSMP kindreds with this mutation to 7. In affected members of a Hungarian family with EBD-MP, Glasz-Bona et al. (2010) identified a heterozygous P25L mutation in the KRT5 gene. Animal Model Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (see 164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Epidermolysis bullosa simplex \- Blistering at acral sites \- 'Mottled' pigmentation of the trunk and proximal extremities \- Discrete 2 to 5-mm hyper- and hypopigmented macules \- Punctate palmoplantar hyperkeratosis (later onset) \- Degeneration of basal epidermal cells \- Basal cell layer contains clumped keratin filaments Nails \- Dystrophic nails \- Thickened nails MISCELLANEOUS \- Onset in childhood of blistering and pigmentary changes \- May have seasonal variance in severity \- Allelic disorder to EBS Dowling-Meara ( 131760 ), EBS Koebner ( 131900 ), and EBS Weber-Cockayne ( 131800 ) \- Disorders with overlapping phenotypes can be caused by mutation in the keratin-14 gene ( 148066 ) MOLECULAR BASIS \- Caused by mutation in the keratin-5 gene (KRT5, 148040.0009 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION	c0432316	6,966	omim	https://www.omim.org/entry/131960	2019-09-22T16:41:33	{"doid": ["0111346"], "mesh": ["C535959"], "omim": ["131960"], "orphanet": ["79397"], "synonyms": ["Alternative titles", "SPECKLED HYPERPIGMENTATION WITH PUNCTATE PALMOPLANTAR KERATOSES AND CHILDHOOD BLISTERING"], "genereviews": ["NBK1369"]}
A number sign (#) is used with this entry because of evidence that AICAR transformylase/IMP cyclohydrolase deficiency is caused by compound heterozygous mutation in the ATIC gene (601731) on chromosome 2q35. One such patient has been reported. Clinical Features Marie et al. (2004) described a 4-year-old girl who presented with a devastating neurologic picture involving profound mental retardation, epilepsy, dysmorphic features, and congenital blindness. Dysmorphic features included cutaneous dimples on the extensor side of knees, elbows, and shoulders. By age 12 months, bilateral atrophic pigmented chorioretinal macular lesions had developed with optic atrophy, and abnormal electroretinograms and visual evoked potentials were observed. Chromatograms of the patient's urine revealed 3 peaks seen neither in control individuals' urine nor in that of ADSL (608222)-deficient patients (103050). The major peak was identified as 5-amino-4-imidazolecarboxamide riboside (AICA-riboside), on the basis of a positive Bratton-Marshall test, spectral analysis, and spiking with the authentic compound. AICA-riboside is the nucleoside corresponding to AICAR (AICA-ribotide, also termed ZMP), an intermediate of the de novo purine biosynthetic pathway. AICA-riboside is formed by dephosphorylation of AICAR, most likely by IMP-GMP 5-prime-nucleotidase. When Marie et al. (2004) incubated fibroblasts from their patient with AICA-riboside, they observed accumulation of AICAR not observed in control cells, suggesting impairment of the final steps of purine biosynthesis, catalyzed by the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase (ATIC; 601731). AICAR transformylase was profoundly deficient, whereas the IMP cyclohydrolase level was 40% of normal. The presence of massive amounts of AICA-riboside in the patient's urine and the accumulation of AICAR and its derivatives in her erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a clear indication of deficiency in the enzyme that utilizes this intermediate de novo purine biosynthesis, the bifunctional enzyme encoded by the ATIC gene. Molecular Genetics Marie et al. (2004) performed sequence analysis of the ATIC gene in their patient with AICA-ribosuria and found compound heterozygosity for mutations. A missense mutation (K426R; 601731.0001) in the transformylase region was inherited from the father, and a frameshift mutation caused by a duplication/deletion event (601731.0002) was inherited from the mother. The missense mutation was located within a conserved region implicated in the binding of a potassium ion in the avian protein (Greasley et al., 2001). This potassium ion has been proposed to play a key role in stabilization of the tertiary structure of the protein. In expression studies, recombinant protein carrying the K426R mutation completely lacked AICAR-TF activity but still showed IMP-CH activity. Pathogenesis In skin fibroblasts derived from the patient reported by Marie et al. (2004), Baresova et al. (2012) found that immunostaining for ATIC was almost undetectable and that there was no signal overlap with other enzymes of the de novo purine synthesis (DNPS) pathway in a purine-depleted medium compared to controls, suggesting impaired assembly of the purinosome. Baresova et al. (2012) suggested that ATIC deficiency and altered purinosome formation could explain the accumulation of AICA-riboside and other cytotoxic intermediates of the DNPS pathway in patient tissues. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Brachycephaly Face \- Prominent forehead Ears \- Low-set ears Eyes \- Congenital blindness \- Optic atrophy Nose \- High nasal bridge \- Anteverted nares Mouth \- Wide mouth \- Thin upper lip CARDIOVASCULAR Heart \- Atrial septal defect GENITOURINARY External Genitalia (Female) \- Prominent clitoris \- Fused labia minora SKIN, NAILS, & HAIR Skin \- Cutaneous dimples (knees, elbows, shoulders) NEUROLOGIC Central Nervous System \- Mental retardation, profound \- Seizures \- Hypotonia LABORATORY ABNORMALITIES \- Positive urinary Bratton-Marshall test \- Elevated urinary and CSF 5-amino-4-imidazolecarboxyamide (AICA-riboside) \- Elevated erythrocyte AICAR (ZMP) \- Deficient fibroblast AICAR-TF activity MISCELLANEOUS \- One patient has been reported (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the AICAR formyltransferase/IMP cyclohydrolase gene (ATIC, 601731.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE DEFICIENCY	c1837530	6,967	omim	https://www.omim.org/entry/608688	2019-09-22T16:07:22	{"mesh": ["C563876"], "omim": ["608688"], "orphanet": ["250977"], "synonyms": ["Alternative titles", "ATIC DEFICIENCY", "AICA-RIBOSURIA DUE TO ATIC DEFICIENCY"]}
Triangular alopecia Other namesTemporal alopecia and Temporal triangular alopecia[1] (TTA) TTA is inherited in an autosomal dominant pattern. Triangular alopecia is hair loss that may be congenital but usually appears in childhood as a focal patch of loss that may be complete or leaving fine vellus hairs behind.[2]:643 Affected individuals are typically entirely healthy. Hair restoration surgery using follicular unit transplantation has been a successful treatment modality for TTA ## Contents * 1 Presentation * 1.1 Association with Other Conditions * 2 Frequency * 3 See also * 4 References ## Presentation[edit] ### Association with Other Conditions[edit] TTA has been associated with several disorders, such as Phakomatosis pigmentovascularis. And a rare syndrome Setleis syndrome. It is inherited by the autosomal dominant trait and is characterized by cutis aplasia or atrophic skin at the temples, which is said to resemble forceps marks. There may also be a coarse facial appearance, anomalies of the eyelashes and eyebrows, and periorbital puffiness.[3] ## Frequency[edit] The suggested frequency for this condition in the general population is around 0.11%. The hair loss is non-progressive and does not expand beyond these areas. It is a non-inflammatory, non-scarring form of hair loss easily confused with alopecia areata. In one report, the condition was incorrectly believed by the parents to be induced by doctors inserting intravenous cannulas into scalp vessels during the neonatal period. The condition is permanent and the affected skin does not change later in life.[4] Of the 53 reported cases of TTA, more than half (55.8%) were detected in childhood between the ages of 2 and 9 years, while 36.5% were detected at birth and only 3.8% (only two cases) in adulthood.[5] ## See also[edit] * Alopecia * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 996. ISBN 978-1-4160-2999-1. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ http://www.medscape.com/viewarticle/585158_5 4. ^ "Other alopecias - congenital triangular alopecia". 5. ^ 26955-temporal-triangular-alopecia-and-a-review-of-52-past-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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Triangular alopecia	c1274874	6,968	wikipedia	https://en.wikipedia.org/wiki/Triangular_alopecia	2021-01-18T18:55:22	{"umls": ["C1274874"], "wikidata": ["Q8196331"]}
Nullisomic is a genetic condition involving the lack of both the normal chromosomal pairs for a species (2n-2).[1] Humans with this condition will not survive.[2] ## Causes[edit] Nullisomy is caused by non-disjunction, during meiosis that causes two of the gametes to have no chromosomal material, leaving the other two gametes to have double the amount of chromosomal material (disomic). Due to the lack of genetic information, the nullisomic gametes are rendered unviable for fertilization.[3] ## See also[edit] * Monosomic * Trisomic ## References[edit] 1. ^ HAKANSSON, ARTUR (2010). "Meiosis In a Nullisomic and in an Ayndetic Godetia Whitneyi". Hereditas. 29 (1): 179–190. doi:10.1111/j.1601-5223.1943.tb02722.x. 2. ^ http://www.molecular-plant-biotechnology.info/mutations/nullisomic.htm Archived December 19, 2007, at the Wayback Machine 3. ^ Cunningham F, Leveno K.J., Bloom S.L., Spong C.Y., Dashe J.S., Hoffman B.L., Casey B.M., Sheffield J.S. (2013). Genetics. In Cunningham F, Leveno K.J., Bloom S.L., Spong C.Y., Dashe J.S., Hoffman B.L., Casey B.M., Sheffield J.S. (Eds), Williams Obstetrics, Twenty-Fourth Edition. Retrieved September 28, 2015 from http://accessmedicine.mhmedical.com/content.aspx?bookid=1057 Archived 2017-09-26 at the Wayback Machine Look up nullisomic in Wiktionary, the free dictionary. This genetic disorder 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Nullisomic	None	6,969	wikipedia	https://en.wikipedia.org/wiki/Nullisomic	2021-01-18T18:51:55	{"wikidata": ["Q3346253"]}
Congenital plasminogen deficiency is a disorder that results in inflamed growths on the mucous membranes, which are the moist tissues that line body openings such as the eyelids and the inside of the mouth. Development of the growths are usually triggered by infections or injury, but they may also occur spontaneously in the absence of known triggers. The growths may recur after being removed. Congenital plasminogen deficiency most often affects the conjunctiva, which are the mucous membranes that protect the white part of the eye (the sclera) and line the eyelids. A characteristic feature of this disorder is ligneous conjunctivitis, in which a buildup of a protein called fibrin causes inflammation of the conjunctiva (conjunctivitis) and leads to thick, woody (ligneous), inflamed growths that are yellow, white, or red. Ligneous conjunctivitis most often occurs on the inside of the eyelids. However, in about one-third of cases, ligneous conjunctivitis over the sclera grows onto the cornea, which is the clear covering that protects the colored part of the eye (the iris) and pupil. Such growths can tear the cornea or cause scarring. These corneal problems as well as obstruction by growths inside the eyelid can lead to vision loss. People with congenital plasminogen deficiency may also develop ligneous growths on other mucous membranes, including the inside of the mouth and the gums; the lining of the nasal cavity; and in females, the vagina. Growths on the mucous membranes that line the gastrointestinal tract may result in ulcers. The growths may also develop in the windpipe, which can cause life-threatening airway obstruction, especially in children. In a small number of cases, affected individuals are born with impaired drainage of the fluid that surrounds and protects the brain and spinal cord (the cerebrospinal fluid or CSF), resulting in a buildup of this fluid in the skull (occlusive hydrocephalus). It is unclear how this feature is related to the other signs and symptoms of congenital plasminogen deficiency. ## Frequency The prevalence of congenital plasminogen deficiency has been estimated at 1.6 per one million people. This condition is believed to be underdiagnosed, because growths in one area are often not recognized as being a feature of a disorder that affects many body systems. Mild cases likely never come to medical attention. ## Causes Congenital plasminogen deficiency is caused by mutations in the PLG gene. This gene provides instructions for making a protein called plasminogen. Enzymes called plasminogen activators convert plasminogen into the protein plasmin, which breaks down another protein called fibrin. Fibrin is the main protein involved in blood clots and is important for wound healing, creating the framework for normal tissue to grow back. Excess fibrin is broken down when no longer needed, and the new, more flexible normal tissue takes its place. PLG gene mutations can decrease the amount of plasminogen that is produced, its function, or both. When the mutations affect plasminogen levels as well as the activity of the protein, affected individuals may be said to have type I congenital plasminogen deficiency, characterized by the ligneous growths previously described. People with mutations that result in normal levels of plasminogen with reduced activity are said to have type II congenital plasminogen deficiency or dysplasminogenemia. This form of the condition often has no symptoms. A reduction in functional plasminogen results in less plasmin to break down fibrin, leading to a buildup of fibrin. The excess fibrin and the resulting inflammation of the tissue result in the inflamed woody growths characteristic of congenital plasminogen deficiency. It is unclear why the excess fibrin builds up in the mucous membranes but does not usually result in abnormal clots in the blood vessels (thromboses). Researchers suggest that other enzymes in the blood may also break down fibrin, helping to compensate for the reduced plasminogen levels. ### Learn more about the gene associated with Congenital plasminogen deficiency * PLG ## 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Congenital plasminogen deficiency	c1968804	6,970	medlineplus	https://medlineplus.gov/genetics/condition/congenital-plasminogen-deficiency/	2021-01-27T08:24:42	{"gard": ["4380"], "mesh": ["C566897"], "omim": ["217090"], "synonyms": []}
Hereditary thermosensitive neuropathy is a rare, demyelinating, hereditary motor and sensory neuropathy characterized by reversible episodes of ascending muscle weakness, paresthesias and areflexia triggered by a febrile episode, with or without pressure palsy. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hereditary thermosensitive neuropathy	c1865856	6,971	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84093	2021-01-23T17:49:05	{"mesh": ["C566575"], "omim": ["602107"], "umls": ["C1865856"], "icd-10": ["G60.0"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive hyper-IgE recurrent infection syndrome-4 (HIES4) is caused by homozygous mutation in the IL6ST gene (600694) on chromosome 5q11. Description Hyper-IgE recurrent infection syndrome-4 (HIES4) is an autosomal recessive immunologic disorder characterized by early childhood onset of recurrent infections and skeletal abnormalities, including craniosynostosis and scoliosis. Patients are susceptible to infections, mainly bacterial infections that affect the respiratory tract, skin, and eye. Immunologic workup shows increased serum IgE, intermittent eosinophilia, and impaired IL6 (147620) and IL27 (608273) downstream signaling that affects the development and function of certain B- and T-cell populations, as well as the acute-phase response; IL11 (147681) signaling in fibroblasts is also affected (summary by Shahin et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (147060). Clinical Features Schwerd et al. (2017) reported a 7-year-old girl, born of consanguineous parents of South Asian origin, with HIES4. She presented in infancy with craniosynostosis and other skeletal anomalies, including congenital hip dislocation, elbow and finger contractures, and progressive scoliosis. At the same time, she developed recurrent infections, including eye infections, chest infections resulting in bronchiectasis, cellulitis, and sepsis associated with a thrombotic brain infarction. She had eczema and global developmental delay with poor speech. Laboratory studies showed increased IgE, intermittent eosinophilia, and a decreased number of class-switched memory B cells. However, levels of antibodies to Haemophilus, Pneumococcus, and tetanus were normal. During infections, she had a delayed or absent acute-phase response, with decreased fibrinogen and C-reactive protein. Shahin et al. (2019) stated that this patient also had retained teeth. Shahin et al. (2019) reported a 12-year-old boy, born of consanguineous Turkish parents, with HIES4. He presented in early infancy with diarrhea, recurrent otitis media, bilateral keratitis, and recurrent bacterial respiratory infections, including pneumonia complicated by empyema and pneumothorax. He also had severe eczema and food allergies. Soon after birth, he was noted to have skeletal abnormalities, including flexion contractures of the hand joints, scaphocephaly suggesting craniosynostosis, scoliosis, crowded teeth, and hip dislocation. There was evidence of a destructive arthropathy. He also had mild global developmental delay. Laboratory studies showed increased serum IgE, eosinophilia, a decline in absolute B-cell numbers, and low central memory T cells. Family history revealed early death of 3 sibs who were likely affected. Shahin et al. (2019) noted that the phenotype of this patient and the patient reported by Schwerd et al. (2017) was remarkably similar to patients with HIES1. Inheritance The transmission pattern of HIES4 in the family reported by schwerd et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In a girl, born of consanguineous parents of South Asian descent, with HIES4, Schwerd et al. (2017) identified a homozygous missense mutation in the IL6ST gene (N404Y; 600694.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived cells showed a complete loss of STAT3 response to IL6 stimulation compared to controls; these defects were rescued by expression of wildtype GP130. Knockdown of GP130 in HEK293 cells using CRISPR/Cas9 technology showed that mutant cells did not phosphorylate STAT1 or STAT3 in response to stimulation with the known ligands IL6, IL11, IL27, OSM (165095), or LIF (159540), but did respond to stimulation with interferon. GP130-null cells transfected with the mutation showed absent response to IL11 stimulation and decreased response to IL6, IL27, and OSM; LIF response was largely intact. Transfection of wildtype GP130 rescued the defect. In vitro functional expression studies in GP130-null human hepatoma cells showed a defective IL6-mediated acute-phase response. The findings were consistent with a loss of function and impaired IL6ST-mediated downstream signaling. Direct sequencing of the IL6ST gene in over 400 patients with craniosynostosis and over 200 patients with HIES did not identify any pathogenic variants. In a boy, born of consanguineous Turkish parents, with HIES4, Shahin et al. (2019) identified a homozygous missense mutation in the IL6ST gene (P498L; 600694.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional studies of patient-derived cells and HEK293 cells transfected with the mutation showed impaired STAT3 response particularly to IL6, IL11, and IL27 compared to controls. These defects could be rescued by expression of wildtype IL6ST. The effects were apparent in both B- and T-cell subsets, as well as fibroblasts. The findings were consistent with a loss-of-function effect and variably impaired downstream IL6ST signaling. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HYPER-IgE RECURRENT INFECTION SYNDROME 4, AUTOSOMAL RECESSIVE	None	6,972	omim	https://www.omim.org/entry/618523	2019-09-22T15:41:35	{"omim": ["618523"]}
A number sign (#) is used with this entry because this form of hypomaturation amelogenesis imperfecta (AI2A4) is caused by homozygous or compound heterozygous mutation in the C4ORF26 gene (ODAPH; 614829) on chromosome 4q21. For a phenotypic description and a discussion of genetic heterogeneity of the hypomaturation type of AI, see AI2A1 (204700). Clinical Features Parry et al. (2012) described 7 members of a consanguineous Omani family (AI-46) with hypomineralized amelogenesis imperfecta. Affected individuals had enamel that was yellowish brown with mild partial developmental enamel hypoplasia. The enamel was prone to rapid functional failure and posteruptive volume loss. Dental radiographs showed the absence of contrast between enamel and dentin radiodensity. Inheritance The transmission pattern of the hypomaturation form of amelogenesis imperfecta in the consanguineous Omani family AI-46 reported by Parry et al. (2012) was consistent with autosomal recessive inheritance. Mapping By SNP microarray analysis of an Omani family (AI-46) segregating a hypomaturation form of amelogenesis imperfecta, Parry et al. (2012) identified a region of homozygosity on chromosome 4. Microsatellite genotyping confirmed that all affected individuals shared a homozygous haplotype that was not shared by unaffected members of the family. Sanger sequencing of exons and intron-exon boundaries of several genes within the region of homozygosity, including ENAM (606585), AMBN (601259), AMTN (610912), and ODAM (614843), did not reveal any novel or potentially pathogenic variation. Molecular Genetics In 9 families with a hypomaturation form of amelogenesis imperfecta, including the Omani family OI-46, Parry et al. (2012) identified homozygous or compound heterozygous mutations in the C4ORF26 gene (614829.0001-614829.0005). All of the mutations were predicted to result in loss of function of C4ORF26. INHERITANCE \- Autosomal recessive HEAD & NECK Teeth \- Amelogenesis imperfecta \- Yellowish brown enamel \- Hypomineralized enamel \- Enamel hypoplasia, mild developmental \- Enamel volume loss, posteruptive \- No contrast between enamel and dentin radiodensity MOLECULAR BASIS \- Caused by mutation in the C4ORF26 gene (C4orf26, 614829.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	AMELOGENESIS IMPERFECTA, HYPOMATURATION TYPE, IIA4	c0399372	6,973	omim	https://www.omim.org/entry/614832	2019-09-22T15:54:06	{"doid": ["0110062"], "mesh": ["C536606"], "omim": ["614832"], "orphanet": ["100033", "88661"]}
## Clinical Features Hudson and Munoz (1997) reported a family with an autosomal dominant neurologic syndrome affecting 7 members over 2 generations. The mother and 6 of her 11 offspring had congenital cataracts. Several members had impaired intellect, and 1 was severely mentally retarded. All members developed dementia or psychosis later in life (most in the fifth decade), with personality changes and emotional instability. Variable neurologic findings included dysphagia, nystagmus, abnormal gait, and abnormal involuntary movements. Postmortem brain examination of 2 patients showed severe neuronal loss in the hippocampal dentate gyrus and widespread alpha-B-crystallin (CRYAB; 123590) expression in oligodendrocytes. The basal ganglia showed only mild histologic changes. Analysis of the CRYAB gene showed no mutations. Hudson and Munoz (2003) noted that adult neurogenesis occurs in the dentate gyrus of the hippocampus and that astrocytes play a role in the process. They hypothesized that the disorder reported by Hudson and Munoz (1997) resulted from a failure of neurogenesis and possible defects in glial cells. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Congenital cataracts \- Blindness \- Nystagmus ABDOMEN Gastrointestinal \- Dysphagia NEUROLOGIC Central Nervous System \- Intellectual impairment \- Dementia (onset in fifth decade) \- Choreiform movements \- Gait abnormalities (less common) \- Atrophy of hippocampal dentate gyrus \- Alpha-B-crystallin expression in oligodendrocytes Behavioral Psychiatric Manifestations \- Personality changes \- Emotional instability \- Psychosis ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	CATARACT, CONGENITAL, WITH MENTAL IMPAIRMENT AND DENTATE GYRUS ATROPHY	c1843257	6,974	omim	https://www.omim.org/entry/607674	2019-09-22T16:08:59	{"mesh": ["C564353"], "omim": ["607674"]}
Diversion colitis Micrograph showing colonic-type mucosa with follicular lymphoid hyperplasia, as is seen in diversion colitis. H&E stain. SpecialtyGastroenterology CausesSurgery with diversion of colon (ileostomy or colostomy) TreatmentShort-chain fatty acid enemas MedicationMesalazine Diversion colitis is an inflammation of the colon which can occur as a complication of ileostomy or colostomy, where symptoms may occur between one month and three years following surgery.[1] It also occurs frequently in a neovagina created by colovaginoplasty, with varying delay after the original procedure.[2] Despite the presence of a variable degree of inflammation the most suggestive histological feature remains the prominent lymphoid aggregates. ## Contents * 1 Symptoms * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Symptoms[edit] People may be asymptomatic but common symptoms are abdominal discomfort, anorectal pain, mucous discharge and rectal bleeding that develops from the inflamed mucosa of the distal, unused colon.[1] ## Diagnosis[edit] Diagnosis is aided by knowing the full clinical history.[3] ## Treatment[edit] In many milder cases after ileostomy or colostomy, diversion colitis is left untreated and disappears naturally. Possible pharmacologic treatments include short-chain fatty acid irrigation, steroid enemas and mesalazine.[4] For surgical candidates, reanastomosis is a reversal procedure carried out to restore bowel continuity that effectively halts the symptoms of diversion colitis.[1] ## References[edit] 1. ^ a b c Tominaga K, Kamimura K, Takahashi K, Yokoyama J, Yamagiwa S, Terai S (April 2018). "Diversion colitis and pouchitis: A mini-review". World Journal of Gastroenterology. 24 (16): 1734–1747. doi:10.3748/wjg.v24.i16.1734. PMC 5922993. PMID 29713128. 2. ^ van der Sluis WB, Bouman MB, Meijerink WJ, Elfering L, Mullender MG, de Boer NH, van Bodegraven AA (March 2016). "Diversion neovaginitis after sigmoid vaginoplasty: endoscopic and clinical characteristics". Fertility and Sterility. 105 (3): 834–839.e1. doi:10.1016/j.fertnstert.2015.11.013. PMID 26632208. 3. ^ Haboubi, Haboubi (April 2000). "Reporting colonic mucosal biopsies in inflammatory conditions: a new approach". Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland. 2 (2): 66–72. doi:10.1046/j.1463-1318.2000.00104.x. PMID 23577987. 4. ^ Geraghty JM, Talbot IC (September 1991). "Diversion colitis: histological features in the colon and rectum after defunctioning colostomy". Gut. 32 (9): 1020–3. doi:10.1136/gut.32.9.1020. PMC 1379042. PMID 1916483. ## External links[edit] Classification D [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Diversion colitis	c0029512	6,975	wikipedia	https://en.wikipedia.org/wiki/Diversion_colitis	2021-01-18T18:55:41	{"umls": ["C0029512"], "wikidata": ["Q5283947"]}
A number sign (#) is used with this entry because nocturnal frontal lobe epilepsy-5 (ENFL5) is caused by heterozygous mutation in the KCNT1 gene (608167) on chromosome 9q34. Description Nocturnal frontal lobe epilepsy-5 is an autosomal dominant focal epilepsy syndrome characterized by childhood onset of clusters of motor seizures during sleep. Some patients may develop behavioral or psychiatric manifestations and/or intellectual disability. The phenotype is more severe than observed in other genetic forms of ENFL (summary by Heron et al., 2012). For a general description and a discussion of genetic heterogeneity of ENFL, see ENFL1 (600513). Clinical Features Derry et al. (2008) reported a family (family B) in which 6 individuals had childhood onset of partial nocturnal seizures associated with psychiatric disorders and cognitive impairment. Age at seizure onset ranged between 1 and 15 years, and all had partial nocturnal seizures. Seizures were typical of frontal lobe epilepsy, with dystonic posturing, prominent vocalization, and hypermotor automatisms. Two also had partial diurnal seizures, and 1 also had rare generalized tonic-clonic seizures. Four patients had refractory seizures and 2 had a history of status epilepticus. Five had a personality/behavioral disorder or depression, and 3 had intellectual disability. One patient, aged 21 years, showed developmental regression; seizure frequency in this patient was between 40 and 60 per night. Derry et al. (2008) excluded linkage to or mutations in several candidate genes, including CHRNA4 (118504), CHRNB2 (118507), and CHRNA2 (118502), all of which encode proteins involved in nicotinic acetylcholine receptors (nAChR). Heron et al. (2012) reported 4 unrelated families with ENFL5, including the family reported by Derry et al. (2008). Affected individuals had a more severe phenotype compared to patients with other genetic forms of ENFL. Those with ENFL5 had an earlier mean age of onset at 6 years of age (compared to 10 years of age in other forms), as well as a significantly higher frequency of psychiatric or behavioral problems, including psychosis, catatonia, and aggression. In addition, 6 individuals from 2 families had varying degrees of intellectual disability. Inheritance The transmission pattern of nocturnal frontal lobe epilepsy-5 in the families reported by Heron et al. (2012) was consistent with autosomal dominant inheritance showing complete penetrance. Mapping By genomewide linkage analysis of the family reported by Derry et al. (2008) (family B), Heron et al. (2012) found linkage to a 2.36-Mb region on chromosome 9q34.3 (maximum parametric lod score of 2.71). Molecular Genetics By whole-exome capture and sequencing of patients from the family with ENFL reported by Derry et al. (2008), Heron et al. (2012) identified a heterozygous mutation in the KCNT1 gene (R928C; 608167.0005). The mutation, which was confirmed by Sanger sequencing and not identified in multiple control samples, segregated with the disorder. Subsequent analysis of this gene in 108 additional unrelated cases with a similar disorder identified 3 more pathogenic mutations in 3 families (608167.0006-608167.0008). INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, focal, partial, motor \- Vocalizations \- Dystonic posturing \- Hypermotor automatisms \- Nocturnal occurrence \- Seizures occur in clusters \- Status epilepticus (in some patients) \- Intellectual disability (in some patients) Behavioral Psychiatric Manifestations \- Behavioral disturbances (in some patients) \- Personality disorder (in some patients) \- Depression (in some patients) \- Aggression (in some patients) \- Psychosis (in some patients) \- Catatonia (in some patients) MISCELLANEOUS \- Onset in childhood (mean 6 years) \- Seizures may be refractory MOLECULAR BASIS \- Caused by mutation in the potassium channel, subfamily T, member 1 gene (KCNT1, 608167.0005 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	EPILEPSY, NOCTURNAL FRONTAL LOBE, 5	c3696898	6,976	omim	https://www.omim.org/entry/615005	2019-09-22T15:53:29	{"doid": ["0060686"], "mesh": ["C579932"], "omim": ["615005"], "orphanet": ["98784"], "genereviews": ["NBK525917"]}
Herxheimer reaction Jarisch-Herxheimer reaction in a patient with syphilis and human immunodeficiency virus infection Pronunciation * English: /ˌjɑːrɪʃ ˈhɛərkshaɪmər/ SpecialtyInfectious disease A Jarisch–Herxheimer reaction is a reaction to endotoxin-like products released by the death of harmful microorganisms within the body during antibiotic treatment. Efficacious antimicrobial therapy results in lysis (destruction) of bacterial cell membranes, and in the consequent release into the bloodstream of bacterial toxins, resulting in a systemic inflammatory response. Jarisch–Herxheimer reactions can be life-threatening as they can cause a significant drop in blood pressure and cause acute end-organ injury, eventually leading to failure. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Treatments * 5 History * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] It comprises part of what is known as sepsis and occurs after initiation of antibacterials when treating Gram-negative infections such as Escherichia coli and louse- and tick-borne infections. It usually manifests in 1–3 hours after the first dose of antibiotics as fever, chills, rigor, hypotension, headache, tachycardia, hyperventilation, vasodilation with flushing, myalgia (muscle pain), exacerbation of skin lesions and anxiety. The intensity of the reaction indicates the severity of inflammation. Reaction commonly occurs within two hours of drug administration, but is usually self-limiting.[1] ## Causes[edit] The Jarisch–Herxheimer reaction is traditionally associated with antimicrobial treatment of syphilis.[2] The reaction is also seen in the other diseases caused by spirochetes: Lyme disease, relapsing fever, and leptospirosis.[3] There have been case reports of the Jarisch–Herxheimer reaction accompanying treatment of other infections, including Q fever, bartonellosis, brucellosis, trichinellosis, and African trypanosomiasis.[2] ## Pathophysiology[edit] Lipoproteins released from treatment of Treponema pallidum infections are believed to induce the Jarisch–Herxheimer reaction.[2] The Herxheimer reaction has shown an increase in inflammatory cytokines during the period of exacerbation, including tumor necrosis factor alpha, interleukin-6 and interleukin-8.[4][5] ## Treatments[edit] Prophylaxis and treatment with an anti-inflammatory agent may stop progression of the reaction. Oral aspirin or ibuprofen every four hours for a day or 60 mg of prednisone orally or intravenously has been used as an adjunctive treatment[citation needed]. However, steroids are generally of no benefit. Patients must be closely monitored for the potential complications (collapse and shock) and may require IV fluids to maintain adequate blood pressure. If available, meptazinol, an opioid analgesic of the mixed agonist/antagonist type, should be administered to reduce the severity of the reaction. Anti TNF-a may also be effective.[6][7] ## History[edit] Both Adolf Jarisch,[8] an Austrian dermatologist, and Karl Herxheimer,[9] a German dermatologist, are credited with the discovery of the Jarisch–Herxheimer reaction. Both Jarisch and Herxheimer observed reactions in patients with syphilis treated with mercury. The reaction was first seen following treatment in early and later stages of syphilis treated with Salvarsan, mercury, or antibiotics. Jarisch thought that the reaction was caused by a toxin released from the dying spirochetes.[10] ## See also[edit] * Jarisch-Bezold reflex * Immune reconstitution inflammatory syndrome, another systemic inflammatory syndrome that arises after antimicrobial treatment ## References[edit] 1. ^ Lukehart, Sheila A. (2017). "Syphilis". In Kasper, Dennis L.; Fauci, Anthony S. (eds.). Harrison's Infectious Diseases (3 ed.). New York: Mc Graw-Hill. p. 666. ISBN 978-1-259-83597-1. 2. ^ a b c Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BS (2013). "The Jarisch-Herxheimer reaction: revisited". Travel Medicine and Infectious Disease. 11 (4): 231–7. doi:10.1016/j.tmaid.2013.04.001. PMID 23632012. 3. ^ Butler T (2017). "The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis". The American Journal of Tropical Medicine and Hygiene. 96 (1): 46–52. doi:10.4269/ajtmh.16-0434. PMC 5239707. PMID 28077740. 4. ^ Vidal V, Scragg IG, Cutler SJ, et al. (December 1998). "Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever". Nat. Med. 4 (12): 1416–20. doi:10.1038/4007. PMID 9846580. 5. ^ Kaplanski G, Granel B, Vaz T, Durand JM (July 1998). "Jarisch–Herxheimer reaction complicating the treatment of chronic Q fever endocarditis: elevated TNFalpha and IL-6 serum levels". J. Infect. 37 (1): 83–4. doi:10.1016/S0163-4453(98)91120-3. PMID 9733392. 6. ^ Fekade, D; Knox, K; Hussein, K; Melka, A; Lalloo, DG; Coxon, RE; Warrell, DA (Aug 1, 1996). "Prevention of Jarisch–Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha". The New England Journal of Medicine. 335 (5): 311–5. doi:10.1056/NEJM199608013350503. PMID 8663853. 7. ^ Coxon, RE; Fekade, D; Knox, K; Hussein, K; Melka, A; Daniel, A; Griffin, GG; Warrell, DA (Mar 1997). "The effect of antibody against TNF alpha on cytokine response in Jarisch–Herxheimer reactions of louse-borne relapsing fever" (PDF). QJM : Monthly Journal of the Association of Physicians. 90 (3): 213–21. doi:10.1093/qjmed/90.3.213. PMID 9093599. 8. ^ Jarisch A (1895). "Therapeutische Versuche bei Syphilis". Wien Med Wochenschr. 45: 721–42. 9. ^ Herxheimer K, Krause D (1902). "Ueber eine bei Syphilitischen vorkommende Quecksilberreaktion". Deutsche Medizinische Wochenschrift. 28 (50): 895–7. doi:10.1055/s-0028-1139096. 10. ^ "The Jarisch–Herxheimer reaction". Lancet. 1 (8007): 340–1. February 1977. doi:10.1016/s0140-6736(77)91140-0. PMC 1056841. PMID 64863. ## External links[edit] Classification D * ICD-10: T78.2 * ICD-9-CM: 995.0 * DiseasesDB: 32939 * v * t * e Adverse drug reactions Antibiotics * Penicillin drug reaction * Sulfonamide hypersensitivity syndrome * Urticarial erythema multiforme * Adverse effects of fluoroquinolones * Red man syndrome * Jarisch–Herxheimer reaction Hormones * Steroid acne * Steroid folliculitis Chemotherapy * Chemotherapy-induced acral erythema * Chemotherapy-induced hyperpigmentation * Scleroderma-like reaction to taxanes * Hydroxyurea dermopathy * Exudative hyponychial dermatitis Anticoagulants * Anticoagulant-induced skin necrosis * Warfarin necrosis * Vitamin K reaction * Texier's disease Immunologics * Adverse reaction to biologic agents * Leukotriene receptor antagonist-associated Churg–Strauss syndrome * Methotrexate-induced papular eruption * Adverse reaction to cytokines Other drugs * Anticonvulsant hypersensitivity syndrome * Allopurinol hypersensitivity syndrome * Vaccine adverse event * Eczema vaccinatum * Bromoderma * Halogenoderma * Iododerma General Skin and body membranes * Acute generalized exanthematous pustulosis * Bullous drug reaction * Drug-induced acne * Drug-induced angioedema * Drug-related gingival hyperplasia * Drug-induced lichenoid reaction * Drug-induced lupus erythematosus * Drug-induced nail changes * Drug-induced pigmentation * Drug-induced urticaria * Stevens–Johnson syndrome * Injection site reaction * Linear IgA bullous dermatosis * Toxic epidermal necrolysis * HIV disease-related drug reaction * Photosensitive drug reaction Other * Drug-induced pseudolymphoma * Fixed drug reaction * Serum sickness-like reaction [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Jarisch–Herxheimer reaction	c0259756	6,977	wikipedia	https://en.wikipedia.org/wiki/Jarisch%E2%80%93Herxheimer_reaction	2021-01-18T18:38:33	{"umls": ["C0259756"], "icd-9": ["995.0"], "icd-10": ["T78.2"], "wikidata": ["Q740731"]}
Burn-McKeown syndrome is a disorder that is present from birth (congenital) and involves abnormalities of the nasal passages, characteristic facial features, hearing loss, heart abnormalities, and short stature. In people with Burn-McKeown syndrome, both nasal passages are usually narrowed (bilateral choanal stenosis) or completely blocked (bilateral choanal atresia), which can cause life-threatening breathing problems in infancy without surgical repair. Typical facial features include narrow openings of the eyelids (short palpebral fissures); a gap (coloboma) in the lower eyelids; widely spaced eyes (hypertelorism); a prominent bridge of the nose; a short space between the nose and the upper lip (philtrum); a small opening of the mouth (microstomia); and large, protruding ears. Some people with Burn-McKeown syndrome have congenital hearing loss in both ears which varies in severity among affected individuals. The hearing loss is described as mixed, which means that it is caused by both changes in the inner ear (sensorineural hearing loss) and changes in the middle ear (conductive hearing loss). Other features that can occur in Burn-McKeown syndrome include mild short stature and congenital heart defects such as patent ductus arteriosus (PDA). The ductus arteriosus is a connection between two major arteries, the aorta and the pulmonary artery. This connection is open during fetal development and normally closes shortly after birth. However, the ductus arteriosus remains open, or patent, in babies with PDA. If untreated, this heart defect causes infants to breathe rapidly, feed poorly, and gain weight slowly; in severe cases, it can lead to heart failure. Intelligence is unaffected in Burn-McKeown syndrome. ## Frequency Burn-McKeown syndrome is a rare disorder; its prevalence is unknown. Only a small number of affected individuals have been described in the medical literature. ## Causes Burn-McKeown syndrome is caused by mutations in the TXNL4A gene or in an area of genetic material near the TXNL4A gene called the promoter region, which controls the production of protein from the gene. The TXNL4A gene provides instructions for making one part (subunit) of a protein complex called the major spliceosome, which is the larger of two types of spliceosomes found in human cells. Spliceosomes help process messenger RNA (mRNA), which is a chemical cousin of DNA that serves as a genetic blueprint for making proteins. Spliceosomes recognize and then remove regions called introns from immature mRNA molecules to help produce mature mRNA. The mutations affecting the TXNL4A gene that cause Burn-McKeown syndrome reduce the amount of protein produced from the gene. Research suggests that reduced quantities of this spliceosome subunit affect the assembly of the major spliceosome and change the production of a particular group of mRNA molecules. The details of these changes and their relationship to the specific signs and symptoms of Burn-McKeown syndrome are unknown. However, mutations in several genes involved in spliceosome formation or function have been shown to cause other conditions with abnormalities affecting the head and face (craniofacial malformations), so craniofacial development is thought to be particularly sensitive to spliceosome problems. ### Learn more about the gene associated with Burn-McKeown syndrome * TXNL4A ## 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Burn-McKeown syndrome	c1837822	6,978	medlineplus	https://medlineplus.gov/genetics/condition/burn-mckeown-syndrome/	2021-01-27T08:25:34	{"gard": ["10041"], "mesh": ["C537411"], "omim": ["608572"], "synonyms": []}
Generalized pustular psoriasis is a severe inflammatory skin disease that can be life-threatening and that is characterized by recurrent episodes of high fever, fatigue, episodic erythematous cutaneous eruptions with sterile cutaneous pustules formation on various parts of the body, and neutrophil leukocytosis. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Generalized pustular psoriasis	c0343055	6,979	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247353	2021-01-23T18:51:56	{"gard": ["12819"], "omim": ["614204", "616106"], "umls": ["C0343055"], "icd-10": ["L40.1"], "synonyms": ["GPP"]}
Excessive menstruation between puberty and 19 years of age is called puberty menorrhagia. Excessive menstruation is defined as bleeding over 80 ml per menstrual period or lasting more than 7 days.[1] The most common cause for puberty menorrhagia is dysfunctional uterine bleeding. The other reasons are idiopathic thrombocytopenic purpura, hypothyroidism, genital tuberculosis, polycystic ovarian disease, leukemia and coagulation disorders.[2] The most common physiological reason for puberty menorrhagia is the immaturity of hypothalamic-pituitary-ovarian axis, leading to inadequate positive feedback and sustained high estrogen levels. Most patients present with anemia due to excessive blood loss. The patient is assessed with a thorough medical history, physical examination (to look for features of anemia), gynaecological examination (to rule out local causes) and laboratory investigations (to rule out coagulopathies and malignancy). It is mandatory to exclude pregnancy. The treatment is determined based on the cause of menorrhagia. In case of puberty menorrhagia due to immaturity of hypothalamic axis, hormonal therapy is beneficial. Treatment for blood loss should be done simultaneously with iron therapy in mild to moderate blood loss and blood transfusion in severe blood loss. ## References[edit] 1. ^ Gillani, Salma (January 2012). "Puberty Menorrhagia : Causes and Management" (PDF). Journal of Medical Sciences (Peshwar). 20 (1): 15–18. 2. ^ Rao, Sanjay (April 2004). "Medical Interventions in Puberty Menorrhagia". Bombay Medical Journal. Retrieved 6 April 2020. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Puberty menorrhagia	c0848610	6,980	wikipedia	https://en.wikipedia.org/wiki/Puberty_menorrhagia	2021-01-18T18:53:57	{"wikidata": ["Q28405104"]}
## Summary ### Clinical characteristics. KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). * EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. * ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with KCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE due to other causes. Less common seizure phenotypes in individuals with KCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported. ### Diagnosis/testing. The diagnosis of KCNT1-related epilepsy is established in a proband with intractable epilepsy and identification of a heterozygous pathogenic variant in KCNT1 by molecular genetic testing. ### Management. Treatment of manifestations. KCNT1-related epilepsy is often refractory to conventional anticonvulsants; stiripentol, benzodiazepines, levetiracetam, and the ketogenic diet have all been well tolerated with limited success; quinidine has been used as an off-label anticonvulsant with success in some individuals; in rare cases of pulmonary hemorrhage due to systemic pulmonary collaterals, embolization has been recommended; developmental support is appropriate. Surveillance. EEG at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen; monitoring of development. Agents/circumstances to avoid: For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). Pregnancy management: For women with ADNFLE, a discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place before conception. Transitioning to a lower-risk medication prior to pregnancy may be possible. ### Genetic counseling. KCNT1-related epilepsy is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo KCNT1 pathogenic variant. The proportion of cases caused by a de novo pathogenic variant varies by phenotype. All individuals diagnosed with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) have the disorder as the result of a de novo pathogenic variant or an inherited variant from an unaffected parent with somatic and/or germline mosaicism. Some individuals diagnosed with KCNT1-related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent. Each child of an individual with KCNT1-related epilepsy has a 50% chance of inheriting the pathogenic variant, and intrafamilial clinical variability and reduced penetrance have been reported. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known. ## Diagnosis No formal diagnostic criteria for KCNT1-related epilepsy have been published to date. KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Less often, KCNT1 pathogenic variants are associated with epilepsy with variable presentation. ### Suggestive Findings KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) should be suspected in individuals with the following history and findings: * Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury * Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency * Developmental plateau or regression following the onset of seizures * Intractability to anticonvulsant medication KCNT1-related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) should be suspected in individuals with the following history and findings: * Frequent brief, nocturnal seizures * Mild to moderate intellectual disability * Psychiatric disease (e.g., depression, anxiety, suicidality, attention deficit hyperactivity disorder) * Family history of ADNFLE or EIMFS KCNT1-related epilepsy has been less frequently identified in individuals with the following phenotypes: * West syndrome * Ohtahara syndrome (early-infantile epileptic encephalopathy) * Early myoclonic encephalopathy * Leukodystrophy/leukoencephalopathy * Focal epilepsy * Multifocal epilepsy ### Establishing the Diagnosis The diagnosis of KCNT1-related epilepsy is established in a proband with intractable epilepsy and identification of a heterozygous pathogenic variant in KCNT1 by molecular genetic testing (see Table 1). Because the phenotype of KCNT1-related epilepsy is indistinguishable from many other inherited disorders with epilepsy, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. Note: (1) Single-gene testing (sequence analysis of KCNT1) is rarely useful and typically NOT recommended. (2) KCNT1-related epilepsy is postulated to occur through a gain-of-abnormal-function mechanism. Large intragenic deletions and duplication have not been reported; testing for intragenic deletions or duplication is not indicated. A seizure multigene panel that includes KCNT1 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 pathogenic 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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. 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 KCNT1-Related Epilepsy View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method KCNT1Sequence analysis 3100% 4 Gene-targeted deletion/duplication analysis 5None reported 4, 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. 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\. Lim 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\. McTague et al [2018] ## Clinical Characteristics ### Clinical Description KCNT1-related epilepsy encompasses a range of epilepsy syndromes. The most common phenotypes reported in individuals with KCNT1-related epilepsy are epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). #### Epilepsy Phenotype EIMFS is an early infantile epileptic encephalopathy characterized by seizures beginning in the first six months of life with associated developmental plateau or regression. The seizures are primarily focal motor, variably with secondary generalization, but also include tonic, clonic, tonic-clonic, myoclonic, and epileptic spasms [McTague et al 2013]. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures progress to become nearly continuous by age six to nine months. Seizures are intractable to multiple anticonvulsants. Rarely, status epilepticus at onset has been described [Zamponi et al 2008]. The characteristic feature on EEG is focal ictal discharges that migrate across contiguous cortical regions and arise independently at multiple foci. An increase in amplitude and frontal predominance over time with post-ictal and interictal suppression has been noted [McTague et al 2018]. Additional neurologic features reported in individuals with KCNT1-related EIMFS include hypotonia (axial>appendicular), decreased head growth with microcephaly developing by age 12 months, strabismus, and profound developmental delay with rare ability to ambulate or verbalize. Additional reported movement disorders include choreoathetosis, dyskinesias, and focal and generalized dystonia. Prognosis for individuals with KCNT1-related EIMFS is currently unknown. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features (see Autosomal Dominant Nocturnal Frontal Lobe Epilepsy). Individuals with KCNT1-related ADNFLE are more likely to develop seizures before adolescence, have cognitive comorbidity, and display psychiatric and behavioral problems than are individuals with ADNFLE due to other causes. Less common epilepsy phenotypes in individuals with a KCNT1 pathogenic variant include: * West syndrome * Ohtahara syndrome (early infantile epileptic encephalopathy) * Early myoclonic encephalopathy * Leukodystrophy/leukoencephalopathy * Focal or multifocal epilepsy Brain MRI and/or CT examination is often normal prior to seizure onset, though recent studies have noted variable delayed myelination, hippocampal volume loss, and cerebellar atrophy [McTague et al 2018]. Temporal lobe pathology as a cause versus consequence has been noted in two individuals with KCNT1-related temporal lobe epilepsy [Hansen et al 2017]. Other. Prenatal history, birth, and neonatal history prior to seizure onset are normal, with no notable dysmorphic features. #### Pulmonary Hemorrhage Three individuals with KCNT1-related EIMFS were reported to have prominent systemic-to-pulmonary collateral artery formation and subsequent pulmonary hemorrhage that developed between age four and 19 months [Kawasaki et al 2017]. Evaluation for pulmonary hemorrhage should be considered if an individual develops acute respiratory failure, heart failure, or hemoptysis. #### Cardiac Arrhythmia Brugada syndrome was reported in one individual with a de novo KCNT1 variant [Juang et al 2014]. An individual with confirmed familial KCNT1-related epilepsy and an unspecified cardiac arrhythmia was reported by Møller et al [2015]. ### Genotype-Phenotype Correlations There is some evidence for a genotype-phenotype correlation. However, disparate phenotypes (e.g., ADNFLE, EIMFS) have been identified in family members with the same pathogenic variant. EIMFS. The majority of pathogenic variants associated with EIMFS occur in either the S5 transmembrane domain or the regulator of potassium conductance domains within the C-terminus. ADNFLE-related pathogenic variants are concentrated in the NAD+ binding domain or more distal C-terminus. Specific correlations between genetic variant and seizure burden, developmental impairment, or medication responsiveness have not yet been elucidated. ### Penetrance Penetrance is reported to be 100% for KCNT1-related EIMFS [Barcia et al 2012, Heron et al 2012] but is reported as reduced in KCNT1-related epilepsy with other seizure phenotypes [Møller et al 2015]. ### Nomenclature In the initial description of EIMFS, Coppola et al [1995] described his cohort of globally arrested infants with frequent focal, "migrating" seizures that were medically intractable as malignant migrating partial seizures of infancy (MMPSI); it has also been variably referred to as migrating partial epilepsy of infancy (MPEI). In 2010, the International League Against Epilepsy reclassified this epilepsy syndrome as EIMFS [Berg et al 2010]. ### Prevalence The prevalence of KCNT1-related epilepsy is unknown. To date, 88 probands with KCNT1-related epilepsy have been reported in the literature. ## Differential Diagnosis Phenotypic and EEG features associated with KCNT1 pathogenic variants are not sufficient to diagnose KCNT1-related epilepsy. All genes known to be associated with early-infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis of KCNT1-related epilepsy including other genes less commonly associated with epilepsy of infancy with migrating focal seizures (SCN1A, SCN2A, SLC12A5, SLC25A22, TBC1D4, PLCB1) and autosomal dominant nocturnal frontal lobe epilepsy (CHRNA4, CHRNB2, DEPDC5, CRH). Note: At seizure onset, it is most important to distinguish KCNT1-related epilepsy from potentially treatable causes of early infantile-onset epileptic encephalopathy, such as neurometabolic disorders, CNS infection, structural brain lesions, and other syndromes (see Table 2). ### Table 2. Treatable Disorders Associated with Early Infantile-Onset Epileptic Encephalopathy View in own window ConditionsGene(s)MOIClinical FindingsTreatment Neuro- metabolic disordersPyridoxine-dependent epilepsyALDH7A1AR * ↑ plasma & urine alpha-aminoadipic semialdehyde * ↑ plasma & CSF pipecolic acid Seizures/encephalopathy responsive to pyridoxine Pyridoxamine 5'-phosphate oxidase deficiency (OMIM 610090)PNPOAR * Lactic acidemia * Hypoglycemia Seizures/encephalopathy responsive to pyridoxal 5-prime phosphate Biotinidase deficiencyBTDAR * Deficient biotinidase enzyme activity in serum or plasma * Ketolactic acidosis, organic aciduria, hyperammonemia * Skin rash, alopecia, recurrent viral or fungal infections Lifelong biotin supplementation Glucose transporter 1 deficiency syndromeSLC2A1AD AR * ↓ CSF glucose concentration * Absence seizures beginning age <3 Ketogenic diet Creatine deficiency syndromesGAMT GATM SCL6A8AR XL * Cerebral creatine deficiency on brain MR spectroscopy * Suggestive ratio of guanidinoacetate, creatine, &/or creatinine in plasma & urine Creatine monohydrate supplementation Holocarboxylase synthetase deficiency (OMIM 253270)HLCSAR * Ketolactic acidosis, organic aciduria, hyperammonemia * Skin rash, alopecia Responsive to biotin Serine biosynthesis disorders (OMIM 601815, 610992, 614023)PHGDG PSAT1 PSPHAR * Congenital or acquired microcephaly, congenital cataracts * ↓ plasma & CSF serine L-serine & glycine supplementation can reduce seizures, improve psychomotor symptoms, & prevent progression depending on subtype OtherInfection of the CNSn/aMRI, blood culture &/or lumbar puncture suggestive of infectionAntibiotic, antiviral, or antifungal therapy Structural brain lesionsn/a(Multi)focal lesions on brain MRI Tuberous sclerosis complexTSC1 TCS2 * MRI brain lesions (subependymal nodules, subependymal giant cell astrocytomas, tubers, focal cortical dysplasias) * Cardiac rhabdomyoma, skin lesions, retinal lesions, renal lesions Consideration of mTOR inhibitor for astrocytoma, additional seizure reduction ARX-associated encephalopathy (OMIM 308350)ARXEnlarged ventricles & T2-weighted signals in basal ganglia on brain MRI AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with KCNT1-related epilepsy, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist * Evaluation by a movement disorder specialist if dictated by clinical presentation * Consideration of echocardiogram to evaluate for pulmonary collaterals * Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities * Cognitive and behavioral assessment * Physical, occupational, and speech therapy evaluation * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Seizures. KCNT1-related epilepsy is often refractory to conventional anticonvulsants. * Stiripentol in combination with a benzodiazepine (commonly clonazepam or clobazam), levetiracetam, and the ketogenic diet have all been well tolerated with limited success [Hmaimess et al 2006, Caraballo et al 2008, Cilio et al 2009, McTague et al 2018]. * Vagal nerve stimulator (VNS) has not been shown to be effective [Zamponi et al 2008]. * Quinidine. Seizure control and developmental progression with off-label use of quinidine was reported in an individual with KCNT1 pathogenic variant p.Arg428Gln [Bearden et al 2014], prompting subsequent treatment trials in individuals with the same and other pathogenic variants with negative results [Mullen et al 2018] and pro-arrhythmic cardiotoxicity. Potential explanations for this variable responsiveness include genetic/epigenetic modifiers of KCNT1 as well as polymorphisms in P-glycoprotein transporters, which actively shuttle quinidine across the blood-brain barrier [Liu et al 2015]. The limited efficacy may also be narrowed by epilepsy type, as a small, randomized, placebo-controlled, crossover clinical trial of KCNT1-related ADNFLE showed no efficacy [Mullen et al 2018]. It has also been suggested that quinidine administered after age four years may be less effective [Abdelnour et al 2018]. In addition, given the increased risk for arrhythmia associated with quinidine treatment, some individuals are not able to achieve adequate serum levels due to the development of life-threating cardiac rhythm abnormalities, thus limiting its utility. * Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. Pulmonary collaterals and pulmonary hemorrhage. Embolization of systemic pulmonary collateral arteries has been used with limited success [Kawasaki et al 2017]. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. Ages 5-21 years * In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. * Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility. * Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention deficit hyperactivity disorder) when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ### Surveillance EEG is recommended at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen. Developmental evaluation and initiation of therapies is recommended at time of diagnosis if not already begun. Following initial EKG and echocardiogram, there is no indication to repeat cardiac monitoring or cardiopulmonary imaging unless clinically indicated or following initiation of quinidine therapy. ### Agents/Circumstances to Avoid No anticonvulsants have been noted to exacerbate KCNT1-related epilepsy. For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the KCNT1 pathogenic variant in the family. Family members who are found to have a heterozygous KCNT1 pathogenic variant are at risk for seizures and cardiac arrhythmias, and thus appropriate screening should be performed. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication (e.g., valproate, phenobarbital, topiramate) may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	KCNT1-Related Epilepsy	None	6,981	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK525917/	2021-01-18T21:16:37	{"synonyms": []}
Chronic leukemia is an increase of abnormal white blood cells. It differs from acute leukemia, and is categorized as myelogenous or lymphocytic. Chronic leukemia may refer to: * Chronic myelogenous leukemia * Chronic lymphocytic leukemia * Hairy cell leukemia Index of articles associated with the same name This article includes a list of related items that share the same name (or similar names). If an internal link incorrectly led you here, you may wish to change the link to point directly to the intended article. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Chronic leukemia	c1279296	6,982	wikipedia	https://en.wikipedia.org/wiki/Chronic_leukemia	2021-01-18T18:55:56	{"umls": ["C1279296"], "wikidata": ["Q5113979"]}
Vogt-Koyanagi-Harada disease is a bilateral, chronic, diffuse granulomatous panuveitis typically characterized by serous retinal detachment and frequently associated with neurological (meningitis), auditory, and dermatological alterations. ## Epidemiology Annual incidence is estimated at 1/400,000. The condition predominantly affects young women and individuals with darker pigmentation (those of Asian, Hispanic, or Native American origin). Children may be affected, but the mean age of onset is about 30 years of age (ranging from 10 to 52 years). ## Clinical description The most common clinical manifestations are headaches (67% of cases), ocular involvement with panuveitis, skin vitiligo, alopecia, and inner ear disturbances. The disease can be divided into four clinical stages. The prodromic stage is characterized by nonspecific symptoms such as fever, headaches, nausea and vertigo, and then by neurologic symptoms such as muscle weakness, hemiparesis, hemiplegia, dysarthria and orbital pain. In the ophthalmologic stage, occurring a few days after the prodromic stage, patients complain of blurred vision, ocular pain, and photophobia or central scotoma (bilateral in 80% of cases). Bilateral, serous, non-rhegmatogenous retinal detachment often occurs. Hearing disturbances (75%) and dizziness may also be present. The convalescent stage, occurring within three months of disease onset, is characterized by the apparition of cutaneous signs such as poliosis involving the eyebrows and eyelashes (and sometimes the scalp and body hair), hair loss, and vitiligo (usually perilimbal). Recurrent uveitis and ophthalmologic complications appear in the final stage, the chronic recurrent stage. ## Etiology Pathogenesis has been linked to immunological disorders targeting the melanocytes, and which involve T-cell-mediated cytotoxicity and apoptosis. However, the etiology is still not completely understood. An association between disease susceptibility and positive blood tests for the HLA-DRB10405 haplotype has been reported. ## Diagnostic methods Diagnosis is clinical. Cerebrospinal fluid analysis revealing pleocytosis can confirm the diagnosis. ## Management and treatment Management should involve a multidisciplinary team with dermatologists, ophthalmologists, and neurologists. High doses of corticosteroids usually provide efficient treatment, but immunosuppressors may also be used. ## Prognosis With early and aggressive treatment, the prognosis is usually favorable, but acute hearing and vision alterations may occur. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States *[FDA]: Food and Drug Administration	Vogt-Koyanagi-Harada disease	c0042170	6,983	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3437	2021-01-23T17:34:19	{"gard": ["7862"], "mesh": ["D014607"], "umls": ["C0042170"], "icd-10": ["H20.8", "H30.8"], "synonyms": ["Uveomenigitic syndrome"]}
During pregnancy, a two-way traffic of immune cells may occur through the placenta. Exchanged cells can multiply and establish long-lasting cell lines that are immunologically active even decades after giving birth. Microchimerism is the presence of a small number of cells that originate from another individual and are therefore genetically distinct from the cells of the host individual. This phenomenon may be related to certain types of autoimmune diseases; however, the mechanisms responsible for this relationship are unclear. The term comes from the prefix "micro" + "chimerism" based on the Chimera of Greek mythology. ## Contents * 1 Types * 1.1 Human * 1.2 Animal * 2 Fetomaternal microchimerism in the brain * 3 Maternal tolerance to paternal-fetal antigens * 4 Fetal tolerance to noninherited maternal antigens * 5 Postnatal tolerance to NIMAs * 6 Benefits of microchimeric cells * 7 Relationship with autoimmune diseases and breast cancer * 7.1 Systemic lupus erythematosus * 7.2 Thyroid disease * 7.3 Sjögren's syndrome * 7.4 Oral lichen planus * 7.5 Breast cancer * 7.6 Other cancers * 8 Role of microchimerism in the wound healing * 9 Stem cells * 9.1 Animal models * 10 Health implications * 11 See also * 12 References * 13 Further reading ## Types[edit] ### Human[edit] In humans (and perhaps in all placentals), the most common form is fetomaternal microchimerism (also known as fetal cell microchimerism or fetal chimerism) whereby cells from a fetus pass through the placenta and establish cell lineages within the mother. Fetal cells have been documented to persist and multiply in the mother for several decades.[1][2] The exact phenotype of these cells is unknown, although several different cell types have been identified, such as various immune lineages, mesenchymal stem cells, and placental-derived cells.[3] A 2012 study at the Fred Hutchinson Cancer Research Center, Seattle, has detected cells with the Y chromosome in multiple areas of the brains of deceased women.[4] Fetomaternal microchimerism occurs during pregnancy and shortly after giving birth for most women. However, not all women who have had children contain fetal cells. Studies suggest that fetomaternal microchimerism could be influenced by killer-cell immunoglobin-like (KIR) ligands.[5] Lymphocytes also influence the development of persisting fetomaternal microchimerism since natural killer cells compose about 70% of lymphocytes in the first trimester of pregnancy. KIR patterns on maternal natural killer cells of the mother and KIR ligands on the fetal cells could have an effect on fetomaternal microchimerism. In one study, mothers with KIR2DS1 exhibited higher levels of fetomaternal microchimerism compared to mothers who were negative for this activating KIR.[5] The potential health consequences of these cells are unknown. One hypothesis is that these fetal cells might trigger a graft-versus-host reaction leading to autoimmune disease. This offers a potential explanation for why many autoimmune diseases are more prevalent in middle-aged women.[6] Another hypothesis is that fetal cells home to injured or diseased maternal tissue where they act as stem cells and participate in repair.[7][8] It is also possible that the fetal cells are merely innocent bystanders and have no effect on maternal health.[9] After giving birth, about 50–75% of women carry fetal immune cell lines. Maternal immune cells are also found in the offspring yielding in maternal→fetal microchimerism, though this phenomenon is about half as frequent as the former.[10] Microchimerism had also been shown to exist after blood transfusions to a severely immunocompromised population of patients who suffered trauma.[11] Other possible sources of microchimerism include gestation,[12] an individual's older sibling, twin sibling, or vanished twin, with the cells being received in utero. Fetal-maternal microchimerism is especially prevalent after abortion or miscarriage.[13] ### Animal[edit] Microchimerism occurs in most pairs of twins in cattle. In cattle (and other bovines), the placentae of fraternal twins usually fuse and the twins share blood circulation, resulting in exchange of cell lines. If the twins are a male–female pair, then XX/XY microchimerism results, and male hormones partially masculinize the heifer (female), creating a martin heifer or freemartin. Freemartins appear female, but are infertile and so cannot be used for breeding or dairy production. Microchimerism provides a method of diagnosing the condition, because male genetic material can be detected in a blood sample.[14] ## Fetomaternal microchimerism in the brain[edit] Several studies have identified male DNA in both the human and mouse brains of mothers following pregnancy of a male fetus.[15][16] It has been suggested that the fetal-derived cells can differentiate into those capable of presenting neurotypical immunomarkers on their surface.[15] There has been no strong evidence to say microchimerism of the maternal brain leads to disease, however, Parkinson’s disease correlates with a higher incidence of brain microchimeras.[15] Alzheimer’s disease studies support nearly the opposite correlation, the more fetal-derived cells present, the lower the chance of the patient having had Alzheimer’s.[16] ## Maternal tolerance to paternal-fetal antigens[edit] There are many mechanisms at the maternal-fetal interface to prevent immune rejection of fetal cells. Nevertheless, systemic immunological changes occur in pregnant women. For example, condition of women suffering from autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis) improves during pregnancy.[17][18] These changes in immune responses during pregnancy extend to maternal components specific to fetal antigens, because of feto-maternal cell transfer and their retention in mother tissues. During pregnancy, numbers of fetal cells in maternal tissues increase and correlate with expansion of CD4+ regulatory T cells (Tregs).[19] Decreased expansion and decidual accumulation of Treg cause pregnancy complications (preeclampsia, abortions).[19] In mice models, most mother’s fetal-specific CD8+ T cells undergo clonal deletion[20] and express low levels of chemokine receptors and ligands – this prevents remaining fetal-specific CD8+ T cells from entering the maternal-fetal interface.[21][22] Mother’s fetal-specific CD4+ T cells proliferate, and due to FOXP3 expression, differentiate into Treg cells.[23] Mice models show that fetal-specific Treg cells are necessary for successful pregnancy.[24] ## Fetal tolerance to noninherited maternal antigens[edit] Fetal T cells accumulate during in utero development. Even though the fetus is exposed to noninherited maternal antigens (NIMAs), fetal CD4<sup+ T cells are capable of alloantigen-induced proliferation, preferentially differentiating to Treg cells and preventing a fetal immune response to maternal antigens.[25] This expanded immune tolerance persists in both mother and offspring after birth and allows microchimeric cells to be retained in tissues. ## Postnatal tolerance to NIMAs[edit] NIMA-specific tolerance causes some interesting immunological phenotypes: sensitization to erythrocyte Rhesus factor (Rh) antigens is reduced among Rh- women born to Rh+ women,[26] long-term kidney allograft survival is improved in NIMA-matched donor-recipient sibling pairs,[27] or acuteness of bone marrow transplantation graft-versus-host disease is reduced, when recipients of donor stem cells are NIMA-matched.[28] Cross-fostering animal studies show that when postnatal NIMA exposure though breastfeeding is eliminated, survival of NIMA-matched allografts is reduced. This suggests that to maintain NIMA-specific tolerance in offspring, breastfeeding is essential, but ingestion of mother’s cells alone does not prime NIMA-specific tolerance. Both prenatal and postnatal exposure to mother’s cells is required to maintain NIMA-specific tolerance.[29] ## Benefits of microchimeric cells[edit] The severity of preexisting autoimmune disorders is reduced during pregnancy and it is most apparent when fetal microchimeric cells levels are highest - during the last trimester.[30][31] These cells can also replace injured maternal cells and recover tissue function (type I diabetes mouse model showed replacement of defective maternal islet cells by fetal-derived pancreatic cells[32]). Fetal microchimeric cells can differentiate into cell types that infiltrate and replace injured cells in models of Parkinson’s disease or myocardial infarction. They also help in wound healing by neoangiogenesis. Seeding of fetal microchimeric cells into maternal tissues has been proposed to promote care of offspring after birth (seeding of maternal breast tissue may promote lactation, and seeding of brain may enhance maternal attention).[29] ## Relationship with autoimmune diseases and breast cancer[edit] Microchimerism has been implicated in autoimmune diseases. Independent studies repeatedly suggested that microchimeric cells of fetal origin may be involved in the pathogenesis of systemic sclerosis.[2][33] Moreover, microchimeric cells of maternal origin may be involved in the pathogenesis of a group of autoimmune diseases found in children, i.e. juvenile idiopathic inflammatory myopathies (one example would be juvenile dermatomyositis).[34] Microchimerism has now been further implicated in other autoimmune diseases, including systemic lupus erythematosus.[35] Contrarily, an alternative hypothesis on the role of microchimeric cells in lesions is that they may be facilitating tissue repair of the damaged organ.[36] Moreover, fetal immune cells have also been frequently found in breast cancer stroma as compared to samples taken from healthy women. It is not clear, however, whether fetal cell lines promote the development of tumors or, contrarily, protect women from developing breast carcinoma.[37][38] ### Systemic lupus erythematosus[edit] The presence of fetal cells in mothers can be associated with benefits when it comes to certain autoimmune diseases. In particular, male fetal cells are related to helping mothers with systemic lupus erythematosus. When kidney biopsies were taken from patients with lupus nephritis, DNA was extracted and run with PCR. The male fetal DNA was quantified and the presence of specific Y chromosome sequences were found. Women with lupus nephritis containing male fetal cells in their kidney biopsies exhibited better renal system functioning. Levels of serum creatinine, which is related to kidney failure, were low in mothers with high levels of male fetal cells.[39] In contrast, women without male fetal cells who had lupus nephritis showed a more serious form of glomerulonephritis and higher levels of serum creatinine.[39] The specific role that fetal cells play in microchimerism related to certain autoimmune diseases is not fully understood. However, one hypothesis states that these cells supply antigens, causing inflammation and triggering the release of different foreign antigens.[39] This would trigger autoimmune disease instead of serving as a therapeutic. A different hypothesis states that fetal microchimeric cells are involved in repairing tissues. When tissues get inflamed, fetal microchimeric cells go to the damaged site and aid in repair and regeneration of the tissue.[39] ### Thyroid disease[edit] Fetal maternal microchimerism may be related to autoimmune thyroid diseases. There have been reports of fetal cells in the lining of the blood and thyroid glands of patients with autoimmune thyroid disease. These cells could become activated after delivery of the baby after immune suppression in the mother is lost, suggesting a role of fetal cells in the pathogenesis of such diseases.[40] Two types of thyroid disease, Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) show similarities to graft vs host disease which occurs after hematopoietic stem cell transplants. Fetal cells colonize maternal tissues like the thyroid gland and are able to survive many years postpartum. These fetal microchimeric cells in the thyroid show up in the blood of women affected by thyroid diseases.[40] ### Sjögren's syndrome[edit] Sjögren's syndrome (SS) is autoimmune rheumatic disease of the exocrine glands. Increased incidence of SS after childbirth suggests a relationship between SS and pregnancy, and this led to hypothesis that fetal microchimerism may be involved in SS pathogenesis. Studies showed presence of the Y-chromosome-positive fetal cells in minor salivary glands in 11 of 20 women with SS but in only one of eight normal controls. Fetal cells in salivary glands suggest that they may be involved in the development of SS.[41] ### Oral lichen planus[edit] Lichen planus (LP) is a T-cell-mediated autoimmune chronic disease of unknown etiology. Females have a three times higher prevalence than men. LP is characterized by T lymphocytes infiltration of the lower levels of epithelium, where they damage basal cells and cause apoptosis. The fetal microchimerism may trigger a fetus versus host reaction and therefore may play a role in the pathogenesis of autoimmune diseases including LP.[42] ### Breast cancer[edit] Pregnancy has a positive effect on the prognosis of breast cancer according to several studies [43][44][45] also it apparently increases the chance of survival after diagnosis of this tumor disease.[46] Possible positive effects of pregnancy could be explained by the persistence of fetal cells in the blood and maternal tissues.[1] Fetal cells are probably actively migrating from peripheral blood into the tumor tissue [47] where they are preferentially settled in the tumor stroma[38] and their concentration decreases as they get closer to the healthy breast tissue.[48] There are two suggested mechanisms by which the fetal cells could have the positive effect on the breast cancer prognosis. First mechanism suggests that fetal cells only oversee cancer cells and they attract components of the immune system if needed. The second option is that the down-regulation of the immune system induced by the presence of fetal cells could ultimately lead to cancer prevention, because women in whom FMC is present produce lower concentrations of inflammatory mediators, which may lead to the development of neoplastic tissue.[49] The effect also depends on the level of microchimerism: Hyperchimerism (too high a degree of microchimerism) can, as well as hypochimerism (low rate of microchimerism), be related to the negative effect of FMC and thus can promote worse prognosis of breast cancer.[50][51] Apparently, women with breast cancer may fail in the process of obtaining and maintaining allogeneic fetal cells. Low concentration and / or complete absence of fetal cells could indicate a predisposition to development of the malignant process. ### Other cancers[edit] Study of S. Hallum shows association between male origin fetal cells and ovarian cancer risk. Presence of Y chromosome was used to detect foreign cells in women’s blood. Microchimerism is a result of pregnancy, possibility that foreign cells were of transfusion or transplantation origin was rejected due to women’s health. Women testing positive for male origin microchimerism cells had reduced hazard rates of ovarian cancer than women testing negative.[52] Pregnancy at older ages can reduce risk of ovarian cancer. Numbers of microchimeric cells declines after pregnancy, and ovarian cancer is most frequent in postmenopausal women. This suggests that fetal microchimerism may play a protective role in ovarian cancer as well. Microchimeric cells also cluster several times more in lung tumors than in surrounding healthy lung tissue. Fetal cells from the bone marrow go to the tumor sites where they may have tissue repair functions.[53] Microchimerism of fetomaternal cell trafficking origin might be associated with the pathogenesis or progression of cervical cancer. Male cells were observed in patients with cervical cancer but not in positive controls. Microchimeric cells might induce the alteration of the woman's immune system and make the cervical tissue more susceptible to HPV infection or provide a suitable environment for tumor growth.[54] ## Role of microchimerism in the wound healing[edit] Microchimeric fetal cells expressed collagen I, III and TGF-β3, and they were identified in healed maternal cesarean section scars. This suggests that these cells migrate to the site of damage due to maternal skin injury signals, and help repair tissue.[55] ## Stem cells[edit] ### Animal models[edit] Fetomaternal microchimerism has been shown in experimental investigations of whether fetal cells can cross the blood brain barrier in mice. The properties of these cells allow them to cross the blood brain barrier and target injured brain tissue.[56] This mechanism is possible because umbilical cord blood cells express some proteins similar to neurons. When these umbilical cord blood cells are injected in rats with brain injury or stroke, they enter the brain and express certain nerve cell markers. Due to this process, fetal cells could enter the brain during pregnancy and become differentiated into neural cells. Fetal microchimerism can occur in the maternal mouse brain, responding to certain cues in the maternal body.[56] ## Health implications[edit] Fetal microchimerism could have an implication on maternal health. Isolating cells in cultures can alter the properties of the stem cells, but in pregnancy the effects of fetal stem cells can be investigated without in vitro cultures. Once characterized and isolated, fetal cells that are able to cross the blood brain barrier could impact certain procedures.[56] For example, isolating stem cells can be accomplished through taking them from sources like the umbilical cord. These fetal stem cells can be used in intravenous infusion to repair the brain tissue. Hormonal changes in pregnancy alter neurogenesis, which could create favorable environments for fetal cells to respond to injury.[56] The true function on fetal cells in mothers is not fully known, however, there have been reports of positive and negative health effects. The sharing of genes between the fetus and mother may lead to benefits. Due to not all genes being shared, health complications may arise as a result of resource allocation.[57] During pregnancy, fetal cells are able to manipulate the maternal system to draw resources from the placenta, while the maternal system tries to limit it.[57] ## See also[edit] * Chimerism * Allotransplantation * Telegony * Epigenetics * Cell-free fetal DNA ## References[edit] 1. ^ a b Bianchi, D. W.; Zickwolf, G. K.; Weil, G. J.; Sylvester, S.; DeMaria, M. A. (23 January 1996). "Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum". Proceedings of the National Academy of Sciences. 93 (2): 705–708. Bibcode:1996PNAS...93..705B. doi:10.1073/pnas.93.2.705. PMC 40117. PMID 8570620. 2. ^ a b Evans, Paul C.; Lambert, Nathalie; Maloney, Sean; Furst, Dan E.; Moore, James M.; Nelson, J. Lee (15 March 1999). "Long-Term Fetal Microchimerism in Peripheral Blood Mononuclear Cell Subsets in Healthy Women and Women With Scleroderma". 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Journal of Reproductive Immunology. 84 (2): 117–123. doi:10.1016/j.jri.2009.11.006. PMID 20116109. 33. ^ Artlett, Carol M.; Smith, J. Bruce; Jimenez, Sergio A. (23 April 1998). "Identification of Fetal DNA and Cells in Skin Lesions from Women with Systemic Sclerosis". New England Journal of Medicine. 338 (17): 1186–1191. doi:10.1056/NEJM199804233381704. PMID 9554859. 34. ^ Artlett CM, Ramos R, Jiminez SA, Patterson K, Miller FW, Rider LG (2000). "Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies. Childhood Myositis Heterogeneity Collaborative Group". Lancet. 356 (9248): 2155–6. doi:10.1016/S0140-6736(00)03499-1. PMID 11191545. S2CID 46327174. 35. ^ Johnson KL, McAlindon TE, Mulcahy E, Bianchi DW (September 2001). "Microchimerism in a female patient with systemic lupus erythematosus". Arthritis and Rheumatism. 44 (9): 2107–11. doi:10.1002/1529-0131(200109)44:9<2107::AID-ART361>3.0.CO;2-9. PMID 11592373. 36. ^ Gilliam AC (February 2006). "Microchimerism and skin disease: true-true unrelated?". The Journal of Investigative Dermatology. 126 (2): 239–41. doi:10.1038/sj.jid.5700061. PMID 16418731. 37. ^ Gadi VK, Nelson JL (October 2007). "Fetal microchimerism in women with breast cancer". Cancer Research. 67 (19): 9035–8. doi:10.1158/0008-5472.CAN-06-4209. PMID 17909006. 38. ^ a b Dubernard, Gil; Aractingi, Sélim; Oster, Michel; Rouzier, Roman; Mathieu, Marie-Christine; Uzan, Serge; Khosrotehrani, Kiarash (February 2008). "Breast cancer stroma frequently recruits fetal derived cells during pregnancy". Breast Cancer Research. 10 (1): R14. doi:10.1186/bcr1860. PMC 2374970. PMID 18271969. 39. ^ a b c d Florim GM, Caldas HC, de Melo JC, Baptista MA, Fernandes IM, Savoldi-Barbosa M, Goldman GH, Abbud-Filho M (April 2015). "Fetal microchimerism in kidney biopsies of lupus nephritis patients may be associated with a beneficial effect". Arthritis Research & Therapy. 17: 101. doi:10.1186/s13075-015-0615-4. PMC 4416327. PMID 25889410. 40. ^ a b Lepez T, Vandewoestyne M, Deforce D (20 May 2013). "Fetal microchimeric cells in autoimmune thyroid diseases: harmful, beneficial or innocent for the thyroid gland?". Chimerism. 4 (4): 111–8. doi:10.4161/chim.25055. PMC 3921191. PMID 23723083. 41. ^ Endo, Y.; Negishi, I; Ishikawa, O (1 May 2002). "Possible contribution of microchimerism to the pathogenesis of Sjogren's syndrome". Rheumatology. 41 (5): 490–495. doi:10.1093/rheumatology/41.5.490. PMID 12011370. 42. ^ Shrivastava, Sandhya; Naik, Rupali; Suryawanshi, Hema; Gupta, Neha (2019). "Microchimerism: A new concept". Journal of Oral and Maxillofacial Pathology. 23 (2): 311. doi:10.4103/jomfp.JOMFP_85_17. PMC 6714269. PMID 31516258. 43. ^ Rosenberg L, Thalib L, Adami HO, Hall P (September 2004). "Childbirth and breast cancer prognosis". International Journal of Cancer. 111 (5): 772–6. doi:10.1002/ijc.20323. PMID 15252849. S2CID 8782090. 44. ^ Olson, Sara H.; Zauber, Ann G.; Tang, Jian; Harlap, Susan (November 1998). "Relation of Time since Last Birth and Parity to Survival of Young Women with Breast Cancer". Epidemiology. 9 (6): 669–671. doi:10.1097/00001648-199811000-00019. PMID 9799180. 45. ^ Anderson, Penny R.; Hanlon, Alexandra L.; Freedman, Gary M.; Nicolaou, Nicos (August 2004). "Parity Confers Better Prognosis in Older Women with Early-Stage Breast Cancer Treated with Breast-Conserving Therapy". Clinical Breast Cancer. 5 (3): 225–231. doi:10.3816/cbc.2004.n.026. PMID 15335456. 46. ^ Warren Andersen S, Newcomb PA, Hampton JM, Titus-Ernstoff L, Egan KM, Trentham-Dietz A (December 2011). "Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis". Breast Cancer Research and Treatment. 130 (3): 975–80. doi:10.1007/s10549-011-1666-0. PMC 4306414. PMID 21769659. 47. ^ Dubernard G, Oster M, Chareyre F, Antoine M, Rouzier R, Uzan S, Aractingi S, Khosrotehrani K (March 2009). "Increased fetal cell microchimerism in high grade breast carcinomas occurring during pregnancy". International Journal of Cancer. 124 (5): 1054–9. doi:10.1002/ijc.24036. PMID 19065666. S2CID 29640302. 48. ^ Nemescu D, Ursu RG, Nemescu ER, Negura L (2016-01-25). "Heterogeneous Distribution of Fetal Microchimerism in Local Breast Cancer Environment". PLOS ONE. 11 (1): e0147675. Bibcode:2016PLoSO..1147675N. doi:10.1371/journal.pone.0147675. PMC 4726590. PMID 26808509. 49. ^ Coussens LM, Werb Z (2002-12-19). "Inflammation and cancer". Nature. 420 (6917): 860–7. Bibcode:2002Natur.420..860C. doi:10.1038/nature01322. PMC 2803035. PMID 12490959. 50. ^ Gadi VK, Malone KE, Guthrie KA, Porter PL, Nelson JL (March 2008). "Case-control study of fetal microchimerism and breast cancer". PLOS ONE. 3 (3): e1706. Bibcode:2008PLoSO...3.1706G. doi:10.1371/journal.pone.0001706. PMC 2248618. PMID 18320027. 51. ^ Dhimolea E, Denes V, Lakk M, Al-Bazzaz S, Aziz-Zaman S, Pilichowska M, Geck P (August 2013). "High male chimerism in the female breast shows quantitative links with cancer". International Journal of Cancer. 133 (4): 835–42. doi:10.1002/ijc.28077. PMID 23390035. S2CID 23272121. 52. ^ Hallum, Sara; Jakobsen, Marianne Antonius; Gerds, Thomas Alexander; Pinborg, Anja; Tjønneland, Anne; Kamper-Jørgensen, Mads (2020). "Male origin microchimerism and ovarian cancer". International Journal of Epidemiology. doi:10.1093/ije/dyaa019. PMID 32065627. 53. ^ Sawicki, J. A. (1 December 2008). "Fetal Microchimerism and Cancer". Cancer Research. 68 (23): 9567–9569. doi:10.1158/0008-5472.CAN-08-3008. PMC 2638004. PMID 19047129. 54. ^ Cha, D (October 2003). "Cervical cancer and microchimerism". Obstetrics & Gynecology. 102 (4): 774–781. doi:10.1016/S0029-7844(03)00615-X. PMID 14551008. 55. ^ Mahmood, Uzma; O’Donoghue, Keelin (April 2014). "Microchimeric fetal cells play a role in maternal wound healing after pregnancy". Chimerism. 5 (2): 40–52. doi:10.4161/chim.28746. PMC 4199806. PMID 24717775. 56. ^ a b c d Tan XW, Liao H, Sun L, Okabe M, Xiao ZC, Dawe GS (1 November 2005). "Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier?". Stem Cells. 23 (10): 1443–52. doi:10.1634/stemcells.2004-0169. PMID 16091558. S2CID 37875663. 57. ^ a b Boddy AM, Fortunato A, Wilson Sayres M, Aktipis A (October 2015). "Fetal microchimerism and maternal health: a review and evolutionary analysis of cooperation and conflict beyond the womb". BioEssays. 37 (10): 1106–18. doi:10.1002/bies.201500059. PMC 4712643. PMID 26316378. ## Further reading[edit] * Müller AC, Jakobsen MA, Barington T, Vaag AA, Grunnet LG, Olsen SF, Kamper-Jørgensen M (October 2015). "Microchimerism of male origin in a cohort of Danish girls". Chimerism. 6 (4): 65–71. doi:10.1080/19381956.2016.1218583. PMC 5293315. PMID 27623703. * Gammill HS, Nelson JL (2010). "Naturally acquired microchimerism". The International Journal of Developmental Biology. 54 (2–3): 531–43. doi:10.1387/ijdb.082767hg. PMC 2887685. PMID 19924635. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Microchimerism	None	6,984	wikipedia	https://en.wikipedia.org/wiki/Microchimerism	2021-01-18T18:37:12	{"mesh": ["D046528"], "wikidata": ["Q222580"]}
Jaw abnormality SpecialtyOral & Maxillofacial surgery A jaw abnormality is a disorder in the formation, shape and/or size of the jaw. In general abnormalities arise within the jaw when there is a disturbance or fault in the fusion of the mandibular processes. The mandible in particular has the most differential typical growth anomalies than any other bone in the human skeleton. This is due to variants in the complex symmetrical growth pattern which formulates the mandible.[1] The mandible in particular plays a significant role in appearance as it is the only moving part of the facial skeleton. This has a large impact upon an individuals’ ability speak, masticate and also influence their overall aesthetic and expressive features of the face. In turn the maxilla faces the same issues if any abnormalities in size or position were to occur.[2] The obvious functional disabilities that arise from jaw abnormalities are very much physically seen as previously stated, but when considering these individuals it must be kept in mind that these conditions may well affect them psychologically; making them feel as though they are handicapped.[3] It is also of the utmost importance when correcting these mandibular anomalies that the teeth result in a good occlusion with the opposing dentition of the maxilla. If this is not done satisfactorily occlusal instability may be created leading to a plethora of other issues. In order to correct mandibular anomalies it is common for a complex treatment plan which would involve surgical intervention and orthodontic input. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Examination * 2.2 Tests * 3 Classification * 3.1 Size * 3.2 Position * 3.3 Orientation * 3.4 Shape * 3.5 Completeness * 4 Treatment * 4.1 Mandibular surgery * 4.2 Genioplasty * 4.3 Maxillary surgery * 5 References * 6 External links ## Signs and symptoms[edit] Individuals with jaw abnormalities have both functional[4][5] and aesthetic[4][5][6][7][8][9][10][11] impairment.[12] Misalignment of teeth creates difficulties in head and neck functions related to chewing,[6][7][8] swallowing, breathing, speech articulation[6][7][8] and lip closure/posture.[13] Affected individuals may also experience TMJ pain and dysfunction,[7][14] which negatively affect the quality of life.[15] A proportion of affected individuals also have psychological problems.[16] ## Diagnosis[edit] Diagnosis of a jaw deformity is a structured process, linking the undertaking of a history, physical examination of the patient, and appraisal of diagnostic studies. This process may involve more than a single discipline of Dentistry – in addition to orthodontic and surgical needs, some patients may also require periodontal, endodontic, complex restorative, and prosthetic considerations.[17] It involves the chief presenting complaint of the patient, which allows the clinician to understand the patient’s perception of the problem – what they think the problem is and what they would like corrected. The patient may find eating difficult or may have problems with speech or the appearance of the teeth or face. However, patients may be hesitant to discuss dissatisfaction with their appearance because they may feel that it is more acceptable to present a functional problem to the clinician. For this reason it is important to reassure patients that their aesthetic problems and the effects of these are perfectly valid concerns. In children, psychological development can be affected due to teasing if they have abnormal appearance of teeth or face. Correction of the abnormality can be extremely beneficial to the patient. The benefits can manifest themselves in many ways including improved peer relationships and social confidence. Motivation on the patient's part is necessary if they are going to undergo lengthy orthodontic treatment and major surgery. In addition, they need to be well informed so that they may give valid consent. In terms of history, the family history and perhaps obstetric history may be relevant, especially when features of a syndrome are present.[18]:200 A medical and dental history is obtained for completeness. The medical history includes questions on the general health of the patient, to assess contraindications to treatment of jaw abnormality. Special emphasis is placed on diseases and medication which cause altered metabolism, that may affect growth and tissue reactions.[19] Allergies are checked (specifically nickel allergies), so that treatment appliances with nickel-containing materials like stainless steel can be replaced with other materials to avoid the risk of allergic reactions.[20] Questions on family history are also relevant, as malocclusions, growth and development may be expressions of genetic patterns.[19] The dental history investigates if the patient has had any previous dental trauma, or past dental experiences, which can serve as a gauge to patient compliance with treatment. ### Examination[edit] The assessment of facial form includes the evaluation of facial soft tissue and dentition. As the human skeleton is not visibly perceptible, bone deformity is inferred and evaluated by facial appearance and dentition.[21] To obtain a 3D assessment of the patient, the skeletal pattern must be measured in different planes: anterior-posterior, vertical, and transverse. This allows for an accurate assessment of the size, position, orientation, shape, and symmetry of the jaws. The anterior-posterior skeletal pattern measures the relationship of the lower jaw to the upper jaw. This is judged with the patient seated upright, head in a neutral horizontal position, and teeth in gentle occlusion. It can be classified into the following classes: * Class I: The ideal relationship whereby the upper jaw lies 2-4mm in front of the lower jaw * Class II: Upper jaw lies more than 4mm in front of the lower jaw * Class III: Upper jaw lies less than 2mm in front of the lower jaw, or in more severe cases, the lower jaw may be in front of the upper jaw. The vertical dimension can be measured by facial thirds, with ideal facial aesthetics showing equality between each vertical third.[22] The face is divided into thirds – hairline to glabella; glabella to subnasale; and subnasale to the lowest part of the chin. Two other clinical indicators can be assessed when analysing vertical dimensions, namely the Frankfort Mandibular Planes Angle (FMPA) and the Lower Facial Height (LFH) – both of which are each recorded as either average, increased, or decreased. * FMPA: This is estimated by the point of intersection between the lower border of the mandible and the Frankfort Horizontal plane. * LFH: The face is divided into thirds, and the proportion of the lower third of the face is compared to the rest. The transverse relationship is a measure of jaw or facial asymmetry. It checks for the alignment of the soft tissue nasion, the middle part of the upper lip at the vermillion border, and the chin point. If present, it is necessary to distinguish between a false and true asymmetry.[23] A false asymmetry arises due to occlusal interferences, which results in a lateral displacement of the mandible, producing a cross-bite in the anterior/buccal region. Elimination of the displacement will return the mandible to a centric position. On the other hand, a true asymmetry indicates unequal facial growth on the left or right side of the jaws. Elimination of any occlusal cross-bites is not only difficult, but unlikely to improve the facial asymmetry. The assessment of the transverse components of the facial width is best described by the "rule of fifths",[24] which sagittally divides the face into five equal parts:[25] * Each transverse fifth should be an eye distance in width. * The middle fifth is marked by the inner canthus of both eyes. * The medial three-fifths of the face is marked from the outer canthus of the eye frames * The outer two-fifths of the face is measured from the lateral canthus to lateral helix of the ear, which represents the width of the ears. ### Tests[edit] It is insufficient to derive at a diagnosis of jaw deformity solely based on the clinical examination. Hence, additional information is gathered from diagnostic tests, which may include dental model analyses and radiographic imaging studies. 1. Dental Model Analyses - Study models for analysis can be made by taking dental impressions, or by 3D intra-oral scanning. They allow for the appraisal of shape and size of jaws and teeth. This can be valuable for the long-term evaluation of development and for the follow up of treatment results. Depending on the type of jaw abnormality, a face bow record for transfer on to the articulator, can sometimes be appropriate for the patient.[26] 2. Radiographs - Radiographic investigations should be based on individual needs and used in conjunction to the clinical examination. As with all other dental radiographs, the benefit gained for the patient with the radiograph must be weighed against the radiation dosage of taking it.[27] In the assessment of jaw abnormalities, the most common radiographs taken used to be the dental panoramic tomography and lateral cephalometry. With the advancement in technology, the use of 3D imaging e.g. Cone Beam Computed Tomography (CBCT) has gained popularity for the use of radiographic examinations of facial bones for purpose of planning complex orthognathic surgery, especially involving significant facial asymmetry.[17] A 3D facial construction model can be utilised in more complex malocclusion to help plan management.[28] ## Classification[edit] ### Size[edit] * Micrognathia Mandibular micrognathia is the condition when lower jaw is smaller than normal.[29] Failure of the ramus to develop will give rise to micrognathia.[30] Micrognathia can be classified as either congenital or acquired. Clinical appearance of some patients with congenital type of mandibular micrognathia can have a severe retrusion of the chin but by actual measurements, the mandible maybe be found to be within the normal limits of variation. This maybe because a posterior placing of the condylar head with regard to the skull or to a steep mandibular angle resulting in an evident jaw retrusion. The acquired type of micrognathia occurs after birth and usually is an effect of a disturbance to temporomandibular joint. Growth of mandible depends on the normally developing condyles and the muscle function For example, trauma or infection that affect mastoid, middle ear or the joint will result in ankylosis of temporomandibular joint leading to mandibular micrognathia.[31] * Macronagthia Macronagthia is a condition of abnormally large jaws. The jaw size is usually proportion to the increase in skeleton size.[31] It is usually due to excessive growth of the mandible and can have features including reverse maxillary to mandibular relationship, reverse overjet or absence of overbite.[30] It can also be cinically presented when the glenoid fossa and condylar head is more anteriorly placed, causing mandibular prognathism.[32] Macronagthism can be associated with other medical conditions :- 1\. Paget’s disease where there is overgrowth of the maxilla, cranium and mandible[31] 2\. Acromegaly, an endocrine disease, can present with enlargement of bones with growth potential such as the mandible, thickened soft tissues and facial features and spade-like hands [33] * Macrogenia or Microgenia Macrogenia and microgenia occur when there is a normal skeletal relationship but the chin, skeletal and soft tissue components, failed to develop in proportion to the skeletal base, resulting in marked protrusive (macrogenia) or retrusive (microgenia) facial profile. Microgenia can be presented when there is inadequate bone depth at the apex of lower anteriors or the base of mandible and vice versa.[30] ### Position[edit] * Transverse A transverse jaw position is known as Laterognathia. This term describes a lateral bite in the lower jaw [34] and is often associated with a unilateral crossbite at an early age [35] This can lead to bone development of an asymmetrical mandibular ramus resulting in asymmetry in the whole of the lower face.[36] Treatment of laterognathism is either possible with orthodontic tooth movement or a surgical relocation of the lower jaw.[37] * Vertical One of the ways in which a jaw can develop abnormally is in the vertical dimension. Abnormal growth can occur in the maxilla and the mandible. The jaw is usually loosely used to refer to the mandible (considered the lower jaw). However, the maxilla is also a jaw and should thus be referred to in this respect as well. The vertical jaw abnormalities relating to the mandible are in relation to excessive vertical growth and excessive horizontal growth, measured by the maxillary-mandibular plane angle (MMPA). The vertical jaw abnormalities relating to the maxilla are in relation to excessive downward displacement (EDD) and insufficient downward displacement (IDD). These terms used to previously be known as vertical maxillary excess and deficiency. This nomenclature changed because excess and deficiency typically refer to size. Whereas when assessing this clinically, one would measure the distance between the central incisors and the upper lip, which, in actual fact, denotes position rather than size. Therefore in order to ‘harmonize with geometry’, EDD and IDD are now used widely.[38] Vertical and Horizontal Mandibular Excess: Simply put, excessive vertical growth is the term used for when the mandible is considered ‘too far down.[39] Whereas in excessive horizontal growth the opposite applies, where the mandible is growing in a more horizontal pattern, in relation to the maxilla. The primary cause of the above two abnormalities in adolescents is due to accelerated and slow mandibular growth. Resulting in either a longer lower face height appearance (vertical growth) or a shorter one (horizontal growth). The length between the columella (base of the nose) and menton (base of the chin) is the variable measurement. This is in relation to the length between the glabella (between eyebrows) and the columella. In a normal case, these lengths would be equal or without a major discrepancy. However, in excess vertical and horizontal growth, the proportions vary and do not equal. The development of the mandible is such that it ossifies in two primary ways; endochondrally and intramembranously. Almost the entire mandible is formed via intramembranous ossification, with just the condyle ossifying endochondrally. This allows the condyle to resist forces exerted on it. One way in which a vertical jaw abnormality can occur is if the condylar growth process is damaged, and thus the intramembranous growth continues along the posterior condylar margin, becoming predominant, thus resulting in a high angle type.[40] Assessing a patient for vertical and horizontal excess The Maxillary Mandibular Plane Angle (MMPA) is important in assessing a patient for vertical jaw abnormality. The important landmarks are the Frankfurt plane and the Mandibular plane. The Frankfurt plane is a line charted from the upper border of external auditory meatus to the lower border of the orbit. It is similar to the ala-tragus line however should not be confused with it. Whereas the Mandibular angle is a line measured along the natural lower border of the patient’s mandible. The intersection of the Frankfurt and Mandibular plane is what determines the pattern of vertical growth. If the intersection occurs behind the occiput i.e. decreased angle, then the patient is considered to have horizontal growth. On the other hand, if the intersection occurs in front of the occiput, then the patient is considered to have vertical growth. The normal range is considered to be between 25-30 degrees in a typical Caucasian person. Those with excess vertical jaw growth are most often seen having an anterior open bite, as the mandible is growing away from the maxilla. Whereas those with excessive horizontal growth are seen as having an overbite. Excessive Downward Displacement and Insufficient Downward Displacement Here on, we will use interchangeably the terms vertical maxillary excess and deficiency with excessive and insufficient downward displacement. In order to understand its manifestations, we need to account for key landmarks such as:[41] · Columella (CM)– The tissue that links the nasal tip to the nasal base, separating the nares. The inferior margin of the nasal septum · Subnasale (SN) – the junction of the upper lip and the columella · Stomion Superios (Sts) – the lower most point on the vermillion of the upper lip · Stomion (Sto) – The point of contact, when lips are competent, in the midline, between the top and bottom lip · Stomion Inferious (Sti) – the upper most point on the vermillion of the lower lip · Soft tissue mention (Me) – The most inferior point on the soft tissue outline of the chin The measurements of the upper lip and lower lip for each patient are ascertained by using the aforementioned landmarks. The length of the upper lip is measured from Sn to Sts. In a typical male and female this measures to 24mm and 21mm respectively (REF). The length of the lower lip is measured from Sti to Me. In a typical male and female this measures to 50mm and 46.5mm respectively.[41] When considering EDD and IDD, the class of the skeletal base is a good adjunct. In other words, EDD and IDD can either appear camouflaged or apparent given the skeletal base and the soft tissue profile accompanying it. For example, the drape of the upper lip can mask the maxillary deficiency to such an extent that it presents as a normal soft tissue profile (REF). Para-nasal hollowing is a key indicator of underlying maxillary deficiency. It is most common in class III patients, but can also present in some class II cases, with bilateral maxillary retrusion.[41] Assessing a patient for vertical and horizontal excess: Arguably the main observation to carry out in a patient to assess maxillary excess or deficiency is the upper incisor/gum show when at rest and smiling. In other words, the relationship between the upper lip and upper central incisors when at rest and smiling.[41] Ensure the patient’s head posture is correct and the lips are at rest to establish the resting lip line. Similarly, to assess the incisor/gum show on smiling, the patient needs to fully smile to allow the upper lip to rise to its maximum height. The average showing of the incisors when the lips are at rest is 1/3 of its clinical crown height. With maxillary excess, more than 1/3 of the incisors would show. When the patient smiles, maxillary excess would manifest as the entire clinical crown and a portion of the gums showing as well.[42] This is regarded as a ‘gummy smile.’ As alluded to previously, the paranasal region is important to consider when assessing a patient for IDD or EDD. Observing the patient from the side view allows a clearer perspective. A lack of bony support for the soft tissues in this region will subsequently produce the depression, known as paranasal hollowing.[42] This indicates a low level antero-posterior maxillary deficiency. Maxillary deficiency usually manifests as an increased naso-labial angle, although this is not a credible indication due to factors such as a short upper lip and/or proclined incisors. Another method to predict if a patient has maxillary deficiency is by the ‘scleral show and eyelid shape.’ The lower eyelid normally rests at the inferior border of the iris, without any sclera showing. If there is any sclera showing, then this is a good sign of infraorbital rim deficiency and maxillary antero-posterior deficiency, two manifestations that are usually seen in Class III patients.[42] ### Orientation[edit] When a jaw is abnormally oriented, malrotations occur. These malrotations are classified according to the axis on which the abnormal rotation occurs. When a jaw is malrotated around the transverse facial axis, it is said to have abnormal pitch. When malrotated around the anteroposterior axis, the jaw has an abnormal roll, a condition also known as cant. Finally, when a jaw is malrotated around the vertical axis, it has abnormal yaw. It can occur in maxilla and/or mandible and could result due to abnormal growth of the jaws in itself or as compensatory growth.[43] ### Shape[edit] Shape refers to figure, the geometric characteristic of an object that is not size, position, or orientation 5. A jaw with abnormal shape is said be distorted.[44] ### Completeness[edit] Completeness means the wholeness of the jaw.[45] When failure of tissues to fuse together that are forming early in pregnancy, defect can happen and jaw is incomplete.[46] For example cleft lip and palate when one of the jaw`s embryological processes failed to fuse together or the agenesis of the condylar process of the mandible, which may be seen in hemifacial microsomia.[46] Clinically, cleft palate presents as opening in the palate that can affect the front palate only or extending from the front to the back palate.[47] Cleft lip is presented clinically with opening of the upper lip which can be a small slit on the upper lip or large opening connected to the nose.[47] The cleft can be unilateral on the upper lip or bilaterally.[48] Cleft lip can happen together with cleft palate.[47] Palatal clefts are one of the most common congenital abnormalities which occur in 1:2500 live births.[46] Embryologically, palate formation takes place in two stages, with the primary palate formed after 6th week followed by secondary palate formation between sixth and eighth weeks.[46] The palate will fuse with the medial nasal process to form the roof of the mouth in order to complete the developmental process.[12] However, if this process is incomplete that is when developmental defect occur.[46] Initially, it is just a common oro-nasal cavity within the embryo with nothing to separate the nose and mouth cavity.[46] This space is occupied with tongue.[46] The primary palate formed when medial nasal prominences fused together to form the intermaxillary segment to demarcate the oral from the nasal components.[46] The formation of secondary palate starts with the growing of tissues vertically and mesially forming the right and left lateral palatal shelves.[46] On the week 8, the tongue will be withdrawn downwards and the right and left lateral palatal shelves will be rapidly elevated, flipped into a horizontal orientation and fuse together from the front to the back two.[46] The right and left lateral palatal shelves contact or fuse with each other at the midline to form the secondary palate two.[46] A lot of growth factors are actively involved in the signalling to the tissues during craniofacial development.[49] These growth factors function to control the cells proliferation, survival and apoptosis.[49] Some of the growth factors that can be implicated in the facial development resulting in craniofacial defect are BMP, FGF, Shh, Wnt and endothelins.[49] One of the environmental factors that has been identified in mice study to have link to cleft lip is teratogen which can interfere the molecular signalling between the growth factors.[48] However, the exact mechanism is still not clear.[48] Another environmental factors that has been actively involved in studies to prevent cleft lip and palate occurrences is the intake of folic acid during pregnancy.[50] 0.4 mg folic acid intake per day has been shown to reduce one third risk of cleft lip (with or without cleft palate) in babies.[50] However, it seems had no apparent effect on the risk of cleft palate alone.[50] There are also studies in mice and dogs reported the protective effect of folic acid supplementation to prevent cleft lip palate occurrence.[48] ## Treatment[edit] Jaw abnormalities are commonly treated with combined surgical (orthognathic surgery) and orthodontic treatment.[12] The procedure is carried out by oral and maxillofacial surgeons and orthodontists in close collaboration.[51] In most cases, the orthodontist will first align the teeth with braces or other appliances, which may worsen the occlusion until after the surgery.[51] This is carried out to show the full degree of abnormality, and to create sufficient space for full correction in the bones.[51] Orthognathic surgery, also known as corrective jaw surgery, is performed to normalise dentofacial deformity and reposition part/all of the upper and/or lower jaws to improve occlusion stability and facial proportions.[12][51] It is the 'mainstay treatment for patients who are too old for growth modification and for dentofacial conditions that are too severe for either surgical or orthodontic camouflage.'[52] The surgery usually involves gaining access to the bone from inside the mouth, revealing and moving the bone into a correct functional position, and fixing it in position with metal plates and screws.[53] These plates are most often left in the bone, but at times require removal due to infection, which would require another operation.[53] Most orthognathic surgeries are performed inside the mouth without any external scarring.[53] ### Mandibular surgery[edit] There are numerous surgical techniques available to correct the position of the mandible. The most popular of these techniques is the sagittal split osteotomy which "enables the body of mandible to be moved forwards or backwards by sliding the split ramus and angle".[18]:203 This provides a lot of bone overlap for healing. Damage to the inferior alveolar bundle is avoided by sectioning the buccal and retromolar cortex of the mandible and the cancellous bone is carefully split. After the mandible has been repositioned, screws or mini-plates can be used to fix the mandible directly. This is instead of fixing it indirectly with intermaxillary fixation (IMF).[18]:203 ### Genioplasty[edit] Reduction or augmentation of the chin may be carried out either on its own or as part of a mandibular or maxillary orthognathic operation.[18]:203 ### Maxillary surgery[edit] The Le Fort classification (which is used for fracture description) generally describes the surgical techniques which are used for maxillary surgery.[18]:203 ## References[edit] 1. ^ Nugent, Karen (May 2011). "DrExam™ Part B MRCS OSCE Revision Guide Book 1 and Book 2MirandaBH AsaadK KaySP DrExam™ Part B MRCS OSCE Revision Guide Book 1: Applied Surgical Science & Critical Care, Anatomy & Surgical Pathology, Surgical Skills and Patient Safety 2010 Libri Faringdon, Oxfordshire 456 £29.99 9781907471056MirandaBH AsaadK KaySP DrExam™ Part B MRCS OSCE Revision Guide Book 2: Clinical Examination, Communication Skills & History Taking 2010 Libri Faringdon, Oxfordshire 264 £29.99 9781907471063". Annals of the Royal College of Surgeons of England. 93 (4): 331. doi:10.1308/rcsann.2011.93.4.331a. ISSN 0035-8843. PMC 3363102. 2. ^ L., Obwegeser, Hugo (2010). Mandibular growth anomalies : terminology, aetiology, diagnosis, treatment. Springer. ISBN 9783642086557. OCLC 715364997. 3. ^ "Jaw Deformities \| Riley Children's Health". www.rileychildrens.org. Retrieved 2018-10-24. 4. ^ a b Baig MA (October 2004). "Surgical enhancement of facial beauty and its psychological significance". Annals of the Royal Australasian College of Dental Surgeons. 17: 64–7. PMID 16479858. 5. ^ a b Palumbo B, Cassese R, Fusetti S, Tartaro GP (2006). "Psychological aspects of orthognathic treatment". Minerva Stomatologica. 55 (1–2): 33–42. PMID 16495871. 6. ^ a b c Stirling J, Latchford G, Morris DO, Kindelan J, Spencer RJ, Bekker HL (June 2007). "Elective orthognathic treatment decision making: a survey of patient reasons and experiences". Journal of Orthodontics. 34 (2): 113–27, discussion 111. doi:10.1179/146531207225022023. PMID 17545299. 7. ^ a b c d Zhou YH, Hägg U, Rabie AB (2001). "Concerns and motivations of skeletal Class III patients receiving orthodontic-surgical correction". The International Journal of Adult Orthodontics and Orthognathic Surgery. 16 (1): 7–17. PMID 11563399. 8. ^ a b c Modig M, Andersson L, Wårdh I (February 2006). "Patients' perception of improvement after orthognathic surgery: pilot study". The British Journal of Oral & Maxillofacial Surgery. 44 (1): 24–7. doi:10.1016/j.bjoms.2005.07.016. PMID 16162374. 9. ^ Williams AC, Shah H, Sandy JR, Travess HC (September 2005). "Patients' motivations for treatment and their experiences of orthodontic preparation for orthognathic surgery". Journal of Orthodontics. 32 (3): 191–202. doi:10.1179/146531205225021096. PMID 16170061. 10. ^ Lee LW, Chen SH, Yu CC, Lo LJ, Lee SR, Chen YR (July 2007). "Stigma, body image, and quality of life in women seeking orthognathic surgery". Plastic and Reconstructive Surgery. 120 (1): 225–31. doi:10.1097/01.prs.0000264100.57630.c7. PMID 17572567. 11. ^ Chen B, Zhang ZK, Wang X (2002). "Factors influencing postoperative satisfaction of orthognathic surgery patients". The International Journal of Adult Orthodontics and Orthognathic Surgery. 17 (3): 217–22. PMID 12353939. 12. ^ a b c d Alanko OM, Svedström-Oristo AL, Tuomisto MT (September 2010). "Patients' perceptions of orthognathic treatment, well-being, and psychological or psychiatric status: a systematic review". Acta Odontologica Scandinavica. 68 (5): 249–60. doi:10.3109/00016357.2010.494618. PMID 20513168. 13. ^ Posnick, Jeffery C. (2014). Orthognathic surgery: Principles & practice. St. Louis, Missouri : Saunders. p. 61. ISBN 9781455726981. 14. ^ Pahkala RH, Kellokoski JK (August 2007). "Surgical-orthodontic treatment and patients' functional and psychosocial well-being". American Journal of Orthodontics and Dentofacial Orthopedics. 132 (2): 158–64. doi:10.1016/j.ajodo.2005.09.033. PMID 17693364. 15. ^ Barros Vde M, Seraidarian PI, Côrtes MI, de Paula LV (2009). "The impact of orofacial pain on the quality of life of patients with temporomandibular disorder". Journal of Orofacial Pain. 23 (1): 28–37. PMID 19264033. 16. ^ Rumsey N, Clarke A, White P, Wyn-Williams M, Garlick W (December 2004). "Altered body image: appearance-related concerns of people with visible disfigurement". Journal of Advanced Nursing. 48 (5): 443–53. doi:10.1111/j.1365-2648.2004.03227.x. PMID 15533082. 17. ^ a b III., HUPP, JAMES R.. TUCKER, MYRON R.. ELLIS, EDWARD (2019). CONTEMPORARY ORAL AND MAXILLOFACIAL SURGERY. [S.l.]: MOSBY. ISBN 978-0323552219. OCLC 1030766831. 18. ^ a b c d e Coulthard, P; Horner, K; Sloan, P; Theaker, E (2013). Master dentistry: volume 1: oral and maxillofacial surgery, radiology, pathology and oral Medicine (3rd ed.). China: Churchill Livingstone. ISBN 9780702055577. 19. ^ a b 1924-2016, Thilander, Birgit (2017-05-17). Essential orthodontics. Bjerklin, Krister, 1946-, Bondemark, Lars, 1955- (First ed.). Hoboken, NJ. ISBN 9781119165699. OCLC 974796239.CS1 maint: numeric names: authors list (link) 20. ^ Kolokitha OE, Chatzistavrou E (January 2009). "A severe reaction to ni-containing orthodontic appliances". The Angle Orthodontist. 79 (1): 186–92. doi:10.2319/111507-531.1. PMID 19123714. 21. ^ "Contemporary Surgical Planning For Jaw Deformities \| Houston Methodist". www.houstonmethodist.org. Retrieved 2018-10-25. 22. ^ A., Quereshy, Faisal (2016). Upper Facial Rejuvenation, An Issue of Atlas of the Oral and Maxillofacial Surgery Clinics of North America, E-Book. Philadelphia: Elsevier Health Sciences. ISBN 9780323462723. OCLC 1015859975. 23. ^ Roberts-Harry D, Sandy J (November 2003). "Orthodontics. Part 2: Patient assessment and examination I". British Dental Journal. 195 (9): 489–93. doi:10.1038/sj.bdj.4810659. PMID 14610554. 24. ^ Peterson's principles of oral and maxillofacial surgery. Miloro, Michael., Ghali, G. E., Larsen, Peter E., Waite, Peter. (2nd. ed.). Hamilton, Ont.: B C Decker. 2004. ISBN 978-1550092349. OCLC 57186698.CS1 maint: others (link) 25. ^ Edler RJ (June 2001). "Background considerations to facial aesthetics". Journal of Orthodontics. 28 (2): 159–68. doi:10.1093/ortho/28.2.159. PMID 11395532. 26. ^ Agrawal M, Agrawal JA, Nanjannawar L, Fulari S, Kagi V (July 2015). "Dentofacial Asymmetries: Challenging Diagnosis and Treatment Planning". Journal of International Oral Health. 7 (7): 128–31. PMC 4513767. PMID 26229387. 27. ^ Eric, Whaites (2013). Essentials of dental radiography and radiology. Drage, Nicholas (Fifth ed.). Edinburgh. ISBN 9780702045998. OCLC 854310114. 28. ^ Cunningham SJ, Johal A (February 2015). "Orthognathic correction of dento-facial discrepancies". British Dental Journal. 218 (3): 167–75. doi:10.1038/sj.bdj.2015.49. PMID 25686434. 29. ^ "Micrognathia". 30. ^ a b c Oral and maxillofacial surgery : an objective-based textbook. Pedlar, Jonathan., Frame, John W. (2nd ed.). Edinburgh: Elsevier/Churchill Livingstone. 2007. ISBN 9780443100734. OCLC 698080410.CS1 maint: others (link) 31. ^ a b c Rajendran, Arya; Sivapathasundharam, B. (2014-02-10). Shafer's textbook of oral pathology. Rajendran, Arya,, Sundaram, Shivapatha (Seventh ed.). New Delhi, India. ISBN 9788131238004. OCLC 882243380. 32. ^ 1958-, Mitchell, Laura (2013-01-24). An introduction to orthodontics. Littlewood, Simon J.,, Nelson-Moon, Zararna,, Dyer, Fiona (Fourth ed.). Oxford, United Kingdom. ISBN 9780199594719. OCLC 812070091.CS1 maint: numeric names: authors list (link) 33. ^ Crispian., Scully (2010). Medical problems in dentistry (6th ed.). Edinburgh: Churchill Livingstone. ISBN 9780702030574. OCLC 465366420. 34. ^ "Laterognathia \| Dr. Madsen". Dr. Madsen. 2015-12-01. Retrieved 2018-10-25. 35. ^ Diéguez-Pérez M, de Nova-García MJ, Mourelle-Martínez MR, González-Aranda C (September 2017). "The influence of crossbite in early development of mandibular bone asymmetries in paediatric patients". Journal of Clinical and Experimental Dentistry. 9 (9): e1115–e1120. doi:10.4317/jced.54110. PMC 5650214. PMID 29075414. 36. ^ O'Byrn BL, Sadowsky C, Schneider B, BeGole EA (April 1995). "An evaluation of mandibular asymmetry in adults with unilateral posterior crossbite". American Journal of Orthodontics and Dentofacial Orthopedics. 107 (4): 394–400. doi:10.1016/s0889-5406(95)70092-7. PMID 7709904. 37. ^ García Y, Sánchez JM, Gómez Rodríguez CL, Romero Flores J (September 2017). "Surgical Management of Laterognathia in Orthofacial Surgery". Journal of Maxillofacial and Oral Surgery. 16 (3): 365–373. doi:10.1007/s12663-015-0870-6. PMC 5493542. PMID 28717296. 38. ^ Gateno, Jaime; Alfi, David; Xia, James J.; Teichgraeber, John F. (December 2015). "A Geometric Classification of Jaw Deformities". Journal of Oral and Maxillofacial Surgery. 73 (12 0): S26–S31. doi:10.1016/j.joms.2015.05.019. ISSN 0278-2391. PMC 4666701. PMID 26608152. 39. ^ Gateno, Jaime; Alfi, David; Xia, James J.; Teichgraeber, John F. (December 2015). "A Geometric Classification of Jaw Deformities". Journal of Oral and Maxillofacial Surgery. 73 (12 Suppl): S26–31. doi:10.1016/j.joms.2015.05.019. ISSN 1531-5053. PMC 4666701. PMID 26608152. 40. ^ Mizoguchi, Itaru; Toriya, Naoko; Nakao, Yuya (2013-11-01). "Growth of the mandible and biological characteristics of the mandibular condylar cartilage". Japanese Dental Science Review. 49 (4): 139–150. doi:10.1016/j.jdsr.2013.07.004. ISSN 1882-7616. 41. ^ a b c d Ayoub, Ashraf; Khambay, Balvinder; Benington, Philip; Green, Lyndia; Moos, Khursheed; Walker, Fraser, eds. (2013-12-20). Handbook of Orthognathic Treatment. doi:10.1002/9781118751695. ISBN 9781118751695. 42. ^ a b c Handbook of orthognathic treatment : a team approach. Ayoub, Ashraf. Hoboken: Wiley. 2013. ISBN 9781118751695. OCLC 861559590.CS1 maint: others (link) 43. ^ Gateno J, Alfi D, Xia JJ, Teichgraeber JF (December 2015). "A Geometric Classification of Jaw Deformities". Journal of Oral and Maxillofacial Surgery. 73 (12 Suppl): S26–31. doi:10.1016/j.joms.2015.05.019. PMC 4666701. PMID 26608152. 44. ^ "Classification of Jaw Deformities". Huston Methodist. 45. ^ "Contemporary Surgical Planning For Jaw Deformities \| Houston Methodist". www.houstonmethodist.org. Retrieved 2018-10-24. 46. ^ a b c d e f g h i j k "Facial and palatal development" (PDF). 47. ^ a b c "Facts about Cleft Lip and Cleft Palate". 2017-06-27. 48. ^ a b c d Yuan X, He X, Zhang X, Liu C, Wang C, Qiu L, Pu W, Fu Y (March 2017). "Comparative Study of Folic Acid and α-Naphthoflavone on Reducing TCDD-Induced Cleft Palate in Fetal Mice". The Cleft Palate-Craniofacial Journal. 54 (2): 216–222. doi:10.1597/15-211. PMID 27018527. 49. ^ a b c Graf D, Malik Z, Hayano S, Mishina Y (February 2016). "Common mechanisms in development and disease: BMP signaling in craniofacial development". Cytokine & Growth Factor Reviews. 27: 129–39. doi:10.1016/j.cytogfr.2015.11.004. PMC 4753105. PMID 26747371. 50. ^ a b c "Folic Acid May Prevent Cleft Lip and Palate". National Institutes of Health (NIH). 2015-09-21. Retrieved 2018-10-24. 51. ^ a b c d Robinson RC, Holm RL (July 2010). "Orthognathic surgery for patients with maxillofacial deformities". AORN Journal. 92 (1): 28–49, quiz 50–2. doi:10.1016/j.aorn.2009.12.030. PMID 20619771. 52. ^ Khechoyan, David (2013). "Orthognathic Surgery: General Considerations". Seminars in Plastic Surgery. 27 (3): 133–136. doi:10.1055/s-0033-1357109. PMC 3805731. PMID 24872758. 53. ^ a b c "Orthognathic surgery \| Cambridge University Hospitals". www.cuh.nhs.uk. Retrieved 2018-10-24. ## External links[edit] Classification D * ICD-10: K07.0-K07.1 * ICD-9-CM: 524.04-524.10 * MeSH: D007569 * v * t * e Dental disease involving the jaw General * Jaw abnormality * malocclusion * Orthodontics * Gnathitis Size * Micrognathism * Maxillary hypoplasia Maxilla and Mandible * Cherubism * Congenital epulis * Torus mandibularis * Torus palatinus Other * Jaw and base of cranium * Prognathism * Retrognathism * Dental arch * Crossbite * Overbite * Temporomandibular joint 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Jaw abnormality	c0235801	6,985	wikipedia	https://en.wikipedia.org/wiki/Jaw_abnormality	2021-01-18T18:56:51	{"mesh": ["D007569"], "umls": ["C0235801"], "icd-9": ["524.04", "524.10"], "icd-10": ["K07.0", "K07.1"], "wikidata": ["Q6165856"]}
In a case of hypothalamic hamartoma, Marcuse et al. (1953) reported that 1 sib had internal hydrocephalus and died at age 6 months, within a day after operation. Another sib had a similar clinical course and died at age 2 months; autopsy was not performed. A double first cousin of the proband likewise had a similar clinical course; postmortem at age 5 months showed 'mature glioma of the brain stem.' See 146510. Encha-Razavi et al. (1992) described 3 unrelated fetuses (one was actually a term neonate who had died a few minutes after birth) in whom, at autopsy, congenital hypothalamic hamartomas were found. Two were associated with skeletal dysplasia. A third was associated with malformations suggestive of Meckel syndrome (249000): heart defect, pulmonary hypoplasia, renal dysplasia, and posterior encephalocele. The first family reported by Encha-Razavi et al. (1992) had, in addition to the fully studied female newborn, an apparently identically affected brother who also died in the newborn period but was not studied neuropathologically. That boy showed micropenis, suggesting hypopituitarism, and had micromelia, short ribs, midline cleft of the upper lip, short nose, alveolar frenula, and macrocephaly. The parents were young, healthy, and unrelated. Neither child had postaxial polydactyly. Encha-Razavi et al. (1992) suggested the designation congenital hypothalamic hamartoma syndrome (CHHS) for a possibly familial disorder that combines orofacial abnormalities and skeletal dysplasia with hypothalamic hamartomas. The familial case reported by Graham et al. (1983) has some similarities. The infant showed abnormal auricles, short nose with flattened bridge, microglossia, micrognathia, cleft palate, short limbs, dislocated hips, and 4-limb postaxial polydactyly. The infant died at 2 hours of age and autopsy showed hypothalamic hamartoblastoma. A sister of the mother died at 17 hours of age and showed 4-limb polydactyly, recessed mandible, and small tongue; autopsy was not done. Because approximately 5% of cases of hypothalamic hamartomas are associated with Pallister-Hall syndrome (PHS; 146510), which is caused by haploinsufficiency of GLI3, Craig et al. (2008) investigated the possibility that HH pathogenesis in sporadic cases is due to a somatic mutation in GLI3. They isolated genomic DNA from peripheral blood and surgically resected HH tissue in 55 patients with sporadic HH and intractable epilepsy. A genomewide screen for loss of heterozygosity (LOH) and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue with Affymetrix 10K SNP microarrays. Additionally, resequencing and fine mapping with SNP genotyping were completed for the GLI3 gene with comparisons between peripheral blood and HH tissue pairs. By analyzing chromosomal copy number data for paired samples on the array, Craig et al. (2008) identified a somatic chromosomal abnormality on chromosome 7p in one HH tissue sample. Resequencing of GLI3 did not identify causative germline mutations but did identify LOH within the GLI3 gene in the HH tissue samples of 3 patients. Further genotyping of 28 SNPs within and surrounding GLI3 identified 5 additional patients exhibiting LOH. Together, these data provided evidence that the development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, nonsyndromic patients with HH and intractable epilepsy. Chromosomal abnormalities including the GLI3 locus were seen in 8 of 55 (15%) of the resected HH tissue samples. Skel \- Skeletal dysplasia \- Micromelia \- Short ribs \- Dislocated hips \- Postaxial polydactyly GU \- Renal dysplasia \- Micropenis Neuro \- Hypothalamic hamartoma \- Hydrocephalus \- Brain stem glioma \- Posterior encephalocele HEENT \- Midline cleft lip \- Short nose \- Alveolar frenula \- Macrocephaly \- Abnormal auricles \- Flattened nasal bridge \- Microglossia \- Micrognathia \- Cleft palate Cardiac \- Congenital heart defect Lung \- Pulmonary hypoplasia Inheritance \- Autosomal recessive Misc \- Infantile death usual Endo \- Hypopituitarism ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HYPOTHALAMIC HAMARTOMAS	c0342418	6,986	omim	https://www.omim.org/entry/241800	2019-09-22T16:26:31	{"mesh": ["C537158"], "omim": ["241800"], "orphanet": ["2113"]}
Brody myopathy Other namesBrody disease (BD) This condition is inherited in an autosomal recessive manner SpecialtyNeurology Brody myopathy, is a rare disorder that affects skeletal muscle function.[1] BD was first characterized in 1969 by Dr. Irwin A. Brody at Duke University Medical Center.[2] Individuals with BD have difficulty relaxing their muscles after exercise.[2] This difficulty in relaxation leads to symptoms including cramps, stiffness, and discomfort in the muscles of the limbs and face.[2] Symptoms are heightened by exercise and commonly progress in severity throughout adulthood.[1] ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Cause[edit] Most cases of BD are inherited through autosomal recessive mutations in ATP2A1, where each copy of the affected individual's gene contain a mutation.[1] The gene involved in BD encodes the fast-twitch skeletal muscle ATPase, SERCA1.[3] SERCA1 is a protein pump that uses ATP to pump Ca2+ ions from the cytosol to the sarcoplasmic reticulum in skeletal muscle.[3] In those with BD, SERCA1 pumps are unable to effectively move Ca2+ across the membrane, leading to increased levels of cytoplasmic Ca2+.[3] Increases in cytoplasmic Ca2+ levels interfere with muscle contraction, leading to the characteristic symptoms of BD.[3] In some cases of BD, no mutations in ATP2A1 have been observed.[1] Disease transmission in cases of non-ATP2A1 BD have been characterized as autosomal dominant pattern of inheritance.[1] These cases have revealed that the cause of the disease likely exhibits genetic heterogeneity, meaning the disease involves mutations in other locations within the genome (although no other loci have been identified in the development of BD as of now).[4] ## Diagnosis[edit] Diagnosis of BD begins with clinical evaluation of individuals for characteristic symptoms of cramping and stiffness of exercised muscles.[2] A few techniques are involved in confirming a diagnosis of BD.[citation needed] Blood testing may be used to measure serum creatine kinase, which ranges from normal to slightly elevated in those with BD.[5] Skeletal muscle biopsies are used to examine muscle fibers. Biopsies in individuals with BD often show variation in muscle fiber size, atrophied fast-twitch muscle fibers, and increased nuclei number.[6] Electromyography (EMG) can be used in diagnosis to rule out myotonia, or muscle stiffness that is detected by EMG. Individuals with BD have stiff muscles but normal EMG results (pseudo-myotonia), where no myotonic discharges are detected.[1] Genetic testing may also be used in the diagnosis of BD to look for mutations in ATP2A1.[7] Since only some forms of the disease are associated with ATP2A1, results of genetic testing do not always confirm a diagnosis of BD, but are useful to rule out other similar disorders.[citation needed] ## Treatment[edit] There is no cure for BD, although treatment options are available for reducing the negative symptoms of BD. The drugs dantrolene and verapamil are used in BD treatment due to their effects on Ca2+.[1] Dantrolene is a muscle relaxer that decreases the symptoms of BD by inhibiting Ca2+ release channels in the sarcoplasmic reticulum, while verapamil sequesters Ca2+ in the sarcoplasmic reticulum of muscle cells by functioning as a Ca2+ channel blocker.[8][9] These drugs act by limiting the amount of Ca2+ from being released from the sarcoplasmic reticulum. When a muscle is stimulated, Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm where it binds to a protein called troponin.[10] This event allows the muscle fibers to overlap, causing a contraction.[10] In BD, Ca2+ levels are high in the cytoplasm, which means Ca2+ can readily bind troponin, leading to muscles that are in an extended state of contraction.[3] ## References[edit] 1. ^ a b c d e f g "Brody myopathy \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-09-07. 2. ^ a b c d Brody IA (July 1969). "Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor". The New England Journal of Medicine. 281 (4): 187–92. doi:10.1056/NEJM196907242810403. PMID 4239835. 3. ^ a b c d e Reference, Genetics Home. "ATP2A1 gene". Genetics Home Reference. Retrieved 2018-09-07. 4. ^ McKusick, Victor; O'Neill, Marla (2017-12-27). "OMIM Entry - # 601003 - BRODY MYOPATHY". www.omim.org. Retrieved 2018-09-25. 5. ^ Poels PJ, Wevers RA, Braakhekke JP, Benders AA, Veerkamp JH, Joosten EM (July 1993). "Exertional rhabdomyolysis in a patient with calcium adenosine triphosphatase deficiency". Journal of Neurology, Neurosurgery, and Psychiatry. 56 (7): 823–6. doi:10.1136/jnnp.56.7.823. PMC 1015068. PMID 8331362. 6. ^ Taylor DJ, Brosnan MJ, Arnold DL, Bore PJ, Styles P, Walton J, Radda GK (November 1988). "Ca2+-ATPase deficiency in a patient with an exertional muscle pain syndrome". Journal of Neurology, Neurosurgery, and Psychiatry. 51 (11): 1425–33. doi:10.1136/jnnp.51.11.1425. PMC 1032814. PMID 2976810. 7. ^ "Brody myopathy - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-09-25. 8. ^ "CALAN - verapamil hydrochloride tablet, film coated" (PDF). FDA. 2009. 9. ^ Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (April 2004). "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia. 59 (4): 364–73. doi:10.1111/j.1365-2044.2004.03658.x. PMID 15023108. 10. ^ a b "Sliding Filament Theory, Sarcomere, Muscle Contraction, Myosin \| Learn Science at Scitable". www.nature.com. Retrieved 2018-09-25. ## External links[edit] Classification D * ICD-10: G71.8 * OMIM: 601003 * MeSH: C536607 C536607, C536607 * DiseasesDB: 35041 External resources * Orphanet: 53347 * v * t * e Genetic disorder, membrane: ATPase disorders ATP1 * ATP1A2 (Alternating hemiplegia of childhood) ATP2 * ATP2A1 (Brody myopathy) * ATP2A2 (Darier's disease, Acrokeratosis verruciformis) * ATP2C1 (Hailey–Hailey disease) ATP7 * ATP7A (Menkes disease) * ATP7B (Wilson's disease) ATP13 * ATP13A2 (Kufor–Rakeb syndrome) Other * Osteopetrosis B1 see also ATPase [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Brody myopathy	c1832918	6,987	wikipedia	https://en.wikipedia.org/wiki/Brody_myopathy	2021-01-18T18:37:08	{"gard": ["9158"], "mesh": ["C536607"], "umls": ["C1832918"], "icd-10": ["G71.8"], "orphanet": ["53347"], "wikidata": ["Q4973199"]}
Lagophthalmos An example of nocturnal lagophthalmos SpecialtyOphthalmology Lagophthalmos is the inability to close the eyelids completely.[1] Blinking covers the eye with a thin layer of tear fluid, thereby promoting a moist environment necessary for the cells of the exterior part of the eye. The tears also flush out foreign bodies and wash them away. This is crucial to maintain lubrication and proper eye health. If this process is impaired, as in lagophthalmos, the eye can suffer abrasions and infections. Lagopthalmos leads to corneal drying and ulceration. ## Contents * 1 Type(s) * 2 Pathophysiology * 3 Treatment * 4 Etymology * 5 References * 6 External links ## Type(s)[edit] Nocturnal lagophthalmos is the inability to close the eyelids during sleep.[2] It may reduce the quality of sleep, cause exposure-related symptoms or, if severe, cause corneal damage (exposure keratopathy). The degree of lagophthalmos can be minor (obscure lagophthalmos) or quite obvious. It is often caused by an anomaly of the eyelid that prevents full closure. Treatment may involve surgery to correct the malposition of the eyelid(s). Punctal plugs may be used to increase the amount of lubrication on the surface of the eyeball by blocking some of the tear-drainage ducts. Eye drops may also be used to provide additional lubrication or to stimulate the eyes to increase tear production. The condition is not widely understood; in one instance, a passenger was removed from a US Airways flight because of it.[3] ## Pathophysiology[edit] Lagophthalmos can arise from a malfunction of the facial nerve.[4] Lagopthalmos can also occur in comatose patients having a decrease in orbicularis tone, in patients having palsy of the facial nerve (seventh cranial nerve), in people with severe exophthalmos and in people with severe skin disorders such as ichthyosis. Today, lagophthalmos may arise after an upper blepharoplasty,[5] which is an operation performed to remove excessive skin overlying the upper eyelid (suprapalpebral hooding) that often occurs with aging. This can make the patient look younger, but if too much skin is removed, the appearance is unnatural and lagophthalmos may occur. ## Treatment[edit] Treatment of lagopthalmos can include both supportive care methods as well as surgical options. If unable to receive surgery, patients should be administered artificial tears at least four times per day to the cornea to preserve the tear film.[6] In preparation for surgery, a patient may undergo a tarsorrhaphy, in which the eye is partially sewn shut temporarily to further protect the cornea as the patient waits for care. Multiple surgical treatments exist for lagopthalmos, but the most prevalent method includes weighing the upper eyelid down by surgically inserting a gold plate.[7] Because of possible complications in conjunction with both the upper and lower eyelid, a second surgery may be required to tighten and elevate the lower eyelid to ensure that both the upper and lower eyelids can fully close and protect the cornea.[6] ## Etymology[edit] The name of the condition derives from the Greek λαγωός (lagoos, "hare"), referring to the myth that hares sleep with their eyes open. ## References[edit] 1. ^ Cline D; Hofstetter HW; Griffin JR. Dictionary of Visual Science. 4th ed. Butterworth-Heinemann, Boston 1997. ISBN 0-7506-9895-0 2. ^ Latkany RL, Lock B, Speaker M (January 2006). "Nocturnal lagophthalmos: an overview and classification". The Ocular Surface. 4 (1): 44–53. PMID 16671223. Archived from the original on 2013-07-29. Retrieved 2013-04-11. 3. ^ Christopher Elliott (2010-09-02). "Kicked off my flight for sleeping with my eyes open". travelersunited.org. Retrieved 2016-07-13. 4. ^ Kliniska Färdigheter: Informationsutbytet Mellan Patient Och Läkare, LINDGREN, STEFAN, ISBN 91-44-37271-X 5. ^ Shorr, N; Goldberg, RA; McCann, JD; Hoenig, JA; Li, TG (2003). "Upper eyelid skin grafting: an effective treatment for lagophthalmos following blepharoplasty". Plast Reconstr Surg. 112 (5): 1444–8. doi:10.1097/01.PRS.0000081477.02812.C9. PMID 14504530. 6. ^ a b "Lagophthalmos Evaluation and Treatment". Aao.org. 2010-07-08. Retrieved 2013-03-16. 7. ^ Nakazawa, H; Kikuchi, Y; Honda, T; Isago, T; Morioka, K; Yoshinaga, Y (2004). "Treatment of paralytic lagophthalmos by loading the lid with a gold plate and lateral canthopexy". Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery. 38 (3): 140–4. PMID 15259671. ## External links[edit] Classification D * ICD-10: H02.2 * ICD-9-CM: 374.2 * DiseasesDB: 32880 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Lagophthalmos	c4022680	6,988	wikipedia	https://en.wikipedia.org/wiki/Lagophthalmos	2021-01-18T18:28:30	{"umls": ["C4022680"], "wikidata": ["Q620918"]}
Diffuse palmoplantar keratoderma-acrocyanosis syndrome is characterised by the association of diffuse palmoplantar keratoderma and acrocyanosis. It has been described in eight members of one family and in two sporadic cases. The mode of inheritance in the familial cases was autosomal dominant. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Diffuse palmoplantar keratoderma-acrocyanosis syndrome	None	6,989	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86918	2021-01-23T18:35:39	{"icd-10": ["Q82.8"], "synonyms": ["Diffuse palmoplantar hyperkeratosis-acrocyanosis syndrome"]}
A rare 46,XY disorder of gonadal development characterized by congenital complete absence of testicular tissue in an individual with an otherwise normal male phenotype and normal karyotype. In addition, a small penis is a frequent finding in anorchid patients. Typical hormonal characteristics are elevated basal levels of gonadotropins (especially FSH), low concentration of testosterone, and lack of increase of plasma testosterone in response to hCG administration. The GnRH test induces a prolonged increase in FSH and LH levels. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Testicular agenesis	c0405582	6,990	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=325124	2021-01-23T18:53:39	{"gard": ["5819"], "mesh": ["C537770"], "icd-10": ["Q55.0"], "synonyms": ["Bilateral anorchia"]}
Laryngocele Representation of a surgical site; laryngocele SpecialtyENT surgery A laryngocele is a congenital anomalous air sac communicating with the cavity of the larynx, which may bulge outward on the neck.[1] It may also be acquired, as seen in glassblowers, due to continual forced expiration producing increased pressures in the larynx which leads to dilatation of the laryngeal ventricle (Sinus of Morgagni). It is also seen in people with chronic obstructive airway disease.[citation needed] ## Additional images[edit] Laryngocele * IL = internal laryngocel AL = external laryngocele H = Hyoid bone T = Vestibular folds S = Vocal folds K = Cricoid cartilage ## References[edit] 1. ^ "Laryngocele" at Dorland's Medical Dictionary ## External links[edit] Classification D * ICD-10: Q31.3 * ICD-9-CM: 748.3 * MeSH: D059608 * DiseasesDB: 7271 * v * t * e Congenital malformations and deformations of respiratory system Upper RT Nose * Choanal atresia * Arrhinia Larynx * Laryngeal cyst * Laryngocele * Laryngomalacia Lower RT Trachea and bronchus * Tracheomalacia * Tracheal stenosis * Bronchomalacia * Tracheobronchomegaly Lung * Bronchiectasis * Pulmonary hypoplasia * Pulmonary sequestration * Congenital cystic adenomatoid malformation [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Laryngocele	c0265761	6,991	wikipedia	https://en.wikipedia.org/wiki/Laryngocele	2021-01-18T18:41:53	{"gard": ["3191"], "mesh": ["D059608"], "umls": ["C0265761"], "icd-9": ["748.3"], "icd-10": ["Q31.3"], "orphanet": ["2372"], "wikidata": ["Q6491969"]}
Diseases linked with the way people live their life Lifestyle diseases are defined as diseases linked with, and often caused by the way people live their life. These are non-communicable diseases. Lifestyle diseases are commonly caused by lack of physical activity, unhealthy eating, alcohol, drugs and smoking, which lead to heart disease, stroke, obesity, type II diabetes and Lung cancer.[1][2] The diseases that appear to increase in frequency as countries become more industrialized and people live longer can include Alzheimer's disease, arthritis, atherosclerosis, asthma, cancer, chronic liver disease or cirrhosis, chronic obstructive pulmonary disease, colitis, irritable bowel syndrome, type 2 diabetes, heart disease, hypertension, metabolic syndrome, chronic kidney failure, osteoporosis, PCOD, stroke, depression, obesity and vascular dementia. Some commenters maintain a distinction between diseases of longevity and diseases of civilization or diseases of affluence.[3] Certain diseases, such as diabetes, dental caries and asthma, appear at greater rates in young populations living in the "western" way; their increased incidence is not related to age, so the terms cannot accurately be used interchangeably for all diseases.[4] ## Contents * 1 Causes of the disease * 2 Death statistics in Australia * 3 Death statistics in the United States * 4 Death statistics in India * 5 Prevention * 6 See also * 7 References * 8 External links ## Causes of the disease[edit] Diet and lifestyle are major factors thought to influence susceptibility to many diseases. Drug abuse, tobacco smoking, and alcohol drinking, as well as a lack of or too much exercise may also increase the risk of developing certain diseases, especially later in life.[5][6][7] In many Western countries, people began to consume more meat, dairy products, vegetable oils, tobacco, sugary foods, sugary beverages, and alcoholic beverages during the latter half of the 20th century. People also developed sedentary lifestyles and greater rates of obesity.[8] Rates of colorectal cancer, breast cancer, prostate cancer, endometrial cancer and lung cancer started increasing after this dietary change. People in developing countries, whose diets still depend largely on low-sugar starchy foods with little meat or fat have lower rates of these cancers.[9] Causes are not just from smoking and alcohol abuse. Adults can develop lifestyle diseases through behavioural factors that impact on them. These can be unemployment, unsafe life, poor social environment, working conditions, stress and home life can change a person’s lifestyle to increase their risk of developing one of these diseases.[10] ## Death statistics in Australia[edit] Between 1995 and 2005 813,000 Australians were hospitalized due to alcohol.[11] In 2014 11.2 million Australians were overweight or obese. In 2013 there were 147,678 deaths within Australia mostly from lifestyle diseases including smoking of tobacco, alcohol use and other drugs, violence and unhealthy weight have impacted on Australians' death rate. The leading cause of death of Australian males was heart disease with 11,016 deaths, followed by lung cancer with 4,995 deaths, and chronic pulmonary disease killing 3,572. All these conditions were mainly attributed to smoking, alcohol abuse or unhealthy lifestyle.[12] In 2013 coronary heart disease was the leading cause of death in 8,750 women, mainly as a result of their lifestyle. Dementia and Alzheimer disease came second, affecting 7,277 females and thirdly, cerebrovascular disease, killing 6,368. These top three causes of deaths could be minimized through lifestyle changes within the Australian population.[13] The table shows that ages of people dying and the top five diseases of which they are dying.[13] 1st 2nd 3rd 4th 5th Age 45-64 Circulatory Coronary Heart Disease Cancer Lung Cancer Cancer Breast Cancer Cancer Colorectal Cancer External Suicide Age 65-74 Circulatory Coronary Heart Disease Cancer Lung Cancer Respiratory COPD Circulatory Cerebro vascular Disease Cancer Colorectal Cancer Age 75-84 Circulatory Coronary Heart Disease Circulatory Cerebro vascular Disease Other Dementia & Alzheimer Disease Cancer Lung Cancer Respiratory COPD Age 85-94 Circulatory Coronary Heart Disease Other Dementia & Alzheimer Disease Circulatory Cerebro vascular Disease Respiratory COPD Respiratory Influenza & Pneumonia ## Death statistics in the United States[edit] In 1900, the top three causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhea/enteritis. Communicable diseases accounted for about 60 percent of all deaths. In 1900, heart disease and cancer were ranked number four and eight respectively. Since the 1940s, the majority of deaths in the United States have resulted from heart disease, cancer, and other degenerative diseases. And, by the late 1990s, degenerative diseases accounted for more than 60 percent of all deaths.[14] Lifestyle diseases have their onset later in an individual's life; they appear to increase in frequency as countries become more industrialized and people live longer.[15] This suggests that the life expectancy at birth of 49.24 years in 1900[16] was too short for degenerative diseases to occur, compared to a life expectancy at birth of 77.8 years in 2004. Also, survivorship to the age of 50 was 58.5% in 1900, and 93.7% in 2007.[17] ## Death statistics in India[edit] According to a report[18] published by ICMR (Indian Council of Medical Research) in 2017, 3 of the 5 leading individual causes of disease burden in India were non-communicable, with ischaemic heart disease and chronic obstructive pulmonary disease as the top two causes and stroke as the fifth leading cause. The range of disease burden or DALY rate among the states in 2016 was 9-fold for ischaemic heart disease, 4-fold for chronic obstructive pulmonary disease, and 6-fold for stroke, and 4-fold for diabetes across India. Of the total death from major disease groups, 62% of all deaths were caused by non-communicable diseases. Distribution of deaths from major disease groups, by age (2016) Death rate per 1,000,000 [percent of total deaths in that age group] Age group Communicable, maternal, neonatal and nutritional diseases Non-communicable diseases Injuries 0–14 years 22.6 [80.8] 3.4 [12.0] 2.0 [7.2] 15–39 years 5.9 [29.1] 6.9 [34.4] 7.3 [36.5] 40–69 years 19.6 [17.4] 82.4 [73.2] 10.5 [9.4] 70+ years 186.7 [23.0] 580.5 [71.6] 43.5 [5.4] All ages 20.5 [27.5] 46 [61.8] 8.0 [10.7] ## Prevention[edit] Prevention is remedies or activities that aim to reduce the likelihood of a disease or disorder affecting people. Lifestyle diseases are preventable for children if parents set them on the correct path, as early life decisions and influences can impact people later on in life.[10] Lifestyle diseases can be prevented through reduction in smoking of tobacco [19] the Australian Government has started this by introducing plain packaging for all tobacco products and increasing the prices of tobacco production.[20] Overweightness and obesity can be prevented through a well balanced lifestyle through healthy eating and exercise. Prevention can come about by a person undertaking 30 minutes of moderate exercise daily or by doing 150 minutes of moderate intensity exercise a week.[21] Examples of moderate exercise includes a brisk walk, swim, bike ride or it can also be everyday life activities like mowing the lawn or house cleaning.[22] In addition, animals studies have suggested that early life exercise can reduce the risk of developing metabolic diseases in adulthood.[23] All causes of lifestyle disease can be prevented through giving up smoking and other drugs, reducing ones intake of alcohol, processed meats (like bacon and sausages), red meats (like pork, beef and lamb), fatty foods and by engaging in daily exercise. However, new studies also show preventive effects on recurrent respiratory tract infections in children through the intake of unprocessed food. Beef, green vegetables and whole dairy can then have a beneficial effect because they are unprocessed compared to processed foods. Beef, unlike other types of red meat, can contribute to the health-promoting effects.[24] ## See also[edit] * Diseases of affluence * Affluenza * Health care in Australia * Healthy living * Healthcare in the United Kingdom ## References[edit] 1. ^ "Lifestyle disease". MedicineNet. Retrieved 2016-05-12. 2. ^ Mathur, Prashant; Mascarenhas, Leena (January 2019). "LIFESTYLE DISEASES: Keeping fit for a better tomorrow". The Indian Journal of Medical Research. 149 (Suppl 1): S129–S135. doi:10.4103/0971-5916.251669. ISSN 0971-5916. PMC 6515727. PMID 31070189. 3. ^ Bitar, Adrienne Rose (January 2018). Diet and the Disease of Civilization. Rutgers University Press. ISBN 978-0-8135-8964-0. 4. ^ Pollan, Michael (2008). In Defense of Food: An Eater's Manifesto. Penguin Press HC, The. ISBN 978-1-59420-145-5. 5. ^ Vaillant, GE; Mukamal, K (June 2001). "Successful aging". Am J Psychiatry. 158: 839–47. doi:10.1176/appi.ajp.158.6.839. PMID 11384887. 6. ^ Fraser, GE; Shavlik, DJ (July 2001). "Ten years of life: Is it a matter of choice?". Arch. Intern. Med. 161: 1645–52. doi:10.1001/archinte.161.13.1645. PMID 11434797. 7. ^ Steyn, K; Fourie, J; Bradshaw, D (1992). "The impact of chronic diseases of lifestyle and their major risk factors on mortality in South Africa". S Afr Med J. 82 (4): 227–31. PMID 1411817. 8. ^ Statistics, c=AU; o=Commonwealth of Australia; ou=Australian Bureau of. "Main Features - Key findings". www.abs.gov.au. Retrieved 2016-05-12. 9. ^ Key, TJ; Allen, NE; Spencer, EA (Sep 2002). "The effect of diet on risk of cancer". The Lancet. 360 (9336): 861–8. doi:10.1016/S0140-6736(02)09958-0. PMID 12243933. 10. ^ a b Vallgårda, Signild (2011-11-01). "Why the concept lifestyle diseases should be avoided". Scandinavian Journal of Public Health. 39 (7): 773–775. doi:10.1177/1403494811421978. ISSN 1403-4948. PMID 21948978. 11. ^ Statistics, c=AU; o=Commonwealth of Australia; ou=Australian Bureau of. "Main Features - Smoking, risky drinking and obesity". www.abs.gov.au. Retrieved 2016-05-12. 12. ^ "Health status (AIHW)". www.aihw.gov.au. Retrieved 2016-05-12. 13. ^ a b "Leading causes of death (AIHW)". www.aihw.gov.au. Retrieved 2016-05-12. 14. ^ National Center for Health Statistics, National Office of Vital Statistics, 1947 for the year 1900 (page 67), for the year 1938 (page 55). 15. ^ Olshansky, S. Jay; Carnes, Bruce A. (2002). The Quest for Immortality: Science at the Frontiers of Aging. W. W. Norton & Company. p. 191. ISBN 978-0393323276. 16. ^ Life expectancy by age, race, and sex, Centers for Disease Control and Prevention, FastStats, 2007, retrieved 2009-06-11 17. ^ Survivorship by age, race, and sex, Centers for Disease Control and Prevention, FastStats, 2007, retrieved 2009-06-11 18. ^ India: Health of the Nation’s States 2017 Published by ICMR. Retrieved: Jan 2020 19. ^ "Preventing and treating ill health (AIHW)". www.aihw.gov.au. Retrieved 2016-05-12. 20. ^ Ageing, Australian Government Department of Health and. "Tobacco product regulation and disclosure". health.gov.au. Retrieved 2016-05-12. 21. ^ "Lifestyle factors (AIHW)". aihw.gov.au. Retrieved 2016-05-12. 22. ^ "WHO \| What is Moderate-intensity and Vigorous-intensity Physical Activity?". www.who.int. Retrieved 2016-05-12. 23. ^ Falcão-Tebas, Filippe; Kuang, Jujiao; Arceri, Chelsea; Kerris, Jarrod P.; Andrikopoulos, Sofianos; Marin, Evelyn C.; McConell, Glenn K. (2018-11-08). "Four weeks of exercise early in life reprograms adult skeletal muscle insulin resistance caused by paternal high fat diet". The Journal of Physiology. 597 (1): 121–136. doi:10.1113/jp276386. ISSN 0022-3751. PMC 6312425. PMID 30406963. 24. ^ Influence of Dietary Advice Including Green Vegetables, Beef, and Whole Dairy Products on Recurrent Upper Respiratory Tract Infections in Children: A Randomized Controlled Trial. van der Gaag E, et al. Nutrients. 2020. PMID: 31968697. https://www.mdpi.com/2072-6643/12/1/272 ## External links[edit] * Media related to Lifestyle disease at Wikimedia Commons [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Lifestyle disease	None	6,992	wikipedia	https://en.wikipedia.org/wiki/Lifestyle_disease	2021-01-18T18:41:24	{"wikidata": ["Q12600757"]}
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-47 (EIEE47) is caused by heterozygous mutation in the FGF12 gene (601513) on chromosome 3q28. Description Early infantile epileptic encephalopathy-47 is a neurologic disorder characterized by onset of intractable seizures in the first days or weeks of life. EEG shows background slowing and multifocal epileptic spikes, and may show hypsarrhythmia. Most patients have developmental regression after seizure onset and show persistent intellectual disability and neurologic impairment, although the severity is variable. Treatment with phenytoin, a voltage-gated sodium channel blocker, may be beneficial (summary by Guella et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Clinical Features Siekierska et al. (2016) reported 2 sibs, born of unrelated Caucasian parents, with early infantile epileptic encephalopathy resulting in death at ages 7 and 3.5 years. The proband developed tonic seizures at age 14 days, and her younger brother had onset of seizures at age 4 weeks. The seizures developed into severe refractory epilepsy associated with EEG abnormalities, including severe background slowing, multifocal epileptic abnormalities, and hypsarrhythmia. This was followed by severely delayed psychomotor development with profound intellectual disability, inability to stand or walk, cerebral visual impairment, feeding difficulties necessitating tube feeding, and absent speech development. Other features included acquired microcephaly, axial hypotonia, and limb ataxia. Funduscopy was normal initially, but later showed pale optic discs. Brain imaging was normal in early infancy, but later showed cerebellar atrophy. The findings were consistent with a progressive and degenerative process. Al-Mehmadi et al. (2016) reported 3 unrelated patients with EIEE47. The patients had a slightly different disease course, despite sharing the same de novo heterozygous mutation (R52H; 601513.0001). Patient 1 was a 3-year-old boy who had onset of intractable seizures on the second day of life, with frequent status epilepticus. EEG showed background slowing and multifocal discharges. He had severe global developmental delay and was nonverbal with poor visual and social interaction, hypotonia with head lag, and could only sit with support. He was tube-fed and had chronic constipation. Brain imaging was normal at onset, but showed enlarged ventricles at age 2 years. Treatment included a ketogenic diet and medications; phenytoin was not used. The second patient was a 16-year-old girl, who developed seizures at age 6 weeks, had severe cognitive impairment with single words, but showed normal motor development and could ambulate. Seizures included generalized tonic-clonic and partial seizures. She was started on phenytoin at age 6, with some improvement. Since age 7, she developed transient ataxia after seizures. Vagal nerve stimulation improved the frequency and intensity of seizures and ataxia. Brain imaging at age 16 months was normal, but showed cerebellar atrophy at age 8 years. She had chronic constipation and required help with all activities of daily living. Patient 3 was an 18-year-old girl had intractable epilepsy since day 2 of life associated with EEG abnormalities. She had moderate intellectual disability, but could read simple books and ambulate with an abnormal gait. She had chronic constipation, hypohidrosis, and reduced lacrimation, suggesting autonomic dysfunction. Brain imaging showed mesial temporal sclerosis and mild prominence of the cerebellar folia. She was treated with phenytoin and vagal nerve stimulation. Guella et al. (2016) reported a 15-year-old girl with EIEE47 who developed tonic seizures on the second day of life. EEG showed background slowing and multifocal spikes. The seizures did not respond to several medications, and she had an allergic reaction to carbamazepine; phenytoin was never used. She had developmental delay with regression at times of increased seizure frequency, moderate intellectual disability with speech delay, and autism. Brain imaging showed an incidental Chiari I malformation. ### Clinical Variability Guella et al. (2016) reported an 11-month-old girl who developed seizures on the third day of life and was found to carry a de novo heterozygous R52H mutation in the FGF12 gene. Initial interictal EEG showed multifocal spikes, and continuous EEG monitoring showed multiple seizures, including during sleep. The seizures were unresponsive to several medications at first, but she did respond to phenytoin on day 20. She had normal development and a normal neurologic examination at age 11 months. Brain imaging on day 4 of life was normal. Guella et al. (2016) noted that the phenotype in this patient was significantly milder than that observed in other patients with the same mutation. Molecular Genetics In 2 sibs with EIEE47, Siekierska et al. (2016) identified a de novo heterozygous missense mutation in the FGF12 gene (R114H; R52H in the B isoform; 601513.0001). The mutation, which was found by exome sequencing, was not present in either parent, suggesting germline mosaicism. In vitro functional expression studies in neuronal cells showed that the mutation changed the voltage dependence of inactivation gating of sodium channels, resulting in a gain-of-function effect and increased neuronal excitability. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta. Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with EIEE47. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that EIEE47 is an FGF12 R52H mutation-specific disease. Guella et al. (2016) identified a de novo heterozygous R52H mutation in 2 unrelated patients with EIEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. The findings significantly expanded the phenotype associated with this specific mutation, suggesting that other genetic and/or environmental factors may be involved. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly, acquired (in some patients) Eyes \- Cortical visual impairment (in some patients) \- Pale optic discs (in some patients) ABDOMEN Gastrointestinal \- Poor feeding \- Chronic constipation MUSCLE, SOFT TISSUES \- Axial hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, refractory \- Multiple seizure types \- Delayed psychomotor development after seizure onset \- Developmental regression \- Inability to walk \- Abnormal gait \- Limb ataxia \- Lack of speech \- Poor speech \- EEG abnormalities \- Background slowing \- Multifocal epileptiform discharges \- Hypsarrhythmia \- Status epilepticus \- Cerebellar atrophy MISCELLANEOUS \- Onset in first days or weeks of life \- Progressive and degenerative disorder \- Variable severity \- At least 1 patient with normal development has been reported \- Phenytoin may be a beneficial treatment \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor 12 gene (FGF12, 601513.0001 ) ▲ 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 47	c4310685	6,993	omim	https://www.omim.org/entry/617166	2019-09-22T15:46:40	{"doid": ["0080425"], "omim": ["617166"], "orphanet": ["442835"], "synonyms": ["Undetermined EOEE"]}
Alpha thalassemia is a blood disorder that reduces the production of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen to cells throughout the body. In people with the characteristic features of alpha thalassemia, a reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues. Affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more serious complications. Two types of alpha thalassemia can cause health problems. The more severe type is known as hemoglobin Bart hydrops fetalis syndrome, which is also called Hb Bart syndrome or alpha thalassemia major. The milder form is called HbH disease. Hb Bart syndrome is characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia. As a result of these serious health problems, most babies with this condition are stillborn or die soon after birth. Hb Bart syndrome can also cause serious complications for women during pregnancy, including dangerously high blood pressure with swelling (preeclampsia), premature delivery, and abnormal bleeding. HbH disease causes mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice). Some affected individuals also have bone changes such as overgrowth of the upper jaw and an unusually prominent forehead. The features of HbH disease usually appear in early childhood, and affected individuals typically live into adulthood. ## Frequency Alpha thalassemia is a fairly common blood disorder worldwide. Thousands of infants with Hb Bart syndrome and HbH disease are born each year, particularly in Southeast Asia. Alpha thalassemia also occurs frequently in people from Mediterranean countries, Africa, the Middle East, India, and Central Asia. ## Causes Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. Both of these genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin. People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the other is inherited from a person's mother. As a result, there are four alleles that produce alpha-globin. The different types of alpha thalassemia result from the loss of some or all of these alleles. Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss of all four alpha-globin alleles. HbH disease is caused by a loss of three of the four alpha-globin alleles. In these two conditions, a shortage of alpha-globin prevents cells from making normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called hemoglobin Bart (Hb Bart) or hemoglobin H (HbH). These abnormal hemoglobin molecules cannot effectively carry oxygen to the body's tissues. The substitution of Hb Bart or HbH for normal hemoglobin causes anemia and the other serious health problems associated with alpha thalassemia. Two additional variants of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these variants tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms. ### Learn more about the genes associated with Alpha thalassemia * HBA1 * HBA2 ## Inheritance Pattern The inheritance of alpha thalassemia is complex. Each person inherits two alpha-globin alleles from each parent. If both parents are missing at least one alpha-globin allele, their children are at risk of having Hb Bart syndrome, HbH disease, or alpha thalassemia trait. The precise risk depends on how many alleles are missing and which combination of the HBA1 and HBA2 genes is affected. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Alpha thalassemia	c0002312	6,994	medlineplus	https://medlineplus.gov/genetics/condition/alpha-thalassemia/	2021-01-27T08:24:37	{"gard": ["621"], "mesh": ["D017085"], "omim": ["604131", "141800", "141850"], "synonyms": []}
Dysplastic nevus Micrograph of a dysplastic nevus showing the characteristic rete ridge bridging, shouldering, and lamellar fibrosis. H&E stain. SpecialtyDermatology A dysplastic nevus or atypical mole is a nevus (mole) whose appearance is different from that of common moles. In 1992, the NIH recommended that the term "dysplastic nevus" be avoided in favor of the term "atypical mole".[1] An atypical mole may also be referred to as an atypical melanocytic nevus,[2] atypical nevus, B-K mole, Clark's nevus, dysplastic melanocytic nevus, or nevus with architectural disorder.[3] Dysplastic nevi often grow to larger than ordinary moles, and may have irregular and indistinct borders. Their color may not be uniform, and may range from light pink to very dark brown. They usually begin flat, but parts may be raised above the skin surface. See ABCDE and "ugly duckling" characteristics below. Dysplastic nevi can be found anywhere, but are most common on the trunk in men, and on the calves in women. There is some controversy in the dermatology community as to whether or not the "dysplastic"/"atypical" nevus exists. Some have argued that the terms "dysplastic" and "atypical" only refer to diagnostic uncertainty, as opposed to biologic uncertainty, and that the lesion is either a nevus or melanoma from the very beginning, as opposed to some kind of "premalignant stage"; it is only the clinician who is unsure. Some have also argued that even if such nevi do exist, studies have shown that clinicians are unable to reliably identify them anyway, meaning there is no point to even using the concept.[4][5][6][medical citation needed] ## Contents * 1 Cancer risk * 2 Precaution for individuals with dysplastic nevi * 3 Biopsy * 4 Dysplastic nevus syndrome * 5 Additional images * 6 See also * 7 References * 8 External links ## Cancer risk[edit] As seen in Caucasian individuals in the United States, those with dysplastic nevi have a lifetime risk of developing melanoma of greater than 10%, compared to less than 1% for those without any dysplastic nevus.[7] ## Precaution for individuals with dysplastic nevi[edit] A dermatoscope. A modern polarized dermatoscope. Although there are limited data to support its efficacy, skin self-examination is frequently recommended for preventing melanoma (by identifying atypical moles that can be removed) or for early detection of existing tumors. Examination by a dermatologist has been shown to be beneficial for early melanoma detection. Some dermatologists recommend that an individual with either histologic diagnosis of dysplastic nevus, or clinically apparent atypical moles should be examined by an experienced dermatologist with dermatoscopy once a year (or more frequently). Melanoma on left foot The abbreviation ABCDE has been useful for helping health care providers and laypersons remember the key characteristics of a melanoma (see "ABCDE" mnemonic below). Changes (in shape, size, color, itching or bleeding) should be brought to the attention of a dermatologist .[8] A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE": * Asymmetrical skin lesion. * Border of the lesion is irregular. * Color: melanomas usually have multiple colors. * Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles. * Evolution: The evolution (i.e. change) of a mole or lesion may be a hint that the lesion is becoming malignant. The E is sometimes omitted, as in the ABCD guideline. A weakness in this system is the D. Many melanomas present themselves as lesions smaller than 6 mm in diameter. An astute physician will examine all abnormal moles, including ones less than 6 mm in diameter. Unfortunately for the average person, many seborrheic keratoses, some lentigo senilis, and even warts may have ABCD characteristics, and cannot be distinguished from a melanoma without a trained eye or dermatoscopy. A recent and novel method of melanoma detection is the "Ugly Duckling Sign".[9][10] It is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person's skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and a dermatologist exam is required. The "Little Red Riding Hood" sign[10] suggests that individuals with fair skin and light colored hair might prove more challenging. These fair-skinned individuals often have lightly pigmented or amelanotic melanomas which will not present with easy to observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope (dermatoscopy) very difficult. A dermatoscope must be used to detect "ugly ducklings" among those with light skin or blonde/red hair. People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma. ## Biopsy[edit] Various differential diagnoses of pigmented skin lesions, including dysplastic nevus, showing the relative incidence of biopsied lesions, and malignancy potential. When an atypical mole has been identified, a skin biopsy takes place in order to best diagnose it. Local anesthetic is used to numb the area, then the mole is biopsied. The biopsy material is then sent to a laboratory to be evaluated by a pathologist. A skin biopsy can be a punch, shave, or complete excision. The complete excision is the preferred method, but a punch biopsy can suffice if the patient has cosmetic concerns (i.e. the patient does not want a scar) and the lesion is small. A scoop or deep shave biopsy is often advocated, but should be avoided due to risk of a recurrent nevus, which can complicate future diagnosis of a melanoma, and the possibility that resulting scar tissue can obscure tumor depth if a melanoma is found to be present and re-excised. Most dermatologists and dermatopathologists use a system devised by the NIH for classifying melanocytic lesions. In this classification, a nevus can be defined as benign, having atypia, or being a melanoma. A benign nevus is read as (or understood as) having no cytologic or architectural atypia. An atypical mole is read as having architectural atypia, and having (mild, moderate, or severe) cytologic (melanocytic) atypia.[11] Usually, cytologic atypia is of more important clinical concern than architectural atypia. Usually, moderate to severe cytologic atypia will require further excision to make sure that the surgical margin is completely clear of the lesion.[citation needed] The most important aspect of the biopsy report is that the pathologist indicates if the margin is clear (negative or free of melanocytic nevus), or if further tissue (a second surgery) is required. If this is not mentioned, usually a dermatologist or clinician will require further surgery if moderate to severe cytologic atypia is present – and if residual nevus is present at the surgical margin. ## Dysplastic nevus syndrome[edit] Main article: Dysplastic nevus syndrome "Dysplastic nevus syndrome" refers to individuals who have high numbers of benign moles and also have dysplastic nevi. A small percent of these individuals are members of melanoma kindreds.[12] Inherited dysplastic nevus syndrome is an autosomal dominant hereditary condition. Dysplastic nevi are more likely to undergo malignant transformation when they occur among members of melanoma families. At least one study indicates a cumulative lifetime risk of nearly 100% in individuals who have dysplastic nevi and are members of melanoma kindreds.[citation needed] Roughly 70% of melanomas arise "de novo" on clear skin growth, whereas the rest arise within atypical moles.[13] Those with dysplastic nevi have an elevated risk of melanoma.[14][15] Such persons need to be checked regularly for any changes in their moles and to note any new ones. In 40-50% of cases, the disorder has been linked with germline mutations in the CDKN2A gene, which codes for p16 (a regulator of cell division). ## Additional images[edit] * Low magnification * Intermediate magnification * Very high magnification ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ "NIH Consensus conference. Diagnosis and treatment of early melanoma". JAMA. 268 (10): 1314–9. Sep 1992. doi:10.1001/jama.1992.03490100112037. PMID 1507379. 2. ^ "dysplastic nevus" at Dorland's Medical Dictionary 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1732. ISBN 978-1-4160-2999-1. 4. ^ https://www.youtube.com/watch?v=TX3kyvFOhak 5. ^ https://www.youtube.com/watch?v=db65kKIegeY 6. ^ https://www.youtube.com/watch?v=QRJql5gED74 7. ^ Dana Baigrie; Laura S. Tanner. "Dysplastic Nevi". StatPearls, at the National Center for Biotechnology Information. Last updated: January 20, 2019 8. ^ Friedman, R; Rigel, D; Kopf, A (1985). "Early detection of malignant melanoma: The role of physician examination and self-examination of the skin". CA Cancer J Clin. 35 (3): 130–51. doi:10.3322/canjclin.35.3.130. PMID 3921200. 9. ^ Scope, Alon. "The "Ugly Duckling" Sign: An Early Melanoma Recognition Tool For Clinicians and the Public". skincancer.org. 10. ^ a b Mascaro, JM Jr; Mascaro, JM (1998). "The dermatologist's position concerning nevi: A vision ranging from 'the ugly duckling' to 'little red riding hood'". Arch Dermatol. 134 (11): 1484–5. doi:10.1001/archderm.134.11.1484. PMID 9828892. 11. ^ Googe, Paul B. (31 March 1995). "Dysplastic nevi" (PDF). DermPath Update. KDL Pathology. 1 (1). Retrieved 18 July 2015. 12. ^ "dysplastic nevus syndrome" at Dorland's Medical Dictionary 13. ^ Pampena R, Kyrgidis A, Lallas A, Moscarella E, Argenziano G, Longo C (2017). "A meta-analysis of nevus-associated melanoma: Prevalence and practical implications". J Am Acad Dermatol. 77: 938–945.e4. doi:10.1016/j.jaad.2017.06.149. PMID 28864306. 14. ^ Pope, DJ; Sorahan, T; Marsden, JR; Ball, PM; et al. (Sep 1992). "Benign pigmented nevi in children Prevalence and associated factors: the West Midlands, United Kingdom Mole Study". Arch. Dermatol. 128 (9): 1201–6. doi:10.1001/archderm.128.9.1201. PMID 1519934. 15. ^ Goldgar, DE; Cannon-Albright, LA; Meyer, LJ; Piepkorn, MW; et al. (Dec 1991). "Inheritance of nevus number and size in melanoma and dysplastic nevus syndrome kindreds". J Natl Cancer Inst. 83 (23): 1726–33. doi:10.1093/jnci/83.23.1726. PMID 1770551. ## External links[edit] Classification D * ICD-10: D48.5 (ILDS D48.540) * ICD-9-CM: 238.2 * ICD-O: M8727/0 * OMIM: 155600 * MeSH: D004416 * Common moles, dysplastic nevi, and risk of melanoma, US National Cancer Institute * 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 [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Dysplastic nevus	c0205748	6,995	wikipedia	https://en.wikipedia.org/wiki/Dysplastic_nevus	2021-01-18T18:50:29	{"mesh": ["D004416"], "icd-9": ["238.2"], "icd-10": ["D48.5"], "orphanet": ["625"], "wikidata": ["Q1269320"]}
The myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the most common and the least severe form of CPT II deficiency (see this term). ## Epidemiology About 300 cases of the myopathic form have been reported in the literature, but this number may under-estimate the disease prevalence. ## Clinical description The age of onset varies between 1 and 61 years of age with 70% of cases first presenting in childhood. The disease is more common in men, probably reflecting an ascertainment bias related to exposure to prolonged exercise. The clinical manifestations are characterized by recurrent attacks of rhabdomyolysis, muscle pain, and weakness triggered usually by prolonged physical exercise and sometimes exacerbated by extremes in temperature; episodes may also be provoked or exacerbated by prolonged fasting, such as may occur with intercurrent viral illness. Episodes of rhabdomyolysis may be associated with extreme elevation of serum creatine phosphokinase (CPK) and myoglobinuria (75% of cases) and can lead to renal failure (in 8-25% of cases, but rarely requiring dialysis). Patients are asymptomatic between episodes of rhabdomyolysis. ## Etiology Several missense mutations in the CPT2 gene result in the myopathic form of CPT II deficiency. In Caucasians, the most frequent mutation (60%) is the p.Ser113Leu mutation, which impairs enzyme stability. ## Diagnostic methods The diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts. ## Differential diagnosis The differential diagnosis should include McArdle disease, Duchenne muscular dystrophy, cytochrome c oxidase deficiency (see these terms), complex II deficiency, complex III deficiency and rhabdomyolysis due to excessive exercise, infections, autoimmune reactions or drug-related neuroleptic syndrome among others. ## Genetic counseling Transmission is autosomal recessive. If the disease-causing mutations are identified in an affected individual, early diagnosis by molecular genetic testing can be offered to at-risk relatives to reduce morbidity and mortality. ## Management and treatment Treatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet combined with exercise restriction in order to avoid muscle pain and rhabdomyolysis. L-carnitine administration and anaplerotic diet therapy with triheptanoin have been suggested for treatment of the disease; however benefits have not been proven. ## Prognosis The myopathic form of CPT II has a good 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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Carnitine palmitoyl transferase II deficiency, myopathic form	c1833508	6,996	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228302	2021-01-23T18:46:45	{"mesh": ["C563461"], "omim": ["255110"], "umls": ["C1833508"], "icd-10": ["E71.3"], "synonyms": ["CPT2, adult-onset form", "CPT2, myopathic form", "CPTII, adult-onset form", "CPTII, myopathic form", "Carnitine palmitoyl transferase II deficiency, adult-onset form", "Carnitine palmitoyl transferase deficiency type 2, adult-onset form", "Carnitine palmitoyl transferase deficiency type 2, myopathic form"]}
Turcot syndrome with polyposis or Turcot syndrome type 2 is a form of familial adematous polyposis, characterized by the concurrence of thousands of colonic adenomatous polyposis or colorectal cancer (CRC) and a primary central nervous system tumor (principally medulloblastoma). It is also associated with pigmented ocular fundus lesions. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Turcot syndrome with polyposis	c2674616	6,997	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99818	2021-01-23T17:13:11	{"mesh": ["C538265"], "omim": ["175100"], "icd-10": ["D12.6"]}
A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy. ## Epidemiology The estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000. DYT5b is much less frequent than autosomal dominant DRD (DYT5a); fewer than 50 patients have been described worldwide to date. ## Clinical description Disease presents in infancy (most frequently in the first year of life) with a progressive hypokinetic-rigid syndrome with generalized dystonia, involuntary jerky movements, postural tremor, or gait disturbances that may fluctuate during the day and show good or excellent responsiveness to levodopa (L-dopa) in most cases (>80%). Eye-rolling movements and/or mild, non-progressive intellectual deficit may be present in some cases. Less frequently, a more severe phenotype of complex encephalopathy can present before the age of 6 months, with marked hypokinesia and progressive truncal hypotonia, combined with focal or generalized dystonia, sometimes with dystonic crises over several days and (often excessive) jerky movements like myoclonus and tremor without diurnal fluctuations. Autonomic disturbances are frequent, such as excessive salivation and sweating, lethargy, constipation, poor feeding and ''pyrexia of unknown origin''. Intellectual deficit, developmental motor delay, bilateral ptosis and oculogyric crises are also frequent. ## Etiology DYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, an enzyme responsible for catalyzing the conversion of L-tyrosine to L-dopa, the precursor of dopamine. For the two most common missense mutations (c.698G>A and c.707T>C) and for heterozygous truncating mutations, no genotype-phenotype correlation has been observed, but mutations in the promoter region are apparently associated with a milder phenotype. ## Diagnostic methods Diagnosis is based on clinical findings and the improvement of symptoms with the administration of oral L-dopa. The finding of homozygous TH mutations confirms diagnosis. Low levels of the dopamine metabolite homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) are found in the cerebrospinal fluid (CSF) of patients with DYT5b. HVA concentrations and the HVA/5-HIAA ratio in CSF appear to correlate with the age of onset and the severity of the phenotype. ## Differential diagnosis Differential diagnoses include different forms of DRD (e.g. autosomal dominant DRD), early onset torsion dystonia, myoclonic dystonia and other types of early-onset parkinsonism. It can also be mistaken for cerebral palsy or spastic paraplegia. Differential diagnoses that need to be considered for the more severe, encephalopathy-like phenotype include febrile infection-related epilepsy syndrome, neonatal hypoxic and ischemic brain injury, other tetrahydrobiopterin (BH4)-related enzyme deficiencies and mitochondrial disorders. ## Antenatal diagnosis Prenatal diagnosis is possible in families with a known TH mutation. ## Genetic counseling DYT5b is inherited in an autosomal recessive manner. Genetic counseling is possible and recommended. ## Management and treatment L-dopa, usually in combination with carbodopa, is the treatment of choice. The less severe phenotype typically shows a significant positive and quick response, but patients with the more severe phenotype frequently show hypersensitivity to L-dopa, with only moderate or no benefit, even after prolonged treatment and careful dosage adjustment, and are more prone to side effects. Dosage should be monitored for side effects and adjusted as necessary. Inhibitors of dopamine degradation like selegiline may be considered alternatively or in addition to L-dopa, but are rarely used in clinical practice. ## Prognosis Prognosis depends on the severity of the disease and if/when patients receive treatment. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Autosomal recessive dopa-responsive dystonia	c2673535	6,998	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101150	2021-01-23T17:37:05	{"gard": ["1902"], "mesh": ["C537537"], "omim": ["605407"], "umls": ["C2673535"], "icd-10": ["G24.1"], "synonyms": ["Autosomal recessive Segawa syndrome", "DYT5b", "Tyrosine hydroxylase deficiency", "Tyrosine hydroxylase-deficient dopa-responsive dystonia"]}
Joubert syndrome with renal defect is a rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with renal disease, in the absence of retinopathy. ## Epidemiology Prevalence is unknown. ## Clinical description In most cases, renal disease manifests as juvenile nephronophthisis, with onset of clinical symptoms in the late first/early second decade of life, although in rare cases there may be infantile NPH, with onset in the first years of life. ## Etiology The most commonly mutated genes in this subtype are NPHP1 (2q13) and RPGRIP1L (16q12.2) with autosomal recessive inheritance. [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 [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Joubert syndrome with renal defect	c1846790	6,999	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=220497	2021-01-23T18:29:00	{"gard": ["10169"], "mesh": ["C536296"], "omim": ["609583", "611560", "614424"], "icd-10": ["Q04.3", "Q61.5"], "synonyms": ["JS-R"]}

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