Datasets:

findzebra
/

corpus

Dataset card Data Studio Files Files and versions Community

Split (1)

train · 30.7k rows

text stringlengths 297 230k	title stringlengths 4 145	cui stringlengths 4 10	idx int64 0 30.7k	source stringclasses 6 values	source_url stringlengths 33 155	retrieved_date timestamp[s]	classification_map stringlengths 2 1.45k
A rare syndromic renal disorder characterized by renal, neurologic and thyroid disease, associated with thrombocytopenia. There have been no further descriptions in the literature since 1978. [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	Thyrocerebrorenal syndrome	c1848813	5,700	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3327	2021-01-23T17:34:43	{"gard": ["1646"], "mesh": ["C536908"], "omim": ["274240"], "umls": ["C1848813"], "synonyms": ["Cutler-Bass-Romshe syndrome"]}
Hepatocyte nuclear factor 1 Beta-associated diseases (HNF1B-associated diseases) are a group of genetic conditions that affect the kidney as well as other organ systems. The most common symptoms are associated with kidney abnormalities. Other signs and symptoms may include diabetes at a young age, genital abnormalities, and problems with pancreas and liver function. Not everyone who has an HNF1B-associated disease will have the same signs and symptoms. HNF1B-associated disease is caused by a mistake (mutation) in the HNF1B gene. This is one of the genes responsible for regulating early development of many of the body’s organs. Mutations in HNF1B are inherited in families in an autosomal dominant pattern. HNF1B-associated disease is diagnosed based on the symptoms, family history and genetic testing. Treatment for this condition is based on the symptoms. Kidney disease and kidney failure may be treated with dialysis and kidney transplant. The long-term outlook for people with HNF1B-associated disease depends on the severity of symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Hepatocyte nuclear factor 1ß (HNF1ß)–associated disease	None	5,701	gard	https://rarediseases.info.nih.gov/diseases/13702/hepatocyte-nuclear-factor-1-hnf1-associated-disease	2021-01-18T18:00:05	{"synonyms": ["Hepatocyte nuclear factor 1 beta–associated disease", "Renal cysts and diabetes"]}
A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-10 (LCA10) is caused by homozygous or compound heterozygous mutations in the CEP290 gene (610142) on chromosome 12q21. Description Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (summary by den Hollander et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000). Clinical Features Den Hollander et al. (2006) reported a consanguineous French Canadian family in which 4 sibs had Leber congenital amaurosis. The sibs were blind or severely visually impaired at birth. Two of the 4 experienced seizures but had no other neurologic symptoms. All 4 had normal cognitive function. Detailed CT scanning revealed no molar-tooth sign, no cerebellar atrophy, and no structural signs of Joubert syndrome (see 213300). McEwen et al. (2007) found that affected individuals from the family reported by den Hollander et al. (2006) had severely impaired olfactory function, whereas heterozygous mutation carriers had mild to severe microsomia. They noted that all patients queried before testing reported self-assumed normal olfactory functioning. They postulated that olfactory dysfunction may be prevalent in patients with ciliary diseases. Using in vivo microscopy of the central retina and colocalized rod and cone vision, Cideciyan et al. (2007) found that patients with LCA10 due to mutations in the CEP290 gene retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. Foveal cones were preserved, and visual brain pathways were anatomically intact. Despite severe blindness and rapid rod cell death, the findings suggested an opportunity for visual restoration of central vision. Papon et al. (2010) studied the otorhinolaryngologic phenotype and examined nasal cilia of 7 LCA patients from 6 families with known CEP290 mutations. In 5 of 7 cases, electron microscopy could be performed, which revealed high levels of respiratory cilia defects, involving the dynein arms, central complex, and/or peripheral microtubules. All patients had rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in neural retina and nasal epithelial cells compared to other tissues. Papon et al. (2010) suggested that the presence of respiratory symptoms in LCA patients might represent additional clinical criteria for CEP290 genotyping. Mapping Using linkage analysis, den Hollander et al. (2006) assigned the gene responsible for LCA in a consanguineous French Canadian family with 4 affected sibs to chromosome 12q21-q22, in a region containing 15 genes, including CEP290 (610142). Joubert syndrome-5 (610188), which is due to mutations in the CEP290 gene, is associated in all patients with congenital amaurosis or retinitis pigmentosa. An in-frame deletion in the Cep290 gene was found in association with early onset in the rd16 mouse (Chang et al., 2006). After extensive evaluation, no gross brain or kidney pathology could be detected in these mice. Molecular Genetics Because of the function of the CEP290 gene and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA10 in the French Canadian family. They sequenced all 53 coding exons and splice junctions and detected only 1 synonymous sequence variant in exon 21 that was not a known SNP. Since the variant was located between the splice donor site and a predicted exonic splice enhancer, den Hollander et al. (2006) reasoned that it may have an effect on the splicing of this exon. However, this could not be confirmed. Subsequent analysis of the complete CEP290 mRNA by RT-PCR revealed an aberrant splice product with insertion of a 128-bp cryptic exon between exons 26 and 27, which introduced a stop codon immediately downstream of exon 26. Sequencing of the genomic DNA surrounding the cryptic exon showed an A-to-G transition 5 bp downstream of the cryptic exon (2991+1655A-G; 610142.0005). The mutation created a strong splice donor site, which presumably led to efficient splicing of the cryptic exon into the CEP290 mRNA. To determine whether this mutation could be a common cause of LCA10, den Hollander et al. (2006) screened 76 unrelated patients with LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients were found to be homozygous for the mutation, and 12 were heterozygous. The mutation was not detected in 223 French Canadian controls, and only 1 of 248 Dutch control individuals was found to be heterozygous for the mutation. Den Hollander et al. (2006) suggested that this mutation may account for up to 21% of LCA cases. Twelve patients who were heterozygous for 2991+1655A-G were analyzed for additional mutations in the 53 coding exons and splice junction of CEP290 by heteroduplex analysis and/or direct sequencing. In all patients, they detected a heterozygous mutation on the other allele. In 9 LCA families in which 2 CEP290 mutations were identified by den Hollander et al. (2006), family members were available for segregation analysis. In all 9 families, segregation of the variants as expected for autosomal recessive inheritance was observed. The patients had no neurologic symptoms typical of Joubert syndrome, had normal cognitive function, and showed no clinical signs of renal disease. The patients studied by den Hollander et al. (2006) originated from various geographic regions, including Canada, Germany, the Netherlands, and Italy. The results suggested a complete loss of function of both CEP290 alleles leads to Joubert syndrome, whereas patients with LCA10 have a small amount of residual CEP290 activity. In a patient with LCA10, Cideciyan et al. (2007) identified compound heterozygosity for 2 mutations in the CEP290 gene: the common splice site defect (610142.0005) and a 5-bp deletion (1260delTAAAG; 610142.0011). [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	LEBER CONGENITAL AMAUROSIS 10	c0339527	5,702	omim	https://www.omim.org/entry/611755	2019-09-22T16:02:52	{"doid": ["0110291"], "mesh": ["D057130"], "omim": ["611755"], "orphanet": ["65"], "genereviews": ["NBK531510"]}
A number sign (#) is used with this entry because of evidence that hypomagnesemia, seizures, and mental retardation-1 (HOMGSMR1) is caused by heterozygous mutation in the CNNM2 gene (607803) on chromosome 10q24. One family with a homozygous mutation has also been reported. Description HOMGSMR1 is characterized by onset of seizures associated with low serum magnesium in the first year of life. Affected individuals show variable degrees of delayed psychomotor development (summary by Arjona et al., 2014). ### Genetic Heterogeneity of Hypomagnesemia, Seizures, and Mental Retardation HOMGSMR2 (618314) is caused by mutation in the ATP1A1 gene (182310) on chromosome 1p13. Clinical Features Arjona et al. (2014) reported 3 unrelated German patients with onset of seizures associated with low serum magnesium in the first year of life. All had delayed psychomotor development, moderate mental retardation, limited speech, and impaired motor skills. Two patients were obese. One patient had autistic features and aggressive behavior. Brain imaging was normal in all 3 patients. Urinary analysis showed abnormally high renal excretion of magnesium, and oral supplementation of magnesium failed to correct the low serum levels. ### Clinical Variability Arjona et al. (2014) reported 2 sibs, born of consanguineous Serbian parents, who presented in the neonatal period with seizures associated with hypomagnesemia. Both had severely delayed psychomotor development, microcephaly, mental retardation, lack of speech, and very limited motor skills. Brain imaging in 1 patient showed myelination defects, opercularization defects, and widened cerebrospinal fluid spaces. Treatment with oral or intravenous magnesium failed to correct the low serum magnesium levels. One child eventually responded to antiepileptic treatment, whereas the other child continued to have generalized myoclonic seizures despite treatment. Molecular Genetics In 3 unrelated German patients with HOMGSMR1, Arjona et al. (2014) identified 2 different de novo heterozygous missense mutations in the CNNM2 gene (607803.0004 and 607803.0005). Two sibs from a consanguineous Serbian family with a similar but more severe disorder were homozygous for a missense mutation (607803.0003). In vitro functional expression studies of all the mutations were consistent with a loss of function. The findings indicated that CNNM2 is essential not only for magnesium homeostasis, but also for early brain development and proper neurologic function. Animal Model Arjona et al. (2014) found that morpholino knockdown of the zebrafish CNNM2 paralog cnnm2a resulted in enlarged pericardial cavities and notochord defects as well as decreased total body magnesium levels. Knockdown of the other CNNM2 paralog, cnnm2b, resulted in enlarged pericardial cavities, renal cysts, accumulation of cerebrospinal fluid in the brain, and decreased total body magnesium levels. Mutant zebrafish also showed maldevelopment of the midbrain/hindbrain boundary, increased spontaneous contractions, and weaker touch-evoked escape behavior compared to controls. INHERITANCE \- Autosomal dominant \- Autosomal recessive (1 family) HEAD & NECK Head \- Microcephaly (1 family) GENITOURINARY Kidneys \- Urinary magnesium wasting NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Poor or absent speech \- Seizures \- Reduced myelination (1 patient) \- Failure of opercularization (1 patient) \- Increased cerebrospinal fluid spaces (1 patient) LABORATORY ABNORMALITIES \- Low serum magnesium MISCELLANEOUS \- De novo mutation in heterozygotes \- Onset in the first year of life \- Seizures may be refractory to treatment \- One consanguineous family with a recessive mutation has been reported (last curated June 2015) \- Patients with recessive mutations have a more severe phenotype MOLECULAR BASIS \- Caused by mutation in the cyclin M2 gene (CNNM2, 607803.0003 ) ▲ 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	HYPOMAGNESEMIA, SEIZURES, AND MENTAL RETARDATION 1	c4225333	5,703	omim	https://www.omim.org/entry/616418	2019-09-22T15:48:56	{"omim": ["616418"], "orphanet": ["34527"], "synonyms": ["HOMGSMR", "Alternative titles"]}
Isolated sulfite oxidase deficiency (ISOD) is a disorder of the nervous system, with a severe "classic" form that starts in the newborn period and a milder, late-onset form that begins later in infancy or early childhood. Classic ISOD appears within the first few days after birth with signs and symptoms of brain dysfunction (encephalopathy) that quickly get worse. Babies with classic ISOD have seizures that are difficult to treat and feeding difficulties. They have muscle stiffness that results in paralysis of the arms and legs (spastic quadriplegia) and episodes of muscle spasms that cause backward arching of the spine (opisthotonus). Because development of the brain is impaired, the head does not grow at the same rate as the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Abnormalities in facial features also become increasingly pronounced with lack of normal head growth. These facial differences include a relatively long and narrow face; deep-set, widely-spaced eyes; elongated openings of the eyes (palpebral fissures); puffy cheeks; a small nose; a large space between the nose and upper lip (a long philtrum); and thick lips. Babies with classic ISOD do not respond to their environment except to startle easily in response to noises, and they do not develop any motor skills such as turning over or sitting up. They usually do not live for more than a few months. Affected individuals who survive past infancy usually develop displacement of the lenses of the eyes (ectopia lentis). Because these individuals do not react to visual stimuli (are behaviorally blind) due to the brain damage associated with classic ISOD, the ectopia lentis has no further impact on their vision. Late-onset ISOD usually begins between the ages of 6 and 18 months, often after an illness involving fever. Individuals with this form of the disorder may not have the seizures and ectopia lentis that usually occur in the classic form. They have developmental delay and may lose skills that they had already developed (developmental regression). Movement problems occur in this form of the disorder, including muscle tensing (dystonia), uncontrolled movements of the limbs (choreoathetosis), and difficulty with coordination (ataxia). The signs and symptoms of late-onset ISOD can gradually get worse (progress), or they can be episodic, which means that they come and go. Some individuals with this form of ISOD survive into childhood or adolescence; because of the rarity of this disorder, their life expectancy is unknown. ## Frequency The prevalence of ISOD is unknown. At least 50 affected individuals have been described in the medical literature. ## Causes ISOD is caused by mutations in the SUOX gene. This gene provides instructions for making an enzyme called sulfite oxidase, which helps break down protein building blocks (amino acids) that contain sulfur when they are no longer needed. Specifically, sulfite oxidase is involved in the final step of this process, in which sulfur-containing molecules called sulfites are converted to other molecules called sulfates by adding an oxygen atom (a process called oxidation). The SUOX gene mutations that cause ISOD impair the function of sulfite oxidase, preventing complete breakdown of sulfur-containing amino acids. As a result, sulfites and other compounds left over from the partial breakdown process abnormally accumulate in the body. Researchers suggest that the nervous system is especially sensitive to this abnormal accumulation, and excessive levels of sulfite compounds that are toxic to the brain are thought to result in the brain damage that occurs in ISOD. It is unclear why most affected individuals have the classic form of the condition while a smaller number develop the milder late-onset form. ### Learn more about the gene associated with Isolated sulfite oxidase deficiency * SUOX ## 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	Isolated sulfite oxidase deficiency	c2931746	5,704	medlineplus	https://medlineplus.gov/genetics/condition/isolated-sulfite-oxidase-deficiency/	2021-01-27T08:25:52	{"gard": ["5062"], "mesh": ["C538141"], "omim": ["272300"], "synonyms": []}
Gigli et al. (1993) described a family in which 3 brothers and 2 sons of 1 of the brothers had progressive weakness and spasticity of lower limbs, epilepsy, and mental retardation. By linkage analysis and haplotype reconstruction, Lo Nigro et al. (2003) excluded linkage of the disorder in the family described by Gigli et al. (1993) to 8 previously mapped loci associated with autosomal dominant spastic paraplegias. Neuro \- Spastic paraparesis \- Leg weakness \- Leg spasticity \- Epilepsy \- Mental retardation Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	SPASTIC PARAPLEGIA, EPILEPSY, AND MENTAL RETARDATION	c1866854	5,705	omim	https://www.omim.org/entry/182610	2019-09-22T16:34:40	{"mesh": ["C536869"], "omim": ["182610"], "orphanet": ["2816"]}
Action myoclonus–renal failure (AMRF) syndrome causes episodes of involuntary muscle jerking or twitching (myoclonus) and, often, kidney (renal) disease. Although the condition name refers to kidney disease, not everyone with the condition has problems with kidney function. The movement problems associated with AMRF syndrome typically begin with involuntary rhythmic shaking (tremor) in the fingers and hands that occurs at rest and is most noticeable when trying to make small movements, such as writing. Over time, tremors can affect other parts of the body, such as the head, torso, legs, and tongue. Eventually, the tremors worsen to become myoclonic jerks, which can be triggered by voluntary movements or the intention to move (action myoclonus). These myoclonic jerks typically occur in the torso; upper and lower limbs; and face, particularly the muscles around the mouth and the eyelids. Anxiety, excitement, stress, or extreme tiredness (fatigue) can worsen the myoclonus. Some affected individuals develop seizures, a loss of sensation and weakness in the limbs (peripheral neuropathy), or hearing loss caused by abnormalities in the inner ear (sensorineural hearing loss). Severe seizures or myoclonus can be life-threatening. When kidney problems occur, an early sign is excess protein in the urine (proteinuria). Kidney function worsens over time, until the kidneys are no longer able to filter fluids and waste products from the body effectively (end-stage renal disease). AMRF syndrome typically begins causing symptoms between ages 15 and 25, but it can appear at younger or older ages. The age of onset and the course of the condition vary, even among members of the same family. Either the movement problems or kidney disease can occur first, or they can begin at the same time. Most people survive 7 to 15 years after the symptoms appear. ## Frequency AMRF syndrome is a rare condition that has been found worldwide. Its exact prevalence is unknown. At least 38 individuals with the condition have been described in the medical literature. ## Causes AMRF syndrome is caused by mutations in the SCARB2 gene. This gene provides instructions for making the LIMP-2 protein, which transports an enzyme called beta-glucocerebrosidase to cellular structures called lysosomes. Lysosomes are specialized compartments that digest and recycle materials. In these compartments, beta-glucocerebrosidase breaks down a fatty substance called glucocerebroside. The LIMP-2 protein remains in the lysosome after transporting beta-glucocerebrosidase and is important for the stability of these structures. SCARB2 gene mutations associated with AMRF syndrome lead to production of an altered LIMP-2 protein that cannot get to the lysosome. As a result, the movement of beta-glucocerebrosidase to lysosomes is impaired. It is thought that a shortage of beta-glucocerebrosidase function in these structures contributes to the signs and symptoms of AMRF syndrome, although the mechanism is unclear. Researchers are working to understand why some people with SCARB2 gene mutations have kidney problems and others do not. ### Learn more about the gene associated with Action myoclonus–renal failure syndrome * SCARB2 ## 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	Action myoclonus–renal failure syndrome	c0751779	5,706	medlineplus	https://medlineplus.gov/genetics/condition/action-myoclonus-renal-failure-syndrome/	2021-01-27T08:25:46	{"mesh": ["D020191"], "omim": ["254900"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-24 (SCAR24) is caused by compound heterozygous mutation in the UBA5 gene (610552) on chromosome 3q22. One such family has been reported. Clinical Features Duan et al. (2016) reported 2 adult sibs, born of unrelated Chinese parents, with onset of gait instability and speech difficulties at 5 and 8 years of age, respectively. Both also had markedly delayed growth in childhood but had achieved a normal body size as adults. Neither had cognitive involvement. Clinical features included gait and limb ataxia, dysarthria, nystagmus, and cataracts. Brain imaging showed cerebellar atrophy. The disorder was progressive, and the proband lost the ability to walk at age 39 years; her younger brother had a mildly spastic gait at age 36 and was still able to work. Inheritance The transmission pattern of SCAR24 in the family reported by Duan et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 sibs, born of unrelated Chinese parents, with SCAR24, Duan et al. (2016) identified compound heterozygous mutations in the UBA5 gene (R246X, 610552.0012 and K310E, 610552.0013). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that both mutant proteins were less stable than the wildtype protein; the R246X protein failed to interact with and activate UFM1 (610553), whereas K310E, like wildtype, retained the ability to interact with UFM1. Animal Model Duan et al. (2016) found that compete knockdown of the Uba5 gene in Drosophila was embryonic lethal. Partial knockdown of Uba5 using siRNA resulted in wing defects, decreased climbing and flight abilities, as well as decreased lifespans compared to wildtype. Histologic studies showed no defects in muscle morphology, but neuron-specific Uba5 knockdown resulted in abnormalities at the neuromuscular junction with a decrease in synaptic size. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor overall growth in childhood \- Normal size as adult HEAD & NECK Eyes \- Cataracts \- Nystagmus NEUROLOGIC Central Nervous System \- Gait ataxia \- Limb ataxia \- Mild spastic gait (in 1 of 2 sibs) \- Dysarthria \- Normal cognition \- Cerebellar atrophy Peripheral Nervous System \- Demyelinating sensorimotor neuropathy (in 1 of 2 sibs) MISCELLANEOUS \- Onset in childhood \- Progressive disorder \- Two Chinese sibs have been reported (last curated September 2016) MOLECULAR BASIS \- Caused by mutation in the ubiquitin like modifier activating enzyme 5 gene (UBA5, 610552.0012 ) ▲ 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	SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 24	c4310699	5,707	omim	https://www.omim.org/entry/617133	2019-09-22T15:46:51	{"omim": ["617133"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-18 (SCAR18) is caused by homozygous mutation in the GRID2 gene (602368) on chromosome 4q22. Description Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by Hills et al., 2013). Clinical Features Utine et al. (2013) reported 3 boys from a consanguineous Turkish kindred with cerebellar ataxia. The 8-year-old proband was described in detail. He presented at age 4 months with nystagmus, hypotonia, and delayed psychomotor development, and later showed unsteady gait, incoordination of gross motor movements, and dysarthria. Physical examination showed poor overall growth, rotatory nystagmus, truncal ataxia, oculomotor apraxia, pale optic disc, dysmetria, and dysdiadochokinesis. There was also evidence of pyramidal tract involvement, with hyperreflexia and extensor plantar responses. Serial brain imaging showed progressive cerebral and cerebellar atrophy. Two male cousins were similarly affected. Hills et al. (2013) reported 3 children from a consanguineous Turkish family with early-onset cerebellar ataxia associated with eye movement abnormalities and intellectual disability. All patients had delayed psychomotor development with hypotonia, truncal and appendicular ataxia, and difficulty walking; 1 patient was wheelchair-bound at age 14 years. All patients also showed occasional or persistent tonic upgaze and nystagmus. Speech was severely limited. An unrelated child of Mexican descent, born of unrelated parents, had a similar phenotype. Brain imaging of 1 patient from the Turkish family and the Mexican patient showed progressive and severe cerebellar atrophy mainly affecting the flocculus. None of the patients had seizures or dysmorphic features. Inheritance The transmission pattern of SCAR18 in the families reported by Hills et al. (2013) was consistent with autosomal recessive inheritance. Mapping By genomewide linkage analysis of a consanguineous Turkish kindred with autosomal recessive spinocerebellar ataxia, Hills et al. (2013) found linkage to chromosome 4q22 (maximum multipoint lod score of 3.608). Molecular Genetics In 3 patients from a consanguineous Turkish family with SCAR18, Utine et al. (2013) identified a homozygous deletion of exons 3 and 4 in the GRID2 gene (602368.0002). The deletion, which was found by genomewide array analysis and confirmed by PCR, segregated with the disorder in the family. Functional studies were not performed. In 3 patients from a consanguineous Turkish family with SCAR18, Hills et al. (2013) identified a homozygous deletion in the GRID2 gene (602368.0003), resulting in a truncated protein. The mutation was found by a combination of linkage analysis, candidate gene investigation, and custom array CGH. A Mexican child with a similar disorder was compound heterozygous for 2 deletions within the GRID2 gene (602368.0004 and 602368.0005). Both Utine et al. (2013) and Hills et al. (2013) noted phenotypic similarities to the phenotype of mutant mice with homozygous deletions in the Grid2 gene (see ANIMAL MODEL). Animal Model Lalouette et al. (1998) showed that mutations in the mouse Grid2 gene are responsible for at least 2 alleles of 'hotfoot' (ho), a recessive mouse mutant phenotype characterized by cerebellar ataxia associated with relatively mild abnormalities of the cerebellum. Using Northern blot and PCR analysis, they identified a 510-bp deletion in the ho(4J) allele and a 4-kb deletion in the ho(TgN371NRA) allele. Lalouette et al. (1998) hypothesized that each of the mutations results in loss of function because the hotfoot phenotype is similar to the Grid2 knockout phenotype (Kashiwabuchi et al., 1995). Hills et al. (2013) noted that the hotfoot mutant mouse has an in-frame deletion of exon 2, as found in a Mexican patient with SCAR18 (see 602368.0004). Using an infrared camera, Hills et al. (2013) observed that hotfoot mice had significantly larger spontaneous and random eye movements, indicating oculomotor dysfunction, compared to controls. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor overall growth (in some patients) HEAD & NECK Eyes \- Oculomotor apraxia \- Tonic upgaze \- Nystagmus \- Esotropia \- Pale optic discs (in some patients) SKELETAL \- Joint contractures (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual impairment \- Poor speech \- Cerebellar ataxia \- Truncal ataxia \- Gait ataxia \- Incoordination \- Dysmetria \- Dysdiadochokinesis \- Dysarthria \- Hyperreflexia (in some patients) \- Extensor plantar response (in some patients) \- Cerebellar atrophy, severe MISCELLANEOUS \- Onset in infancy \- Patients need support with walking or are wheelchair-bound \- Two consanguineous Turkish families have been reported (last curated January 2015) MOLECULAR BASIS \- Caused by mutation in the ionotropic glutamate receptor, delta 2 gene (GRID2, 602368.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 18	c4015505	5,708	omim	https://www.omim.org/entry/616204	2019-09-22T15:49:40	{"doid": ["0080042"], "omim": ["616204"], "orphanet": ["363429", "363432"], "synonyms": ["SCAR18", "Autosomal recessive congenital cerebellar ataxia due to ionotropic glutamate receptor delta-2 subunit deficiency"]}
A rare disorder characterised by hemolytic anemia, associated with metabolic acidosis and 5-oxoprolinuria in moderate forms, and with progressive neurological symptoms and recurrent bacterial infections in the most severe forms. ## Epidemiology This disease has been detected in at least 70 patients in more than 50 families worldwide. ## Etiology Several mutations have been identified in the gene encoding glutathione synthetase, localized to chromosome 20q11.2. Glutathione synthetase catalyses the last step in the synthesis of glutathione and a deficiency results in low levels of glutathione. Acidosis is due to reduced feedback inhibition of gamma-glutamyl cysteine synthetase in the gamma-glutamyl cycle, which ultimately leads to overproduction and accumulation of 5-oxoproline. ## Diagnostic methods The diagnosis usually involves the following: clinical findings, the finding of 5-oxoprolinuria, low levels of glutathione, low activity of glutathione synthetase, and mutation analysis of the glutathione synthetase gene. ## Differential diagnosis Other causes of 5-oxoprolinuria include 5-oxoprolinase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netimicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis. ## Antenatal diagnosis Antenatal diagnosis is possible. ## Genetic counseling Transmission is autosomal recessive. ## Management and treatment Management includes correction of the acidosis, supplementation with antioxidants and avoidance of drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides. ## Prognosis A long-term follow up study of 28 patients with glutathione synthetase deficiency has showed that the factors most predictive of survival and long-term outcome are early diagnosis, correction of acidosis and early supplementation with vitamin C and vitamin 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	Glutathione synthetase deficiency	c0398746	5,709	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=32	2021-01-23T18:31:46	{"gard": ["10047"], "mesh": ["C536835"], "omim": ["231900", "266130"], "umls": ["C0398746", "C1291643"], "icd-10": ["D55.1"], "synonyms": ["Pyroglutamicaciduria"]}
A number sign (#) is used with this entry because of evidence that variation in the CNTNAP2 gene (604569) on chromosome 7q35-q36 influences susceptibility to autism. For another form of susceptibility to autism in the 7q35-q36 region, see AUTS10 (611016). Description Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). For a discussion of genetic heterogeneity of autism, see 209850. Mapping To study the genetics of autism, Alarcon et al. (2002) divided the syndrome into component autism-related traits (endophenotypes), hypothesizing that quantitative trait loci (QTLs) related to one or more of these traits might underlie putative or significant regions of autism linkage. They performed nonparametric linkage analyses in 152 families segregating autism, focusing on 3 traits derived from the Autism Diagnostic Interview: 'age at first word,' 'age at first phrase,' and a composite measure of 'repetitive and stereotyped behaviors.' Using nonparametric multipoint linkage analysis, they found the strongest QTL evidence for the age at first word on 7q35-q36, and subsequent linkage analyses of additional markers and association analyses of the same region supported the initial result. Moreover, the peak fine-mapping result for repetitive behaviors localized to a region overlapping this language QTL. The authors suggested that a putative autism susceptibility locus on distal chromosome 7q may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder. Cytogenetics Poot et al. (2010) reported a boy with autism, delayed motor development, mild ataxia with poor coordination, hyperactivity, poor speech development, outbursts, and some features of Tourette syndrome (137580). The authors described a highly complex chromosomal rearrangement involving at least 3 breaks in chromosome 1 and 7 breaks in chromosome 7 on the paternally derived chromosome. There was a de novo paracentric inversion inv(7)(q32.1q35) that disrupted the CNTNAP2 gene (604569). Additionally, 2 CNTNAP2 gene segments were inserted into a gene-poor region on the chromosome 1q31.2 region. There was also a de novo deletion encompassing the distal part of intron 1 and exon 2 of CNTNAP2, and a de novo deletion of chromosome 1q41, spanning 15 annotated genes including KCTD3 (613272) and USH2A (608400), which has been reported as an autism susceptibility locus (AUTS11; 610836). Poot et al. (2010) suggested that haploinsufficiency for the CNTNAP2 gene may have caused the Tourette syndrome features, and that the combination of CNTNAP2 disruption and 1q41 deletion may have acted together to result in full-blown autism. Molecular Genetics Following up on the work of Alarcon et al. (2002), Alarcon et al. (2008) described results from 2 complementary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism (209850). A 2-stage association study across a 10-Mb 7q35 language-related autism quantitative trait locus (QTL) in trios demonstrated significant association with CNTNAP2 (rs270102; 604569.0002), a strong a priori candidate. Male-only-containing families were identified as primarily responsible for this association signal, consistent with a strong male affection bias in autism and other language-based disorders. Gene expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provided convergent evidence for involvement of CNTNAP2, a neurexin family member, in autism, and demonstrated a connection between genetic risk for autism and specific brain structures. Arking et al. (2008) performed a 2-stage genetic study in which genomewide linkage and family-based association mapping were followed up by association and replication studies in an independent sample. They identified a common polymorphism in CNTNAP2 (604569.0003) that was significantly associated with autism susceptibility. Importantly, the genetic variant displayed a parent-of-origin and gender effect recapitulating the inheritance of autism. Bakkaloglu et al. (2008) identified a de novo chromosome 7q inversion disrupting autism susceptibility candidate-2 (AUTS2; 607270) and CNTNAP2 in a child with cognitive and social delay. By in situ and biochemical analyses they confirmed expression of CNTNAP2 in relevant brain regions and demonstrated the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. They comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, they identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients, and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species tested. One variant at a highly conserved position, I869T (604569.0004), was inherited by 4 affected children in 3 unrelated families, but was not found in 4,010 control chromosomes. Overall, these resequencing data were interpreted as demonstrating a modest nonsignificant increase in the burden of rare variants in cases versus controls. Bakkaloglu et al. (2008) concluded that in light of other studies (Alarcon et al. (2008), Arking et al. (2008)) showing a relationship between autism and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggested that rare variants may also contribute to the pathophysiology of autism spectrum disorder (ASD) but place limits on the magnitude of this contribution. A genomewide association study by Ma et al. (2009) of 438 Caucasian families with 1,390 individuals with autism and validation in an additional cohort of 2,390 samples from 457 families did not show a significant association between autism and rs270102, which was the tagging SNP in the study of Alarcon et al. (2008). No tested markers linking to the CNTNAP2 gene were significant after correction. [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	AUTISM, SUSCEPTIBILITY TO, 15	c2677504	5,710	omim	https://www.omim.org/entry/612100	2019-09-22T16:02:20	{"omim": ["612100"]}
Ciuffo et al. (1985) reported a family in which the 62-year-old mother and her 36-year-old son and 28-year-old daughter had a seemingly 'new' syndrome of pulmonary valve stenosis, secundum type of atrial septal defect, and unique EKG changes: superior axis (-88 degrees in the mother) and absence of anterior forces in the precordial leads. The mother, the proband, had successful balloon pulmonary valvuloplasty at age 62 years. The son had corrective surgery for the ASD and PS at age 13 years. The daughter had surgical transpulmonary valvuloplasty at age 11 years. The presence of ASD was indicated by widely and fixedly split second heart sound. Cardiac \- Pulmonary valve stenosis \- Secundum type atrial septal defect \- Superior axis and absence of anterior forces on EKG \- Wide fixed split second heart sound Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	PULMONIC STENOSIS, ATRIAL SEPTAL DEFECT, AND UNIQUE ELECTROCARDIOGRAPHIC ABNORMALITIES	c1867407	5,711	omim	https://www.omim.org/entry/178650	2019-09-22T16:35:23	{"mesh": ["C566733"], "omim": ["178650"], "synonyms": ["Alternative titles", "CIUFFO SYNDROME"]}
Papillon-Lefevre syndrome Other namesPalmoplantar keratoderma with periodontitis Papillon–Lefèvre syndrome has an autosomal recessive pattern of inheritance. SpecialtyDermatology, medical genetics Papillon–Lefèvre syndrome (PLS), also known as palmoplantar keratoderma with periodontitis,[1][2] is an autosomal recessive[3] genetic disorder caused by a deficiency in cathepsin C.[4][5] ## Contents * 1 Presentation * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Eponym * 6 See also * 7 References * 8 External links ## Presentation[edit] PLS is characterized by periodontitis and palmoplantar keratoderma.[6] The severe destruction of periodontium results in loss of most primary teeth by the age of 4 and most permanent teeth by age 14. Hyperkeratosis of palms and soles of feet appear in first few years of life. Destructions of periodontium follows almost immediately after the eruption of last molar tooth. The teeth are involved in roughly the same order in which they erupt. ## Cause[edit] Mutations in the cathepsin C gene (CTSC), located at human chromosome 11q14.1-q14.3, are the cause of PLS.[4][7] The disorder is inherited in an autosomal recessive manner.[4] This means the defective gene responsible for the disorder is located on an autosome (chromosome 11 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. ## Diagnosis[edit] Early diagnosis and treatment is important to allow for prompt treatment to prevent long-term consequences such as tooth loss.[8] A diagnosis can be made by a urine analysis for low/no activity of the enzyme cathepsin C.[8] A full patient history and identification of characteristic physical symptoms is another way to identify this syndrome. However, often the symptoms are visually similar to other, milder, conditions, and it is only with the eruption of infant teeth that tissue degeneration or inflammation become apparent, often in conjunction with a sudden abnormality of skin colour.[8] Another physical diagnosis is to identify abnormal accumulation of calcium within the skull.[8] Genetic testing at the molecular level can look for alterations in the CTSC gene which are known to cause Papillon–Lefèvre syndrome, however this diagnostic service is only available at specialized laboratories.[8] ## Treatment[edit] In 2006, retinoids and antibiotics have been used with a successful dental maintenance for one year.[9] In the past, only extraction of all teeth and construction of a complete denture were made. An alternative to rehabilitation with conventional dental prothesis after total loss of the natural teeth was proposed by Drs. Ahmad Alzahaili and his teacher Jean-François Tulasne (developer of the partial bone graft technique used). This approach entails transplanting bone extracted from the cortical external surface of the parietal bone to the patient’s mouth, affording the patient the opportunity to lead a normal life.[10][11][12] Notwithstanding this treatment does not scope the disease itself. Actually, it is the repositioning of bone from calvaria to the maxillary bones, and placement of dental implants in a completely edentulous maxilla when the patient has already lost all teeth. An already developed method to reconstruct maxillae in edentulous elderly people by other dental professionals. There's still no real treatment to help those who suffer from this disease to keep all their natural teeth, though their exfoliation and loss can be delayed. The maintenance of teeth is done by dental professionals with a procedure called scaling and root planing with the use of systemic antibiotics. The syndrome should be diagnosed as earlier as possible, so the teeth can be kept longer in the mouth, helping the development of the maxillary bones. ## Eponym[edit] It is named for M. M. Papillon and Paul Lefèvre.[13][14] ## See also[edit] * Porokeratosis plantaris discreta * List of cutaneous conditions * List of dental abnormalities associated with cutaneous conditions ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 245000 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 3. ^ Ullbro C, Crossner CG, Nederfors T, Alfadley A, Thestrup-Pedersen K (2003). "Dermatalogical and oral findings in a cohort of 47 patients with Papillon-Lefevre syndrome". J Am Acad Dermatol. 48 (3): 345–351. doi:10.1067/mjd.2003.197. PMID 12637913. 4. ^ a b c Wani A, Devkar N, Patole M, Shouche Y (2006). "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". J. Periodontol. 77 (2): 233–237. doi:10.1902/jop.2006.050124. PMID 16460249. 5. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 214. ISBN 0-7216-2921-0. 6. ^ Cagli NA, Hakki SS, Dursun R, et al. (Dec 2005). "Clinical, genetic, and biochemical findings in two siblings with Papillon-Lefèvre Syndrome". J. Periodontol. 76 (12): 2322–2329. doi:10.1902/jop.2005.76.12.2322. PMID 16332247. 7. ^ Online Mendelian Inheritance in Man (OMIM): 602365 8. ^ a b c d e "Papillon Lefèvre Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2018-04-17. 9. ^ Ahuja V, Shin RH, Mudgil A, Nanda V, Schoor R (November 2005). "Papillon-Lefèvre syndrome: a successful outcome". J. Periodontol. 76 (11): 1996–2001. doi:10.1902/jop.2005.76.11.1996. PMID 16274321. 10. ^ Zuhaili, Dr. Ahmed; Tulasne, Dr. Jean Francois (September 2014). "Dr. Ahmed Zuhaili performs yet another groundbreaking surgery". Dental Tribune Middle East and Africa. No. 6: 14. 11. ^ Alchab, Dr. Izdihar. "Papillon–Lefèvre syndrome treatment with partial bone graft technique". Cone Beam International No. 4, 2014. No. 4: 16–17. 12. ^ Zuhaili, Dr. Ahmed; Tulasne, Dr. Jean Francois. "Dr. Ahmed Zuhailee Does It Again By Performing Life Changing Surgery For His Patient With Papillon-lefevre Syndrome". French Dental Clinic UAE. Archived from the original on 2014-12-21. 13. ^ synd/1804 at Who Named It? 14. ^ M. M. Papillon, P. Lefèvre. Deux cas de kératodermie palmaire et plantaire symétrique familiale (maladie de Meleda) chez le frère et la soeur. Coexistence dans les deux cas d’altérations dentaires graves. Bulletin de la Société française de dermatologie et de vénéorologie, Paris, 1924, 31: 82-87. ## External links[edit] Classification D * OMIM: 245000 * MeSH: D010214 * DiseasesDB: 9583 External resources * Orphanet: 678 * Keratosis palmoplantar periodontopathy; Papillon Lefevre Syndrome at NIH's Office of Rare Diseases [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	Papillon–Lefèvre syndrome	c0030360	5,712	wikipedia	https://en.wikipedia.org/wiki/Papillon%E2%80%93Lef%C3%A8vre_syndrome	2021-01-18T18:38:09	{"gard": ["3100"], "mesh": ["D010214"], "umls": ["C0030360"], "orphanet": ["678"], "wikidata": ["Q2050791"]}
Sequeiros and Martins da Silva (1988) studied a large family with 6 cases of sudden infant death syndrome (SIDS; 272120) and at least 4 cases of infantile sleep apnea ('near-miss SIDS') that occurred in 2 successive generations. They postulated that a structural CNS defect or a delay in maturation inherited in an autosomal dominant manner predisposes to SIDS in this family, with peak risk at about age 3 months. Survivors may suffer from recurrent episodes of infantile apnea or be completely asymptomatic. Somnograms remained abnormal as late as age 5 years. Misc \- Frequent sudden infant death syndrome Neuro \- Infantile sleep apnea Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	APNEA, CENTRAL SLEEP	c0520680	5,713	omim	https://www.omim.org/entry/107640	2019-09-22T16:44:52	{"mesh": ["D020182"], "omim": ["107640"]}
Mucopolysaccharidosis type I (MPS I) is a condition that affects many parts of the body. This disorder was once divided into three separate syndromes: Hurler syndrome (MPS I-H), Hurler-Scheie syndrome (MPS I-H/S), and Scheie syndrome (MPS I-S), listed from most to least severe. Because there is so much overlap between each of these three syndromes, MPS I is currently divided into the severe and attenuated types. Children with MPS I often have no signs or symptoms of the condition at birth, although some have a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). People with severe MPS I generally begin to show other signs and symptoms of the disorder within the first year of life, while those with the attenuated form have milder features that develop later in childhood. Individuals with MPS I may have a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," an enlarged liver and spleen (hepatosplenomegaly), and a large tongue (macroglossia). Vocal cords can also enlarge, resulting in a deep, hoarse voice. The airway may become narrow in some people with MPS I, causing frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). People with MPS I often develop clouding of the clear covering of the eye (cornea), which can cause significant vision loss. Affected individuals may also have hearing loss and recurrent ear infections. Some individuals with MPS I have short stature and joint deformities (contractures) that affect mobility. Most people with the severe form of the disorder also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Carpal tunnel syndrome develops in many children with this disorder and is characterized by numbness, tingling, and weakness in the hand and fingers. Narrowing of the spinal canal (spinal stenosis) in the neck can compress and damage the spinal cord. While both forms of MPS I can affect many different organs and tissues, people with severe MPS I experience a decline in intellectual function and a more rapid disease progression. Developmental delay is usually present by age 1, and severely affected individuals eventually lose basic functional skills (developmentally regress). Children with this form of the disorder usually have a shortened lifespan, sometimes living only into late childhood. Individuals with attenuated MPS I typically live into adulthood and may or may not have a shortened lifespan. Some people with the attenuated type have learning disabilities, while others have no intellectual impairments. Heart disease and airway obstruction are major causes of death in people with both types of MPS I. ## Frequency Severe MPS I occurs in approximately 1 in 100,000 newborns. Attenuated MPS I is less common and occurs in about 1 in 500,000 newborns. ## Causes Mutations in the IDUA gene cause MPS I. The IDUA gene provides instructions for producing an enzyme that 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 IDUA gene reduce or completely eliminate the function of the IDUA enzyme. The lack of IDUA enzyme activity 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 that cause molecules to build up inside the lysosomes, including MPS I, 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 the movement of molecules inside the cell. ### Learn more about the gene associated with Mucopolysaccharidosis type I * IDUA ## 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	Mucopolysaccharidosis type I	c0086795	5,714	medlineplus	https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-i/	2021-01-27T08:25:15	{"gard": ["10335"], "mesh": ["D008059"], "omim": ["607014", "607015", "607016"], "synonyms": []}
Oculopharyngeal muscular dystrophy is a genetic condition characterized by muscle weakness that begins in adulthood, typically after age 40. The term "oculopharyngeal" refers to the eyes (oculo-) and a part of the throat called the pharynx (-pharyngeal). Affected individuals usually first experience weakness of the muscles in both eyelids that causes droopy eyelids (ptosis). Ptosis can worsen over time, causing the eyelid to impair vision, and in some cases, limit eye movement. Along with ptosis, affected individuals develop weakness of the throat muscles that causes difficulty swallowing (dysphagia). Dysphagia begins with dry food, but over time, liquids can also become difficult to swallow. Dysphagia can cause saliva to accumulate and a wet-sounding voice. Many people with oculopharyngeal muscular dystrophy also have weakness and wasting (atrophy) of the tongue. These problems with food intake may cause malnutrition, choking, or a bacterial lung infection called aspiration pneumonia. Individuals with oculopharyngeal muscular dystrophy frequently have weakness in the muscles near the center of the body (proximal muscles), particularly muscles in the shoulders, upper legs, and hips (limb-girdle muscles). The weakness slowly gets worse, and people may need the aid of a cane or a walker. Rarely, affected individuals need wheelchair assistance. Rarely, individuals have a severe form of oculopharyngeal muscular dystrophy with muscle weakness that begins before age 45, and have trouble walking independently by age 60. These individuals often also have disturbances in nerve function (neuropathy), a gradual loss of intellectual functioning (cognitive decline), and psychiatric symptoms such as depression or strongly held false beliefs (delusions). ## Frequency In Europe, the prevalence of oculopharyngeal muscular dystrophy is estimated to be 1 in 100,000 people. This condition is much more common in the French-Canadian population of the Canadian province of Quebec, where it is estimated to affect 1 in 1,000 individuals. Oculopharyngeal muscular dystrophy is also seen more frequently in the Bukaran Jewish population of Israel, affecting 1 in 700 people. ## Causes Mutations in the PABPN1 gene cause oculopharyngeal muscular dystrophy. The PABPN1 gene provides instructions for making a protein that is found throughout the body. The PABPN1 protein plays an important role in processing molecules called messenger RNAs (mRNAs), which serve as genetic blueprints for making proteins. PABPN1 alters a region at the end of mRNA molecules that protects mRNA from being broken down. The PABPN1 protein also is involved in transporting mRNA within the cell. The PABPN1 protein contains an area where 10 copies of the protein building block (amino acid) alanine occur in a row. This stretch of alanines is known as a polyalanine tract. The role of the polyalanine tract in normal PABPN1 protein function is unknown. Mutations in the PABPN1 gene that cause oculopharyngeal muscular dystrophy result in a PABPN1 protein with an abnormally long (extended) polyalanine tract that includes between 11 and 18 alanines. Typically, affected individuals with shorter polyalanine tracts tend to have milder signs and symptoms that develop later in life compared to those with longer polyalanine tracts. The extra alanines cause the PABPN1 protein to form nonfunctional clumps within muscle cells. These clumps (called intranuclear inclusions) accumulate and are thought to impair the normal functioning of muscle cells, eventually causing cell death. The resulting loss of muscle cells over time most likely causes the muscle weakness seen in people with oculopharyngeal muscular dystrophy. In severe cases, it is likely that intranuclear inclusions affect nerve cells as well as muscle cells. ### Learn more about the gene associated with Oculopharyngeal muscular dystrophy * PABPN1 ## Inheritance Pattern Most cases of oculopharyngeal muscular dystrophy are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, some individuals have mutations in both copies of the PABPN1 gene that lead to expanded polyalanine tracts. These individuals tend to have more severe signs and symptoms that develop earlier in life compared to individuals with a mutation in one copy of the gene. In most cases, an affected person has one parent with 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	Oculopharyngeal muscular dystrophy	c0270952	5,715	medlineplus	https://medlineplus.gov/genetics/condition/oculopharyngeal-muscular-dystrophy/	2021-01-27T08:25:07	{"gard": ["7245"], "mesh": ["D039141"], "omim": ["164300"], "synonyms": []}
## Description Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis. When hemangiomata are associated, the condition is known as Maffucci syndrome (614569). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to osteosarcoma (Schwartz et al., 1987). ### Classification of the Enchondromatoses In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; spondyloenchondrodysplasia (607944), type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978). Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas). Clinical Features Vaz and Turner (1986) described a case of Ollier disease associated with ovarian juvenile granulosa cell tumor and precocious pseudopuberty. Tamimi and Bolen (1984) had described the same association. Halal and Azouz (1991) reported the case of a boy who had platyspondyly and metaphyseal manifestations of enchondromatosis with severe involvement of the hands and feet compatible with generalized enchondromatosis, or Spranger type VI enchondromatosis. The father was short of stature and had only moderate platyspondyly. Both the father and the son had consanguineous parents. Halal and Azouz (1991) suggested that platyspondyly may be (1) a manifestation of the carrier state for an autosomal recessive trait; (2) a minor expression of the same autosomal recessive trait in an affected individual since the father's parents were also consanguineous and some of his sibs were reported to have prominent joints; or (3) less likely, variable expression of an autosomal dominant trait in the father and son. Inheritance Most cases of Ollier disease have been sporadic (Halal and Azouz, 1991). There are a few instances of familial occurrence. Steudel (1892) described 2 affected brothers, and Rossberg (1959) reported affected brother and sister whose paternal grandfather was also affected. Lamy et al. (1954) observed 3 affected sibs, and Carbonell Juanico and Vineta Teixido (1962) reported affected brother and sister. Dominant inheritance with reduced penetrance is possible. Population Genetics Sun et al. (1985) reported that 9 patients with Maffucci syndrome seen at the Mayo Clinic developed chondrosarcoma. From a review of the English literature since 1973, they concluded that the incidence of chondrosarcoma in this disorder is 17.8%. This conclusion is suspect. The difficulties of stating the frequency of malignancy in von Recklinghausen neurofibromatosis and multiple exostoses from hospital records or reports is well known (McKusick, 1988). Molecular Genetics In a case of human enchondromatosis, Hopyan et al. (2002) had identified a mutant type I receptor for parathyroid hormone and parathyroid hormone-related protein (PTHR1; 168468) that signaled abnormally in vitro and caused enchondroma-like lesions in transgenic mice. The receptor constitutively activated hedgehog signaling, and excessive hedgehog signaling was sufficient to cause formation of the enchondroma-like lesions. The mutation (R150C) was heterozygous and was found in enchondroma specimens from 2 of 6 individuals with Ollier enchondromatosis. The 2 affected individuals were unrelated males with mild to moderate disease severity. In 1 of these men, the R150C mutation was carried in the germline and was inherited from the father, who had mild skeletal dysplasia but no evidence of enchondromas, similar to the findings in the father and son reported by Halal and Azouz (1991). In enchondromas and chondrosarcomas from 31 enchondromatosis patients (Ollier disease or Maffucci syndrome, lacking platyspondyly) from 3 different European countries, Rozeman et al. (2004) failed to find evidence of the R150C mutation described by Hopyan et al. (2002), nor did they find any other mutation in the PTHR1 gene. PTHR1 protein expression was studied using immunohistochemistry, revealing normal expression. Rozeman et al. (2004) concluded that enchondromatosis is not caused by the PTHR1 R150C mutation found by Hopyan et al. (2002), although they stated that the discrepancy in findings may have been caused by the R150C mutation being a founder mutation in the Canadian population, or may reflect that the patients of Hopyan et al. (2002) belonged to a different, rare subclass of enchondromatosis instead of having Ollier disease. Couvineau et al. (2008) analyzed the coding sequence of PTHR1, IHH (168470), PTHRP (168470), and GNAS1 (139320) in leukocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. Couvineau et al. (2008) identified 3 previously undescribed heterozygous missense mutations in PTHR1 in patients with Ollier disease. Two mutations (G121E; A122T) were present only in enchondromas, and 1 (R255H) in both enchondroma and leukocyte DNA. The 3 amino acid substitutions in PTHR1 identified by Couvineau et al. (2008) impaired the ability of the mutant receptor to stimulate cAMP production, due to either a decrease in receptor expression and ligand affinity (G121E; R255H) or suboptimal agonist-induced cAMP production despite normal PTHR1 expression (A122T). Structural modeling of PTHR1 indicated that the deleterious mutations associated with Ollier disease and located within the N-ted all lie within the structured core of the N-ted. Couvineau et al. (2008) noted that 3 of the 5 patients with Ollier disease in whom PTHR1 mutations were identified in enchondromas did not have similar mutations in peripheral blood leukocytes and that multiple enchondromas were present in these patients. The authors thus suggested that the mutations occurred during development, resulting in genetic mosaicism in these individuals. Couvineau et al. (2008) also suggested that the presence of PTHR1 mutations may not be sufficient to induce enchondromas and that a combination of genetic events, germline and/or somatic, is required for the development of enchondromas. Pansuriya et al. (2011) reported somatic heterozygous mutations in IDH1 (147700; 395G-T; R132H) or IDH2 (147650; 516G-C; R172S) in 87% of enchondromas and in 70% of spindle cell hemangiomas. In total, 35 of 43 (81%) individuals with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Eight tumor samples had subthreshold peaks at the position in IDH1 expected to encode mutations resulting in R132C or R132H substitutions and mutations were confirmed in 7 of these tumors by the hydrolysis probe assay. Pansuriya et al. (2011) showed that IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were absent in DNA isolated from the blood, muscle, or saliva of the subjects. Fourteen of 16 subjects had identical mutations in separate lesions. Of 68 tumors from subjects with Ollier disease, 17 (25%) showed mutant protein expression, whereas 51 (75%) were negative. Within tumors that were positive for IDH1 R132H staining, Pansuriya et al. (2011) observed a mixture of cells that did and did not express the mutant protein, a pattern that the authors referred to as intraneoplastic mosaicism. Within these tumors, the percentage of tumor cells staining positive for IDH1 R132H ranged from 50 to 95%. Pansuriya et al. (2011) also reported mutations in IDH1 or IDH2 in 40 of 101 (40%) solitary central tumors, 7 of 13 (54%) dedifferentiated chondrosarcomas, and 3 of 3 (100%) periosteal chondrosarcomas. Amary et al. (2011) analyzed 74 tumors from 40 individuals (32 with Ollier disease, 8 with Maffucci syndrome) for mutations in IDH1 (altering arg132) and IDH2 (altering arg140 and arg172). A large proportion (90.5%) of the tumors harbored one of these mutations: 62 of 68 cartilaginous tumors had an IDH1 mutation, and 1 tumor had an IDH2 mutation. Samples from multiple tumors (range, 2-6; mean, 2.8 per subject) were available from 19 of the 40 individuals. Of these 19, 15 were found to have the same mutation in each of their tumor samples that were examined. Tumors from 3 individuals (2 tumors each) had wildtype IDH1 and IDH2 sequences (subjects 2, 10, and 25). One tumor in subject 21 harbored a mutation causing an R132S substitution, whereas the second tumor had wildtype sequences. Sequencing all coding regions of IDH1, IDH2, and PTH1R for the 3 tumors with wildtype sequences for IDH1 and IDH2 from which frozen tissue was available for such analysis did not reveal mutations. The rare IDH1, IDH2, and PTH1R mutations previously reported in these genes were not detected in the remaining 4 paraffin-embedded tumors with wildtype sequences. Additional sequencing of 12 of the 62 tumors with IDH1 mutations did not reveal common PTH1R mutations. Amary et al. (2011) detected the same R132C mutation in both nonlesional tissue and tumors from 2 of 12 subjects with Ollier disease (subject 1, bone marrow; subject 6, blood), using a custom-made Taqman assay and MassARRAY but not by capillary sequencing. Amary et al. (2011) also found a strong correlation between the presence of mutations and high levels of 2HG and between the absence of mutations and low 2HG levels in a series of central cartilaginous tumors and 1 hemangioma derived from subjects with Ollier disease or Maffucci syndrome and from those with solitary neoplasms (p less than 0.0001). However, 2 tumors with wildtype sequences from a subject with Maffucci syndrome had high levels of 2HG, and the third tumor with wildtype sequences, from a subject with multiple tumors (subject 2), had low levels of 2HG. Amary et al. (2011) suggested a model in which IDH1 mutations are early post-zygotic events in individuals with these syndromes, implying that the mutations are required for tumorigenesis. Oncology \- Chondrosarcoma \- Ovarian juvenile granulosa cell tumor with precocious pseudopuberty Radiology \- Enchondromata Inheritance \- ? Autosomal dominant form Misc \- Most cases sporadic Skel \- Osteochondromatosis \- Asymmetric tubular bone abnormality Skin \- Hemangiomata (Maffucci type) ▲ 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	ENCHONDROMATOSIS, MULTIPLE, OLLIER TYPE	c0014084	5,716	omim	https://www.omim.org/entry/166000	2019-09-22T16:37:03	{"doid": ["4624"], "mesh": ["D004687"], "omim": ["166000"], "icd-10": ["Q78.4"], "orphanet": ["296"], "synonyms": ["Alternative titles", "OLLIER DISEASE", "OSTEOCHONDROMATOSIS", "DYSCHONDROPLASIA"]}
A number sign (#) is used with this entry because of evidence that Kabuki syndrome-2 (KABUK2) is caused by mutation in the KDM6A gene (300128) on chromosome Xp11. Description Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981). For a discussion of genetic heterogeneity of Kabuki syndrome, see KABUK1 (147920). Clinical Features Lederer et al. (2012) studied 2 girls and a boy with Kabuki syndrome. The 2-year-old boy and 13-year-old girl had a typical Kabuki syndrome phenotype, including long palpebral fissures, lateral eversion of the lower eyelid, and moderate to severe intellectual disability; they also displayed long halluces. The facial features of the 10-year-old girl were not as classic, but she displayed many characteristics of the disorder, including lateral sparseness of the eyebrows, long eyelashes, strabismus, long palpebral fissures, large and prominent ears, persistent fetal fingertip pads, aortic coarctation, areolar fullness in infancy, and hirsutism; she also had mild developmental delay. Diagnosis Adam et al. (2019) reported consensus diagnostic criteria for Kabuki syndrome that were developed by an international group of experts after a systematic review of the literature. The authors proposed that a definitive diagnosis could be made in a patient at any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features at some point of life. Typical dysmorphic features included long palpebral fissures with eversion of the lateral third of the lower eyelid and 2 or more the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent, or cupped ears; and (4) persistent fingertip pads. Criteria for probable and possible diagnoses were also included. Molecular Genetics By array CGH analysis in 2 unrelated Belgian girls with Kabuki syndrome who were negative for mutation in the MLL2 gene (602113), Lederer et al. (2012) identified de novo Xp11.3 microdeletions, both of which contained part or all of the KDM6A gene (300128). In the 13-year-old girl, the deletion included KDM6A exons 21 through 29 and CXORF36 (300959), whereas in the 10-year-old girl, the deletion completely removed KDM6A, CXORF36, DUSP21 (300678) and FUNDC1 (300871). Sequencing of the KDM6A gene and targeted array CGH in a cohort of 22 MLL2-negative Kabuki syndrome patients revealed a de novo intragenic deletion in a 2-year-old Italian boy (300128.0001). Miyake et al. (2013) analyzed the KDM6A gene in 32 patients with Kabuki syndrome who were negative for mutation in the MLL2 gene and identified nonsense mutations in 2 male patients and a 3-bp deletion in a female patient (300128.0002-300128.0004). The 3 mutation-positive patients all had severe developmental delay and intellectual disability, but the female patient had fewer dysmorphic features than the male patients, who displayed a more severe phenotype with multiple organ involvement. Peripheral leukocyte genomic DNA from the female patient showed a random pattern of X inactivation, in a 57:43 ratio. Miyake et al. (2013) suggested that the mutation type as well as X-inactivation pattern in affected organs in females may determine the severity of Kabuki syndrome. Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 4 KDM6A mutations, 3 of which were novel. In 2 brothers with Kabuki syndrome, who were negative for mutation in the MLL2 gene, Lederer et al. (2014) identified a 4-bp deletion in the KDM6A gene (300128.0006). Their mother and maternal grandmother, who also carried the mutation, exhibited attenuated phenotypes. Lederer et al. (2014) reviewed the clinical features of all reported patients with KDM6A mutations and stated that the family reported by them represented the first instance of hereditary X-linked Kabuki syndrome. Van Laarhoven et al. (2015) identified KMT2A mutations in 4 (10%) of 40 patients clinically diagnosed with Kabuki syndrome, including 2 patients with microdeletions that encompassed KDM6A. Genotype/Phenotype Correlations Miyake et al. (2013) screened 81 patients with Kabuki syndrome for mutations in the MLL2 and KDM6A genes and identified KDM6A mutations in 5 (6.2%) and MLL2 mutations in 50 (60.7%). Of the 5 KDM6A mutations, including 2 that were novel, 4 were protein-truncating and 1 was an in-frame deletion in the Jumonji C domain. High-arched eyebrows, short fifth fingers, and infantile hypotonia were less commonly seen in patients with KDM6A mutations than in those with MLL2 mutations. All of the patients with KDM6A mutations had short stature and postnatal growth retardation, compared with only half of the patients with MLL2 mutations. Among the 2 female patients with KDM6A mutations, one with an in-frame deletion (300128.0004) had a random X-inactivation pattern, whereas the other with a frameshift mutation (300128.0005) showed marked skewing. INHERITANCE \- X-linked dominant GROWTH Height \- Less than third centile Weight \- Less than third centile HEAD & NECK Head \- Occipitofrontal circumference less than third centile Ears \- Prominent ears \- Large auricle \- Cupped ears (in some patients) Eyes \- Arched eyebrows \- Sparse lateral eyebrows \- Long palpebral fissure \- Long eyelashes \- Eversion of lateral third of lower eyelid \- Strabismus Nose \- Broad and/or depressed tip of nose \- Short columella Mouth \- High-arched palate \- Cleft palate (rare) Teeth \- Dental malocclusion \- Hypodontia \- Abnormal dentition \- Neonatal teeth (rare) CARDIOVASCULAR Heart \- Congenital heart disease \- Atrial septal defect (in some patients) \- Atrioventricular septal defect (rare) \- Pulmonary valve stenosis (rare) \- Hypoplastic right ventricle (rare) Vascular \- Aortic coarctation (in some patients) CHEST Breasts \- Areolar fullness in infancy ABDOMEN Gastrointestinal \- Feeding difficulties in infancy SKELETAL \- Joint hyperlaxity Hands \- Persistent fetal fingertip pads \- Brachydactyly (in some patients) SKIN, NAILS, & HAIR Hair \- Hirsutism \- Long eyelashes Sparse lateral eyebrows NEUROLOGIC Central Nervous System \- Developmental delay, mild to severe \- Hypotonia \- Seizures Behavioral Psychiatric Manifestations \- Behavioral difficulties METABOLIC FEATURES \- Neonatal hypoglycemia MISCELLANEOUS \- Severity of phenotype may vary with X-inactivation patterns and/or mutation type MOLECULAR BASIS \- Caused by mutation in the lysine (K)-specific demethylase-6A gene (KDM6A, 300128.0001 ) ▲ 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	KABUKI SYNDROME 2	c0796004	5,717	omim	https://www.omim.org/entry/300867	2019-09-22T16:19:20	{"doid": ["0060473"], "mesh": ["C537705"], "omim": ["300867"], "orphanet": ["2322"], "genereviews": ["NBK62111"]}
Not to be confused with Central sleep apnea. Central hypoventilation syndrome Other namesOndine's curse, primary alveolar hypoventilation, alveolar hypoventilation secondary to neurologic disease, idiopathic acquired central hypoventilation syndrome Ondine by John William Waterhouse (1849–1917) SpecialtyNeurology Central hypoventilation syndrome (CHS) is a sleep-related breathing disorder that causes ineffective breathing, apnea, or respiratory arrest during sleep (and during wakefulness in severe cases). CHS can either be congenital (CCHS) or acquired (ACHS) later in life. The condition can be fatal if untreated. CCHS was once known as Ondine's curse. ACHS can develop as a result of severe injury or trauma to the brain or brainstem.[1] Congenital cases are very rare and involve a failure of autonomic control of breathing. In 2006, there were only about 200 known cases worldwide. As of 2008, only 1000 total cases were known.[2] The diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases.[3] However, as there have been cases where asymptomatic family members also were found to have CCHS, it may be that these figures only reflect those found to require mechanical ventilation. In all cases, episodes of apnea occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake. Although rare, cases of long-term untreated CCHS have been reported and are termed late onset CCHS (LO-CCHS).[4] There have, however, even been cases of LO-CCHS where family members found to have it have been asymptomatic.[5] Again, lack of awareness in the medical community may cause such a delay.[6] CCHS susceptibility is not known to be affected by gender.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 History * 7 Etymology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] CHS is associated with respiratory arrests during sleep and, in some cases, to neuroblastoma (tumors of the sympathetic ganglia), Hirschsprung disease (partial agenesis of the enteric nervous system),[7] dysphagia (difficulty swallowing) and anomalies of the pupilla. Other symptoms include darkening of skin color from inadequate amounts of oxygen, drowsiness, fatigue, headaches, and an inability to sleep at night. Patients with CHS also have a sensitivity to sedatives and narcotics, which makes respiration even more difficult. A low concentration of oxygen in the red blood cells also may cause hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension, culminating in cor pulmonale or a failure of the right side of the heart.[8] Associated complications may also include gastro-esophageal reflux, ophthalmologic issues, seizures, recurrent pneumonia, developmental delays, learning disabilities, episodes of fainting, and temperature disregulation.[9] ## Causes[edit] CHS is exhibited typically as a congenital disorder, but in rare circumstances, can also result from severe brain or spinal trauma or injury (such as after an automobile accident, stroke, asphyxiation, brain tumor, encephalitis, poisoning, as a complication of neurosurgery) or due to particular neurodegenerative conditions such as Parkinson's disease, multiple system atrophy, or multiple sclerosis. Long and Allen (1984) were the first to report the abnormal brainstem auditory evoked responses in an alcoholic woman who recovered from Ondine's curse. These investigators hypothesized that their patient's brainstem was poisoned — not destroyed — by her chronic alcoholism.[10] Medical investigation of patients with this syndrome has led to a deeper understanding of how the body and brain regulate breathing on a molecular level. PHOX2B, a transcription factor involved in the development of neurons,[11] can be associated with this condition.[12][13][14][15] This homeobox gene is important for the normal development of the autonomic nervous system.[citation needed] The disease used to be classified as a "neurocristopathy",[16][17] or disease of the neural crest because part of the autonomic nervous system (such as sympathetic ganglia) derives from the neural crest. However, this denomination is no longer favored because essential neurons of the autonomic nervous system, including those that underlie the defining symptom of the disease (respiratory arrests), are derived from the neural tube (the medulla), not from the neural crest, although such mixed embryological origins are also true for most other neurocristopathies.[citation needed] ## Diagnosis[edit] Children with CCHS develop life-threatening episodes of apnea with cyanosis, usually in the first months of life. Medical evaluation excludes lesions of the brain, heart, and lungs but demonstrates impaired responses to build-up of carbon dioxide (hypercapnia) and decreases of oxygen in the circulation (hypoxia), the two strongest stimuli to increase breathing rate.[citation needed] Polysomnography shows that hypoventilation is most marked during slow-wave sleep. In the most severe cases, hypoventilation is present during other nonrapid eye movement sleep stages and even wakefulness. A subset of CCHS patients are at very high risk for developing malignant neural crest-derived tumors, such as neuroblastoma. The sequence of PHOX2B reveals mutations in 91% of the cases.[7] As in many disorders that are very rare, an infant with this unusual form of sleep apnea suffers from the probability that their physician has most likely never seen another case and will not recognize the diagnosis. In some locations, such as France, optimal management of patients, once identified, has been aided by the creation of a national registry and the formation of a network of centers.[citation needed] ## Treatment[edit] People generally require tracheostomy and lifetime mechanical ventilation on a ventilator in order to survive. However, it has now been shown that biphasic cuirass ventilation can effectively be used without the need for a tracheotomy. Other potential treatments for CHS include oxygen therapy and medicine for stimulating the respiratory system. Currently, problems arise with the extended use of ventilators, including fatal infections and pneumonia.[18] ## Prognosis[edit] Most people with CCHS (unless they have the Late Onset form) do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is diaphragm pacing.[19] ## History[edit] CCHS was first described in 1962 by Severinghaus and Mitchell in three patients following surgery to the upper cervical spinal cord and brainstem.[20] ## Etymology[edit] Its name is a reference to the story of Ondine and Hans, characters in Ondine, a 1938 play by Jean Giraudoux based on traditions tracing back through Undine (a novella of 1811) to earlier European folk tales. The water-spirit Ondine tells her future husband Hans, whom she had just met, that "I shall be the shoes of your feet ... I shall be the breath of your lungs". Ondine makes a pact with her uncle the King of the Ondines that if Hans ever deceives her he will die. After their honeymoon, Hans is reunited with his first love Princess Bertha and Ondine leaves Hans only to be captured by a fisherman six months later. On meeting Ondine again on the day of his wedding to Bertha, Hans tells her that "all the things my body once did by itself, it does now only by special order ... A single moment of inattention and I forget to breathe". Hans and Ondine kiss, after which he dies. ## See also[edit] * Medicine portal * Our Curse, an Oscar-nominated 2013 short documentary film about a child with Ondine's curse ## References[edit] 1. ^ Jazeela Fayyaz, DO (2017-12-05). Zab Mosenifar, M (ed.). "Hypoventilation Syndromes". Medscape. 2. ^ "Congenital central hypoventilation syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 5 June 2015. 3. ^ a b Congenital Central Hypoventilation Syndrome at eMedicine 4. ^ Windisch W, Hennings E, Storre J, Matthys H, Sorichter S (2004). "Long-term survival of a patient with congenital central hypoventilation syndrome despite the lack of continuous ventilatory support". Respiration. 71 (2): 195–8. doi:10.1159/000076685. PMID 15031579. 5. ^ Bygarski, Elizabeth; Paterson, Melanie; Lemire, Edmond G. (April 26, 2013). "Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series". Journal of Medical Case Reports. 7 (1): 117. doi:10.1186/1752-1947-7-117. PMC 3651317. PMID 23622117. 6. ^ Lovell BL, Bullock RE, Anderson KN (March 2010). "An unusual presentation of congenital central hypoventilation syndrome (Ondine's Curse)". Emerg Med J. 27 (3): 237–8. doi:10.1136/emj.2009.072215. PMID 20304901. 7. ^ a b Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C (2005). "The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype". Chest. 127 (1): 72–9. doi:10.1378/chest.127.1.72. PMID 15653965. 8. ^ "Primary alveolar hypoventilation: Ondine's curse". A.D.A.M. Medical Encyclopedia. U.S. National Library of Medicine. September 17, 2010. 9. ^ "CCHS Family Network". 10. ^ Long, K. J.; Allen, N. (October 1984). "Abnormal brain-stem auditory evoked potentials following Ondine's curse". Arch. Neurol. 41 (10): 1109–10. doi:10.1001/archneur.1984.04050210111028. PMID 6477223. 11. ^ Longo, Dan L. (2012). "Chapter 264. Disorders of Ventilation". Harrison's principles of internal medicine (18th ed.). New York: McGraw-Hill. ISBN 9780071748896. 12. ^ Gaultier C; Amiel J; Dauger S; et al. (2004). "Genetics and early disturbances of breathing control". Pediatr. Res. 55 (5): 729–33. doi:10.1203/01.PDR.0000115677.78759.C5. PMID 14739359. 13. ^ Gaultier C, Trang H, Dauger S, Gallego J (2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatr. Res. 58 (1): 1–6. doi:10.1203/01.PDR.0000166755.29277.C4. PMID 15901893. 14. ^ Todd ES, Weinberg SM, Berry-Kravis EM, et al. (2006). "Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology". Pediatr. Res. 59 (1): 39–45. doi:10.1203/01.pdr.0000191814.73340.1d. PMID 16327002. 15. ^ "Gene secret of 'mythical curse'". BBC News. 5 May 2003. (The article misspells PHOX2B as "Thox2b".) 16. ^ Kincaid PK, Dietrich RB, Pais MJ (1994). "Pediatric case of the day. Neurocristopathy (Ondine-Hirschsprung syndrome)". Radiographics. 14 (5): 1139–43. doi:10.1148/radiographics.14.5.7991820. PMID 7991820. 17. ^ Poceta, J. S.; Strandjord, T. P.; Badura, R. J.; Milstein, J. M. (1987). "Undine curse and neurocristopathy". Pediatr. Neurol. 3 (6): 370–2. doi:10.1016/0887-8994(87)90011-7. PMID 3508086. 18. ^ "Death by Nap: Boy Risks Death if He Nods off". 2010-08-17. 19. ^ Takeda, S.; Fujii, Y.; Kawahara, H.; Nakahara, K.; Matsuda H. (1996). "Central alveolar hypoventilation syndrome (Undine's curse) with gastroesophageal reflux". Chest. 110 (3): 850–852. doi:10.1378/chest.110.3.850. PMID 8797441. 20. ^ Severinghaus J.W.; Mitchell, R. A. (1962). "Undine's curse — failure of respiratory center automaticity while awake". Clin Res. 10: 122. ## External links[edit] Classification D * ICD-10: G47.35 * ICD-9-CM: 327.25 * OMIM: 209880 * MeSH: D020182 * DiseasesDB: 32976 External resources * MedlinePlus: 000078 * eMedicine: article/1002927 * GeneReviews: Congenital central hypoventilation syndrome * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring [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	Central hypoventilation syndrome	c1859049	5,718	wikipedia	https://en.wikipedia.org/wiki/Central_hypoventilation_syndrome	2021-01-18T18:28:53	{"gard": ["8535"], "mesh": ["C536209"], "icd-9": ["348.8"], "orphanet": ["99803", "661"], "wikidata": ["Q979129"]}
For a phenotypic description and a discussion of genetic heterogeneity of familial abdominal aortic aneurysm, see AAA1 (100070). Mapping Shibamura et al. (2004) performed a whole-genome scan of AAA using affected relative-pair (ARP) linkage analysis that included covariates to allow for genetic heterogeneity. They identified a region on chromosome 4 with a lod score of 3.73 (P = 0.0012) near marker D4S1644 (4q31) when including sex and the number of affected first-degree relatives of the proband as covariates. [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	AORTIC ANEURYSM, FAMILIAL ABDOMINAL, 2	c1853364	5,719	omim	https://www.omim.org/entry/609782	2019-09-22T16:05:40	{"doid": ["7693"], "mesh": ["C565229"], "omim": ["609782", "100070"], "orphanet": ["86"], "synonyms": []}
Acute intermittent porphyria Other namesSwedish porphyria, pyrroloporphyria, intermittent acute porphyria Porphobilinogen SpecialtyMedical genetics Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the porphobilinogen deaminase. It is the most common of the acute porphyrias.[1][2][3] ## Contents * 1 Signs and symptoms * 1.1 Acute attacks * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Society * 6 References * 7 External links ## Signs and symptoms[edit] The clinical presentation of AIP is highly variable and non-specific. The patients are typically asymptomatic, with most gene carriers having no family history because the condition had remained latent for several generations. The syndrome marked by acute attacks affects only 10% of gene carriers.[4] The mean age at diagnosis is 33 years old.[5] Like other porphyrias, AIP is more likely to present in women.[6] A distinguishing feature of AIP that separates it from other porphyrias is the absence of photosensitive cutaneous symptoms that occur in addition to acute attacks.[7] ### Acute attacks[edit] AIP is one of the four porphyrias that presents as an acute attack. 90% of affected individuals never experience an acute attack and are asymptomatic, while an estimated 5% of affected individuals experience repeat attacks.[8] Attacks are most common in young adult women and are rare before puberty or after menopause.[9] Severe acute attacks may require hospitalization. Patients usually experience symptoms in attacks that last from several hours to a few days. Between attacks, patients are asymptomatic. The most frequent presenting symptoms are abdominal pain and tachycardia.[10] The abdominal pain is typically severe, colicky, poorly localized, and often associated with pain in back and legs.[11][12] Patients may also present with vomiting and constipation, but diarrhea is unusual.[13] The onset of back and leg pain is characterized by severe pain and stiffness in back and thighs followed by loss of tendon reflexes and paralysis.[14] Psychiatric symptoms are present, such as paranoid schizophrenia-like features but rarely psychosis and hallucinations.[15] The acute attacks classically present with dark-red photosensitive urine (often called port-wine urine), but this is a nonspecific symptom.[16] Physical examination often shows no abnormalities.[17] Hyponatremia is the most common electrolyte abnormality during acute attacks, occurring in 40% of patients and presenting as SIADH.[18] Hypomagnesemia is also common. There are no pathognomonic signs or symptoms. The most common identified triggers for acute attacks are medications, weight loss diets, and surgery.[19] Many medications have been associated with AIP including antibiotics, hormonal contraceptives, seizure medications, anesthetics, and HIV treatment drugs.[20] ## Pathophysiology[edit] Porphyrias are caused by mutations in genes that encode enzymes in heme synthesis. In normal physiology, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. Heme is produced in all cells, but 80% of all heme is produced in erythropoietic cells in bone marrow and 15% in parenchymal cells in the liver, where turnover of hemoproteins is high. In AIP, over 100 mutations have been identified on the long arm of chromosome 11 at the HMBS gene, which codes for the cytoplasmic enzyme porphobilinogen deaminase.[21] This deficiency prevents heme synthesis, which can not be completed and the metabolite porphobilinogen accumulates in the cytoplasm.[22] AIP is an autosomal dominant porphyria resulting in about 50% normal activity of the affected enzyme.[23] The penetrance of AIP is incomplete with only 10% of gene carriers experiencing acute attacks suggesting role for other modifying genes or environment.[24][25][26] The exact mechanism of acute attacks is not clear. The most favored hypothesis is that porpholobilinogen buildup causes a toxic effects on neurons. The autonomic and peripheral nervous system are more vulnerable than the central nervous system because they are not protected by the blood-brain barrier.[27] This explains findings such as abdominal pain and tachycardia. Some individuals may be more likely to develop paresis based on increased susceptibility of neurons to toxins.[28] ## Diagnosis[edit] The initial diagnosis of acute porphyria is confirmed by urinalysis, including the common method, the Watson-Schwartz test. Elevated urine porphobilinogen confirms diagnosis of AIP, hereditary coproporphyria (HCP), or variegate porphyria (VP). A positive test should be indicated with an increase of five times normal, not just a slight increase which can occur with dehydration. To distinguish between AIP from HCP and VP, fecal porphyrin levels are normal in AIP but elevated in HCP and VP. Rapid, accurate diagnosis is important. Delays in diagnosis may result in permanent neurological damage or death. ## Treatment[edit] If drugs have caused the attack, discontinuing the offending substances is essential. A high-carbohydrate (10% glucose) infusion is recommended, which may aid in recovery.[citation needed] Hemin(Hematin) Hematin and heme arginate is the treatment of choice during an acute attack. Heme is not a curative treatment, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious.[citation needed] Pain is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible due to its severity. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.[29] Seizures often accompany this disease. Most seizure medications exacerbate this condition due to their induction of cytochrome P450. Treatment can be problematic: Barbiturates and primidone must be avoided as they commonly precipitate symptoms.[30] Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control.[citation needed] ## Society[edit] One of the many hypothesized diagnoses of the artist Vincent van Gogh is that he and his siblings, in particular his brother Theo, suffered from AIP and syphilis.[31] Another theorized sufferer was King George III of the United Kingdom[32] who even had a medallion struck to commemorate his "curing". His descendant Prince William of Gloucester was reliably diagnosed with variegate porphyria in 1968.[33] It is probable that the philosopher Jean-Jacques Rousseau suffered from porphyria.[34][35][36][37] It has even been suggested that Vlad III, Prince of Wallachia, more commonly known by his surname Dracula, suffered from porphyria. ## References[edit] 1. ^ Whatley SD, Roberts AG, Llewellyn DH, Bennett CP, Garrett C, Elder GH (September 2000). "Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene". Human Genetics. 107 (3): 243–8. doi:10.1007/s004390000356. PMID 11071386. 2. ^ Solis C, Martinez-Bermejo A, Naidich TP, Kaufmann WE, Astrin KH, Bishop DF, Desnick RJ (November 2004). "Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias". Archives of Neurology. 61 (11): 1764–70. doi:10.1001/archneur.61.11.1764. PMID 15534187. 3. ^ Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias at eMedicine 4. ^ Narang, Neatu; Banerjee, A; Kotwal, J; Kaur, Jasmeet; Sharma, YV; Sharma, CS (April 2003). "Psychiatric Manifestations in three cases of Acute Intermittent Porphyria". Medical Journal, Armed Forces India. 59 (2): 171–173. doi:10.1016/S0377-1237(03)80075-8. ISSN 0377-1237. PMC 4923792. PMID 27407502. 5. ^ Elder, George; Harper, Pauline; Badminton, Michael; Sandberg, Sverre; Deybach, Jean-Charles (September 2013). "The incidence of inherited porphyrias in Europe". Journal of Inherited Metabolic Disease. 36 (5): 849–857. doi:10.1007/s10545-012-9544-4. ISSN 1573-2665. PMID 23114748. 6. ^ Puy, Hervé; Gouya, Laurent; Deybach, Jean-Charles (2010-03-13). "Porphyrias". Lancet. 375 (9718): 924–937. doi:10.1016/S0140-6736(09)61925-5. ISSN 1474-547X. PMID 20226990. 7. ^ Stein, Penelope; Badminton, Mike; Barth, Julian; Rees, David; Stewart, M. Felicity; British and Irish Porphyria Network (May 2013). "Best practice guidelines on clinical management of acute attacks of porphyria and their complications". Annals of Clinical Biochemistry. 50 (Pt 3): 217–223. doi:10.1177/0004563212474555. ISSN 1758-1001. PMID 23605132. 8. ^ Elder, George; Harper, Pauline; Badminton, Michael; Sandberg, Sverre; Deybach, Jean-Charles (2012-11-01). "The incidence of inherited porphyrias in Europe". Journal of Inherited Metabolic Disease. 36 (5): 849–857. doi:10.1007/s10545-012-9544-4. ISSN 0141-8955. PMID 23114748. 9. ^ Besur, Siddesh; Hou, Wehong; Schmeltzer, Paul; Bonkovsky, Herbert L. (2014-11-03). "Clinically important features of porphyrin and heme metabolism and the porphyrias". Metabolites. 4 (4): 977–1006. doi:10.3390/metabo4040977. ISSN 2218-1989. PMC 4279155. PMID 25372274. 10. ^ Besur, Siddesh; Schmeltzer, Paul; Bonkovsky, Herbert L. (September 2015). "Acute Porphyrias". The Journal of Emergency Medicine. 49 (3): 305–312. doi:10.1016/j.jemermed.2015.04.034. ISSN 0736-4679. PMID 26159905. 11. ^ Besur, Siddesh; Schmeltzer, Paul; Bonkovsky, Herbert L. (September 2015). "Acute Porphyrias". The Journal of Emergency Medicine. 49 (3): 305–312. doi:10.1016/j.jemermed.2015.04.034. ISSN 0736-4679. PMID 26159905. 12. ^ Kauppinen, Raili (15–21 Jan 2005). "Porphyrias". Lancet. 365 (9455): 241–252. doi:10.1016/s0140-6736(05)70154-9. ISSN 1474-547X. PMID 15652607. 13. ^ Kauppinen, Raili (15–21 Jan 2005). "Porphyrias". Lancet. 365 (9455): 241–252. doi:10.1016/s0140-6736(05)70154-9. ISSN 1474-547X. PMID 15652607. 14. ^ Pischik, E.; Kauppinen, R. (2009-02-16). "Neurological manifestations of acute intermittent porphyria". Cellular and Molecular Biology (Noisy-Le-Grand, France). 55 (1): 72–83. ISSN 1165-158X. PMID 19268005. 15. ^ Narang, Neatu; Banerjee, A; Kotwal, J; Kaur, Jasmeet; Sharma, YV; Sharma, CS (April 2003). "Psychiatric Manifestations in three cases of Acute Intermittent Porphyria". Medical Journal, Armed Forces India. 59 (2): 171–173. doi:10.1016/S0377-1237(03)80075-8. ISSN 0377-1237. PMC 4923792. PMID 27407502. 16. ^ Yuan, Tao; Li, Yu-Hui; Wang, Xi; Gong, Feng-Ying; Wu, Xue-Yan; Fu, Yong; Zhao, Wei-Gang (2015-07-20). "Acute Intermittent Porphyria: A Diagnostic Challenge for Endocrinologist". Chinese Medical Journal. 128 (14): 1980–1981. doi:10.4103/0366-6999.160621. ISSN 0366-6999. PMC 4717930. PMID 26168842. 17. ^ Karim, Zoubida; Lyoumi, Said; Nicolas, Gael; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé (September 2015). "Porphyrias: A 2015 update". Clinics and Research in Hepatology and Gastroenterology. 39 (4): 412–425. doi:10.1016/j.clinre.2015.05.009. ISSN 2210-7401. PMID 26142871. 18. ^ Karim, Zoubida; Lyoumi, Said; Nicolas, Gael; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé (September 2015). "Porphyrias: A 2015 update". Clinics and Research in Hepatology and Gastroenterology. 39 (4): 412–425. doi:10.1016/j.clinre.2015.05.009. ISSN 2210-741X. PMID 26142871. 19. ^ Bonkovsky, Herbert L.; Maddukuri, Vinaya C.; Yazici, Cemal; Anderson, Karl E.; Bissell, D. Montgomery; Bloomer, Joseph R.; Phillips, John D.; Naik, Hetanshi; Peter, Inga (December 2014). "Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium". The American Journal of Medicine. 127 (12): 1233–1241. doi:10.1016/j.amjmed.2014.06.036. ISSN 1555-7162. PMC 4563803. PMID 25016127. 20. ^ Dhital, Rashmi; Basnet, Sijan; Poudel, Dilli Ram; Bhusal, Khema Raj (2017-06-06). "Acute intermittent porphyria: a test of clinical acumen". Journal of Community Hospital Internal Medicine Perspectives. 7 (2): 100–102. doi:10.1080/20009666.2017.1317535. ISSN 2000-9666. PMC 5473191. PMID 28638573. 21. ^ Herrick, Ariane L.; McColl, Kenneth E. L. (April 2005). "Acute intermittent porphyria". Best Practice & Research. Clinical Gastroenterology. 19 (2): 235–249. doi:10.1016/j.bpg.2004.10.006. ISSN 1521-6918. PMID 15833690. 22. ^ Kauppinen, R.; Mustajoki, S.; Pihlaja, H.; Peltonen, L.; Mustajoki, P. (1995). "Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene". Human Molecular Genetics. 4 (2): 215–222. doi:10.1093/hmg/4.2.215. ISSN 0964-6906. PMID 7757070. 23. ^ Whatley, Sharon D.; Badminton, Michael N. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Acute Intermittent Porphyria", GeneReviews®, University of Washington, Seattle, PMID 20301372, retrieved 2018-11-01 24. ^ Aarsand AK, Petersen PH, Sandberg S (April 2006). "Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria". Clinical Chemistry. 52 (4): 650–6. doi:10.1373/clinchem.2005.060772. PMID 16595824. 25. ^ Lannfelt L, Wetterberg L, Gellerfors P, Lilius L, Floderus Y, Thunell S (November 1989). "Mutations in acute intermittent porphyria detected by ELISA measurement of porphobilinogen deaminase". Journal of Clinical Chemistry and Clinical Biochemistry. 27 (11): 857–62. CiteSeerX 10.1.1.634.1622. doi:10.1515/cclm.1989.27.11.857. PMID 2607315. 26. ^ Pischik E, Kauppinen R (2015). "An update of clinical management of acute intermittent porphyria". The Application of Clinical Genetics. 8: 201–14. doi:10.2147/TACG.S48605. PMC 4562648. PMID 26366103. 27. ^ Laiwah, A C; Goldberg, A; Moore, M R (May 1983). "Pathogenesis and treatment of acute intermittent porphyria: discussion paper". Journal of the Royal Society of Medicine. 76 (5): 386–392. doi:10.1177/014107688307600512. ISSN 0141-0768. PMC 1439174. PMID 6864706. 28. ^ Chen, Brenden; Solis-Villa, Constanza; Hakenberg, Jörg; Qiao, Wanqiong; Srinivasan, Ramakrishnan R.; Yasuda, Makiko; Balwani, Manisha; Doheny, Dana; Peter, Inga (November 2016). "Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease". Human Mutation. 37 (11): 1215–1222. doi:10.1002/humu.23067. ISSN 1059-7794. PMC 5063710. PMID 27539938. 29. ^ American Porphyria Foundation. "About Porphyria: Acute Intermittent Porhyria" Archived April 25, 2008, at the Wayback Machine, 2007, 30. ^ Marcucci L (2004). PathCards. Baltimore, MD: Lippincott Willians & Wilkins. pp. 105–106. ISBN 978-0-7817-4399-0. 31. ^ Arnold WN (1992). Vincent van Gogh : chemicals, crises, and creativity. Boston: Birkhäuser. ISBN 978-0-8176-3616-6.[page needed] 32. ^ Macalpine I, Hunter R (January 1966). "The "insanity" of King George 3d: a classic case of porphyria". British Medical Journal. 1 (5479): 65–71. doi:10.1136/bmj.1.5479.65. PMC 1843211. PMID 5323262. 33. ^ Röhl JC, Warren M, Hunt D (1998). Purple secret : genes, 'madness' and the royal houses of Europe. London: Corgi Books. ISBN 978-0-552-14550-3.[page needed] 34. ^ Bartolo A (1995). "Le maschere dell'io: Rousseau e la menzogna autobiografica" [The ego masks: Rousseau and the autobiographical lie]. Schena (in Italian): 113. 35. ^ "Jean-Jacques Rousseau l'errante" [Jean-Jacques Rousseau the wanderer]. La Letteratura e Noi - diretto da Romano Luperini (in Italian). Retrieved 18 November 2015. 36. ^ Mejía-Rivera O (8 June 2012). "Las enfermedades de Jean-Jacques Rousseau" [The diseases of Jean-Jacques Rousseau]. Revista Aleph (in Spanish). Retrieved 18 November 2015. 37. ^ Androutsos G, Geroulanos S (December 2000). "[Acute intermittent porphyria: a new hypothesis to explain Jean-Jacques Rousseau's urinary disorders]". Progres en Urologie. 10 (6): 1282–9. PMID 11217576. ## External links[edit] Classification D ICD-10: E80.2 * ICD-9-CM: 277.1 * OMIM: 176000 * MeSH: D017118 * DiseasesDB: 171 External resources * eMedicine: med/1880 * GeneReviews: Hydroxymethylbilane Synthase (HMBS) Deficiency * v * t * e Heme metabolism disorders Porphyria, hepatic and erythropoietic (porphyrin) early mitochondrial: * ALAD porphyria * Acute intermittent porphyria cytoplasmic: * Gunther disease/congenital erythropoietic porphyria * Porphyria cutanea tarda/Hepatoerythropoietic porphyria late mitochondrial: * Hereditary coproporphyria * Harderoporphyria * Variegate porphyria * Erythropoietic protoporphyria Hereditary hyperbilirubinemia (bilirubin) unconjugated: * Gilbert's syndrome * Crigler–Najjar syndrome * Lucey–Driscoll syndrome conjugated: * Dubin–Johnson syndrome nd sheet * Rotor syndrome [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	Acute intermittent porphyria	c0162565	5,720	wikipedia	https://en.wikipedia.org/wiki/Acute_intermittent_porphyria	2021-01-18T18:31:30	{"gard": ["5732"], "mesh": ["D017118"], "umls": ["C0162565"], "icd-9": ["277.1"], "icd-10": ["E80.2"], "orphanet": ["79276"], "wikidata": ["Q424247"]}
A number sign (#) is used with this entry because hypomaturation-type amelogenesis imperfecta IIA5 (AI2A5) is caused by homozygous mutation in the SLC24A4 gene (609840) on chromosome 14q32. Description Autosomal recessive amelogenesis imperfecta of the pigmented hypomaturation type is characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989). Clinical Features Parry et al. (2013) described 2 consanguineous Pakistani families with autosomal recessive amelogenesis imperfecta. In family AI-112, the 3 affected individuals had yellow-brown enamel that showed increased opacity. The enamel volume was within normal limits in all teeth, with normal crown morphology and cusp patterns. The 2 affected cousins in family AI-131 showed a similar phenotype leading to premature enamel loss. Wang et al. (2014) described a 5.5-year-old Turkish girl, born of first-cousin parents, who had soft, creamy yellow enamel that tended to chip. Extensive caries were observed. The enamel of erupting first molars exhibited normal thickness but showed no contrast with underlying dentin, indicating enamel maturation defects. Molecular Genetics By homozygosity mapping followed by whole-exome sequencing, Parry et al. (2013) identified a homozygous mutation in the SLC24A4 gene (R339X; 609840.0002) in affected members of a consanguineous Pakistani family (AI-112) with amelogenesis imperfecta. By Sanger sequencing of the coding regions and intron-exon boundaries of SLC24A4 in 37 individuals with AI from diverse ethnic backgrounds, they identified a different homozygous mutation (S499C; 609840.0003) in affected members of another consanguineous Pakistani family (AI-131). The mutations segregated with the phenotype in the families, and the heterozygous carriers had teeth with a normal appearance. In a Turkish girl with AI, Wang et al. (2014) identified a homozygous mutation in the SLC24A4 gene (A146V; 609840.0004). Animal Model Parry et al. (2013) examined teeth from 6-month-old Slc24a4 knockout mice and observed gross enamel defects when compared with wildtype mice. The enamel in the knock-out mice was present near the cervical margin where the tooth erupts from the mandibular bone, but the enamel was missing from the remainder of the tooth. By scanning electron microscopy, Parry et al. (2013) observed that the affected enamel was irregular and poorly mineralized compared to wildtype enamel. INHERITANCE \- Autosomal recessive HEAD & NECK Teeth \- Amelogenesis imperfecta \- Soft enamel \- Discolored enamel (yellow-brown) \- Normal enamel volume \- Premature loss of enamel \- Caries \- No contrast between enamel and dentin on radiographs MOLECULAR BASIS \- Caused by mutation in the solute carrier family 24 (sodium/potassium/calcium exchanger), member 4 gene (SLC24A4, 609840.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	AMELOGENESIS IMPERFECTA, HYPOMATURATION TYPE, IIA5	c0399372	5,721	omim	https://www.omim.org/entry/615887	2019-09-22T15:50:43	{"doid": ["0110063"], "mesh": ["C536606"], "omim": ["615887"], "orphanet": ["100033", "88661"]}
## Clinical Features Bixler et al. (1969) described 2 sisters who had hypertelorism, microtia, and clefting of the lip, palate, and nose. In addition, they showed psychomotor retardation, atretic auditory canals, conductive hearing loss, mild micrognathia, microcephaly, thenar hypoplasia, and ectopic kidneys. Both had congenital heart malformations, as did several relatives on the mother's side. The parents were normal and unrelated. Schweckendiek et al. (1976) described identical male twins with HMC syndrome. Baraitser (1982) described a 1-month-old male infant with unilateral left-sided cleft lip, a cleft palate, gross hypertelorism, narrow palpebral fissures and a broad bifid nose. Both pinnae were malformed and the external meatus were stenosed. There was no cardiac murmur, and the renal tract appeared normal. Amiel et al. (2001) reported 2 additional unrelated cases of hypertelorism, microtia, and facial clefting syndrome. Both patients were males of normal intelligence. GU \- Ectopic kidney Neuro \- Psychomotor retardation Inheritance \- Autosomal recessive Limbs \- Thenar hypoplasia \- Syndactyly, toes 2 and 3 \- Short fifth finger Skel \- Vertebral anomalies Ears \- Microtia \- Atretic auditory canals \- Conductive deafness Head \- Microcephaly Facies \- Facial cleft \- Mild micrognathia \- Cleft nose \- Broad nasal tip Eyes \- Hypertelorism Mouth \- Microstomia \- Cleft lip \- Cleft palate Cardiac \- Congenital heart defect ▲ 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	HYPERTELORISM, MICROTIA, FACIAL CLEFTING SYNDROME	c0220742	5,722	omim	https://www.omim.org/entry/239800	2019-09-22T16:26:46	{"doid": ["14670"], "mesh": ["C537632"], "omim": ["239800"], "orphanet": ["2213"], "synonyms": ["Alternative titles", "HMC SYNDROME"]}
X-linked myotubular myopathy Other namesXLMTM This condition is inherited in an X-linked recessive manner. X-linked myotubular myopathy (MTM) is a form of centronuclear myopathy (CNM) associated with myotubularin 1. Genetically inherited traits and conditions are often referred to based upon whether they are located on the "sex chromosomes" (the X or Y chromosomes) versus whether they are located on "autosomal" chromosomes (chromosomes other than the X or Y). Thus, genetically inherited conditions are categorized as being sex-linked (e.g., X-linked) or autosomal. Females have two X-chromosomes, while males only have a single X chromosome, and a genetic abnormality located on the X chromosome is much more likely to cause clinical disease in a male (who lacks the possibility of having the normal gene present on any other chromosome) than in a female (who is able to compensate for the one abnormal X chromosome). The X-linked form of MTM is the most commonly diagnosed type. Almost all cases of X-linked MTM occurs in males. Females can be "carriers" for an X-linked genetic abnormality, but usually they will not be clinically affected themselves. Two exceptions for a female with a X-linked recessive abnormality to have clinical symptoms: one is a manifesting carrier and the other is X-inactivation. A manifesting carrier usually has no noticeable problems at birth; symptoms show up later in life. In X-inactivation, the female (who would otherwise be a carrier, without any symptoms), actually presents with full-blown X-linked MTM. Thus, she congenitally presents (is born with) MTM.[1] Thus, although MTM1 mutations most commonly cause problems in boys, these mutations can also cause clinical myopathy in girls, for the reasons noted above. Girls with myopathy and a muscle biopsy showing a centronuclear pattern should be tested for MTM1 mutations.[1] ## Contents * 1 Presentation * 2 Genetics * 3 Research * 4 References * 5 External links ## Presentation[edit] This condition is found almost always in male infants. It is one of the severest congenital muscle diseases and is characterized by marked muscle weakness, hypotonia and feeding and breathing difficulties.[citation needed] ## Genetics[edit] This condition is caused by mutations in the myotubularin (MTM1) gene which is located on the long arm of the X chromosome (Xq28). Many clinicians and researchers use the abbreviations XL-MTM, XLMTM or X-MTM to emphasize that the genetic abnormality for myotubular myopathy (MTM) is X-linked (XL), having been identified as occurring on the X chromosome. The specific gene on the X chromosome is referred to as MTM-1. In theory, some cases of CNM may be caused by an abnormality on the X chromosome, but located at a different site from the gene MTM1, but currently MTM1 is the only X-linked genetic mutation site identified for myotubular or centronuclear myopathy. Clinical suspicion for X-linked inheritance would be a disease affecting multiple boys (but no girls) and a pedigree chart showing inheritance only through the maternal (mother’s) side of each generation.[citation needed] ## Research[edit] Audentes Therapeutics is developing an experimental gene therapy to treat the condition. A clinical trial was halted in 2020 after two boys participating in the trial died of liver inflammation and sepsis.[2] ## References[edit] 1. ^ a b Jungbluth H, Sewry C, Buj-Bello A, Kristiansen M, Ørstavik K, Kelsey A, Manzur A, Mercuri E, Wallgren-Pettersson C, Muntoni F (2003). "Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation". Neuromuscul Disord. 13 (1): 55–9. doi:10.1016/S0960-8966(02)00194-3. PMID 12467733. S2CID 11161762. 2. ^ Anonymous (2020). "Two boys die in gene therapy trial". Science. 369 (6499): 13. ## External links[edit] * GeneReview/NCBI/NIH/UW entry on X-Linked Myotubular Myopathy Classification D * ICD-10: G71.2 * OMIM: 310400 * MeSH: C538647 External resources * Orphanet: 596 * v * t * e Diseases of muscle, neuromuscular junction, and neuromuscular disease Neuromuscular- junction disease * autoimmune * Myasthenia gravis * Lambert–Eaton myasthenic syndrome * Neuromyotonia Myopathy Muscular dystrophy (DAPC) AD * Limb-girdle muscular dystrophy 1 * Oculopharyngeal * Facioscapulohumeral * Myotonic * Distal (most) AR * Calpainopathy * Limb-girdle muscular dystrophy 2 * Congenital * Fukuyama * Ullrich * Walker–Warburg XR * dystrophin * Becker's * Duchenne * Emery–Dreifuss Other structural * collagen disease * Bethlem myopathy * PTP disease * X-linked MTM * adaptor protein disease * BIN1-linked centronuclear myopathy * cytoskeleton disease * Nemaline myopathy * Zaspopathy Channelopathy Myotonia * Myotonia congenita * Thomsen disease * Neuromyotonia/Isaacs syndrome * Paramyotonia congenita Periodic paralysis * Hypokalemic * Thyrotoxic * Hyperkalemic Other * Central core disease Mitochondrial myopathy * MELAS * MERRF * KSS * PEO General * Inflammatory myopathy * Congenital myopathy * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and 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	X-linked myotubular myopathy	c0410203	5,723	wikipedia	https://en.wikipedia.org/wiki/X-linked_myotubular_myopathy	2021-01-18T18:32:14	{"gard": ["11925"], "mesh": ["C538647", "D020914"], "orphanet": ["596"], "wikidata": ["Q3331454"]}
This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (April 2016) Vocal Cord Dysfunction Other namesParadoxical Vocal Fold Motion (PVFM) or Paradoxical Vocal Cord Movement (PVCM) SpecialtyOtorhinolaryngology Vocal cord dysfunction (VCD), is a pathology affecting the vocal folds (commonly referred to as the vocal cords)[1] characterized by full or partial vocal fold closure causing difficulty and distress during respiration, especially during inhalation.[1] Due to the similarity in symptoms, VCD attack are often mistaken for asthma attacks or laryngospasms. Symptoms of VCD are not always present.[2] Rather, they often occur episodically, often defined as "attacks," where the sufferer will be symptomatic for a short period of time.[1] Although several contributing factors have been identified, the exact cause of VCD is unknown.[3] Diagnosis of VCD may include a series of evaluations including pulmonary function tests, medical imaging, and the evaluation or visualization of the vocal folds during an episode through the use of videolaryngoscopy.[3] Such evaluations can also help to rule out other conditions that can affect the upper and lower airway.[3] Treatment of VCD often combines behavioural, medical and psychological approaches, most often including an otolaryngologist, a psychologist, and a Speech-Language Pathologist.[1] Although information on the incidence and prevalence of VCD is limited, it is known to occur most frequently in young women.[4] ## Contents * 1 Signs and symptoms * 1.1 Presentation * 1.2 Potential comorbidities * 2 Causes * 3 Risk factors * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatments * 5.1 Behavioral approaches * 5.2 Medical approaches * 5.3 Psychological approaches * 6 Prognosis * 7 Epidemiology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Many of the symptoms are not limited to the disorder, as they may resemble a number of conditions that affect the upper and lower airway. Such conditions include asthma, angioedema, vocal cord tumors, and vocal cord paralysis.[5][6][7][8] People with vocal cord dysfunction often complain of "difficulty in breathing in” or “fighting for breath”,[6] which can lead to subjective respiratory distress,[5] and in severe cases, loss of consciousness.[4] They may report tightness in the throat or chest, choking, stridor on inhalation and wheezing, which can resemble the symptoms of asthma.[5][6][7] These episodes of dyspnea can be recurrent and symptoms can range from mild to severe and prolonged in some cases.[5] Agitation and a sense of panic are not uncommon and can result in hospitalization.[6] Different subtypes of vocal cord dysfunction are characterized by additional symptoms. For instance, momentary aphonia can be caused by laryngospasm, an involuntary spasm of the vocal cords[5] and a strained or hoarse voice may be perceived when the vocal cord dysfunction occurs during speech.[5] Many of the symptoms are not specific to vocal cord dysfunction and can resemble a number of conditions that affect the upper and lower airway. ### Presentation[edit] Open vocal cords as seen during normal inhalation Closed vocal cords as seen during a VCD episode (or when speaking) VCD can mimic asthma, anaphylaxis, collapsed lungs, pulmonary embolism, or fat embolism, which can lead to an inaccurate diagnosis and inappropriate, potentially harmful, treatment.[9] Some incidences of VCD are misdiagnosed as asthma, but are unresponsive to asthma therapy, including bronchodilators and steroids.[citation needed] Among adult patients, women tend to be diagnosed more often.[10] Among children and teenage patients, VCD has been linked with high participation in competitive sports and family orientation towards high achievement.[citation needed] Vocal cord dysfunction co-occurs with asthma approximately 40% of the time.[11] This frequently results in a misdiagnosis of asthma alone. Even young children can tell the difference between an asthma attack (primarily difficulty exhaling) and a VCD attack (primarily difficulty inhaling).[citation needed] Knowing the difference between the two will help those who have both know when to use the rescue inhaler prescribed or when to use the breathing recovery exercises trained by a speech-language pathologist.[citation needed] Episodes can be triggered suddenly or develop gradually and triggers are numerous. Primary causes are believed to be gastroesophageal reflux disease (GERD), extra-esophageal reflux (EERD), exposure to inhaled allergens, post-nasal drip, exercise, or neurological conditions that can cause difficulty inhaling only during waking.[11] Published studies emphasize anxiety or stress as a primary cause while more recent literature indicates a likely physical etiology.[citation needed] This disorder has been observed from infancy through old age, with the observation of its occurrence in infants leading some to believe that a physiological cause such as reflux or allergy is likely. Certain medications, such as antihistamines for allergies, cause drying of the mucous membranes, which can cause further irritation or hypersensitivity of the vocal cords.[citation needed] ### Potential comorbidities[edit] VCD has long been strongly associated with a variety of psychological or psychogenic factors, including conversion disorder, major depression, obsessive-compulsive disorder, anxiety (especially in adolescents), stress (particularly stress relating to competitive sports), physical and sexual abuse, post-traumatic stress disorder, panic attacks, factitious disorder and adjustment disorder.[10][5][6][4] It is important to note that anxiety and depression may occur in certain patients as a result of having VCD, rather than being the cause of it.[10][5] Psychological factors are important precipitating factors for many patients with VCD; although exercise is also a major trigger for episodes of VCD, some patients experience VCD co-occurring with anxiety regardless of whether or not they are physically active at the time of the VCD/anxiety episode.[4] Experiencing or witnessing a traumatic event related to breathing (such as a near-drowning or life-threatening asthma attack, for example), has also been identified as a risk factor for VCD.[10] VCD has also been associated with certain neurologic diseases including Arnold-Chiari malformation, cerebral aqueduct stenosis, cortical or upper motor neuron injury (such as that resulting from stroke), amyotrophic lateral sclerosis (ALS), parkinsonism syndromes and other movement disorders.[10][4] However, this association occurs only rarely.[4] In addition, it has been associated with Ehlers-Danlos Syndromes, a group of connective tissue disorders.[12] ## Causes[edit] The exact cause of VCD is not known, and it is unlikely that a single underlying cause exists.[5][6] Several contributing factors have been identified, which vary widely among VCD patients with different medical histories.[10] Physical exercise (including, but not limited to, competitive athletics) is one of the major triggers for VCD episodes, leading to its frequent misdiagnosis as exercise-induced asthma.[10][5][6] Other triggers include airborne pollutants and irritants such as smoke, dust, gases, soldering fumes, cleaning chemicals such as ammonia, perfumes, and other odours.[5][4] Gastroesophageal reflux disease (GERD) and rhinosinusitis (inflammation of the paranasal sinuses and nasal cavity) may also play a role in inflaming the airway and leading to symptoms of VCD as discussed below.[5][4] Laryngeal hyperresponsiveness is considered the most likely physiologic cause of VCD, brought on by a range of different triggers that cause inflammation and/or irritation of the larynx (voice box).[10][6] The glottic closure reflex (or laryngeal adductor reflex) serves to protect the airway, and it is possible that this reflex becomes hyperactive in some individuals, resulting in the paradoxical vocal fold closure seen in VCD.[10][4] Two major causes of laryngeal inflammation and hyperresponsiveness are gastroesophageal reflux disease (GERD) and postnasal drip (associated with rhinosinusitis, allergic or nonallergic rhinitis, or a viral upper respiratory tract infection (URI)).[10][5][6][4] Rhinosinusitis is very common among patients with VCD and for many patients, VCD symptoms are ameliorated when the rhinosinusitis is treated.[5] GERD is also common among VCD patients, but only some experience an improvement in VCD symptoms when GERD is treated.[5][6] Other causes of laryngeal hyperresponsiveness include inhalation of toxins and irritants, cold and dry air, episodic croup and laryngopharyngeal reflux (LPR).[6] ## Risk factors[edit] The following increase an individual's chances for acquiring VCD:[13] * Upper airway inflammation (allergic or non-allergic rhinitis, chronic sinusitis, recurrent upper respiratory infections) * Gastroesophageal reflux disease * Past traumatic event that involved breathing (e.g. near-drowning, suffocation) * Severe emotional trauma or distress * Female gender * Playing a wind instrument * Playing a competitive or elite sport ## Diagnosis[edit] The most effective diagnostic strategy is to perform laryngoscopy during an episode, at which time abnormal movement of the cords, if present, can be observed. If the endoscopy is not performed during an episode, it is likely that the vocal folds will be moving normally, a 'false negative' finding.[citation needed] Spirometry may also be useful to establish the diagnosis of VCD when performed during a crisis or after a nasal provocation test.[14] With spirometry, just as the expiratory loop may show flattening or concavity when expiration is affected in asthma, so may the Inspiratory loop show truncation or flattening in VCD. Of course, testing may well be negative when symptoms are absent.[15] ### Differential diagnosis[edit] The symptoms of VCD are often inaccurately attributed to asthma,[5] which in turn results in the unnecessary and futile intake of corticosteroids, bronchodilators and leukotriene modifiers,[7] although there are instances of comorbidity of asthma and VCD.[16] The differential diagnosis for vocal cord dysfunction includes vocal fold swelling from allergy, asthma, or some obstruction of the vocal folds or throat. Anyone suspected of this condition should be evaluated and the vocal folds (voice box) visualized. In individuals who experience a persistent difficulty with inhaling, consideration should be given to a neurological cause such as brain stem compression, cerebral palsy, etc.[17] The main difference between VCD and asthma is the audible stridor or wheezing that occurs at different stages of the breath cycle: VCD usually causes stridor on the inhalation, while asthma results in wheezing during exhalation.[5][6][7] Patients with asthma usually respond to the usual medication and see their symptoms resolve.[6][7] Clinical measures that can be done to differentiate VCD from asthma include:[6] * rhinolaryngoscopy: A patient with asthma will have normal vocal cord movement, while one with VCD will display vocal cord abduction during inhalation[6] * spirometry: A change in the measure following the administration of a bronchodilator is suggestive of asthma rather than VCD[6][7] * chest radiography: The presence of hyperinflation and peribronchial thickening are indicative of asthma, as patients with VCD will show normal results.[6] ## Treatments[edit] Once a diagnosis of VCD has been confirmed by a medical professional, a specific treatment plan can be implemented. If vocal cord dysfunction is secondary to an underlying condition, such as asthma, gastroesophageal reflux disease (GERD), or postnasal drip, it is important to treat the primary condition as this will help control VCD symptoms.[4] Conventional treatments for VCD are often multidisciplinary and include speech-language pathology, psychotherapy, behavioral therapy, use of anti-anxiety and anti-depressant medications, medical interventions, and hypnotherapy.[4][18][19] There is no uniform approach.[19] The information from randomized, blinded studies is limited.[18] ### Behavioral approaches[edit] Speech-language pathologists provide behavioral treatment of VCD. Speech therapy usually involves educating the client on the nature of the problem, what happens when symptoms are present, and then comparing this to what happens during normal breathing and phonation.[1] Intervention goals target teaching a client breathing and relaxation exercises so that they can control their throat muscles and keep the airway open, allowing air to flow in and out.[4] Breathing techniques can be taught to reduce tension in the throat, neck, and upper body and bring attention to the flow of air during respiration.[20] Diaphragm support during breathing decreases muscle tension in the larynx.[20] These techniques are meant to move awareness away from the act of breathing in and focus on the auditory feedback provided by the air moving in and out.[4] Other techniques can involve breathing through a straw and panting, which widens the opening of the throat by activating the Posterior cricoarytenoid (PCA) muscle.[4][19] Endoscopic feedback can also be used to show a patient what is happening when they are doing simple tasks such as taking a deep breath or speaking on an inspiration.[1] This provides the client with visual information so that they can actually see what behaviours help to open the throat and what behaviors constrict the throat.[1] Respiratory muscle strength training, a form of increased resistance training using a hand-held breathing device has also been reported to alleviate symptoms.[1] Speech therapy has been found to eliminate up to 90% of ER visits in patients suffering from VCD.[19] ### Medical approaches[edit] Medical often works in conjunction with behavioral approaches. A pulmonary or ENT (otolaryngologist) specialist will screen for and address any potential underlying pathology that may be associated with VCD. Managing GERD has also been found to relieve laryngospasm, a spasm of the vocal cords that makes breathing and speaking difficult.[21] Non-invasive positive pressure ventilation can be used if a patient's vocal cords adduct (close) during exhalation.[4] Mild sedatives have also been employed to reduce anxiety as well as reduce acute symptoms of VCD.[4][19] Benzodiazepines are an example of one such treatment, though they have been linked to a risk of suppression of the respiratory drive.[19] While Ketamine, a dissociative anesthetic, does not suppress respiratory drive, it has been thought to be associated with laryngospasms.[19] For more severe VCD cases, physicians may inject botulinum toxin into the vocal (thyroarytenoid) muscles to weaken or decrease muscle tension.[4][1] Nebulized Lignocaine can also been used in acute cases and helium-oxygen inhalation given by face mask has been used in cases of respiratory distress.[4][21][22] ### Psychological approaches[edit] Psychological interventions including psychotherapy, cognitive behavioural therapy (CBT), Biofeedback, and teaching self-hypnosis are also suggested to treat VCD.[18] Intervention is generally targeted at making the client aware of stressors that may trigger VCD symptoms, to implement strategies to reduce stress and anxiety, and to teach techniques for coping with their symptoms.[18][1] CBT can focus on bringing awareness to negative thought patterns and help reframe them by focusing on problem solving strategies.[18] Psychologists may also use relaxation to reduce distress when a patient is experiencing symptoms.[4][1] Biofeedback can be a helpful addition to psychotherapy. The aim of Biofeedback is to educate the client on what happens to the vocal cords during breathing and to help them learn to control their symptoms.[4] Choosing an intervention strategy needs to be assessed by a multidisciplinary team and individualized therapy planned carefully, keeping the characteristics of each patient in mind.[18] ## Prognosis[edit] The natural prognosis of VCD in both children and adults is not well described in the literature.[7] Additionally, there is currently no research that has studied whether the underlying cause of VCD makes a difference in the resolution of symptoms or in the long-term prognosis of the impairment.[23] Information on the prognosis of VCD after acute therapies is also limited. Minimal response has been documented with the continued treatment of asthma in people with VCD using inhaled bronchodilators, corticosteroids and other asthma medications.[23] While using Botox in VCD has limited reports, those that are available report successful resolution of exercise-induced VCD symptoms for up to 2 months.[23] Outcomes of chronic VCD treatment are similarly limited. When pediatric patients undergoing hypnosis therapy were studied, more than half saw either a reduction or resolution of VCD.[23] Even though it is widely used, no long-term studies have been done to study the prognosis of VCD after psychotherapy.[23] Speech therapy is the main course of treatment for long-term management of VCD and includes a variety of techniques such as relaxed-throat breathing, respiratory retraining therapy, and vocal hygiene counselling.[5] Most studies agree that symptoms of VCD improve in patients and few continue to require asthma medications six months post speech therapy intervention.[7][23] Significant improvements were reported for respiratory retraining therapy, including fewer episodes of dyspnea per month and decreased respiratory stress severity.[24] For those adolescent patients who recovered from VCD, the average time before the symptoms were resolved was 4–5 months.[7] However, some adolescents had VCD symptoms even 5 years post VCD onset, regardless of intervention.[7] It has been noted that some patients do not respond to standard VCD therapies and continue to express recurrent symptoms.[23] ## Epidemiology[edit] There is currently a limited amount of information available on the incidence and prevalence of VCD, and the various rates reported in the literature are most likely an underestimate.[4][25] Although VCD is thought to be rare overall, its prevalence among the population at large is not known.[6] However, numerous studies have been conducted on its incidence and prevalence among patients presenting with asthma and exertional dyspnea. A VCD incidence rate of 2% has been reported among patients whose primary complaint was either asthma or dyspnea; the same incidence rate has also been reported among patients with acute asthma exacerbation.[6][25] Meanwhile, much higher VCD incidence rates have also been reported in asthmatic populations, ranging from 14% in children with refractory asthma to 40% in adults with the same complaint.[25] It has also been reported that the VCD incidence rate is as high as 27% in non-asthmatic teenagers and young adults.[25] Data on the prevalence of VCD is also limited. An overall prevalence of 2.5% has been reported in patients presenting with asthma.[19] Among adults with asthma considered "difficult to control", 10% were found to have VCD while 30% were found to have both VCD and asthma.[6] Among children with severe asthma, a VCD prevalence rate of 14% has been reported.[6] However, higher rates have also been reported; among one group of schoolchildren thought to suffer from exercise-induced asthma, it was found that 26.9% actually had VCD and not asthma.[4] Among intercollegiate athletes with exercise-induced asthma, the VCD rate has been estimated at 3%.[4] In patients presenting with symptoms of dyspnea, prevalence rates ranging from 2.8% to 22% have been reported in various studies.[6][4][19] It has been reported that two to three times more females than males suffer from VCD.[6][4][25] VCD is especially common in females who suffer from psychological problems.[4] There is an increased risk associated with being young and female.[4] Among patients suffering from VCD, 71% are over the age of 18.[6] In addition, 73% of those with VCD have a previous psychiatric diagnosis.[6] VCD has also been reported in newborns with gastroesophageal reflux disorder (GERD).[4] ## See also[edit] * Puberphonia ## References[edit] 1. ^ a b c d e f g h i j k Colton RH, Casper JK, Leonard R (2011). Understanding Voice Problems (4th ed.). Lippincott Williams & Wilkins. pp. 325–326, 348–349. ISBN 978-1-60913-874-5. 2. ^ American Speech and Hearing Association. "Paradoxical Vocal Fold Movement (PVFM)". www.asha.org. Retrieved 26 September 2018. 3. ^ a b c Dowdall J, Thompson C. "Paradoxical Vocal Fold Motion". Uptodate. Retrieved 26 September 2018. 4. ^ 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 Ibrahim WH, Gheriani HA, Almohamed AA, Raza T (March 2007). "Paradoxical vocal cord motion disorder: past, present and future". Postgraduate Medical Journal. 83 (977): 164–72. doi:10.1136/pgmj.2006.052522. PMC 2599980. PMID 17344570. 5. ^ a b c d e f g h i j k l m n o p q r Deckert J, Deckert L (2010). "Vocal cord dysfunction". American Family Physician. 81 (2): 156–9. PMID 20082511. 6. ^ 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 Gimenez LM, Zafra H (April 2011). "Vocal cord dysfunction: an update". Annals of Allergy, Asthma & Immunology. 106 (4): 267–74, quiz 275. doi:10.1016/j.anai.2010.09.004. PMID 21457874. 7. ^ a b c d e f g h i j Noyes BE, Kemp JS (June 2007). "Vocal cord dysfunction in children". Paediatric Respiratory Reviews. 8 (2): 155–63. doi:10.1016/j.prrv.2007.05.004. PMID 17574160. 8. ^ Benninger C; Parsons JP; Mastronarde JG (2011-01-01). "Vocal cord dysfunction and asthma.". Current Opinion in Pulmonary Medicine. 17 (1): 45–9. ISSN 1070–5287. 9. ^ Vlahakis NE, Patel AM, Maragos NE, Beck KC (December 2002). "Diagnosis of vocal cord dysfunction: the utility of spirometry and plethysmography". Chest. American College of Chest Physicians. 122 (6): 2246–9. doi:10.1378/chest.122.6.2246. PMID 12475872. 10. ^ a b c d e f g h i j Hoyte FC (February 2013). "Vocal cord dysfunction". Immunology and Allergy Clinics of North America. 33 (1): 1–22. doi:10.1016/j.iac.2012.10.010. PMID 23337061. 11. ^ a b Mathers-Schmidt BA (May 2001). "Paradoxical vocal fold motion: a tutorial on a complex disorder and the speech-language pathologist's role". American Journal of Speech-Language Pathology. 10 (2): 111–25. doi:10.1044/1058-0360(2001/012). 12. ^ "Talk: Children with Ehlers-Danlos Syndrome and Airway Dysfunction (2011 ACR/ARHP Annual Scientific Meeting)". acr.confex.com. Retrieved 2019-02-18. 13. ^ Hoyte FC (Feb 2013). "Vocal cord dysfunction". Immunology and Allergy Clinics of North America. 33 (1): 1–22. doi:10.1016/j.iac.2012.10.010. PMID 23337061. 14. ^ Olivier CE, Argentão DG, Lima RP, da Silva MD, dos Santos RA (2013). "The nasal provocation test combined with spirometry establishes paradoxical vocal fold motion in allergic subjects". Allergy and Asthma Proceedings. 34 (5): 453–8. doi:10.2500/aap.2013.34.3681. PMID 23998243. 15. ^ Weiss P, Rundell KW (November 2009). "Imitators of exercise-induced bronchoconstriction". Allergy, Asthma, and Clinical Immunology. 5 (1): 7. doi:10.1186/1710-1492-5-7. PMC 2794850. PMID 20016690. 16. ^ Doshi DR, Weinberger MM (June 2006). "Long-term outcome of vocal cord dysfunction". Annals of Allergy, Asthma & Immunology. 96 (6): 794–9. doi:10.1016/s1081-1206(10)61341-5. PMID 16802766. 17. ^ Maschka DA, Bauman NM, McCray PB, Hoffman HT, Karnell MP, Smith RJ (November 1997). "A classification scheme for paradoxical vocal cord motion". The Laryngoscope. 107 (11 Pt 1): 1429–35. doi:10.1097/00005537-199711000-00002. PMID 9369385. S2CID 27174840. 18. ^ a b c d e f Guglani L, Atkinson S, Hosanagar A, Guglani L (8 August 2014). "A systematic review of psychological interventions for adult and pediatric patients with vocal cord dysfunction". Frontiers in Pediatrics. 2: 82. doi:10.3389/fped.2014.00082. PMC 4126208. PMID 25152871. 19. ^ a b c d e f g h i Denipah N, Dominguez CM, Kraai EP, Kraai TL, Leos P, Braude D (January 2017). "Acute Management of Paradoxical Vocal Fold Motion (Vocal Cord Dysfunction)". Annals of Emergency Medicine. 69 (1): 18–23. doi:10.1016/j.annemergmed.2016.06.045. PMID 27522309. S2CID 29171884. 20. ^ a b Schwartz SK (2004). The source for voice disorders : adolescent & adult. East Moline, IL: LinguiSystems. ISBN 978-0-7606-0504-2. 21. ^ a b Kendall KA, Louie S (December 2003). "Severe obstructive airway disorders and diseases: vocal fold dysfunction". Clinical Reviews in Allergy & Immunology. 25 (3): 221–31. doi:10.1385/CRIAI:25:3:221. PMID 14716068. S2CID 12175841. 22. ^ Tilles SA (November 2003). "Vocal cord dysfunction in children and adolescents". Current Allergy and Asthma Reports. 3 (6): 467–72. doi:10.1007/s11882-003-0056-z. PMID 14531966. S2CID 25328704. 23. ^ a b c d e f g Morris MJ, Allan PF, Perkins PJ (2006). "Vocal cord dysfunction: etiologies and treatment". Clinical Pulmonary Medicine. 13 (2): 73–86. doi:10.1097/01.cpm.0000203745.50250.3b. S2CID 18108490. 24. ^ Patel RR, Venediktov R, Schooling T, Wang B (August 2015). "Evidence-Based Systematic Review: Effects of Speech-Language Pathology Treatment for Individuals With Paradoxical Vocal Fold Motion". American Journal of Speech-Language Pathology. 24 (3): 566–84. doi:10.1044/2015_AJSLP-14-0120. PMID 25836980. 25. ^ a b c d e Katial RK, Hoyte FC (2014). Mackay IM, Rose NR (eds.). Diseases in DDx of Asthma: Vocal Cord Dysfunction. Encyclopedia of medical immunology: Volume 3. Berlin: Springer. pp. 245–251. ## External links[edit] Classification D * ICD-10: J38.3 * ICD-9-CM: 478.3-478.5 * MeSH: D064706 * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Vocal cord dysfunction	c0859897	5,724	wikipedia	https://en.wikipedia.org/wiki/Vocal_cord_dysfunction	2021-01-18T18:59:49	{"mesh": ["D064706"], "icd-9": ["478.3", "478.5"], "wikidata": ["Q1718230"]}
Necrobiotic xanthogranuloma is a rare, chronic and progressive, non-Langerhans cell histiocytosis disease typically characterized by multiple, indurated, asymptomatic to pruritic, yellow-orange plaques or nodules that tend to ulcerate and are usually located in the periorbital area, trunk and/or extremities. Strong association with paraproteinemia and/or malignant lymphoproliferative disease has 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	Necrobiotic xanthogranuloma	c1275339	5,725	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158011	2021-01-23T18:23:36	{"gard": ["10951"], "mesh": ["D058252"], "umls": ["C1275339"], "icd-10": ["D76.3"]}
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, seizures, abnormal gait, and craniofacial dysmorphism (including coarse features, depressed nasal bridge, anteverted nares, broad nasal tip, prominent maxilla and upper lip, wide mouth, abnormal gingiva, and widely spaced teeth). Additional reported manifestations are ocular anomalies, cardiac defects, gastrointestinal problems, and autistic features. Brain imaging may show thin corpus callosum, white matter abnormalities, or dilated ventricles. [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	Intellectual disability-seizures-abnormal gait-facial dysmorphism syndrome	c4539927	5,726	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=513456	2021-01-23T17:37:35	{"omim": ["617616"], "synonyms": ["Skraban-Deardorff syndrome"]}
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: "MODY 4" – news · newspapers · books · scholar · JSTOR (March 2018) (Learn how and when to remove this template message) MODY 4 SpecialtyEndocrinology MODY 4 is a form of maturity onset diabetes of the young. MODY 4 arises from mutations of the PDX1 homeobox gene on chromosome 13. Pdx-1 is a transcription factor vital to the development of the embryonic pancreas. Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin. MODY 4 is so rare that only a single family has been well-studied. A child born with pancreatic agenesis (absence of the pancreas) was found to be homozygous for Pdx-1 mutations. A number of older relatives who were heterozygous had mild hyperglycemia or diabetes. None were severely insulin-deficient and all were controlled with either diet or oral hypoglycemic agents. ## References[edit] ## External links[edit] Classification D * OMIM: 606392 * MeSH: C563451 * v * t * e Disease of the pancreas and glucose metabolism Diabetes * Types * type 1 * type 2 * gestational * MODY 1 2 3 4 5 6 * Complications * See Template:Diabetes Abnormal blood glucose levels * Hyperglycaemia * Oxyhyperglycemia * Hypoglycaemia * Whipple's triad Insulin disorders * Insulin resistance * Hyperinsulinism * Rabson–Mendenhall syndrome Other pancreatic disorders * Insulinoma * Insulitis * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular lesions) [1] This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it. * v * t * e 1. ^ Stoffers, Doris A.; Ferrer, Jorge; L. Clarke, William; Habener, Joel (1997). "Early-onset type-II diabetes mellitus (MODY4) linked to IPF1". Nature Genetics. 17: 138–139. doi:10.1038/ng1097-138. [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	MODY 4	c1833382	5,727	wikipedia	https://en.wikipedia.org/wiki/MODY_4	2021-01-18T18:48:45	{"mesh": ["C563451"], "wikidata": ["Q6717005"]}
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: "Abortion in Afghanistan" – news · newspapers · books · scholar · JSTOR (June 2018) (Learn how and when to remove this template message) Abortion in Afghanistan is affected by the religious constraints from the national religion, Islam, and by the extremely high birthrates. Afghanistan has one of the highest fertility rates, but its levels are decreasing since the fall of the Taliban, as aid workers can now enter the country to help with fertility and decrease mortality rates.[1] Afghan law is influenced by Islamic law, which comes from the Qur’an.[2][3] These laws state that abortion is only legal if it is performed to save the life of the mother or if the child is going to be born with a severe disability.[4] This interpretation of Islamic law is based in Islamic medicine, as Muslims cherish the sanctity of human life and believe God does not cause harm or illnesses that are incurable.[5] Due to these constraints, women choose either to pursue an abortion illegally or be shunned by society due to a pregnancy outside of the socially accepted norms.[6] Contraception is approved by Islam when it prevents the formation of the zygote and prevents implantation in the uterus.[3] ## Contents * 1 Birthrates & fertility * 2 Religious limitations * 2.1 Stigmatization of abortions * 3 Current legislation * 4 Access to abortions * 4.1 Safety of the procedure * 5 References ## Birthrates & fertility[edit] Afghanistan has one of the highest fertility rates in the world, with very few women actively using contraceptive methods, despite support from the government and conformance with religious ethics.[5][1] Only 22.5% of people utilize contraceptive measures in comparison to the United States, where 74.1% of people utilize contraception.[7] In the 1990s, the average woman in Afghanistan had 8 children throughout her lifetime, but this decreased in the mid-2000s to 6.3 and by the end of 2010 to 5.1.[1] Since the Taliban's fall in 2001, fertility levels are decreasing, stemming from the Taliban's belief in not educating girls, child brides, and not providing healthcare for women.[1] The decreased presence of the Taliban has allowed an entrance of aid workers to the country to provide educational funding for schools, family planning, and more access to birth control. The uncontrolled high fertility rates make it difficult for Afghanistan to manage the poverty level and improve other social conditions, which leaves a high dependence on aid from other countries. High fertility rates cause high birthrates, which contribute to the high fetal mortality rate.[8] Afghanistan has the highest fetal mortality rate in the world, with 110.6 deaths per 1000 births.[7] Mothers are also 19.9 years old on average at her first birth. As access to education across Afghanistan is increasing due to the fall of the Taliban, the fetal mortality rate is also decreasing. In rural areas the mortality rate still remains high, but aid workers are being sent to many regions of the country after receiving training on deliveries and care for newborns.[6] ## Religious limitations[edit] Islamic law comes from the Qur'an, which they believe comes from God and Muslims use it to dictate their every day actions. The religious laws of Islam dictate strict policies on gender interactions. One of these requirements is that women use a female gynecologist.[9] Islamic rule says that males in the medical field should only treat females if there are no other females in the field to care for them. Women are more likely to seek care from a female gynecologist to conform to their religious convictions.[4] A suggested improvement is to increase the number of female doctors in Afghanistan to encourage seeking professional help rather than nonprofessional help.[citation needed] Islamic medicine ideals are based on the sanctity of human life, which states that God created humans and did not create diseases or other ailments that do not have cures or other solutions that humans have the ability to discover.[3] Muslim teachings say that human life begins at conception because the fetus is able to perform actions within the womb that humans outside of the womb are able to perform, such as movement and digestion.[3] This means that the fetus has a soul. This means that the fetus has rights, which the mother is responsible for protecting until delivery. This leads to the overriding belief that abortion should be avoided whenever possible.[10] Any action that would take away the soul of the fetus is illegal. This includes a pregnant mother being murdered, leading to the murderer being tried for both deaths; or if the father dies while the mother is pregnant, the estate will not be divided until the birth of the child, because the fetus has rights to the estate and the father's inheritances.[3] However, in cases of rape, abortion is not permitted because one crime cannot be solved with another crime, and having an abortion for reasons other than the health of the mother and the baby is considered a crime. If a fetus is predicted to die right after birth, the mother and the father must make the decision, considering all factors, that they feel aligns best with the Qur'an.[3] Islam approves certain forms of contraception as well. Contraceptive methods are acceptable when they prevent ovulation and formation of the zygote.[3] Once the zygote has formed, which means the egg and the sperm have fused, it is considered a human life and thus is protected as such. Ethicists believe that the proper use of contraceptives prevents the need for abortion and the consideration of the moral dilemma.[10] ### Stigmatization of abortions[edit] Due to the religious views on abortion, society stigmatizes women who receive abortions. Many women account that they are stuck deciding between whether to have an abortion or have a child outside of marriage, both of which cause them to be ostracized from society.[6] Some reasons that lead women to pursue abortions to avoid being ostracized include drug and/or alcohol addicted husbands, poverty, and being single. Due to the constraints that the government places on access to abortions, women must pursue abortion through illegal means to avoid being shunned by their families or punished criminally.[4] The culture in Afghanistan, developed both from the government and religion, makes women believe that it is their job to have children. This social role for women does not take into account that Afghanistan has an extremely high birthrate, ranked 12th in the world, with little access to education on family planning and contraceptive usage.[5][7] ## Current legislation[edit] Afghan legislation is based heavily on Islam, with the preamble of their constitution referencing Allah.[11] Article 3 of Chapter 1 outlines that no law in Afghanistan should contradict Islam.[11] The Afghan Independent Human Rights Commission was created to protect human rights and as a response to Shia Family Law, which violates human rights.[12][13] The heavy influence of religious beliefs on the law leads to strict laws surrounding abortion. Chapter 4 of the Afghanistan Penal Code outlines the consequences for performing abortions. It states that abortions outside of saving the life of the mother or if the baby's life is endanger, interpreted as a severe disability or low quality of life, are illegal.[2] Article 402 says that anyone who purposefully kills a fetus will be sentenced to no more than 7 years in prison. Article 403 says that anyone who performs the abortion will either be imprisoned or fined up to approximately 12,000 Afghanis (US$165). If the person performing the abortion is a doctor they will be punished to the fullest extent of the law.[2] ## Access to abortions[edit] Few legal cases allow women to seek abortion care. Women are able to get an abortion when their life is endangered by the pregnancy, or if the baby will be born with severe deformities or disabilities.[4] Religious ethical committees must rule on the ethics and legality of the abortion before it can be carried out.[10] After ethical approval of the abortion, the woman must obtain approval from a gynecologist, three general practitioners, a counselor, and permission of the doctor.[4] One additional situation that occasionally allows abortion to occur is poverty. This is especially prominent in areas that the Taliban is still present in. Within Taliban controlled areas, poverty based abortions are generally approved more often because they have too many children.[6] Women often pursue abortions through illegal means because of the few cases that allow abortions legally. They believe it is necessary in order to avoid shame from their husbands, families, and society. This leads women to having to fund the abortion themselves, which can be difficult because of the social norm that implies that it is women's job to have children and thus they don't have jobs outside of taking care of the house and the family.[4] Many women would prefer not to have children, but lack knowledge on how to limit the number of children they have outside of abortion. When pursuing abortions, they many times need to use uneducated midwives who don't know how to properly perform the procedure or deal with complications. Another option they have is to use expensive private clinics, which leads to the issue of funding the expenditure. Since women are typically unemployed, rounding up the funds for an abortion can be difficult. The price of an abortion has decreased from 250,000 Afghanis (US$3,500) to 17,500 Afghanis (US$250).[6] This decrease has been seen because of the increasing need of abortions. But the price is still 15,000 Afghani (US$150) higher than the average price of an abortion in the United States, where abortions are legal and generally publicly accepted.[6] ### Safety of the procedure[edit] Afghanistan is in the top 16 countries worldwide for the highest mortality rate from abortion.[14] The healthcare system in Afghanistan is also not at a level to properly care for pregnant mothers.[4] Every 2 hours there is a pregnancy-related death in Afghanistan.[6] The high maternal mortality is due to lack of post procedure care. Although the procedure is illegal in most cases, women still pursue abortions, motivating aid workers to make it safer. International aid workers are working to improve the safety of the procedures by educating midwives and nurses about how to improve care for their patients and limit the mortality of the procedure.[6] Aid workers hope to decrease the stigma surrounding the procedure so that there is lower mortality. ## References[edit] 1. ^ a b c d Nasser, Haya El; Overberg, Paul. "Fertility rate drops in Afghanistan, but will it continue?". USA Today. USA Today. Retrieved 13 May 2018. 2. ^ a b c "Abortion in Afghanistan". Women In Afghanistan. Word Press. 2015-11-05. Retrieved 23 May 2018. 3. ^ a b c d e f g Athat, Shahidi. "Islam and Abortion". Islamic Horizons. 45 (4): 40–41. 4. ^ a b c d e f g Hasrat-Nazimi, Waslat. "Afghan women use abortion as a way out". DW Made for Minds. Deutsche Welle. Retrieved 13 May 2018. 5. ^ a b c Abortion Policies: A Global Review. New York: United Nations. 2001. pp. 17–18. 6. ^ a b c d e f g h Rasmussen, Sune (2017-04-26). "'I Am a Criminal. What is My Crime?': the Human Toll of Abortion in Afghanistan". The Guardian. Guardian News and Media. Retrieved 11 May 2018. 7. ^ a b c "The World Factbook: Afghanistan". Central Intelligence Agency. Retrieved 18 May 2018. 8. ^ Constable, Pamela. "Afghan babies have been dying in huge numbers for decades. Now, something is changing". World Views. The Washington Post. Retrieved 13 May 2018. 9. ^ "Rules Regarding Looking, Touching and Examining". Al-Islam.org. Ahlul Bayt Digital Islamic Library Project. Retrieved 16 May 2018. 10. ^ a b c Bowen, Donna Lee (1997). "Abortion, Islam, and the 1994 Cairo Population Conference". International Journal of Middle East Studies. 29 (2): 161–184. doi:10.1017/s002074380006445x. 11. ^ a b "The Constitution ::: Embassy of Afghanistan". www.afghanembassy.us. Retrieved 2018-06-10. 12. ^ "Afghanistan Independent Human Rights Commission". www.aihrc.org.af. Retrieved 2018-06-10. 13. ^ "The Shia Family Law". www.mtholyoke.edu. Retrieved 2018-06-10. 14. ^ Ansari, Nasratullah (February 2015). "Assessing Post-Abortion Care in Health Facilities in Afghanistan: A Cross-Sectional Study". BMC Pregnancy and Childbirth. 15 (1): 6. doi:10.1186/s12884-015-0439-x. PMC 4320442. PMID 25645657. * v * t * e Abortion in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Abortion in Afghanistan	None	5,728	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Afghanistan	2021-01-18T19:02:05	{"wikidata": ["Q19568841"]}
Psychomotor symptom of catatonia, abnormal maintenance of postures Not to be confused with Cataplexy. For the band, see Catalepsy (band). "Cataleptic" redirects here. For the poetry term, see catalectic. Catalepsy SpecialtyPsychiatry Catalepsy (from Ancient Greek katálēpsis, κατάληψις, "seizing, grasping") is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Historical cases * 4 Artistic depictions * 4.1 Literature * 4.2 Other media * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Female patient with depression and catalepsy Rigidity of the body produced by catalepsy Symptoms include a rigid body, rigid limbs, limbs staying in same position when moved (waxy flexibility), no response, loss of muscle control, and slowing down of bodily functions, such as breathing.[2] ## Causes[edit] Catalepsy is a symptom of certain nervous disorders or conditions such as Parkinson's disease and epilepsy. It is also a characteristic symptom of cocaine withdrawal, as well as one of the features of catatonia.[citation needed] It can be caused by schizophrenia treatment with anti-psychotics,[3] such as haloperidol,[4] and by the anesthetic ketamine.[5] Protein kinase A has been suggested as a mediator of cataleptic behavior.[6] Unsuggested waxy catalepsy, sometimes accompanied by spontaneous anesthesia, is seen as an indicator of hypnotic trance.[7] Suggested or induced rigid catalepsy, of extended limbs or even the entire body, sometimes tested with heavy weights, has been a staple of stage hypnosis shows and even academic demonstrations of hypnotism since the late 18th century, as proof of extraordinary physical abilities possible in trance states.[citation needed] Such demonstrations have also been performed by Asian martial artists to prove the presence of "ki" or "chi" power, a kind of psychological or spiritual resource.[citation needed] ## Historical cases[edit] Armand D'Angour suggests that reports (such as that recounted in Plato's Symposium) of Socrates, in about 429 BC, standing perfectly still for hours on end during the Athenian campaign against Potidaea while seemingly deep in thought, are 'too extreme to be considered wholly a matter of rational choice,' and that 'it is reasonable to suppose that it was the symptom of an underlying physiological or psychological condition', such as catalepsy. [8] St. Teresa of Avila experienced a prolonged bout of catalepsy that began in 1539. This episode was precipitated by the stress she was suffering at the Carmelite Convent of the Incarnation. Her legs became rigid, leaving her an invalid for three years. Teresa endured intermittent attacks of catalepsy from then on.[9] ## Artistic depictions[edit] In the arts, catalepsy is often used for dramatic effect, sometimes as a plot device. ### Literature[edit] Friar Laurence ...Take thou this vial, being then in bed, And this distilléd liquor drink thou off; When presently through all thy veins shall run A cold and drowsy humour, for no pulse Shall keep his native progress, but surcease: No warmth, no breath, shall testify thou livest; The roses in thy lips and cheeks shall fade To paly ashes, thy eyes' windows fall, Like death, when he shuts up the day of life; Each part, deprived of supple government, Shall, stiff and stark and cold, appear like death: And in this borrow'd likeness of shrunk death Thou shalt continue two and forty hours, And then awake as from a pleasant sleep... William Shakespeare Romeo and Juliet Act IV scene I (Account of character Jem Rodney, the molecatcher) ...coming up to him he saw that Marner's eyes were set like a dead man's, and he spoke to him and shook him, and his limbs were stiff, and his hands clutched the bag as if they'd been made of iron...No, no; it was no stroke that would let a man stand on his legs, like a horse between the shafts, and then walk off as soon as you can say "Gee!" But there might be such a thing as a man's soul being loose from his body, and going out and in, like a bird out of its nest and back; and that was how folks got over-wise, for they went to school in this shell-less state to those who could teach them more than their neighbours could learn with their five senses and the parson. (Narrator) ...a peculiar interest had been centred in him ever since he had fallen at a prayer meeting into a mysterious rigidity and suspension of consciousness which, lasting for an hour or more, had been mistaken for death. George Eliot Silas Marner In William Shakespeare's tragedy Romeo and Juliet the kindly Friar Laurence (in the course of a botched attempt to help the lovers) provides Juliet with a catalepsy-inducing potion so effective that Romeo tragically imagines his beloved's death-like trance to be actual death and poisons himself in despair just before she awakens from her stupor \- leading her to kill herself with his dagger upon discovering his suicide. In Alexandre Dumas, père's novel The Count of Monte Cristo, the Abbé Faria has fits of catalepsy from time to time, before eventually dying from one. In Eugène Sue's The Mysteries of Paris, the villain Jacques Ferrand experiences a fit described as cataleptic in his final confrontation with Rodolphe, blinded by lamplight and hallucinating with visions of his fantasized Cecily. In George Eliot's Silas Marner, the main character Silas Marner frequently has cataleptic fits and seizures, an affliction which adds to his uncanny reputation as a wizard or 'cunning man' among the superstitious natives of his adopted village of Raveloe. In Arthur Conan Doyle's "The Adventure of the Resident Patient", a man feigns catalepsy to gain access to a neurologist's rooms; the doctor attempts to treat him with amyl nitrite. In Ford Madox Ford's The Good Soldier, the protagonist Dowell experiences catalepsy following the death of his wife. In Robert A. Heinlein's Stranger in a Strange Land, the main character Valentine Michael Smith is believed to have catalepsy when he is returned to Earth. In Edgar Allan Poe's "The Premature Burial", the narrator develops catalepsy. He fears being mistakenly declared dead and buried alive, and goes to great lengths to prevent this. In another of Poe's short stories, "The Fall of the House of Usher", Madeline Usher has catalepsy, and is buried alive by her unstable brother Roderick. Catalepsy is also depicted in "Berenice", thus becoming one of the recurrent themes in Poe's fiction. In Poppy Z. Brite's Exquisite Corpse, the main character—Comptom, a serial killer (recreation of Jeffery Dahmer's life story) facing a lifetime sentence—uses shamanistic techniques to induce catalepsy, and, convincingly appearing deceased, is able to escape prison. In Émile Zola's short story "La Mort d'Olivier Becaille" ("The Death of Olivier Becaille"), the title character is buried alive and notes that "I must have fallen into one of those cataleptic states that I had read of". In Sax Rohmer's Fu Manchu novels, Dr. Fu-Manchu has a serum that induces a state of catalepsy so extreme as to be indistinguishable from death. In Charles Dickens's novel Bleak House, Mrs. Snagsby has violent spasms before becoming cataleptic and being carried upstairs like a grand piano. In Hegel's Lectures on the History of Philosophy: Greek Philosophy to Plato, Hegel describes Socrates as having catalepsy caused by magnetic somnambulism when in deep meditation. In Charles Williams's novel Many Dimensions, Sir Giles Tumulty says to Lord Arglay, the Chief Justice of England: "You are a louse-brained catalept, Arglay." In Philip K. Dick's novel Now Wait for Last Year, Kathy Sweetscent becomes immobilized by withdrawal from JJ-180, an alien (and highly addictive) drug. "My God, Kathy thought as she stood gazing down at the record by her feet. I can't free myself; I'm going to remain here, and they'll find me like this and know something's terribly wrong. This is catalepsy!" In the second chapter of Álvares de Azevedo's Noite na Taverna, character Solfieri rescues a woman who has catalepsy from inside a coffin. In Sheridan Le Fanu's novella The Room in the Dragon Volant a naïve young man falls foul of a criminal gang who employ a curious, bulbocapnine-like drug which induces catalepsy - as a result of which he narrowly escapes premature burial. In the Ted Hughes poem titled "Conjuring in Heaven" from Crow (poetry), the eponymous character is left in a state of catalepsy.[10] ### Other media[edit] In the old time radio show Suspense theater, episode titled "Dead Ernest." Episodes number 205, 1946, and number 244, 1947. [11] In the movie Son of Dracula (1943,Universal Pictures), vampire hunter Professor Lazlo (J. Edward Bromberg) describes a vampire as being in a "cataleptic state" between sunrise and sunset, but practically "invincible" during the nighttime, to Dr. Harry Brewster( Frank Craven), as they look for answers to a number of strange situations involving Count Alucard (Lon Chaney Jr.). ## See also[edit] * Catatonia * Mood disorder#Depressive disorders ## References[edit] 1. ^ "Definition of Catalepsy". 2. ^ Sanberg PR, Bunsey MD, Giordano M, Norman AB (October 1988). "The catalepsy test: its ups and downs". Behav. Neurosci. 102 (5): 748–59. doi:10.1037/0735-7044.102.5.748. PMID 2904271. 3. ^ Rasmussen K, Hsu MA, Noone S, Johnson BG, Thompson LK, Hemrick-Luecke SK (November 2007). "The orexin-1 antagonist SB-334867 blocks antipsychotic treatment emergent catalepsy: implications for the treatment of extrapyramidal symptoms". Schizophr Bull. 33 (6): 1291–97. doi:10.1093/schbul/sbm087. PMC 2779883. PMID 17660489. 4. ^ Hattori K, Uchino S, Isosaka T, et al. (March 2006). "Fyn is required for haloperidol-induced catalepsy in mice". J. Biol. Chem. 281 (11): 7129–35. doi:10.1074/jbc.M511608200. PMID 16407246. 5. ^ Miller, Ronald (2005). Miller's Anesthesia. New York: Elsevier/Churchill Livingstone. ISBN 978-0-443-06656-6. 6. ^ Adams MR, Brandon EP, Chartoff EH, Idzerda RL, Dorsa DM, McKnight GS (October 1997). "Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice". Proc. Natl. Acad. Sci. U.S.A. 94 (22): 12157–61. Bibcode:1997PNAS...9412157A. doi:10.1073/pnas.94.22.12157. PMC 23735. PMID 9342379. 7. ^ <Milton H. Erickson, edited by Ernest Rossi "Collected Papers of Milton H. Erickson, Irvington 1980> 8. ^ D'Angour, Armand (2019). Socrates in Love. Bloomsbury Publishing, London, page 76. 9. ^ St. Teresa of Avila, The Life of St. Teresa de Avila, 1565, chapters V, VI, and VII. 10. ^ Hughes, T. (1972). Crow: From the Life and Songs of the Crow. London: Faber & Faber. 11. ^ Old Time Radio Researcher's Group https://otrr.org. Youtube: Old Time Radio, Suspense, Dead Earnest. https://www.youtube.com/watch?v=Ncb1N6InWLw or https://www.youtube.com/watch?v=YFUwDHzh2Fs ## External links[edit] Classification D * ICD-10: F20.2, F44.2 * ICD-9-CM: 295.2, 300.11 * MeSH: D002375 * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Catalepsy	c0007370	5,729	wikipedia	https://en.wikipedia.org/wiki/Catalepsy	2021-01-18T19:02:06	{"mesh": ["D002375"], "icd-9": ["300.11", "295.2"], "icd-10": ["F20.2", "F44.2"], "wikidata": ["Q918193"]}
Spitz nevus Spitz nevus SpecialtyOncology, Dermatology Prognosisbenign A Spitz nevus is a benign skin lesion. A type of melanocytic nevus, it affects the epidermis and dermis.[1] It is also known as an epithelioid and spindle-cell nevus,[2] and misleadingly as a benign juvenile melanoma,[2]:691 and Spitz's juvenile melanoma[3]). The name juvenile melanoma is generally no longer used as it is neither a melanoma, nor does it occur only in children.[4] ## Contents * 1 Pathophysiology * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 Eponym * 6 See also * 7 References * 8 External links ## Pathophysiology[edit] Micrograph of a Spitz nevus showing the characteristic vertically arranged nests of cells ("hanging bananas"). H&E stain. The cause of Spitz nevi is not yet known. There is an association with sunburn, but causation is not established.[1] Genetic studies of Spitz nevi have shown that most cells have the normal number of chromosomes, however a minority (25%) of cells have been shown to contain extra copies of parts of some chromosomes, such as the short arm of chromosome 11 (11p).[1] ## Diagnosis[edit] Various differential diagnoses of pigmented skin lesions, by relative incidence and malignancy potential, including "Spitz, Reed or spindle nevus" at top right. On histopathology, Spitz nevi characteristically have vertically arranged nests of nevus cells that have both a spindled and an epithelioid morphology. Apoptotic cells may be seen at the dermoepidermal junction. The main histologic differential diagnoses are pigmented spindle cell nevus and malignant melanoma. ## Treatment[edit] Surgical removal is usually performed, even though it is benign.[citation needed] ## Epidemiology[edit] Spitz nevi are uncommon. Their annual incidence was estimated in a coastal population of sub-tropical Queensland to be 1.4 cases per 100,000 people. For comparison, the annual incidence of melanoma in the same population, which is high by world standards[5] is 25.4 cases per 100,000 people.[4] Although they are most commonly found on people in their first two decades of life,[1] the age range for people with Spitz nevi is from 6 months to 71 years, with a mean age of 22 years and a median age of 19 years.[4] ## Eponym[edit] The lesion is named after Sophie Spitz, the pathologist who originally described it in 1948.[6] ## See also[edit] * List of cutaneous conditions * List of genes mutated in pigmented cutaneous lesions * Melanoma with features of a Spitz nevus ## References[edit] Wikimedia Commons has media related to Spitz nevus. 1. ^ a b c d LeBoit, PE, Burg G, Weedon D, Sarasin A. (Eds) World Health Organization Classification of Tumours: Pathology and Genetics of Skin Tumours. Lyon: IARCPress. 2006. 2. ^ a b James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. 1728–30. ISBN 978-1-4160-2999-1. 4. ^ a b c Crotty, K. Spitz Naevus: Histological features and distinction from malignant melanoma. Australasian Journal of Dermatology. 38 (suppl): S49-S53. 1997. 5. ^ Ries LAG, et al., eds. SEER Cancer Statistics Review, 1975–2000. Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1-9. 6. ^ Spitz S. Melanomas of childhood. Am. J. Pathol.1948;24:591-609. ## External links[edit] Classification D * ICD-10: D22 (ILDS D22.L32) * ICD-O: M8770/0 * MeSH: D018332 * DiseasesDB: 29807 External resources * eMedicine: article/1059623 * 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	Spitz nevus	c0206739	5,730	wikipedia	https://en.wikipedia.org/wiki/Spitz_nevus	2021-01-18T18:44:23	{"gard": ["10412"], "mesh": ["D018332"], "icd-10": ["D22"], "wikidata": ["Q2311457"]}
Group of blood cancers that usually begin in the bone marrow For the journal, see Leukemia (journal). For animal diseases, see Leucosis. Leukemia Other namesLeukaemia A Wright's stained bone marrow aspirate smear from a person with B-cell acute lymphoblastic leukemia. Pronunciation * /luːˈkiːmiːə/[1] SpecialtyHematology and oncology SymptomsBleeding, bruising, feeling tired, fever, increased risk of infections[2] Usual onsetAll ages,[3] most common in 60s and 70s.[4] It is the most common malignant cancer in children, but the cure rates are also higher for them. CausesInherited and environmental factors[5] Risk factorsSmoking, family history, ionizing radiation, some chemicals, prior chemotherapy, Down syndrome.[3][5] Diagnostic methodBlood tests, bone marrow biopsy[2] TreatmentChemotherapy, radiation therapy, targeted therapy, bone marrow transplant, supportive care[3] PrognosisFive-year survival rate 57% (USA)[4] Frequency2.3 million (2015)[6] Deaths353,500 (2015)[7] Leukemia, also spelled leukaemia, is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells.[8] These blood cells are not fully developed and are called blasts or leukemia cells.[2] Symptoms may include bleeding and bruising, fatigue, fever, and an increased risk of infections.[2] These symptoms occur due to a lack of normal blood cells.[2] Diagnosis is typically made by blood tests or bone marrow biopsy.[2] The exact cause of leukemia is unknown.[5] A combination of genetic factors and environmental (non-inherited) factors are believed to play a role.[5] Risk factors include smoking, ionizing radiation, some chemicals (such as benzene), prior chemotherapy, and Down syndrome.[5][3] People with a family history of leukemia are also at higher risk.[3] There are four main types of leukemia—acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)—as well as a number of less common types.[3][9] Leukemias and lymphomas both belong to a broader group of tumors that affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues.[10][11] Treatment may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed.[3] Certain types of leukemia may be managed with watchful waiting.[3] The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world.[9] Five-year survival rate is 57% in the United States.[4] In children under 15, the five-year survival rate is greater than 60% or even 90%, depending on the type of leukemia.[12] In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.[12] In 2015, leukemia was present in 2.3 million people worldwide and caused 353,500 deaths.[6][7] In 2012 it newly developed in 352,000 people.[9] It is the most common type of cancer in children, with three-quarters of leukemia cases in children being the acute lymphoblastic type.[3] However, over 90% of all leukemias are diagnosed in adults, with CLL and AML being most common in adults.[3][13] It occurs more commonly in the developed world.[9] ## Contents * 1 Classification * 1.1 General classification * 1.2 Specific types * 1.3 Pre-leukemia * 2 Signs and symptoms * 3 Causes * 3.1 Radiation * 3.2 Genetic conditions * 3.3 Non-ionizing radiation * 4 Diagnosis * 5 Treatment * 5.1 Acute lymphoblastic * 5.2 Chronic lymphocytic * 5.2.1 Decision to treat * 5.2.2 Treatment approach * 5.3 Acute myelogenous * 5.4 Chronic myelogenous * 5.5 Hairy cell * 5.6 T-cell prolymphocytic * 5.7 Juvenile myelomonocytic * 5.8 Teeth * 6 Prognosis * 7 Epidemiology * 7.1 United States * 7.2 UK * 8 History * 8.1 Etymology * 9 Society and culture * 10 Research directions * 11 Pregnancy * 12 See also * 13 References * 14 External links ## Classification[edit] Four major kinds of leukemia Cell type Acute Chronic Lymphocytic leukemia (or "lymphoblastic") Acute lymphoblastic leukemia (ALL) Chronic lymphocytic leukemia (CLL) Myelogenous leukemia ("myeloid" or "nonlymphocytic") Acute myelogenous leukemia (AML or myeloblastic) Chronic myelogenous leukemia (CML) Play media An explanation of acute leukemia ### General classification[edit] Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms: * Acute leukemia is characterized by a rapid increase in the number of immature blood cells. The crowding that results from such cells makes the bone marrow unable to produce healthy blood cells resulting in low hemoglobin and low platelets. Immediate treatment is required in acute leukemia because of the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children. * Chronic leukemia is characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected. This divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias: * In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell. * In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets. Combining these two classifications provides a total of four main categories. Within each of these main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme. ### Specific types[edit] * Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. It also affects adults, especially those 65 and older. Standard treatments involve chemotherapy and radiotherapy. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia. While most cases of ALL occur in children, 80% of deaths from ALL occur in adults.[14] * Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 85%.[15] It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease. * Acute myelogenous leukemia (AML) occurs far more commonly in adults than in children, and more commonly in men than women. It is treated with chemotherapy. The five-year survival rate is 20%.[16] Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia. * Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. It is treated with imatinib (Gleevec in United States, Glivec in Europe) or other drugs.[17] The five-year survival rate is 90%.[18][19] One subtype is chronic myelomonocytic leukemia. * Hairy cell leukemia (HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but does not fit neatly into this category. About 80% of affected people are adult men. No cases in children have been reported. HCL is incurable but easily treatable. Survival is 96% to 100% at ten years.[20] * T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease.[21] Despite its overall rarity, it is the most common type of mature T cell leukemia;[22] nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months. * Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.[23] * Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV, it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally. Human T-cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world. * Clonal eosinophilias (also called clonal hypereosinophilias) are a group of blood disorders characterized by the growth of eosinophils in the bone marrow, blood, and/or other tissues. They may be pre-cancerous or cancerous. Clonal eosinophilias involve a "clone" of eosinophils, i.e., a group of genetically identical eosinophils that all grew from the same mutated ancestor cell.[24] These disorders may evolve into chronic eosinophilic leukemia or may be associated with various forms of myeloid neoplasms, lymphoid neoplasms, myelofibrosis, or the myelodysplastic syndrome.[25][26][24] ### Pre-leukemia[edit] * Transient myeloproliferative disease, also termed transient leukemia, involves the abnormal proliferation of a clone of non-cancerous megakaryoblasts. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops in a baby during pregnancy or shortly after birth, and resolves within 3 months or, in ~10% of cases, progresses to acute megakaryoblastic leukemia. Transient myeloid leukemia is a pre-leukemic condition.[27][28][29] ## Signs and symptoms[edit] Common symptoms of chronic or acute leukemia[30] The most common symptoms in children are easy bruising, pale skin, fever, and an enlarged spleen or liver.[31] Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae). White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional. This could cause the person's immune system to be unable to fight off a simple infection or to start attacking other body cells. Because leukemia prevents the immune system from working normally, some people experience frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections. Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor. Some people experience other symptoms, such as feeling sick, having fevers, chills, night sweats, feeling fatigued and other flu-like symptoms. Some people experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.[32] If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. Uncommon neurological symptoms like migraines, seizures, or coma can occur as a result of brain stem pressure. All symptoms associated with leukemia can be attributed to other diseases. Consequently, leukemia is always diagnosed through medical tests. The word leukemia, which means 'white blood', is derived from the characteristic high white blood cell count that presents in most afflicted people before treatment. The high number of white blood cells is apparent when a blood sample is viewed under a microscope, with the extra white blood cells frequently being immature or dysfunctional. The excessive number of cells can also interfere with the level of other cells, causing further harmful imbalance in the blood count. Some people diagnosed with leukemia do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells that disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For a person with aleukemia, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.[33] ## Causes[edit] There is no single known cause for any of the different types of leukemias. The few known causes, which are not generally factors within the control of the average person, account for relatively few cases.[34] The cause for most cases of leukemia is unknown. The different leukemias likely have different causes. Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances.[35] Among adults, the known causes are natural and artificial ionizing radiation, a few viruses such as human T-lymphotropic virus, and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies.[36][37][38] Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults.[36] Cohort and case-control studies have linked exposure to some petrochemicals and hair dyes to the development of some forms of leukemia. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit.[34] Viruses have also been linked to some forms of leukemia. For example, human T-lymphotropic virus (HTLV-1) causes adult T-cell leukemia.[39] A few cases of maternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported.[36] Children born to mothers who use fertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.[40] ### Radiation[edit] Large doses of Sr-90 emission from nuclear reactor accidents, nicknamed bone seeker increases the risk of bone cancer and leukemia in animals, and is presumed to do so in people.[41] ### Genetic conditions[edit] Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies.[36] The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers.[36] In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia.[37] For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia.[36] Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia.[42] Chronic myelogenous leukemia is associated with a genetic abnormality called the Philadelphia translocation; 95% of people with CML carry the Philadelphia mutation, although this is not exclusive to CML and can be observed in people with other types of leukemia.[43][44][45][46] ### Non-ionizing radiation[edit] Whether or not non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power.[47] They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause some cases of childhood leukemia.[47] No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated.[47] Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization concludes that ELF exposure, if later proven to be causative, would account for just 100 to 2400 cases worldwide each year, representing 0.2 to 4.9% of the total incidence of childhood leukemia for that year (about 0.03 to 0.9% of all leukemias).[48] ## Diagnosis[edit] The increase in white blood cells in leukemia. Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms. Sometimes, blood tests may not show that a person has leukemia, especially in the early stages of the disease or during remission. A lymph node biopsy can be performed to diagnose certain types of leukemia in certain situations. Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the person. When concerns arise about other damages due to leukemia, doctors may use an X-ray, MRI, or ultrasound. These can potentially show leukemia's effects on such body parts as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound). CT scans can be used to check lymph nodes in the chest, though this is uncommon. Despite the use of these methods to diagnose whether or not a person has leukemia, many people have not been diagnosed because many of the symptoms are vague, non-specific, and can refer to other diseases. For this reason, the American Cancer Society estimates that at least one-fifth of the people with leukemia have not yet been diagnosed.[33] ## Treatment[edit] Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is effective. ### Acute lymphoblastic[edit] Further information: Acute lymphoblastic leukemia § Treatment Management of ALL is directed towards control of bone marrow and systemic (whole-body) disease. Additionally, treatment must prevent leukemic cells from spreading to other sites, particularly the central nervous system (CNS) e.g. monthly lumbar punctures.[clarification needed] In general, ALL treatment is divided into several phases: * Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs (prednisone, L-asparaginase, and vincristine) for the first month of treatment. * Consolidation therapy or intensification therapy to eliminate any remaining leukemia cells. There are many different approaches to consolidation, but it is typically a high-dose, multi-drug treatment that is undertaken for a few months. People with low- to average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). People who are high-risk receive higher drug doses of these drugs, plus additional drugs. * CNS prophylaxis (preventive therapy) to stop the cancer from spreading to the brain and nervous system in high-risk people. Standard prophylaxis may include radiation of the head and/or drugs delivered directly into the spine. * Maintenance treatments with chemotherapeutic drugs to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves lower drug doses, and may continue for up to three years. * Alternatively, allogeneic bone marrow transplantation may be appropriate for high-risk or relapsed people.[49] ### Chronic lymphocytic[edit] Further information: Chronic lymphocytic leukemia § Treatment #### Decision to treat[edit] Hematologists base CLL treatment on both the stage and symptoms of the individual person. A large group of people with CLL have low-grade disease, which does not benefit from treatment. Individuals with CLL-related complications or more advanced disease often benefit from treatment. In general, the indications for treatment are: * Falling hemoglobin or platelet count * Progression to a later stage of disease * Painful, disease-related overgrowth of lymph nodes or spleen * An increase in the rate of lymphocyte production[50] #### Treatment approach[edit] Most CLL cases are incurable by present treatments, so treatment is directed towards suppressing the disease for many years, rather than curing it. The primary chemotherapeutic plan is combination chemotherapy with chlorambucil or cyclophosphamide, plus a corticosteroid such as prednisone or prednisolone. The use of a corticosteroid has the additional benefit of suppressing some related autoimmune diseases, such as immunohemolytic anemia or immune-mediated thrombocytopenia. In resistant cases, single-agent treatments with nucleoside drugs such as fludarabine,[51] pentostatin, or cladribine may be successful. Younger and healthier people may choose allogeneic or autologous bone marrow transplantation in the hope of a permanent cure.[52] ### Acute myelogenous[edit] Further information: Acute myeloid leukemia § Treatment Many different anti-cancer drugs are effective for the treatment of AML. Treatments vary somewhat according to the age of the person and according to the specific subtype of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease, while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. Consolidation and maintenance treatments are intended to prevent disease recurrence. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.[53] ### Chronic myelogenous[edit] Further information: Chronic myelogenous leukemia § Treatment There are many possible treatments for CML, but the standard of care for newly diagnosed people is imatinib (Gleevec) therapy.[54] Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of people will be able to keep the disease in check for at least five years,[54] so that CML becomes a chronic, manageable condition. In a more advanced, uncontrolled state, when the person cannot tolerate imatinib, or if the person wishes to attempt a permanent cure, then an allogeneic bone marrow transplantation may be performed. This procedure involves high-dose chemotherapy and radiation followed by infusion of bone marrow from a compatible donor. Approximately 30% of people die from this procedure.[54] ### Hairy cell[edit] Further information: Hairy cell leukemia § Treatment Decision to treat People with hairy cell leukemia who are symptom-free typically do not receive immediate treatment. Treatment is generally considered necessary when the person shows signs and symptoms such as low blood cell counts (e.g., infection-fighting neutrophil count below 1.0 K/µL), frequent infections, unexplained bruises, anemia, or fatigue that is significant enough to disrupt the person's everyday life. Typical treatment approach People who need treatment usually receive either one week of cladribine, given daily by intravenous infusion or a simple injection under the skin, or six months of pentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.[55] Other treatments include rituximab infusion or self-injection with Interferon-alpha. In limited cases, the person may benefit from splenectomy (removal of the spleen). These treatments are not typically given as the first treatment because their success rates are lower than cladribine or pentostatin.[56] ### T-cell prolymphocytic[edit] Further information: T-cell prolymphocytic leukemia § Treatment Most people with T-cell prolymphocytic leukemia, a rare and aggressive leukemia with a median survival of less than one year, require immediate treatment.[57] T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs.[57] Many different treatments have been attempted, with limited success in certain people: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone CHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycin VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.[57] Some people who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.[57] ### Juvenile myelomonocytic[edit] Further information: Juvenile myelomonocytic leukemia § Treatment Treatment for juvenile myelomonocytic leukemia can include splenectomy, chemotherapy, and bone marrow transplantation.[58] ### Teeth[edit] Before dental work it is recommended that the person's physician be consulted. Dental work is recommended before chemotherapy or radiation therapy. Those in remission can be treated per normal.[59] ## Prognosis[edit] The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world.[9] The average five-year survival rate is 61% in the United States.[4] In children under 15, the five-year survival rate is greater (60 to 85%), depending on the type of leukemia.[12] In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.[12] Outcomes depend on whether it is acute or chronic, the specific abnormal white blood cell type, the presence and severity of anemia or thrombocytopenia, the degree of tissue abnormality, the presence of metastasis and lymph node and bone marrow infiltration, the availability of therapies and the skills of the health care team. Treatment outcomes may be better when people are treated at larger centers with greater experience.[60] ## Epidemiology[edit] Deaths due to leukemia per million persons in 2012 0-7 8-13 14–22 23–29 30–34 35–39 40–46 47–64 65–85 86–132 In 2010, globally, approximately 281,500 people died of leukemia.[61] In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it.[62] This represents about 3% of the almost seven million deaths due to cancer that year, and about 0.35% of all deaths from any cause.[62] Of the sixteen separate sites the body compared, leukemia was the 12th most common class of neoplastic disease, and the 11th most common cause of cancer-related death.[62] Leukemia occurs more commonly in the developed world.[63] ### United States[edit] About 245,000 people in the United States are affected with some form of leukemia, including those that have achieved remission or cure. Rates from 1975 to 2011 have increased by 0.7% per year among children.[64] Approximately 44,270 new cases of leukemia were diagnosed in the year 2008 in the US.[65] This represents 2.9% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States, and 30.4% of all blood cancers.[66] Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia.[65] A type of leukemia is the second most common form of cancer in infants (under the age of 12 months) and the most common form of cancer in older children.[67] Boys are somewhat more likely to develop leukemia than girls, and white American children are almost twice as likely to develop leukemia than black American children.[67] Only about 3% cancer diagnoses among adults are for leukemias, but because cancer is much more common among adults, more than 90% of all leukemias are diagnosed in adults.[65] Race is a risk factor in the United States. Hispanics, especially those under the age of 20, are at the highest risk for leukemia, while whites, Native Americans, Asian Americans, and Alaska Natives are at higher risk than African Americans.[68] More men than women are diagnosed with leukemia and die from the disease. Around 30 percent more men than women have leukemia.[69] ### UK[edit] Overall, leukaemia is the eleventh most common cancer in the UK (around 8,600 people were diagnosed with the disease in 2011), and it is the ninth most common cause of cancer death (around 4,800 people died in 2012).[70] ## History[edit] See also: Timeline of leukemia Rudolf Virchow Leukemia was first described by anatomist and surgeon Alfred-Armand-Louis-Marie Velpeau in 1827. A more complete description was given by pathologist Rudolf Virchow in 1845. Around ten years after Virchow's findings, pathologist Franz Ernst Christian Neumann found that the bone marrow of a deceased person with leukemia was colored "dirty green-yellow" as opposed to the normal red. This finding allowed Neumann to conclude that a bone marrow problem was responsible for the abnormal blood of people with leukemia. By 1900 leukemia was viewed as a family of diseases as opposed to a single disease. By 1947 Boston pathologist Sidney Farber believed from past experiments that aminopterin, a folic acid mimic, could potentially cure leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them were actually cured. This, however, led to further experiments. In 1962, researchers Emil J. Freireich, Jr. and Emil Frei III used combination chemotherapy to attempt to cure leukemia. The tests were successful with some people surviving long after the tests.[71] ### Etymology[edit] Observing an abnormally large number of white blood cells in a blood sample from a person, Virchow called the condition Leukämie in German, which he formed from the two Greek words leukos (λευκός), meaning "white", and haima (αἷμα), meaning "blood".[72] ## Society and culture[edit] According to Susan Sontag, leukemia was often romanticized in 20th-century fiction, portrayed as a joy-ending, clean disease whose fair, innocent and gentle victims die young or at the wrong time. As such, it was the cultural successor to tuberculosis, which held this cultural position until it was discovered to be an infectious disease.[73] The 1970 romance novel Love Story is an example of this romanticization of leukemia.[74] In the United States, around $5.4 billion is spent on treatment a year.[75] ## Research directions[edit] Significant research into the causes, prevalence, diagnosis, treatment, and prognosis of leukemia is being performed. Hundreds of clinical trials are being planned or conducted at any given time.[76] Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care in remission or after cures. In general, there are two types of leukemia research: clinical or translational research and basic research. Clinical/translational research focuses on studying the disease in a defined and generally immediately applicable way, such as testing a new drug in people. By contrast, basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause leukemic changes in isolated cells in the laboratory or how the DNA changes inside leukemia cells as the disease progresses. The results from basic research studies are generally less immediately useful to people with the disease.[77] Treatment through gene therapy is currently being pursued. One such approach used genetically modified T cells, known as chimeric antigen receptor T cells (CAR-T cells), to attack cancer cells. In 2011, a year after treatment, two of the three people with advanced chronic lymphocytic leukemia were reported to be cancer-free[78] and in 2013, three of five subjects who had acute lymphocytic leukemia were reported to be in remission for five months to two years.[79] Subsequent studies with a variety of CAR-T types continue to be promising.[80] As of 2018, two CAR-T therapies have been approved by the Food and Drug Administration. CAR-T treatment has significant side effects,[81] and loss of the antigen targeted by the CAR-T cells is a common mechanism for relapse.[80] The stem cells that cause different types of leukaemia are also being researched.[82] ## Pregnancy[edit] Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.[83] How it is handled depends primarily on the type of leukemia. Nearly all leukemias appearing in pregnant women are acute leukemias.[84] Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester.[83] Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with Interferon-alpha hormones.[83] Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.[83][84] ## See also[edit] * Acute erythroid leukemia * Antileukemic drugs, medications used to kill leukemia cells * Cancer-related fatigue * Hematologic diseases, the large class of blood-related disorders, including leukemia * Multiple myeloma ## References[edit] 1. ^ "Leukemia". Merriam-Webster. Archived from the original on 6 October 2014. 2. ^ a b c d e f "What You Need To Know About™ Leukemia". National Cancer Institute. 23 December 2013. Archived from the original on 6 July 2014. Retrieved 18 June 2014. 3. ^ a b c d e f g h i j "A Snapshot of Leukemia". NCI. Archived from the original on 4 July 2014. Retrieved 18 June 2014. 4. ^ a b c d "SEER Stat Fact Sheets: Leukemia". National Cancer Institute. 2011. Archived from the original on 16 July 2016. 5. ^ a b c d e Hutter, JJ (June 2010). "Childhood leukemia". Pediatrics in Review. 31 (6): 234–41. doi:10.1542/pir.31-6-234. PMID 20516235. 6. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 7. ^ a b GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 8. ^ "Leukemia". NCI. 1 January 1980. Archived from the original on 27 May 2014. Retrieved 13 June 2014. "Cancer that starts in blood-forming tissue, such as the bone marrow, and causes large numbers of abnormal blood cells" 9. ^ a b c d e World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.13. ISBN 978-9283204299. 10. ^ Vardiman, JW; Thiele, J; Arber, DA; Brunning, RD; Borowitz, MJ; Porwit, A; Harris, NL; Le Beau, MM; Hellström-Lindberg, E; Tefferi, A; Bloomfield, CD (30 July 2009). "The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes". Blood. 114 (5): 937–51. doi:10.1182/blood-2009-03-209262. PMID 19357394. S2CID 3101472. 11. ^ Cătoi, Alecsandru Ioan Baba, Cornel (2007). Comparative oncology. Bucharest: The Publishing House of the Romanian Academy. p. Chapter 17. ISBN 978-973-27-1457-7. Archived from the original on 10 September 2017. 12. ^ a b c d American Cancer Society (2 March 2014). "Survival rates for childhood leukemia". Archived from the original on 14 July 2014. 13. ^ "Chronic Lymphocytic Leukemia (CLL) - Hematology and Oncology". MSD Manual Professional Edition. Retrieved 1 February 2020. 14. ^ "Key Statistics for Acute Lymphocytic Leukemia (ALL)". American Cancer Society. 8 January 2019. Retrieved 9 December 2019. 15. ^ Finding Cancer Statistics » Cancer Stat Fact Sheets »Chronic Lymphocytic Leukemia Archived 16 April 2008 at the Wayback Machine National Cancer Institute. 16. ^ "Survival: Acute Myeloid Leukaemia". Cancer Research UK. 10 July 2019. Retrieved 2 December 2019. 17. ^ "Novartis Oncology". Archived from the original on 5 November 2013. 18. ^ Patients with Chronic Myelogenous Leukemia Continue to Do Well on Imatinib at 5-Year Follow-Up Archived 15 May 2013 at the Wayback Machine Medscape Medical News 2006. 19. ^ Updated Results of Tyrosine Kinase Inhibitors in CML Archived 29 December 2007 at the Wayback Machine ASCO 2006 Conference Summaries. 20. ^ Else, M., Ruchlemer, R., Osuji, N. (2005). "Long remissions in hairy cell leukemia with purine analogs: a report of 219 patients with a median follow-up of 12.5 years". Cancer. 104 (11): 2442–8. doi:10.1002/cncr.21447. PMID 16245328. S2CID 43282431.CS1 maint: multiple names: authors list (link) 21. ^ Matutes Estella (1998). "T-cell prolymphocytic leukemia". Cancer Control. 5 (1): 19–24. doi:10.1177/107327489800500102. PMID 10761013. Archived from the original on 11 February 2009. 22. ^ Valbuena JR, Herling M, Admirand JH, Padula A, Jones D, Medeiros LJ (March 2005). "T-cell prolymphocytic leukemia involving extramedullary sites". American Journal of Clinical Pathology. 123 (3): 456–64. doi:10.1309/93P4-2RNG-5XBG-3KBE. PMID 15716243. Archived from the original on 15 May 2013. 23. ^ Elaine Sarkin Jaffe, Nancy Lee Harris, World Health Organization, International Agency for Research on Cancer, Harald Stein, J. W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 978-92-832-2411-2.CS1 maint: multiple names: authors list (link) 24. ^ a b Reiter A, Gotlib J (2017). "Myeloid neoplasms with eosinophilia". Blood. 129 (6): 704–714. doi:10.1182/blood-2016-10-695973. PMID 28028030. 25. ^ Gotlib J (2015). "World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management". American Journal of Hematology. 90 (11): 1077–89. doi:10.1002/ajh.24196. PMID 26486351. S2CID 42668440. 26. ^ Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254. S2CID 18338178. 27. ^ Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I (October 2016). "Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update". Current Hematologic Malignancy Reports. 11 (5): 333–41. doi:10.1007/s11899-016-0338-x. PMC 5031718. PMID 27510823. 28. ^ Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC 5391620. PMID 28179280. 29. ^ Seewald L, Taub JW, Maloney KW, McCabe ER (September 2012). "Acute leukemias in children with Down syndrome". Molecular Genetics and Metabolism. 107 (1–2): 25–30. doi:10.1016/j.ymgme.2012.07.011. PMID 22867885. 30. ^ Reference list is found at image description page in Wikimedia Commons 31. ^ Clarke, RT; Van den Bruel, A; Bankhead, C; Mitchell, CD; Phillips, B; Thompson, MJ (October 2016). "Clinical presentation of childhood leukaemia: a systematic review and meta-analysis". Archives of Disease in Childhood. 101 (10): 894–901. doi:10.1136/archdischild-2016-311251. PMID 27647842. 32. ^ "Leukemia". Columbia Electronic Encyclopedia, 6th Edition. Retrieved 4 November 2011. 33. ^ a b American Cancer Society (2010). "How is Leukemia Diagnosed?". Detailed Guide: Leukemia – Adult Chronic. American Cancer Society. Archived from the original on 5 April 2010. Retrieved 4 May 2010. 34. ^ a b Ross JA, Kasum CM, Davies SM, Jacobs DR, Folsom AR, Potter JD (August 2002). "Diet and risk of leukemia in the Iowa Women's Health Study". Cancer Epidemiol. Biomarkers Prev. 11 (8): 777–81. PMID 12163333. Archived from the original on 10 September 2017. 35. ^ Radivoyevitch, T; Sachs, R K; Gale, R P; Molenaar, R J; Brenner, D J; Hill, B T; Kalaycio, M E; Carraway, H E; Mukherjee, S (2015). "Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation". Leukemia. 30 (2): 285–294. doi:10.1038/leu.2015.258. PMID 26460209. S2CID 22100511. 36. ^ a b c d e f Wiernik, Peter H. (2001). Adult leukemias. New York: B. C. Decker. pp. 3–15. ISBN 978-1-55009-111-3. 37. ^ a b Robinette, Martin S.; Cotter, Susan; Van de Water (2001). Quick Look Series in Veterinary Medicine: Hematology. Teton NewMedia. p. 105. ISBN 978-1-893441-36-1. 38. ^ Stass, Sanford A.; Schumacher, Harold R.; Rock, William R. (2000). Handbook of hematologic pathology. New York, N.Y: Marcel Dekker. pp. 193–194. ISBN 978-0-8247-0170-3. 39. ^ Leonard, Barry (1998). Leukemia: A Research Report. DIANE Publishing. p. 7. ISBN 978-0-7881-7189-5. 40. ^ Rudant J, Amigou A, Orsi L, Althaus T, Leverger G, Baruchel A, Bertrand Y, Nelken B, Plat G, Michel G, Sirvent N, Chastagner P, Ducassou S, Rialland X, Hémon D, Clavel J (2013). "Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE)". Pediatr Blood Cancer. 60 (2): 301–8. doi:10.1002/pbc.24192. PMID 22610722. S2CID 26010916. 41. ^ "Sr-90 is known to increase the risk of bone cancer and leukemia in animals, and is presumed to do so in people; from google (nuclear reactor emit tritium) result 1, 2, 3". Archived from the original on 20 July 2017. 42. ^ Pasmant, E; Ballerini, P; Lapillonne, H; Perot, C; Vidaud, D; Leverger, G; Landman-Parker, J (2009). "SPRED1 disorder and predisposition to leukemia in children". Blood. 114 (5): 1131. doi:10.1182/blood-2009-04-218503. PMID 19643996. 43. ^ Salesse, Stephanie; Verfaillie, Catherine M. (9 December 2002). "BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia". Oncogene. 21 (56): 8547–8559. doi:10.1038/sj.onc.1206082. ISSN 0950-9232. PMID 12476301. 44. ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. 2 February 2011. Archived from the original on 16 February 2017. Retrieved 15 February 2017. 45. ^ "Do We Know What Causes Chronic Myeloid Leukemia?". www.cancer.org. Archived from the original on 16 February 2017. Retrieved 15 February 2017. 46. ^ "What is chronic myeloid leukaemia? (CML) – Understanding – Macmillan Cancer Support". www.macmillan.org.uk. Archived from the original on 16 February 2017. Retrieved 15 February 2017. 47. ^ a b c Non-Ionizing Radiation, Part 1: Static and Extremely Low-Frequency (ELF) Electric and Magnetic Fields (IARC Monographs on the Evaluation of the Carcinogenic Risks). Geneva: World Health Organisation. 2002. pp. 332–333, 338. ISBN 978-92-832-1280-5. Archived from the original on 6 December 2008. 48. ^ "WHO \| Electromagnetic fields and public health". Archived from the original on 16 February 2009. Retrieved 18 February 2009. 49. ^ Hoffbrand, A.V.; Moss, P.A.H.; Pettit, J.E. (2006). Essential haematology (5th ed.). Malden, Mass.: Blackwell Pub. ISBN 978-1-4051-3649-5. 50. ^ National Cancer Institute (1 January 1980). "Chronic Lymphocytic Leukemia (PDQ) Treatment: Stage Information". Archived from the original on 17 October 2007. Retrieved 4 September 2007. 51. ^ Eichhorst BF; Busch R; Hopfinger G; Pasold R; Hensel M; Steinbrecher C; Siehl S; Jäger U; Bergmann M; Stilgenbauer S; Schweighofer C; Wendtner CM; Döhner H; Brittinger G; Emmerich B; Hallek M; German CLL Study Group. (2006). "Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia". Blood. 107 (3): 885–91. doi:10.1182/blood-2005-06-2395. PMID 16219797. 52. ^ Gribben JG (January 2008). "Stem cell transplantation in chronic lymphocytic leukemia". Biol. Blood Marrow Transplant. 15 (1 Suppl): 53–8. doi:10.1016/j.bbmt.2008.10.022. PMC 2668540. PMID 19147079. 53. ^ American Cancer Society (22 March 2012). "Typical treatment of acute myeloid leukemia (except promyelocytic M3)". Detailed Guide: Leukemia – Acute Myeloid (AML). American Cancer Society. Archived from the original on 12 November 2012. Retrieved 31 October 2012. 54. ^ a b c Fausel C (October 2007). "Targeted chronic myeloid leukemia therapy: seeking a cure" (PDF). J Manag Care Pharm. 13 (8 Suppl A): 8–12. PMID 17970609. Archived from the original (PDF) on 28 May 2008. Retrieved 18 May 2008. 55. ^ Robak, T; Jamroziak, K; Gora-Tybor, J; Blonski, J. Z.; Kasznicki, M; Dwilewicz-Trojaczek, J; Wiater, E; Zdunczyk, A; Dybowicz, J; Dmoszynska, A; Wojtaszko, M; Zdziarska, B; Calbecka, M; Kostyra, A; Hellmann, A; Lewandowski, K; Stella-Holowiecka, B; Sulek, K; Gawronski, K; Skotnicki, A. B.; Nowak, W; Zawilska, K; Molendowicz-Portala, L; Kloczko, J; Sokolowski, J; Warzocha, K; Seferynska, I; Ceglarek, B; Konopka, L (2007). "Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: Final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial". Blood. 109 (9): 3672–5. doi:10.1182/blood-2006-08-042929. PMID 17209059. 56. ^ Saven, A; Burian, C; Adusumalli, J; Koziol, J. A. (1999). "Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia". Blood. 93 (8): 2471–7. doi:10.1182/blood.V93.8.2471. PMID 10194424. 57. ^ a b c d Dearden CE, Matutes E, Cazin B (September 2001). "High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H". Blood. 98 (6): 1721–6. doi:10.1182/blood.V98.6.1721. PMID 11535503. S2CID 26664911. 58. ^ "JMMLfoundation.org". JMMLfoundation.org. Archived from the original on 25 January 2009. Retrieved 29 August 2010. 59. ^ Mancheno Franch, A.; Gavalda Esteve, C.; Sarrion Perez, MG. (2011). "Oral manifestations and dental management of patient with leukocyte alterations". Journal of Clinical and Experimental Dentistry: e53–e59. doi:10.4317/jced.3.e53. ISSN 1989-5488. 60. ^ Stock, W (2010). "Adolescents and young adults with acute lymphoblastic leukemia". Hematology. American Society of Hematology. Education Program. 2010: 21–9. doi:10.1182/asheducation-2010.1.21. PMID 21239766. 61. ^ Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA (December 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. hdl:10536/DRO/DU:30050819. PMID 23245604. S2CID 1541253. 62. ^ a b c Mathers, Colin D, Cynthia Boschi-Pinto, Alan D Lopez and Christopher JL Murray (2001). "Cancer incidence, mortality and survival by site for 14 regions of the world" (PDF). Global Programme on Evidence for Health Policy Discussion Paper No. 13. World Health Organization.CS1 maint: multiple names: authors list (link) 63. ^ World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.13. ISBN 978-9283204299. 64. ^ Amitay, EL; Keinan-Boker, L (1 June 2015). "Breastfeeding and Childhood Leukemia Incidence: A Meta-analysis and Systematic Review". JAMA Pediatrics. 169 (6): e151025. doi:10.1001/jamapediatrics.2015.1025. PMID 26030516. 65. ^ a b c "Leukemia Facts & Statistics." Archived 16 April 2009 at the Wayback Machine The Leukemia & Lymphoma Society. Retrieved 2 July 2009. 66. ^ Horner MJ, Ries LAG, Krapcho M, Neyman N, et al. (eds). "SEER Cancer Statistics Review, 1975–2006". Surveillance Epidemiology and End Results (SEER). Bethesda, MD: National Cancer Institute. Archived from the original on 26 September 2009. Retrieved 3 November 2009. "Table 1.4: Age-Adjusted SEER Incidence and U.S. Death Rates and 5-Year Relative Survival Rates By Primary Cancer Site, Sex and Time Period"CS1 maint: multiple names: authors list (link) 67. ^ a b James G. Gurney, Malcolm A. Smith, Julie A. Ross (1999) Cancer Incidence and Survival among Children and Adolescents, United States SEER program 1975–1995, chapter on Leukemia Archived 24 December 2010 at the Wayback Machine Cancer Statistics Branch, National Cancer Institute, available online from the SEER web site Archived 24 December 2010 at the Wayback Machine 68. ^ Childhood Blood Cancers \| The Leukemia & Lymphoma Society Archived 5 September 2012 at the Wayback Machine 69. ^ Facts 2012 from The Leukemia & Lymphoma Society Archived 14 October 2012 at the Wayback Machine 70. ^ "Leukaemia (all subtypes combined) statistics". Cancer Research UK. Archived from the original on 7 October 2014. Retrieved 27 October 2014. 71. ^ Patlak, M (2002). "Targeting leukemia: From bench to bedside". FASEB Journal. 16 (3): 273. doi:10.1096/fj.02-0029bkt. PMID 11874976. S2CID 221751708. 72. ^ "Leukemia: MedlinePlus Medical Encyclopedia". MedlinePlus. 8 May 2019. Retrieved 16 May 2019. 73. ^ Sontag, Susan (1978). Illness as Metaphor. New York: Farrar, Straus and Giroux. pp. 18. ISBN 978-0-374-17443-9. 74. ^ Bey, Bridget (2017). Cancer as Metaphor: The Metaphorical Implications of Romanticized Illness in Young Adult Fiction (English Honors thesis). Trinity University. p. 5-6. 75. ^ "A Snapshot of Leukemia". NCI. Archived from the original on 4 July 2014. Retrieved 18 June 2014. 76. ^ "Search of: leukemia — List Results — ClinicalTrials.gov". Archived from the original on 15 September 2010. 77. ^ "Understanding Clinical Trials for Blood Cancers" (PDF). Leukemia and Lymphoma Society. Archived from the original (PDF) on 5 January 2011. Retrieved 19 May 2010. 78. ^ Jaslow, Ryan. "New Leukemia Therapy Destroys Cancer by Turning Blood Cells into "Assassins"". CBSnews.com HealthPop section. Archived from the original on 31 March 2014. Retrieved 11 August 2011. 79. ^ Coghlan, Andy (26 March 2013) Gene therapy cures leukaemia in eight days Archived 15 May 2015 at the Wayback Machine The New Scientist, Retrieved 15 April 2013 80. ^ a b Zhao, Juanjuan; Song, Yongping; Liu, Delong (14 February 2019). "Clinical trials of dual-target CAR T cells, donor-derived CAR T cells, and universal CAR T cells for acute lymphoid leukemia". Journal of Hematology & Oncology. 12 (1): 17. doi:10.1186/s13045-019-0705-x. ISSN 1756-8722. PMC 6376657. PMID 30764841. 81. ^ Zheng, Ping-Pin; Kros, Johan M.; Li, Jin (2018). "Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts". Drug Discovery Today. 23 (6): 1175–1182. doi:10.1016/j.drudis.2018.02.012. hdl:1765/105338. PMID 29501911. 82. ^ "How we're beating leukaemia". Leukaemia & Lymphoma Research. Archived from the original on 27 September 2013. Retrieved 24 September 2013. 83. ^ a b c d Shapira T, Pereg D, Lishner M (September 2008). "How I treat acute and chronic leukemia in pregnancy". Blood Rev. 22 (5): 247–59. doi:10.1016/j.blre.2008.03.006. PMID 18472198. 84. ^ a b Koren G, Lishner M (2010). "Pregnancy and commonly used drugs in hematology practice". Hematology Am Soc Hematol Educ Program. 2010: 160–5. doi:10.1182/asheducation-2010.1.160. PMID 21239787. S2CID 21832575. ## External links[edit] Classification D * ICD-10: C91-C95 * ICD-9-CM: 208.9 * ICD-O: 9800–9940 * MeSH: D007938 * DiseasesDB: 7431 External resources * MedlinePlus: 001299 * eMedicine: article/1201870 * Scholia: Q29496 Wikimedia Commons has media related to Leukemias. * Leukemia at Curlie * Leukaemia information from Cancer Research UK * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia Authority control * GND: 4035487-8 * LCCN: sh85076285 * NARA: 10639801 * NDL: 00562843 * NSK: 000180835 [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	Leukemia	c0023418	5,731	wikipedia	https://en.wikipedia.org/wiki/Leukemia	2021-01-18T18:38:35	{"mesh": ["D007938"], "umls": ["C0023418"], "wikidata": ["Q29496"]}
Melanocortin 4 receptor (MC4R) deficiency is the commonest form of monogenic obesity identified so far. MC4R deficiency is characterised by severe obesity, an increase in lean body mass and bone mineral density, increased linear growth in early childhood, hyperphagia beginning in the first year of life and severe hyperinsulinaemia, in the presence of preserved reproductive function. ## Epidemiology The prevalence in the general population is probably around 1 in 2000. The prevalence of MC4R mutations has been estimated at between 0.5 and 1% in obese adults (body mass index >30) with higher values among populations with severe childhood-onset obesity and variability between ethnic groups. ## Etiology MC4R is a G protein-coupled receptor involved in the hypothalamic leptin-melanocortin signalling pathway. Activation of the MC4R plays a key role in the maintenance of energy homeostasis and is associated with suppression of food intake. The majority of patients described so far are carriers of heterozygous mutations in the MC4R gene (18q22). Rare homozygous carriers have been described and display a more severe phenotype. However, one homozygous patient with complete absence of MC4R function has been reported and did not display hyperinsulinaemia. ## Diagnostic methods The majority of MC4R deficient cases reported so far have been identified through genetic screening of large cohorts of obese patients, however, diagnosis may be suspected on the basis of the clinical features of the disorder and confirmed by detection of a MC4R mutation. ## Genetic counseling MC4R deficiency is transmitted in a codominant manner, with expressivity and penetrance varying between ethnic groups. ## Management and treatment At present, there is no specific treatment for MC4R deficiency. However, future development of small molecule MC4R agonists might lead to the generation of highly effective treatments for this disorder. ## Prognosis As with other forms of obesity, the prognosis is dependent on the complications present, with obese patients being at increased risk of cardiovascular disease, cancer and type 2 diabetes. [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	Obesity due to melanocortin 4 receptor deficiency	c0028754	5,732	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=71529	2021-01-23T18:28:04	{"mesh": ["D009765"], "omim": ["601665", "618406"], "icd-10": ["E66.8"], "synonyms": ["MC4R deficiency"]}
A number sign (#) is used with this entry because of evidence that cerebrocostomandibular syndrome (CCMS) is caused by heterozygous mutation in the SNRPB gene (182282) on chromosome 20p13. Description Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (Zeevaert et al., 2009). See CDG2G (611209) for a cerebrocostomandibular-like syndrome. Clinical Features In a female and 2 male sibs, McNicholl et al. (1970) described a syndrome of mental retardation, palatal defects (short hard palate with central hole, absent soft palate, absent uvula), micrognathia, glossoptosis, and severe costovertebral abnormalities. A barking cough in one suggested tracheal cartilage abnormality as in the case of Smith et al. (1966) which bore other similarities. In the family reported by McNicholl et al. (1970), the normal father and mother were 40 and 33, respectively, at the birth of the first affected child. The condition has also been designated 'rib gap defects with micrognathia' (Miller et al., 1972). The 'gaps' occur in the posterior portion of the ribs and may lead to 'flail chest.' Silverman et al. (1980) gave an extensive review of 22 cases. They pointed out that familial cases are seemingly unusual and stated that 'the possibility exists that some teratogenic agent has played a role in the clustering of cases since 1963...' Cleft palate and glossoptosis often contribute to the presenting sign, neonatal respiratory distress. Intrauterine and postnatal growth retardation are common. Deficiency in the posterior portion of affected ribs by roentgenography is a sine qua non for diagnosis. Leroy et al. (1981) provided the first evidence of dominant inheritance; a mother and her son and daughter (by different fathers) were affected. The 3 patients were intellectually normal, but indistinct speech was commented on. The authors suggested that mental defect may not be inherent to CCMS but rather a frequent consequence of neonatal respiratory distress. Schroer and Meyer (1985) reported an isolated case in a 15-year-old girl. Hennekam et al. (1985) reported 2 affected brothers who also had spina bifida. Trautman et al. (1985) reported CCMS in the sib of a patient reported by Silverman et al. (1980). This observation lends support to autosomal recessive inheritance. Drossou-Agakidou et al. (1991) described a sibship with 2 sets of dizygotic twins with CCMS. All 4 had Pierre-Robin anomalad and rib dysplasia. Cerebral involvement was evident in 2 who had had perinatal asphyxia. Plotz et al. (1996) described 2 more sporadic cases of this syndrome in males, one of whom died at 12 hours, and the other at 10 months. A detailed review of 48 previously reported cases showed that respiratory distress, gaps of posterior ribs, and micrognathia were virtually constant manifestations. Males were affected in 28 of 47 cases. Approximately two-thirds of patients had cleft palate and glossoptosis. Microcephaly was found in 11 of 28 cases. Defects of the heart and kidneys were uncommon. Merlob et al. (1987) described affected father and daughter. Prenatal diagnosis was made by ultrasonography in the case of the daughter. The most prominent ultrasonographic sign was the unusual shape of the ribs, which were very short and defective. The diagnosis can be confirmed in utero by ultrasound examination of the fetal mandible and head. Hennekam and Goldschmeding (1998) described a newborn with complete absence of ossification of the ribs, extreme micrognathia, absence of external ear canals and the inner ears, and diminished mobility in the upper limbs. They suggested that this represents an unusually severe expression of the CCM syndrome. Myogenic factor-5 (MYF5; 159990), goosecoid (GSC; 138890), and CBFA1 (RUNX2; 600211) were discussed as candidate genes, on the basis of their role in bone formation and the phenotype of knockout mice. Kirk et al. (1999) described a family in which 2 sibs had apparently absent ribs and severe micrognathia on prenatal ultrasonography. The pregnancies were terminated at 19 and 12 weeks' gestation, respectively. At autopsy, the first fetus showed severe micrognathia, a U-shaped defect of the soft palate, marked postnuchal edema, absent olfactory bulbs, and cribriform plate and rib abnormalities. The ribs consisted of cartilage anteriorly, with only a small amount of fibrous tissue present laterally and posteriorly. The second fetus, at 12 weeks' gestation, had agnathia, with a large U-shaped defect of the soft palate. There was moderate postnuchal edema. The ribs were unossified and there were gaps in the cartilage where primitive mesenchyme was present posteriorly and laterally. These findings were consistent with a severe form of cerebrocostomandibular syndrome. The early fetal histopathology in both cases suggested a possible mechanism by which the characteristic 'rib gaps' of cerebrocostomandibular syndrome may develop, with evidence for abnormal function of a gene or genes involved in regulation of rib chondrogenesis. James and Aftimos (2003) reported an infant and her father with typical features of CCMS. The child was diagnosed on prenatal ultrasound and was found to have the previously unreported prenatal finding of an omphalocele. James and Aftimos (2003) reviewed 28 cases of familial CCMS and determined that families suggestive of autosomal recessive and autosomal dominant inheritance are not distinguishable on the basis of clinical manifestations. Tooley et al. (2016) tabulated the clinical and radiologic findings in 16 patients with CCMS, of whom 8 had previously been reported, including 6 by Lynch et al. (2014), 1 by Watson et al. (2014), and 1 by Ramaswamy et al. (2016). Severe micrognathia and reduced numbers of ribs with gaps were consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis were common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defects were observed. Microcephaly and significant developmental delay were present in a small minority of patients. Key radiologic findings included narrow thorax, multiple posterior rib gaps, and abnormal costotransverse articulation. A novel finding in 2 patients was bilateral accessory ossicles arising from the hyoid bone. Molecular Genetics Using a combination of whole-exome and Sanger sequencing in 10 unrelated families with CCMS, Lynch et al. (2014) identified heterozygosity for 6 different regulatory mutations in the SNRPB gene (see, e.g., 182282.0001-182282.0004) in 9 of 10 probands. All patients had micrognathia and posterior rib gaps. The authors noted that although intellectual disability is reported to be a common feature of CCMS, it was not prevalent in this cohort: 2 of the 14 patients for whom this information was provided had mild learning disabilities and another patient was reported to have mild neurocognitive delay. One patient with 'classic CCMS' was negative for sequence or copy-number variants in the coding regions and UTRs of the SNRPB gene. In 5 unrelated French patients with CCMS, who were negative for mutation in the NABP1 (OBFC2A; 612103) and NABP2 (OBFC2B; 612104) genes, Bacrot et al. (2015) identified heterozygosity for 4 missense mutations (see, e.g., 182282.0001 and 182282.0002) and 1 splice site mutation (182282.0004) in the SNRPB gene. All of the patients had Pierre-Robin sequence and posterior rib gaps, but no intellectual disability. Tooley et al. (2016) studied 16 patients with CCMS, including 8 who were previously reported (Lynch et al., 2014; Watson et al., 2014; Ramaswamy et al., 2016). SNRPB mutations were identified in 8 of the 9 patients for whom DNA was available and in whom mutations had not previously been reported; mutations in 7 of these patients had previously been described (see, e.g., 182282.0001 and 182282.0002). The authors concluded that CCMS is caused by specific SNRPB mutations in the vast majority of cases. ### Exclusion Studies In a male Taiwanese infant with features consistent with CCMS, offspring of nonconsanguineous parents, Su et al. (2010) screened 3 candidate genes identified by Hennekam and Goldschmeding (1998) (MYF5, GSC, and RUNX2), as well as the TCOF1 (606847) gene for mutations. No mutations were found in the coding exons or splice sites of the 4 genes. INHERITANCE \- Autosomal dominant GROWTH Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly Face \- Severe micrognathia (requiring surgical correction) \- Malar hypoplasia \- Long philtrum Ears \- Low-set ears \- Hearing loss, conductive \- Posteriorly rotated ears Eyes \- Epicanthal folds Mouth \- Glossoptosis \- Cleft soft palate \- Short palate \- High-arched palate \- Severely restricted mouth opening Teeth \- Dental anomalies Neck \- Pterygium colli \- Accessory ossicle adjacent to hyoid bone (in some patients) \- Redundant posterior neck skin (in some patients) CARDIOVASCULAR Heart \- Ventricular septal defect \- Atrial septal defect \- Patent ductus arteriosus RESPIRATORY \- Neonatal respiratory distress (requiring tracheostomy in most patients) Airways \- Abnormal tracheal cartilaginous ring Lung \- Alveolar hypoplasia CHEST External Features \- Bell-shaped thorax \- Small thorax Ribs Sternum Clavicles & Scapulae \- Rudimentary rib \- Anomalous rib insertion to vertebrae \- Posterior rib gap defects \- Absent twelfth rib ABDOMEN Gastrointestinal \- Gastroesophageal reflux \- Nasogastric tube or gastrostomy feeding required (in most patients) \- Anteriorly placed anus (rare) \- Anal stenosis (rare) GENITOURINARY Kidneys \- Renal cyst \- Renal ectopia \- Horseshoe kidney SKELETAL Spine \- Sacral fusion \- Scoliosis Pelvis \- Congenital hip dislocation Limbs \- Hypoplastic humerus \- Flexion contracture (elbow) Hands \- Fifth finger clinodactyly Feet \- Calcaneal epiphyseal stippling NEUROLOGIC Central Nervous System \- Mental retardation (50% patients, likely secondary to neonatal hypoxia) \- Porencephaly VOICE \- Nasal speech PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios MISCELLANEOUS \- Forty percent of patients die in the first year \- De novo mutation (in most patients) MOLECULAR BASIS \- Caused by mutation in the small nuclear ribonucleoprotein polypeptides B and B1 gene (SNRPB, 182282.0001 ) ▲ 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	CEREBROCOSTOMANDIBULAR SYNDROME	c0265342	5,733	omim	https://www.omim.org/entry/117650	2019-09-22T16:43:33	{"doid": ["0111248"], "mesh": ["C562538"], "omim": ["117650"], "orphanet": ["1393"], "synonyms": ["Alternative titles", "RIB GAP DEFECTS WITH MICROGNATHIA"]}
A rare intestinal disease characterized by potentially life-threatening inflammatory bowel necrosis predominantly affecting preterm neonates. Patients may present with feeding intolerance, lethargy, temperature instability, abdominal distention, blood-stained stools, diarrhea, bilious vomiting, apnea, and signs of sepsis. Radiographic features include pneumatosis intestinalis, portal venous gas, presence of fixed, dilated intestinal loops, bowel wall edema, and (in case of bowel perforation) pneumoperitoneum. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Necrotizing enterocolitis	c0520459	5,734	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391673	2021-01-23T18:23:46	{"gard": ["9767"], "mesh": ["D020345"], "umls": ["C0520459"], "icd-10": ["P77"]}
Fear, hatred towards, demonization of, or prejudice against people generally referred to as Tatars Part of a series on Discrimination General forms * Age * Class (Caste) * Physical Disability * Education * Economic * Employment * Genetics * Hair texture * Height * Housing * Language * Looks * Race / Ethnicity / Nationality * Rank * Religion * Sanity * Sex * Sexual orientation * Size * Skin color Specific forms Social * Acephobia * Adultism * Amatonormativity * Anti-albinism * Anti-autism * Anti-homelessness * Anti-intellectualism * Anti-intersex * Anti-left handedness * Anti-Masonry * Antisemitism (Judeophobia) * Aporophobia * Audism * Biphobia * Clannism * Cronyism * Drug use * Elitism * Ephebiphobia * Fatism * Gerontophobia * Heteronormativity * Heterosexism * HIV/AIDS stigma * Homophobia * Leprosy stigma * Lesbophobia * Misandry * Misogyny * Nepotism * Pedophobia * Perpetual foreigner * Pregnancy * Reverse * Sectarianism * Supremacism * Black * White * Transphobia * Non-binary * Transmisogyny * Vegaphobia * Xenophobia Religious * Ahmadiyya * Atheism * Baháʼí Faith * Buddhism * Catholicism * Christianity * post–Cold War era * Druze * Falun Gong * Hinduism * Persecution * Islam * Persecution * Jehovah's Witnesses * Judaism * Persecution * LDS or Mormon * Neopaganism * Eastern Orthodox * Oriental Orthodox * Copts * Protestantism * Rastafarianism * Shi'ism * Sufism * Sunnism * Zoroastrianism Ethnic/national * African * Albanian * American * Arab * Armenian * Australian * Austrian * Azerbaijani * British * Canadian * Catalan * Chechen * Chilean * Chinese * Croat * Dutch * English * Estonian * European * Filipino * Finnish * French * Georgian * German * Greek * Haitian * Hazara * Hispanic * Hungarian * Igbo * Indian * Indonesian * Iranian * Irish * Israeli * Italian * Japanese * Jewish * Khmer * Korean * Kurdish * Malay * Manchu * Mexican * Middle Eastern * Mongolian * Montenegrin * Pakistani * Pashtun * Polish * Portuguese * Quebec * Romani * Romanian * Russian * Scottish * Serb * Slavic * Somali * Soviet * Tatar * Thai * Tibetan * Turkish * Ukrainian * Venezuelan * Vietnamese * Western Manifestations * Blood libel * Bullying * Compulsory sterilization * Counter-jihad * Cultural genocide * Defamation * Democide * Disability hate crime * Dog-whistle politics * Eliminationism * Ethnic cleansing * Ethnic conflict * Ethnic hatred * Ethnic joke * Ethnocide * Forced conversion * Freak show * Gay bashing * Gendercide * Genital modification and mutilation * Genocide * examples * Glass ceiling * Hate crime * Hate group * Hate speech * online * Homeless dumping * Indian rolling * Lavender scare * LGBT hate crimes * Lynching * Mortgage * Murder music * Occupational segregation * Persecution * Pogrom * Purge * Red Scare * Religious persecution * Religious terrorism * Religious violence * Religious war * Scapegoating * Segregation academy * Sex-selective abortion * Slavery * Slut-shaming * Trans bashing * Victimisation * Violence against women * White flight * White power music * Wife selling * Witch-hunt Policies * Age of candidacy * Blood purity * Blood quantum * Crime of apartheid * Disabilities * Catholic * Jewish * Ethnocracy * Ethnopluralism * Gender pay gap * Gender roles * Gerontocracy * Gerrymandering * Ghetto benches * Internment * Jewish quota * Jim Crow laws * Law for Protection of the Nation * McCarthyism * MSM blood donation restrictions * Nonpersons * Numerus clausus (as religious or racial quota) * Nuremberg Laws * One-drop rule * Racial quota * Racial steering * Redlining * Same-sex marriage (laws and issues prohibiting) * Segregation * age * racial * religious * sexual * Sodomy law * State atheism * State religion * Ugly law * Voter suppression Countermeasures * Affirmative action * Anti-discrimination law * Cultural assimilation * Cultural pluralism * Diversity training * Empowerment * Feminism * Fighting Discrimination * Hate speech laws by country * Human rights * Intersex rights * LGBT rights * Masculism * Multiculturalism * Nonviolence * Racial integration * Reappropriation * Self-determination * Social integration * Toleration Related topics * Allophilia * Anti-cultural, anti-national, and anti-ethnic terms * Bias * Christian privilege * Civil liberties * Cultural assimilation * Dehumanization * Diversity * Ethnic penalty * Eugenics * Internalized oppression * Intersectionality * Male privilege * Masculism * Medical model of disability * autism * Multiculturalism * Net bias * Neurodiversity * Oikophobia * Oppression * Police brutality * Political correctness * Polyculturalism * Power distance * Prejudice * Prisoner abuse * Racial bias in criminal news * Racism by country * Religious intolerance * Second-generation gender bias * Snobbery * Social exclusion * Social model of disability * Social stigma * Stereotype * threat * The talk * White privilege * v * t * e Anti-Tatar sentiment or Tatarophobia (Russian: Татарофобия, romanized: Tatarofobiya) refers to the fear, hatred towards, demonization of, or prejudice against people generally referred to as Tatars, including but not limited to Volga, Siberian, and Crimean Tatars, although negative attitudes against the latter are by far the most severe, largely in part due to the long history of Soviet media only depicting them in a negative way and promoting negative stereotypes to help politically justify their deportation and marginalization. ## Contents * 1 Against Crimean Tatars * 1.1 Soviet era * 1.2 In modern times * 2 Against Volga Tatars * 3 See also * 4 References ## Against Crimean Tatars[edit] ### Soviet era[edit] After the deportation of the Crimean Tatars in May 1944, the government strongly promoted existing negative stereotypes of Crimean Tatars and built up upon them; declaring them to be "traitors", "bourgeoisie", "counter-revolutionary", and falsely implied that they were "Mongols" with no historical connection to the Crimean peninsula. Political agitation by party members encouraged other citizens at deportation destinations to abuse them and conferences in Crimea dedicated to promoting and sharing anti-Crimean-Tatar sentiments was held. Traces of Crimean Tatar presence in the peninsula were wiped off the peninsula after the deportation in 1944, with thousands of villages previously bearing Tatar names being given new Russian names, officially detatarizing the peninsula. The deported Crimean Tatars who worked in Central Asia lived under the "special settler" regime, which deprived them of many civil rights that other Soviet citizens enjoyed and confined them within a small perimeter.[1] People involved in the Crimean Tatar civil rights movement repeatedly noted similarities between the conditions suffered by designated "special settlers" and victims of apartheid as well as Palestinians in occupied territories.[2][3][4] ### In modern times[edit] While still very prevalent in modern society, Tatarophobia generates more controversy and pushback in modern times than it did in the past. While no longer officially a state-mandated institution, it remains pervasive throughout government and society; a notable example being when Russian consul Vladimir Andreev demanded that none of the invited Russian citizens attend the debut of Haytarma, a film about Crimean Tatar twice Hero of the Soviet Union Amet-khan Sultan, because it did not depict the Crimean Tatar population in a sufficiently negative light. Andreev admitted that he did not actually see the movie when he told people not to attend, but said that he felt it would be historically inaccurate because it was directed by a Crimean Tatar.[5][6] Confusion about different Tatar peoples has been taken advantage of by propaganda, which will celebrate the relative equality experienced by Volga Tatar in order to lead uneducated recipients of propaganda to confuse them with Crimean Tatars and be led to believe that interethnic relations are overwhelmingly positive. It is not unusual for Volga Tatars to be praised and lauded as brotherly peoples by the same institutions that simultaneously engage in Tatarophobia against Crimean Tatars, and it is not unusual for the relative lack of hostility towards Volga Tatars to be pointed out as an excuse to avoid correcting xenophobia towards Crimean Tatars. Despite the Crimean Tatar language being very distant from the Kazan Tatar language, the Soviet Union long opposed the request by the Crimean Tatar civil rights movement for their autonomy to be restored in Crimea, and offered to create an autonomous region in Tatarstan for them instead - insulting much of the Crimean Tatar leadership.[7][8][9] ## Against Volga Tatars[edit] Historically the Volga Tatars have been lauded as a "model minority" in Russia and the Soviet Union and treated much better than the Crimean Tatars. Nevertheless, prejudices against Volga Tatars exists and there have been some attempts to de-Tatarize Tatarstan by Russian nationalists.[10][11] In 2007, a young Tatar man was stabbed to death by a group of people on his way to work in St. Petersburg. The Tatar community stated that the murder was racially motivated and a consequence of Islamophobia.[12] After Elmira Abdrazakova was crowned Miss Russia in 2013, she was bombarded with racial slurs.[13] ## See also[edit] * Deportation of the Crimean Tatars * Racism in the Soviet Union * Racism in Russia * Turkophobia ## References[edit] 1. ^ Williams, Brian Glyn (2015). The Crimean Tatars: From Soviet Genocide to Putin's Conquest. Oxford University Press. pp. 105–114. ISBN 9780190494704. 2. ^ Appazov, Refat (2001). Следы в сердце и в памяти. Simferopol: Dolya. 3. ^ Ablyazov, Emir (8 December 2017). "Четыре обыска Юрия Османова". goloskrimanew.ru. Retrieved 2020-12-03. 4. ^ The Ukrainian Quarterly. Ukrainian Congress Committee of America. 2004. p. 54. 5. ^ Uehling, Greta (2015). "Genocide's Aftermath: Neostalinism in Contemporary Crimea". Genocide Studies and Prevention. 9. 6. ^ Izmirli, Idil (16 June 2013). "Russian consul general to Crimea resigns following offensive comments" (PDF). The Ukrainian Weekly: 2. 7. ^ Chernykh, Aleksandr (2015). Татары Перми: история и культура (in Russian). Saint Petersburg: Санкт-Петербург Mametov. p. 65. ISBN 9785040071074. OCLC 978278427. 8. ^ Eminov, Ruslan (27 January 2016). "Национального Движения Крымских Татар (Попытка краткого анализа участника движения)". litsovet.ru. 9. ^ Williams, Brian Glyn (2001). The Crimean Tatars: The Diaspora Experience and the Forging of a Nation. BRILL. p. 92. ISBN 9789004121225. 10. ^ Halim, Aydar (1997). Убить империю!: Кипарис домой вернулся, или, "Хотят ли русские войны" (in Russian). Kazan: Kalkan. p. 319. ISBN 978-5-87898-118-7. OCLC 605977944. 11. ^ USAK Yearbook of International Politics and Law 2010, Vol. 3. USAK Books. p. 373. ISBN 9786054030262. OCLC 1030115376. 12. ^ "Tatars Say St. Petersburg Murder Was Racist Attack". RadioFreeEurope/RadioLiberty. 13 July 2007. Retrieved 2020-11-01. 13. ^ Kurmasheva, Alsu (5 May 2013). "Ethnic Tatar Miss Russia Winner Targeted By Ethnic Slurs On Internet". rferl.org. * v * t * e Anti-cultural, -national or -ethnic sentiment * African * Albanian * American * Arab * Armenian * Australian * Austrian * Azerbaijani * British * Buddhist * Canadian * Catalan * Chechen * Chilean * Chinese * Christian * Croat * Czech * Dutch * English * Estonian * European * Filipino * Finnish * French * Georgian * German * Greek * Haitian * Hazara * Hindu * Hispanic * Hungarian * Igbo * Indian * Indonesian * Iranian * Irish * Israeli * Italian * Japanese * Jewish * Khmer * Korean * Kurdish * Malay * Manchu * Mexican * Middle Eastern * Mongolian * Montenegrin * Muslim * Pakistani * Pashtun * Polish * Portuguese * Quebec * Romani * Romanian * Russian * Scottish * Serb * Shia * Slavic * Somali * Soviet * Sufi * Sunni * Swede * Tatar * Thai * Tibetan * Turkish * Ukrainian * Venezuelan * Vietnamese * Western [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	Tatarophobia	None	5,735	wikipedia	https://en.wikipedia.org/wiki/Tatarophobia	2021-01-18T18:47:05	{"wikidata": ["Q85805264"]}
Atrophic lichen planus (LP) is a rare form of lichen planus, which is a condition that affects the skin and/or mouth. In atrophic LP, specifically, affected people develop pale papules or plaques with an atrophic (broken down tissue) center. Although these papules can be found anywhere on the body, they most commonly affect the trunk and/or legs on skin areas previously affected by classic lichen planus. The exact underlying cause of atrophic LP is unknown. Treatment is not always necessary as some cases of atrophic LP resolve on their own. Mild cases can often be managed with topical steroids, while more intensive therapies may be required for severe 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	Atrophic lichen planus	c0023647	5,736	gard	https://rarediseases.info.nih.gov/diseases/12675/atrophic-lichen-planus	2021-01-18T18:02:00	{"umls": ["C0023647"], "icd-10": ["L43.8"], "orphanet": ["254449"], "synonyms": ["Atrophic LP"]}
A number sign (#) is used with this entry because of evidence that late-onset or sporadic Parkinson disease (PD) can have more than one genetic and/or environmental cause. Description Parkinson disease was first described by James Parkinson in 1817. It is the second most common neurodegenerative disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50 (Polymeropoulos et al., 1996). ### Reviews Warner and Schapira (2003) reviewed the genetic and environmental causes of Parkinson disease. Feany (2004) reviewed the genetics of Parkinson disease and provided a speculative model of interactions among proteins implicated in PD. Lees et al. (2009) provided a review of Parkinson disease, with emphasis on diagnosis, neuropathology, and treatment. ### Genetic Heterogeneity of Parkinson Disease Several loci for autosomal dominant Parkinson disease have been identified, including PARK1 (168601) and PARK4, caused by mutation in or triplication of the alpha-synuclein gene (SNCA; 163890), respectively, on 4q22; PARK5 (191342), caused by mutation in the UCHL1 gene on 4p13; PARK8 (607060), caused by mutation in the LRRK2 gene (609007) on 12q12; PARK11 (607688), caused by mutation in the GIGYF2 gene (612003) on 2q37; PARK13 (610297), caused by mutation in the HTRA2 gene (606441) on 2p13; PARK17 (614203), caused by mutation in the VPS35 gene (601501) on 16q11; and PARK18 (614251), caused by mutation in the EIF4G1 gene (600495) on 3q27. Several loci for autosomal recessive early-onset Parkinson disease have been identified: PARK2 (600116), caused by mutation in the gene encoding parkin (PARK2; 602544) on 6q26; PARK6 (605909), caused by mutation in the PINK1 gene (608309) on 1p36; PARK7 (606324), caused by mutation in the DJ1 gene (PARK7; 602533) on 1p36; PARK14 (612953), caused by mutation in the PLA2G6 gene (603604) on 22q13; PARK15 (260300), caused by mutation in the FBXO7 gene (605648) on 22q12-q13; PARK19A (615528) and PARK19B (see 615528), caused by mutation in the DNAJC6 gene (608375) on 1p32; and PARK20 (615530), caused by mutation in the SYNJ1 gene (604297) on 21q22. PARK3 (602404) has been mapped to chromosome 2p13; PARK10 (606852) has been mapped to chromosome 1p34-p32; PARK16 (613164) has been mapped to chromosome 1q32. See also PARK21 (616361). A locus on the X chromosome has been identified (PARK12; 300557). There is also evidence that mitochondrial mutations may cause or contribute to Parkinson disease (see 556500). Susceptibility to the development of the more common late-onset form of Parkinson disease has been associated with polymorphisms or mutations in several genes, including GBA (606463), MAPT (157140), MC1R (155555), ADH1C (103730), and genes at the HLA locus (see, e.g., HLA-DRA, 142860). Each of these risk factors independently may have a modest effect on disease development, but together may have a substantial cumulative effect (Hamza et al., 2010). Susceptibility to PD may also be conferred by expanded trinucleotide repeats in several genes causing other neurologic disorders usually characterized by spinocerebellar ataxia (SCA), including the ATXN2 (601517), ATXN3 (607047), TBP (600075), and ATXN8OS (603680) genes. Clinical Features The diagnosis of classic idiopathic PD is primarily clinical, with manifestations including resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The disease is progressive and usually has an insidious onset in mid to late adulthood. Pathologic features of classic PD include by a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies, intracellular inclusions, in surviving neurons in various areas of the brain, particularly the SN (Nussbaum and Polymeropoulos, 1997). Autosomal recessive juvenile Parkinson disease (PARK2; 600116), however, does not have Lewy body pathology (Nussbaum and Polymeropoulos, 1997). Many other diseases, both genetic and nongenetic, have parkinsonian motor features ('parkinsonism'), which most likely result from loss or dysfunction of the dopaminergic neurons in the SN, but may or may not have Lewy bodies on pathology. Thus, accurate diagnosis may be difficult without pathologic examination. Dementia with Lewy bodies (DLB; 127750) shows parkinsonism with Lewy bodies. However, parkinsonism without Lewy bodies characterizes progressive supranuclear palsy (PSP; 601104), frontotemporal dementia with parkinsonism (600274), autosomal dominant (128230) and recessive (605407) forms of Segawa syndrome, X-linked recessive Filipino type of dystonia (314250), multiple systems atrophy, and cerebrovascular disease. Other Features In a retrospective analysis, Paleacu et al. (2005) found that 76 (32%) of 234 PD patients reported hallucinations. All experienced visual hallucinations, most commonly of human images, and 6 also reported mood congruent auditory hallucinations. The presence of hallucinations was correlated with family history of dementia and lower scores on the Mini-Mental State Examination (MMSE). Neither the dose nor duration of L-DOPA treatment was a significant variable for hallucinations. Using PET scan, Ballanger et al. (2010) showed that 7 PD patients with visual hallucinations had increased binding to serotonin 2A receptors (HTR2A; 182135) in the ventral visual pathway compared to 7 PD patients without visual hallucinations. Areas of the ventral visual pathway that showed increased HTR2A binding included the bilateral inferooccipital gyrus, the right fusiform gyrus, and the inferotemporal cortex. The findings suggested that abnormalities in serotonin 2A receptor neurotransmission may be involved in the pathogenesis of visual hallucinations in PD. Using single-photon emission CT with a radiolabeled ligand for several beta-2 (CHRNB2; 118507)-containing nicotinic acetylcholine receptors (nAChR), Fujita et al. (2006) showed that 10 nondemented PD patients had a widespread significant global decrease in nAChRs compared to 15 controls. The most significant decrease was in the thalamus. Some studies have observed an increased risk of Parkinson disease among individuals with melanoma (155600) (see, e.g., Constantinescu et al., 2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism may be involved in the pathogenesis of PD. From 2 existing study cohorts of 38,641 men and 93,661 women who were free of PD at baseline, Gao et al. (2009) found an association between decreasing darkness of natural hair color in early adulthood and increased PD risk. The pooled relative risks (RR) for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for black, brown, blond, and red hair, respectively. These results were significant after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for onset before age 70 years. In a case-control study of 272 PD cases and 1,185 controls, there was an association between the cys151 SNP of the MC1R gene (R151C; 155555.0004), which confers red hair, and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD. Hernandez (2009) independently noted the association. Dong et al. (2014) did not find a significant association between the R151C MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. Tell-Marti et al. (2015) did not find a significant association between the R151C MC1R variant and Parkinson disease among 870 Spanish PD patients and 736 controls. In a study of 157,036 individuals, who did not have PD at baseline, over a 14 to 20-year follow-up period, Gao et al. (2009) identified 616 incident PD cases. A family history of melanoma in a first-degree relative was associated with a higher risk of PD (RR, 1.85; p = 0.004) after adjusting for smoking, ethnicity, caffeine intake, and other covariates. There was no association between a family history of colorectal, lung, prostate, or breast cancer and PD risk. The findings supported the notion that melanoma and Parkinson disease share common genetic components. Inheritance There has been much controversy regarding the genetics of Parkinson disease, as no specific pattern of inheritance is readily apparent, and reports of Parkinson disease and parkinsonism may not necessarily refer to the same disease entity (Nussbaum and Polymeropoulos, 1997). However, a familial component to Parkinson disease and parkinsonism has long been recognized. Gowers (1900) is believed to have been the first to observe that patients with PD often had an affected relative, and he suggested that hereditary factors may be important. Bell and Clark (1926) reviewed published pedigrees of 'paralysis agitans' and reported an additional one. Allan (1937) described impressive pedigrees from North Carolina. ### Twin Studies Kissel and Andre (1976) described a pair of female MZ twins, both of whom had a combination of parkinsonism and anosmia. Olfactory impairment is frequent in PD (Ward et al., 1983). Both twins reported onset of symptoms at age 36 years, which is unusually early, particularly for women (Kessler, 1978). Kissel and Andre (1976) noted that 2 families with the same association had previously been reported and they suggested a causative role for a genetically determined anomaly of dopamine metabolism. Duvoisin et al. (1981) found zero concordance for Parkinson disease in the first 12 monozygotic twin pairs examined in an on-going twin study. There was evidence of premorbid personality differences between probands and cotwins dating back to late adolescence or early adult years. Among 43 monozygotic and 19 dizygotic twin pairs, Ward et al. (1983) found that only 1 monozygotic twin pair was definitely concordant for PD. Ward et al. (1983) noted that concordance for PD is no more frequent in twins than would be expected from the incidence of the disease, and concluded that major factors in the etiology of PD must be nongenetic. ### Mendelian Inheritance Spellman (1962) described a family in which multiple members in 4 generations had parkinsonism beginning in their thirties and progressing rapidly to death in 2 to 12 years. Tune et al. (1982) described Parkinson disease in 4 persons in 3 generations. Several of these also had manic-depressive illness. Barbeau and Pourcher (1982, 1983) suggested that mendelian inheritance obtains in some cases, particularly in those whose illness started before the age of 40. In this early-onset group, there was a 46% incidence of familial cases. They divided Parkinson disease into 4 etiologic categories: postencephalitic, idiopathic, genetic, and symptomatic. They proposed the existence of 2 genetic subtypes: an akineto-rigid subtype transmitted as an autosomal recessive and a subtype with prominent tremor, dominant inheritance, and a high prevalence of family members with essential tremor. Lazzarini et al. (1994) found that the cumulative risk of PD among sibs of probands with affected parents was increased significantly over that for sibs of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. Furthermore, in 80 multicase families, age-adjusted ratios approaching 0.5 and similar proportions of affected parents and sibs, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD. Payami et al. (1995) studied age of onset of 137 patients with idiopathic Parkinson disease. The 21 probands with an affected parent, aunt, or uncle were younger at onset of PD (47.7 +/- 8.8 years) than were the 11 probands with an affected sib only (60.3 +/- 12.9 years) and the 105 probands with no affected relatives (59.2 +/- 11.4 years). Age of onset of affected family members differed significantly between generations (p = 0.0001) and was earlier, by an average of 17 years, in the proband generation than in the parental generation. The data were consistent with genetic anticipation and suggested the involvement of an unstable trinucleotide repeat. Markopoulou et al. (1995) studied a Greek-American kindred with 98 individuals in 6 generations. Sixteen individuals in 3 generations developed parkinsonism, which appeared to be transmitted in an autosomal dominant manner with evidence of anticipation. No pathologic data were presented. Plante-Bordeneuve et al. (1995) studied 14 families in which the proband and at least one relative were affected by clinically typical Parkinson disease, based on Parkinson Disease Society brain bank diagnostic criteria (Hughes et al., 1992). No clinical differences were found between 31 individuals with familial Parkinson disease and 31 age-matched sporadic Parkinson disease controls. In the 14 families, genetic transmission was compatible with autosomal dominant transmission with several cases of male-to-male transmission. Although the total segregation ratio was 0.25, this was age-dependent, with a penetrance of zero below age 30 and a penetrance of 0.43 over the age of 70. Age at onset was identical within a generation but it was 26 +/- 4.6 years earlier in children than parents of the 8 multigenerational kindreds studied, suggesting an anticipation phenomenon. Bonifati et al. (1995) used epidemiologic methods to determine the frequency of clinical features of familial Parkinson disease. By studying 100 consecutive Parkinson disease cases presenting to their clinic, family history for Parkinson disease was positive in 24% of Parkinson disease cases and in only 6% of spouse controls. In a larger study of 22 nonconsecutive Parkinson disease families with at least 2 living and personally examined cases, the crude segregation ratios were similar for parents and sibs, with lifetime cumulative risks approaching 0.4. These data supported autosomal dominant inheritance with a strong age factor in penetrance. Nussbaum and Polymeropoulos (1997) reviewed the genetics of Parkinson disease. They stated that for the previous 40 years, research into Parkinson disease had predominantly been the province of epidemiologists interested in pursuing the connection between the disorder and environmental factors such as viral infection or neurotoxins. Hereditary influences were discounted because of a high discordance rate among monozygotic twins found in studies that were later shown to be inadequate and inconclusive. On the other hand, a positive family history was recognized as a major risk factor for the disease and it became increasingly apparent from neuropathologic studies that the common, idiopathic form of Parkinson disease had a specific pathologic correlate in the form of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia, and olfactory tracts. They referred to the 'particularly prescient paper' of Sommer and Rocca (1996), in which the authors suggested that autosomal dominant PD may be caused by a missense mutation in a cellular protein that changes its physical-chemical properties, leading to accumulation of the abnormal protein and neuronal death. This hypothesis has received substantial support. Maher et al. (2002) collected information involving the nuclear families of 948 consecutively ascertained Parkinson disease index cases from 3 U.S. medical centers. They performed segregation analysis to assess evidence for the presence of a mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the 3 institutions. They concluded that the analyses supported the presence of a rare major mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provided evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. Maher et al. (2002) also found evidence for a mendelian gene influencing susceptibility to the disease. It was not evident whether these 2 analyses were modeling the same gene or different genes with different effects on PD. Genes influencing penetrance may interact with environmental factors or other genes to increase the risk of PD. Such gene-environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disorder. In a comparison of 221 PD patients with age at onset of 50 years or younger, 266 PD patients with age at onset of 50 years or greater, and 409 unaffected controls, Marder et al. (2003) found a similar relative risk (RR) of PD among first-degree relatives of both the early- and late-onset groups (RR = 2.9 and 2.7, respectively) compared to those of controls. There was also an increased risk of PD in sibs of affected patients (RR = 7.9 for early-onset and 3.6 for late-onset) compared to those of controls. Parents of the early-onset group were not at a significantly increased risk compared to those of controls (RR = 1.7), and parents of the late-onset group were at a higher increased risk compared to those of controls (RR = 2.5). Marder et al. (2003) concluded that the pattern was consistent with an autosomal recessive contribution to the inheritance of early- but not late-onset PD, but also noted that genetic factors are important in both groups. ### 'Familial Component' Zareparsi et al. (1998) performed complex segregation analyses using kindreds of 136 Parkinson disease patients randomly ascertained from a clinic population. They rejected the hypotheses of a nontransmissible environmental factor, a major gene or type (sporadic), and all mendelian inheritance (dominant, recessive, additive, decreasing). They concluded that familial clustering of PD in this dataset was best explained by a 'rare familial factor' which is transmitted in a nonmendelian fashion and influences the age at onset of PD. Montgomery et al. (1999) used a previously reported PD test battery to check for mild signs of motor slowing, impaired sense of smell, and depressed mood in first-degree relatives of patients with Parkinson disease, most of whom were considered sporadic cases. Abnormalities on the test battery were found in 22.5% of first-degree relatives, all of whom were judged normal on standard neurologic examination, but in only 9% of age-matched controls. The authors interpreted this familial clustering of minimal parkinsonian tendencies as an indication of genetic predisposition to Parkinson disease even in sporadic cases. Sveinbjornsdottir et al. (2000) reviewed the medical records and confirmed the diagnosis of Parkinson disease in 772 living and deceased patients in whom the diagnosis had been made in Iceland during the previous 50 years. With the use of an extensive computerized database containing genealogic information on 610,920 people in Iceland over the past 11 centuries, they conducted several analyses to determine whether the patients were more related to each other than random members of the population. They found that there was a genetic component to Parkinson disease, including a subgroup of 560 patients with late-onset disease (onset after 50 years of age): patients with Parkinson disease were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. There was no highly penetrant mendelian pattern of inheritance, and both early and late-onset forms often skipped generations. The risk ratio for Parkinson disease was 6.7 for sibs, 3.2 for offspring, and 2.7 for nephews and nieces of patients with late-onset Parkinson disease. Racette et al. (2002) described a very large Amish pedigree with classic idiopathic Parkinson disease in multiple members. They examined 113 members and classified 67 as having no evidence of PD, 17 as clinically definite PD, 6 as clinically probable PD, and 23 as clinically possible PD. The mean age at onset of the clinically definite subjects was 56.7 years. The mean kinship coefficient in the subjects with PD and those with PD by history was higher (p = 0.007) than in a group of age-matched normal Amish control subjects, providing evidence that PD is inherited in this family. Sequence analysis did not reveal any mutations in known PD genes. No single haplotype cosegregated with the disease in any of the chromosomal regions previously found to be linked to PD. ### Environmental Factors Some findings suggest that environmental factors may be more important than genetic factors in familial aggregation of Parkinson disease. Calne et al. (1987) reported 6 families in which onset of symptoms tended to occur at approximately the same time regardless of the age of the patient. In a hospital-based survey, Teravainen et al. (1986) concluded that there is a trend toward lower age of onset of Parkinson disease. Calne and Langston (1983) advanced the view that in most cases the cause is an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age. Finding parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine (meperidine; MPTP) drug users (Langston et al., 1983) revived interest in reexamining environmental factors. Barbeau et al. (1985) also postulated that Parkinson disease is the result of environmental factors acting on genetically susceptible persons against a background of 'normal' aging. Nathans (2005) noted the remarkable coincidence that the abbreviation MPTP, for the drug that causes Parkinson disease by selectively damaging dopaminergic neurons, is coincidentally the code for the first 4 amino acids of human, mouse, and rat tyrosine hydroxylase, the enzyme which marks all dopaminergic neurons. In a case-control study of 418 Chinese PD patients and 468 controls, Tan et al. (2007) found a significant association between caffeine intake and decreased risk of PD (p = 2.01 x 10(-5)). The odds ratio was 0.48 for moderate and high caffeine intake and 0.71 for low intake. No difference was observed with genotyping for a common SNP in the CYP1A2 gene (124060), which influences the level of caffeine metabolism. The findings suggested that caffeine and its main metabolite paraxanthine are both neuroprotective. ### Multifactorial Inheritance Analysis of the experience at the Mayo Clinic led Kondo et al. (1973) to conclude that irregular dominant transmission is untenable and that multifactorial inheritance with heritability of about 80% is more likely. Young et al. (1977) favored multifactorial inheritance but could not exclude autosomal dominance with reduced penetrance, especially for some families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance. Vaughan et al. (2001) reviewed the genetics of parkinsonism. They suggested that nigral degeneration with Lewy body formation and the resulting clinical picture of Parkinson disease may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. Also see review of Parkinson disease by Nussbaum and Ellis (2003). ### Mitochondrial Inheritance Another theory of parkinsonism suggests that genetic predisposition may be transmitted through mitochondrial inheritance (Di Monte, 1991); see 556500. Schapira (1995) reviewed nuclear and mitochondrial genetics in Parkinson disease. He stated that Gowers (1900) had noted the occurrence of PD in relatives and suggested that hereditary factors are important. From a study of Parkinson disease in twins, Tanner et al. (1999) concluded that 'no genetic component was evident when the disease begins after age 50 years.' Parker et al. (1999) and Simon (1999) pointed out that whereas this may be true as far as mendelian (nuclear) genetic mechanisms are concerned, this may not be true for mitochondrial factors in Parkinson disease. Since MZ and DZ twins each receive all of their mitochondrial DNA from their mother, differences in concordance rates between MZ and DZ twins cannot be used to address the potential influence of mitochondrial genetic factors. To test the hypothesis that mitochondrial variation contributes to Parkinson disease expression, van der Walt et al. (2003) genotyped 10 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in 609 white patients with Parkinson disease and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio = 0.55; 95% CI 0.34-0.91; p = 0.02) or K (odds ratio = 0.52; 95% CI 0.30-0.90; p = 0.02) demonstrated a significant decrease in risk of Parkinson disease versus individuals carrying the most common haplogroup H. Furthermore, a specific SNP that defines these 2 haplogroups, 10398G (516002.0002), is strongly associated with this protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; p = 0.0001). The 10398G SNP causes a nonconservative amino acid change from threonine to alanine within the ND3 (516002) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men. In addition, the 9055A SNP of ATP6 (516060) demonstrated a protective effect for women. Van der Walt et al. (2003) concluded that ND3 is an important factor in Parkinson disease susceptibility among white individuals and could help explain the role of complex I in Parkinson disease expression. Clinical Management Gill et al. (2003) delivered glial cell line-derived neurotrophic factor (GDNF; 600837) directly into the putamen of 5 Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the MRIs that disappeared after lowering the concentration of GDNF. After 1 year, there were no serious clinical side effects, a 39% improvement in the off-medication motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living subscore. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. Voon et al. (2007) evaluated 21 patients with Parkinson disease who developed pathologic gambling (606349) after receiving pharmacologic treatment with dopaminergic agonists. Compared to 42 PD patients without compulsive behaviors, those who developed pathologic gambling had a younger age at PD onset, higher novelty seeking (601696), tended to have medication-induced hypomania or mania, impaired planning, and a personal or family history of alcohol use disorders (103780). L-DOPA is predominantly metabolized to the inactive 3-O-methyldopa by COMT (116790). Entacapone is a COMT inhibitor that acts to prolong the half-life of L-DOPA and yields prolonged therapeutic benefits. A val158-to-met (V158M) polymorphism in the COMT gene (rs4680; 116790.0001) confers increased (val) or decreased (met) COMT activity. In a randomized control trial of 33 PD patients, Corvol et al. (2011) found that those homozygous for the high-activity val158 allele had significantly increased COMT inhibition by entacapone and significantly better bioavailability of and clinical response to L-DOPA compared to patients homozygous for the low-activity met158 allele. The findings indicated that homozygosity for the val158 allele in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone in heterozygous patients was not studied. Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein (163890) toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking. Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein, a key protein involved in Parkinson disease. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons. Mapping ### Evidence for Genetic Heterogeneity Polymeropoulos et al. (1996) demonstrated genetic linkage between an autosomal dominant form of PD and genetic markers on 4q21-q23. The locus was designated PARK1 (168601). In 94 Caucasian families, Scott et al. (1997) could not demonstrate linkage to 4q21-q23. They also found no linkage even when the 22 families from their study with at least 1 case of early-onset PD were examined separately. Gasser et al. (1997) excluded linkage in 13 multigenerational families with Parkinson disease, with the exception of 1 family for which they achieved a maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23 region. Scott et al. (2001) described a genetic linkage study conducted in 1995-2000 in which a complete genomic screen was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. Significant evidence for linkage was found in 5 distinct chromosomal regions: chromosome 6 in the parkin gene (PARK2; 602544) in families with at least 1 individual with PD onset at younger than 40 years (lod = 5.47); chromosomes 17q (lod = 2.62), 8p (lod = 2.22), and 5q (lod = 1.50) overall and in families with late-onset PD; and 9q (lod = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. The data suggested that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic, late-onset PD. Pankratz et al. (2002) studied 160 multiplex families with PD in which there was no evidence of mutations in the parkin gene, and used multipoint nonparametric linkage analysis to identify PD susceptibility genes. For those individuals with a more stringent diagnosis of verified PD, the highest lod scores were observed on the X chromosome and on chromosome 2 (lod scores equal to 2.1 and 1.9, respectively). Analyses performed with all available sib pairs, i.e., all examined individuals treated as affected regardless of their final diagnostic classification, yielded even greater evidence of linkage to the X chromosome and to chromosome 2 (lod scores equal to 2.7 and 2.5, respectively). Evidence of linkage was also found to chromosomes 4, 5, and 13 (lod scores greater than 1.5). Pankratz et al. (2002) considered their findings consistent with those of other linkage studies that had reported linkage to chromosomes X and 5. Pankratz et al. (2003) studied 754 affected individuals, comprising 425 sib pairs, to identify PD susceptibility genes. Genomewide, nonparametric linkage analyses revealed potential loci on chromosomes 2, X, 10, and 14. The authors hypothesized that gene-by-gene interactions are important in PD susceptibility. ### Associations Pending Confirmation Maraganore et al. (2005) performed a 2-tiered, genomewide association study of PD including 443 sib pairs discordant for PD and 332 case-unrelated control pairs. A SNP (rs7702187) within the semaphorin-5A gene (SEMA5A; 609297) on chromosome 5p had the lowest combined p value (p = 7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which was consistent with hypotheses regarding PD pathogenesis. Gao et al. (2009) conducted a genomewide linkage screen of 5,824 SNPs in 278 families of European non-Hispanic descent to localize regions that harbor susceptibility loci for Parkinson disease. These 278 families included 158 families included in a previous screen (Scott et al., 2001) and 120 families not previously screened. In the overall screen of all 278 families, the highest multipoint MLOD scores were obtained under a dominant model of inheritance in an 11-cM interval on chromosome 3q25 (MLOD = 2.0) and a 9-cM interval on chromosome 18q11 (MLOD = 1.8). Since the combined screen did not detect linkage overall in regions previously implicated, Gao et al. (2009) suspected that clinical and locus heterogeneity might exist. They stratified the dataset into previously screened and unscreened families. In the 120 families not previously screened, Gao et al. (2009) achieved significant evidence for linkage on chromosome 18q11 (maximum lod score = 4.1) and suggestive evidence on chromosome 3q25 (maximum lod score = 2.5). There was little evidence for linkage to these regions overall in the original 158 families. Simulation studies suggested that these findings were likely due to locus heterogeneity rather than random statistical error. See also PARK18 (614251), which is caused by mutation in the EIF4G1 gene (600495) on 3q27. To identify susceptibility variants for Parkinson disease, Satake et al. (2009) performed a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan. They identified a novel susceptibility locus on chromosome 4p15. Four SNPs (rs11931532, rs12645693, rs4698412, and rs4538475) reached p less than 5 x 10(-7) in the combined analysis. The 4 SNPs were located 4.1 kb downstream of intron 8 of the BST1 gene (600387). Satake et al. (2009) also identified a locus on chromosome 1q32 (PARK16; 613164), replicated by Simon-Sanchez et al. (2009), and replicated associations on 4q22 (see PARK1, 168601) and 12q12 (see PARK8, 607060). Tan et al. (2010) confirmed associations at the PARK16, PARK1, and PARK8 loci in 433 PD patients and 916 controls, all of Chinese ethnicity. However, they did not identify a significant association at the BST1 locus. By a genomewide association study of 2,000 individuals with late-onset PD and 1,986 unaffected controls, all of European ancestry from the NeuroGenetics Research Consortium (NGRC), Hamza et al. (2010) found an association between PD and rs11248051 in the GAK gene (602052) on chromosome 4p (p = 3.1 x 10(-4); odds ratio (OR) of 1.32). When combined with data from a previous study (Pankratz et al., 2009), metaanalysis of the combined dataset of 2,843 patients yielded a significant association (p = 3.2 x 10(-9); OR, 1.46). Hamza et al. (2010) designated this possible locus PARK17, but that symbol has been used for a confirmed PD locus on chromosome 16q13 (see 614203). They also found a significant association between PD and rs3129882 in intron 1 of the HLA-DRA (142860) gene on chromosome 6p21.3 (p = 2.9 x 10(-8)). The authors designated this possible locus PARK18, but that symbol has been used for a confirmed PD locus on chromosome 3q27 (see 614251). The association was significant even after adjusting for age, sex, and genetic substructure among Americans of European descent (as defined by Jewish ancestry and country of origin). The findings were replicated in 2 datasets comprising 1,447 patients, and metaanalysis of the 3 populations showed a combined p value of 1.9 x 10(-10) and odds ratio of 1.26. The HLA association was uniform across all genetic and environmental risk strata, and was strong in both sporadic (p = 5.5 x 10(-10)) and late-onset (p = 2.4 x (10-8)) disease. A data repository of expression QTL indicated that rs3129882 is a cis-acting regulatory variant that correlated significantly with expression levels of HLA-DRA, HLA-DQA2 (613503), and HLA-DRB5 (604776). Hamza et al. (2010) suggested that their findings supported the involvement of the immune system in the pathogenesis of Parkinson disease. However, Mata et al. (2011) failed to replicate the associations between Parkinson disease and the loci at chromosome 4p and 6p21 in a study of 1,445 PD patients and 1,161 controls from northern Spain. The SNPs studied included rs11248051 in the GAK gene and rs3129882 in the HLA-DRA gene. Mata et al. (2011) concluded that the loci designated PARK17 and PARK18 by Hamza et al. (2010) required further validation. Molecular Genetics Investigating the postulate that PD may have an environmental cause, Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics are detoxified by hepatic cytochrome P450. They studied one such system in 40 patients with Parkinson disease and 40 controls, and found that significantly more patients than controls had partially or totally defective 4-hydroxylation of debrisoquine (608902). Poor metabolizers had earlier onset of disease. Bordet et al. (1994) investigated a genetic polymorphism of the cytochrome P450 CYP2D6 gene (124030) in 105 patients with idiopathic Parkinson disease and 15 patients with diffuse Lewy body disease. They found no relationship between the CYP2D6 gene associated with poor metabolism of debrisoquine with either idiopathic Parkinson disease or diffuse Lewy body disease. Sandy et al. (1996) found no significant differences in CYP2D6 allelic frequencies between early-onset Parkinson disease cases (51 years of age or less) and controls. Kurth et al. (1993) found a single-strand conformation polymorphism in intron 13 of the monoamine oxidase B gene (309860) and found a significantly higher frequency of 1 allele in their parkinsonian population compared with the control group. Ho et al. (1995), however, were unable to substantiate this claim. Parboosingh et al. (1995) failed to find pathogenic mutations in either copper/zinc (147450) or manganese (147460) superoxide dismutase or in catalase (115500) in a single-strand conformation analysis of 107 unrelated patients with Parkinson disease, which included both familial and sporadic cases. Polymeropoulos (1997) noted that Polymeropoulos et al. (1997) had reported a total of 4 families in which mutation in the alpha-synuclein gene (SNCA; 163890) could be shown to be responsible for early-onset Parkinson disease. However, mutation was not detected in 50 individuals with sporadic Parkinson disease or in 2 other families with late onset of the illness. Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron 13 G (309860) and COMT L (V158M; 116790.0001) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism. The demonstration of linkage of idiopathic Parkinson disease to 17q21 (Scott et al., 2001) made the tau gene (MAPT; 157140) a good candidate as a susceptibility gene for idiopathic PD. Martin et al. (2001) tested 5 single-nucleotide polymorphisms (SNPs) within the MAPT gene for association with PD in a sample of 1,056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center. They used family-based tests of association. The sample consisted of 426 affected and 579 unaffected family members; 51 individuals had unclear PD status. Both individual SNPs and SNP haplotypes in the MAPT gene were analyzed. Significant evidence of association was found for 3 of the 5 SNPs tested. Strong evidence of association was found with haplotype analysis, with a positive association with 1 haplotype (p = 0.009) and a negative association with another haplotype (p = 0.007). Substantial linkage disequilibrium (p less than 0.001) was detected between 4 of the 5 SNPs. The study was interpreted as implicating MAPT as a susceptibility gene for idiopathic Parkinson disease. Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004) gene that influenced GSK3B transcriptional activity and correlated with enhanced phosphorylation of MAPT in vitro, respectively. Conditional logistic regression analysis of the genotypes of 302 Caucasian PD patients and 184 Chinese PD patients found an association between the GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005) concluded that GSK3B polymorphisms interact with MAPT haplotypes to modify disease risk in PD. Among 52 Finnish patients with PD, Mattila et al. (2002) found an increased frequency of the interleukin 1-beta gene (IL1B; 147720) -511 polymorphism compared to controls (allele frequency of 0.96 in PD and 0.73 in controls; p = 0.001). The calculated relative risk of PD for patients carrying at least one IL1B allele was 8.8. West et al. (2002) reported that a single-nucleotide polymorphism within the parkin core promoter, -258T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro, and functionally affects gene transcription. In a population-based series of 296 PD cases and 184 controls, the -258G allele was associated with idiopathic PD (odds ratio 1.52, P less than 0.05). Excess of nitric oxide (NO) has been shown to exert neurotoxic effects in the brain. Moreover, inhibition of 2 enzyme isoforms of nitric oxide synthase (NOS; see 163731), neuronal NOS (nNOS) and inducible NOS (iNOS), results in neuroprotective effects in the MPTP model of PD. Levecque et al. (2003) performed a community-based case-control study of 209 PD patients enrolled in a French health insurance organization for agricultural workers and 488 European controls. Associations were observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS 22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01), and a T-to-C polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS 18. Moreover, a significant interaction of the nNOS polymorphisms with current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS 29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a modifier gene in PD. Chan et al. (2003) found that the slow acetylator (243400) genotype for N-acetyltransferase-2 (NAT2; 612182) was associated with PD in Hong Kong Chinese. The frequency of slow acetylator genotype was significantly higher in 99 patients with PD than in 126 control subjects (68.7% vs 28.6%) with an odds ratio of 5.53 after adjusting for age, sex, and smoking history. In a subgroup analysis, smoking had no modifying effect on the association between genotype and PD. In 2 apparently sporadic patients with Parkinson disease, Marx et al. (2003) found an arg621-to-cys (R621C) mutation in synphilin-1 (603779.0001). Li et al. (2002) reported genetic linkage of a locus controlling age at onset in Alzheimer disease (AD; 104300) and PD to a 15-cM region on chromosome 10q. Li et al. (2003) combined gene expression studies on hippocampus obtained from AD patients and controls with their previously reported linkage data to identify 4 candidate genes. Allelic association studies for age-at-onset effects in 1,773 AD patients and 1,041 relatives and 635 PD patients and 727 relatives further limited association to GSTO1 (605482) (p = 0.007) and a second transcribed member of the GST omega class, GSTO2 (612314) (p = 0.005), located next to GSTO1. The authors suggested that GSTO1 may be involved in the posttranslational modification of IL1B. Theuns et al. (2006) pointed out that it is widely accepted that genetic causes of susceptibility to complex diseases reflect a different spectrum of sequence variants than mutations that dominate monogenic disorders. This spectrum includes mutations that alter gene expression; in particular, promoter mutations have been shown to result in inherited diseases, including neurodegenerative brain diseases. They pointed to the fact that in Parkinson disease, 2 variants in the 5-prime regulatory region of NR4A2 (601828.0001 and 601828.0002) were found to be associated with familial PD and markedly reduced NR4A2 mRNA levels. Also, multiple association studies showed that variations in the 5-prime regulatory regions of SNCA (163890) and PARK2 (602544) increase PD susceptibility, with some variations increasing disease risk by modulating gene transcription. In Alzheimer disease (104300), promoter mutations in PSEN1 (104311) can explain the increased risk for early-onset AD by decreasing expression levels of PSEN1 in neurons. Considering 4 putative PD risk regions, SNCA, MAPT, GAK, and HLA-DRA in 2,000 late-onset PD patients and 1,986 unaffected controls from the NGRC population, Hamza et al. (2010) found that the risk of Parkinson disease was doubled for individuals who had 4 risk alleles (OR of 2.49, p = 6.5 x 10(-8)), and was increased 5-fold for individuals who had 6 or more risk alleles (OR of 4.95, p = 5.5 x 10(-13)). These findings supported the notion that Parkinson disease risk is due to cumulative effects of risk factors that each have a modest individual effect. ### Association with the Glucocerebrosidase (GBA) Gene An association has been reported between parkinsonism and type I Gaucher disease (230800) (Neudorfer et al., 1996; Tayebi et al., 2001; Bembi et al., 2003), the most prevalent, recessively inherited disorder of glycolipid storage. Simultaneous occurrence of Parkinson disease and Gaucher disease is marked by atypical parkinsonism generally presenting by the fourth through sixth decades of life. The combination progresses inexorably and is refractory to conventional anti-Parkinson therapy (Varkonyi et al., 2003). Aharon-Peretz et al. (2004) studied the association of Parkinson disease with Gaucher disease, which is caused by mutation in the GBA gene (606463), which encodes the lysosomal enzyme glucocerebrosidase. They screened 99 Ashkenazi patients with idiopathic Parkinson disease, 74 Ashkenazi patients with Alzheimer disease, and 1,543 healthy Ashkenazi Jews for the 6 GBA mutations that are most common among Ashkenazi Jews. One or 2 mutant GBA alleles were found in 31 patients with Parkinson disease (31.3%): 28 were heterozygous and 3 were homozygous for one of these mutations. Among the 74 patients with Alzheimer disease, 3 (4.1%) were carriers of Gaucher disease. Among the 1,543 controls, 95 (6.2%) were carriers of Gaucher disease. Patients with Parkinson disease had significantly greater odds of being carriers of Gaucher disease than did patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0). Among the patients with Parkinson disease, those who were carriers of Gaucher disease were younger than those who were not carriers (mean age at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al. (2004) suggested that some GBA mutations are susceptibility factors for Parkinson disease. Toft et al. (2006) did not find an association between PD and 2 common GBA mutations (L444P; 606463.0001 and N370S; 606463.0003) among 311 Norwegian patients with Parkinson disease. Mutant GBA alleles were identified in 7 (2.3%) patients and 8 (1.7%) controls. Tan et al. (2007) identified a heterozygous GBA L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish patients with PD carried a GBA mutation, compared to 4.2% of elderly and 6.35% of young controls. The proportion of severe GBA mutation carriers among patients was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and were associated with decreased age at PD onset. Gan-Or et al. (2008) concluded that genetic variance in the GBA gene is a risk factor for PD. Gutti et al. (2008) identified the GBA L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variants that may contribute to PD. Mata et al. (2008) identified heterozygosity for either the GBA L444P or N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 patients with Lewy body dementia, and 2 (0.4%) of 554 control subjects individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. In a 16-center worldwide study comprising 5,691 PD patients (including 780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis), Sidransky et al. (2009) demonstrated a strong association between GBA mutations and Parkinson disease. Direct sequencing for only the L444P or N370S mutations identified either mutation in 15% of Ashkenazi patients and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either mutation was found in 3% of patients and less than 1% of controls. However, full gene sequencing identified GBA mutations in 7% of non-Ashkenazi patients. The odds ratio for any GBA mutation in patients compared to controls was 5.43 across all centers. Compared to PD patients without GBA mutations, patients with GBA mutations presented earlier with the disease, were more likely to have affected relatives, and were more more likely to have atypical manifestations, including cognitive defects. Sidransky et al. (2009) concluded that while GBA mutations are not likely a mendelian cause of PD, they do represent a susceptibility factor for development of the disorder. Neumann et al. (2009) identified 14 different heterozygous mutations in the GBA gene, in 33 (4.18%) of 790 British patients with Parkinson disease and in 3 (1.17%) of 257 controls. Three novel mutations (see, e.g., D443N; 606463.0048) were identified, and most common mutations were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3 patients; 606463.0008). Four (12%) patients had a family history of the disorder, whereas 29 (88%) had sporadic disease. The mean age at onset was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen (about 50%) patients with GBA mutations developed cognitive decline, including visual hallucinations. The male to female ratio of GBA carriers within the PD group was 5:2, which was significantly higher than that of the whole study group. Most patients responded initially to L-DOPA treatment. Neuropathologic examination of 17 GBA mutation carriers showed typical PD changes, with widespread and abundant alpha-synuclein pathology, and most also had neocortical Lewy body pathology. The prevalence of GBA mutations in British patients with sporadic PD was 3.7%, indicating that mutations in the GBA gene may be the most common risk factor for development of PD in this population. In an accompanying letter, Gan-Or et al. (2009) found that the data presented by Neumann et al. (2009) indicated that patients with mild GBA mutations had a later age at onset (62.9 years vs 49.8 years) and lower frequency of cognitive symptoms (25% vs 55.6%) compared to patients with severe GBA mutations. Alcalay et al. (2010) identified mutations in the GBA gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. There were 18 heterozygous L444P carriers, 38 heterozygous N370S carriers, and 2 homozygous N370S carriers. Six of the 64 patients had a GBA mutation and another mutation in the LRRK2 or PRKN (PARK2; 602544) genes. ### Modifier Genes Plaitakis et al. (2010) identified a 1492T-G polymorphism in the GLUD2 gene (S445A; 300144.0001) that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease. Among 584 Greek patients, 1492G hemizygous males developed PD 8 to 13 years earlier than did patients with the T (p = 0.003), the G/T (p less than 0.001), or the T/T (p = 0.01) genotype. Among 224 North American patients, 1492G hemizygotes also developed PD earlier than those with other genotypes, but the mean age differences reached statistical significance only when G hemizygotes were compared to G/T heterozygotes (mean age difference: 13.1 years, p less than 0.05). The substitution was demonstrated to confer a gain of function, which Plaitakis et al. (2010) postulated may increase glutamate oxidation and the production of reactive oxygen species in the brain. ### Associations Pending Confirmation For discussion of a possible association between Parkinson disease and variation in the PARL gene, see 607858.0001. For discussion of a possible association between Parkinson disease and variation in the ABCA7 gene, see 605414. For discussion of a possible association between Parkinson disease and variation in the RIC3 gene, see 610509.0001. Genotype/Phenotype Correlations Mutations in the LRRK2 gene (609007) and the GBA gene commonly predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common LRRK2 G2019S mutation (609007.0006) and for 8 GBA mutations. Among all patients, 117 (19.5%) were heterozygous for GBA mutations, and 82 (13.7%) were heterozygous for the LRRK2 G2019S mutation, including 8 patients carrying both GBA and LRRK2 mutations. There were 6 (1.0%) homozygotes or compound heterozygotes GBA mutations carriers, and 1 (0.2%) patient homozygote for G2019S. Carriers of LRRK2 G2019S or GBA mutations had a significantly earlier average age at onset (57.5 and 57.7 years) than noncarriers (61.0 years); the 8 with mutations in both genes had a similar average age at onset (57.4 years). A phenotypic comparison of those with the G2019S mutation, GBA mutations, and noncarriers of these mutations showed that more of those with the G2019S mutation reported muscle stiffness/rigidity (p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness/bradykinesia (p = 0.021). However, the most common presenting symptom in both groups was tremor (about 50%). These results suggested distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD in some cases. Pathogenesis Nussbaum and Polymeropoulos (1997) stated that the motor symptoms in Parkinson disease are generally thought to result from the deficiency or dysfunction of dopamine or dopaminergic neurons in the substantia nigra, regardless of etiology. Auluck et al. (2002) found that Lewy bodies and Lewy neurites in postmortem brain tissue from Parkinson disease patients immunostained for the molecular chaperones HSP70 (see 140550) and HSP40 (see 604572), suggesting that chaperones may play a role in Parkinson disease progression, as was demonstrated in their studies in flies carrying mutated alpha-synuclein (163890) in which coexpression of human HSP70 mitigated the loss of dopaminergic neurons. Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin (RELN; 600514) fragment in CSF from 19 patients with AD compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia, PSP, and PD. Cooper et al. (2006) found that the earliest defect following alpha-synuclein expression in yeast was a block in endoplasmic reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphate Ypt1p, which associated with cytoplasmic alpha-synuclein inclusions. Elevated expression of Rab1 (179508), the mammalian Ypt1 homolog, protected against alpha-synuclein-induced dopaminergic neuron loss in animal models of PD. Thus, Cooper et al. (2006) concluded that synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable. Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2 (604480) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of PD. Outeiro et al. (2007) concluded that their results suggest a link between neurodegeneration and aging. Muqit et al. (2006) provided a review of the role of mitochondrial dysfunction, including oxidative damage and apoptosis, in the pathogenesis of Parkinson disease. Elstner et al. (2009) performed whole-genome expression profiling of isolated substantia nigra neurons taken from 8 patients with PD and 9 controls. Four differentially expressed genes were identified in candidate PD pathways: MTND2 (516001, p = 7.14 x 10(-7)); PDXK (179020, p = 3.27 x 10(-6)); SRGAP3 (606525, p = 5.65 x 10(-6)); TRAPPC4 (610971, p = 5.81 x 10(-6)). Population-based studies found an association between rs2010795 in the PDXK gene and increased risk of PD in German (p = 0.00032), British (p = 0.028), and Italian (p = 0.0025) cohorts (combined p = 1.2 x 10(-7); OR of 1.3) totaling 1,232 PD patients and 2,802 controls. Elstner et al. (2009) suggested that vitamin B6 status and metabolism may influence disease risk in PD. However, neither Guella et al. (2010) nor Vilarino-Guell et al. (2010) could replicate the association with rs2010795 in their respective studies of 920 Italian PD patients and 920 Italian controls and of 6 independent populations from Europe, North America, and Asia totaling 1,977 PD patients and 1,907 controls. In brains from patients with Parkinson disease, Minones-Moyano et al. (2011) found decreased expression of MIRN34B (611374) and MIRN34C (611375) in areas with variable neuropathologic affectation at different clinical stages of the disease, including the amygdala, frontal cortex, substantia nigra, and cerebellum. Misregulation of MIRN34B/C was detected in pre-motor stages of the disease as well, particularly in the amygdala. Depletion of MIRN34B or MIRN34C in differentiated dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress, and reduction in total cellular ATP content. Downregulation of these miRNAs was associated with a decrease in the expression of DJ1 (602533) and PARK2 (602544), 2 genes associated with PD, in cell studies and in patient brain tissue. The findings suggested that early deregulation of MIRN34B and MIRN34C can trigger downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability in PD. Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of monocyte-specific eQTLs among Alzheimer disease (104300) and Parkinson disease variants, and of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis (180300) and multiple sclerosis (126200). Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants. Using an unbiased screen targeting endogenous gene expression, Mittal et al. (2017) discovered that the beta-2-adrenoreceptor (B2AR; 109690) is a regulator of the alpha-synuclein gene (SNCA; 163890). B2AR ligands modulate SNCA transcription through histone H3 lysine-27 acetylation (H3K27ac) of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the B2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a B2AR antagonist, propanolol, correlated with increased risk. B2AR activation protected model mice and patient-derived cells. Thus, Mittal et al. (2017) conclude that B2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies. Sulzer et al. (2017) showed that a defined set of peptides that are derived from alpha-synuclein (163890) act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson disease. Sulzer et al. (2017) suggested that these responses may explain the association of Parkinson disease with specific MHC alleles. Burbulla et al. (2017) studied dopaminergic neurons derived from patients with idiopathic and familial (homozygous for DJ1 c.192G-C, 602533.0005) Parkinson disease. The authors identified a time-dependent pathologic cascade beginning with mitochondrial oxidant stress, leading to oxidized dopamine accumulation, and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, Parkinson disease neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathologic phenotypes observed in human neurons. Thus, Burbulla et al. (2017) dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in Parkinson disease pathogenesis. Population Genetics Trenkwalder et al. (1995) used a door-to-door survey to investigate the prevalence of parkinsonism in a rural Bavarian population of individuals older than 65 years. In this population, the prevalence of Parkinson disease was 0.71%; drug-induced parkinsonism, 0.41%; vascular parkinsonism, 0.20%; multiple systems atrophy, 0.31%; Fahr disease, 0.10%; and normal pressure hydrocephalus, 0.41%. Fifty percent of these cases were newly diagnosed. In a community-based survey of Singaporeans (9,000 Chinese, 3,000 Malays, and 3,000 Indians) aged 50 years and older, Tan et al. (2004) found that the prevalence rate of PD was approximately 0.30%, which is comparable to that of Western countries. In a study of over 14,000 twin pairs in the Swedish Twin Registry, Wirdefeldt et al. (2004) found that only 2 twin pairs were concordant for PD, suggesting that environmental factors were more important in the development of the disease in this population. History Parkinson disease was first described by physician James Parkinson as a 'shaking palsy' in 1817. Stien (2005) proposed that William Shakespeare (1564-1616) referred to the disease as a 'palsy' of old age in several of his plays, indicating that the first European reference to the disease occurred in the late 16th century. Zhang et al. (2006) provided a detailed review of early Chinese descriptions of Parkinson disease, including contemporary therapeutic recommendations. The evidence from classic sources of traditional Chinese medicine strongly suggested that PD was known to medical scholars in China as early as 425 B.C.; the first clear description of a clinical case occurred during the Jin dynasty in late 12th century A.D. Animal Model Clarke et al. (2000) studied the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration, and in Parkinson and Huntington (143100) diseases. In all models the kinetics of neuronal death were exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death in any neuron is random. Clarke et al. (2000) argued that their findings are most simply accommodated by a '1-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies in that the likelihood that a mutant neuron can be rescued by treatment is not diminished by age, and therefore treatment at any stage of illness is likely to confer benefit. Progressive postnatal depletion of dopaminergic cells has been demonstrated in weaver mice, a mouse model of Parkinson disease associated with homozygosity for a mutation in the H54 region of Girk2, a putative G protein inward rectifier protein potassium channel. Bandmann et al. (1996) found no mutations of the pore region in KCNJ6 (600877), the human homolog, in 50 cases of Parkinson disease, 23 of which were index cases of familial Parkinson disease. Transgenic Drosophila expressing human alpha-synuclein carrying the ala30-to-pro (A30P; 163890.0002) mutation faithfully replicate essential features of human Parkinson disease, including age-dependent loss of dopaminergic neurons, Lewy body-like inclusions, and locomotor impairment. Scherzer et al. (2003) characterized expression of the entire Drosophila genome at presymptomatic, early, and advanced disease stages. Fifty-one signature transcripts were tightly associated with A30P alpha-synuclein expression. At the presymptomatic stage, expression changes revealed specific pathology. In age-matched transgenic Drosophila expressing the arg406-to-trp mutation in tau (157140.0003), the transcription of mutant alpha-synuclein-associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Landau et al. (2005) found that Fas (TNFRSF6; 134637)-deficient lymphoproliferative mice developed a PD phenotype, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, after treatment with MPTP at a dose that caused no phenotype in wildtype mice. Mice with mutated Fasl (TNFSF6; 134638) and generalized lymphoproliferative disease had an intermediate phenotype. Treatment of cultured midbrain neurons with Fasl to induce Fas signaling protected them from MPTP toxicity. Mice lacking only Fas exon 9, which encodes the death domain, but retaining the intracellular Fas domain and cell surface expression of Fas, were resistant to MPTP. Peripheral blood lymphocytes from patients with idiopathic PD showed a highly significant deficit in their ability to upregulate Fas after mitogen stimulation. Landau et al. (2005) concluded that reduced FAS expression increases susceptibility to neurodegeneration and that FAS has a role in neuroprotection. ### Therapeutic Strategies Kordower et al. (2000) tested lentiviral vector delivery of glial cell line-derived neurotrophic factor (GDNF; 600837), or lenti-GDNF, for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson disease. The authors injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with MPTP, a neurotoxin known to specifically damage dopamine neurons. Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. Kordower et al. (2000) concluded that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients. Luo et al. (2002) noted that a disinhibited and overactive subthalamic nucleus (STN) alters basal ganglia network activity in PD, and that electrical inhibition, pharmacologic silencing, and STN ablation can improve the motor symptoms in PD, presumably by leading to suppression of firing activity of neurons in the substantia nigra (SN). Using a recombinant adeno-associated virus to transduce excitatory glutaminergic neurons in the rat STN with glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the inhibitory neurotransmitter GABA, Luo et al. (2002) showed that the neurons expressed the GAD gene and changed from largely excitatory to predominantly inhibitory, resulting in decreased excitatory and increased inhibitory response in the substantia nigra. Moreover, the increased inhibitory tone provided neuroprotection to the dopaminergic cells in response to toxic insult. Rats with the transduced gene showed significant improvement from the parkinsonian behavioral phenotype. Luo et al. (2002) emphasized the plasticity in neurotransmission in the mammalian brain. Teismann et al. (2003) showed that cyclooxygenase-2 (COX2; 600262), the rate-limiting enzyme in prostaglandin E2 synthesis, is upregulated in brain dopaminergic neurons of both PD and the MPTP mouse model of that disorder. They demonstrated further that targeting COX2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, they provided evidence that COX2 inhibition prevents the formation of the oxidant species of dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supported a critical role for COX2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD. The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Kreitzer and Malenka (2007) showed that excitatory synapses onto indirect-pathway medium spiny neurons exhibit higher release probability and larger NMDA receptor currents than direct-pathway synapses. Moreover, indirect-pathway medium spiny neurons selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor (126450) activation. In models of Parkinson disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo in mice reduced parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. Kravitz et al. (2010) reported direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons, achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of BAC transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 (126449) or D2 receptors. Bilateral excitation of indirect-pathway medium spiny projection neurons elicited a parkinsonian state distinguished by increased freezing, bradykinesia, and decreased locomotor initiations. In contrast, activation of direct-pathway medium spiny projection neurons reduced freezing and increased locomotion. In a mouse model of Parkinson disease, activation of the direct pathway completely rescued deficits in freezing, bradykinesia, and locomotor initiation. Kravitz et al. (2010) concluded that their data establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits. Chan et al. (2007) found that dopamine-containing neurons in the substantia nigra in mice relied on L-type voltage-gated calcium channels (see, e.g., CACNA1S, 114208) to drive pacemaking. The reliance on these calcium channels increased with age, and juvenile neurons tended to use sodium-powered cation channels. The mechanism used by juvenile neurons remained latent in adulthood, but pharmacologic (isradipine) or gene-mediated blocking of the calcium channels in adult neurons induced a reversion to the juvenile form of pacemaking. Such blocking of calcium influx protected dopamine-containing neurons in both in vitro and in vivo mouse models of Parkinson disease. The findings were consistent with a theory of pathogenesis in which activity-dependent calcium influx results in intracellular calcium accumulation that becomes toxic to these neurons with age. Sotnikova et al. (2006) developed a novel acute mouse model of severe dopamine deficiency using Dat (SLC6A3; 126455)-null mice and pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient Dat-null (DDD) mice demonstrated severe akinesia, rigidity, tremor, and ptosis, similar to behaviors observed in patients with Parkinson disease. Interestingly, DDD mice were able to swim in water, indicating that certain movements and conditions can occur independently of dopamine. Dopamine agonists such as L-DOPA temporarily restored locomotion in DDD mice, and amphetamine derivatives showed effectiveness in reducing motor abnormalities in DDD mice. Sotnikova et al. (2006) noted that the DDD mouse model provides a unique opportunity to screen potential therapeutic agents for the treatment of Parkinson disease. Berman et al. (2011) found that Slc1a1 (133550)-null mice developed age-dependent progressive loss of dopaminergic neurons in the substantia nigra, with more than 40% of these neurons lost by age 12 months, and microglial activation in the substantia nigra. Mutant mice showed impaired motor performance compared to wildtype mice. These features were similar to those found in humans with Parkinson disease. Dopaminergic neurons in the Slc1a1-null mice showed evidence of increased oxidative stress. Long-term treatment of mutant mice with N-acetylcysteine resulted in increased levels of glutathione, prevented dopaminergic neuronal loss, and resulted in improved motor performance. Berman et al. (2011) suggested that the Slc1a1-null mouse may be a useful model for the chronic neuronal oxidative stress that occurs in PD. INHERITANCE \- Autosomal dominant \- Multifactorial HEAD & NECK Face \- Masked facies Nose \- Decreased sense of smell ABDOMEN Gastrointestinal \- Dysphagia \- Constipation GENITOURINARY Bladder \- Urinary urgency NEUROLOGIC Central Nervous System \- Parkinsonism \- Bradykinesia \- Rigidity \- Postural instability \- Resting tremor \- Micrographia \- Gait disturbances \- Shuffling gait \- Dystonia \- Dysarthria \- Monotonous speech \- Dysautonomia may occur \- Visual hallucinations may occur \- Dementia may occur \- Sleep disturbances \- Neuronal loss and gliosis in the substantia nigra pars compacta \- Loss of dopaminergic neurons \- Intracellular Lewy bodies \- Aggregation of SNCA-immunopositive inclusions Behavioral Psychiatric Manifestations \- Depression MISCELLANEOUS \- Onset mid to late adulthood \- Insidious onset \- Progressive disorder \- Levodopa-responsive MOLECULAR BASIS \- Susceptibility conferred by mutation in the acid beta glucosidase gene (GBA, 606463.0001 ) \- Susceptibility conferred by mutation in the alcohol dehydrogenase IC, gamma polypeptide gene (ADH1C, 103730.0003 ) \- Susceptibility conferred by mutation in the TATA box binding protein gene (TBP, 600075.0001 ) \- Susceptibility conferred by mutation in the ataxin 2 gene (ATXN2, 601517.0001 ) \- Susceptibility conferred by mutation in the microtubule-associated protein tau gene (MAPT, 157140.0021 ) ▲ 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	PARKINSON DISEASE, LATE-ONSET	c3160718	5,737	omim	https://www.omim.org/entry/168600	2019-09-22T16:36:35	{"omim": ["168600"], "synonyms": ["Alternative titles", "PARK"], "genereviews": ["NBK1208", "NBK1223"]}
## Description Atrial fibrillation is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). For a discussion of genetic heterogeneity of atrial fibrillation, see 608583. Mapping Gudbjartsson et al. (2009) expanded the genomewide association study on atrial fibrillation in Iceland, which had identified risk variants on 4q25 (see 611494), and tested the most significant associations in samples from Iceland, Norway, and the United States. This sample consisted of 2,385 atrial fibrillation, or atrial flutter, cases and 33,752 controls who were genotyped using the Illumina HumanHap300 or HumanHapCNV370 bead chips. A variant in the ZFHX3 (104155) gene on chromosome 16q22, the T allele of single-nucleotide polymorphism (SNP) rs7193343, was associated significantly with atrial fibrillation (odds ratio 1.21, P = 1.4 x 10(-10)). This variant was also associated with ischemic stroke (odds ratio = 1.11, P = 0.00054) and cardioembolic stroke (odds ratio = 1.22, P = 0.00021) in a combined analysis of 5 stroke samples. The association of rs7193343 with atrial fibrillation was not significant in a Han Chinese population from Hong Kong consisting of 286 atrial fibrillation cases and 2,763 controls. However, the T allele at rs7193343 is much more frequent in the Han Chinese population than in samples from persons of European descent (0.68 vs 0.14-1.20, respectively). Benjamin et al. (2009) conducted a metaanalysis of genomewide association studies for atrial fibrillation in participants from 5 community-based cohorts. Metaanalyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) atrial fibrillation cases identified a locus for atrial fibrillation at chromosome 16q22 represented by the SNP rs2106261 located in an intron of the ZFHX3 gene (risk ratio of 1.19; P = 2.3 x 10(-7)). This association was replicated in an independent cohort from the German Atrial Fibrillation Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined risk ratio for the 2 groups = 1.25; combined P = 1.8 x 10(-15)). [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	ATRIAL FIBRILLATION, FAMILIAL, 8	c2751607	5,738	omim	https://www.omim.org/entry/613055	2019-09-22T15:59:54	{"doid": ["0050650"], "mesh": ["C567802"], "omim": ["613055", "608583"], "orphanet": ["334"], "synonyms": []}
A number sign (#) is used with this entry because this form of hypoplastic amelogenesis imperfecta (AI1E) is caused by mutation in the gene encoding amelogenin (AMELX; 300391). Description Amelogenesis imperfecta is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988). Clinical Features Witkop (1957) was the first to describe a hypomaturation form of AI. In this form, both dentitions are affected. In males, primary teeth are opaque ground-glass white, and secondary teeth are mottled yellow-brown and white. Enamel is of normal thickness, moderately soft, and does not contrast from dentin on x-ray. The teeth chip and abrade more easily than normal teeth, but the loss of enamel is not as rapid as in the hypocalcified form (Witkop and Sauk, 1976). Because of the appearance of the teeth in this form, referred to as snow-capped (Witkop and Sauk, 1976; Escobar et al., 1981) in its most marked form, confusion with fluorosis sometimes occurs. The condition has been observed in areas essentially devoid of fluoride in drinking water and has occurred in family members through 3 generations who have resided in different areas of the country (Witkop and Rao, 1971). Rushton (1964), Witkop (1967), and Sauk et al. (1972) pointed out differences in affected males and heterozygous females which may be based on the Lyon phenomenon. Affected males have only a very thin, smooth layer of enamel which appears nearly homogeneous. The females have enamel that in parts is much thicker, giving a vertically grooved appearance to the teeth. Wide variation in the involvement in females is also consistent with the Lyon hypothesis. Backman (1988) described the clinical manifestations of amelogenesis imperfecta in 51 families from a northern Swedish county. Two of these families, families 22 and 41, were later found to have mutations in the AMELX gene (see 300391.0002 and 300391.0001, respectively). Family 22 had 7 affected individuals in 3 generations. All 5 females had hypoplastic AI but the surface of the enamel varied greatly: in 2 it was rough and in 3 it was pitted. In all 5, some of the teeth were seemingly unaffected. The 1 male who was studied had hypoplastic AI with thin, smooth enamel. Family 41 had 17 affected individuals in 4 generations. The 5 males with permanent teeth and 1 boy with primary teeth were described as having hypomaturation AI. Some carrier females had vertically ridged teeth with alternating bands of normal and hypoplastic enamel mainly present on the anterior teeth. Mottled opaque, white areas were also present, indicating hypomineralization. The intensity and extent of enamel defect varied from tooth to tooth and also between the women. Hu et al. (2012) described 2 families segregating X-linked amelogenesis imperfecta with a characteristic snow-capped enamel phenotype. Affected family members exhibited minor variations in their enamel, but all had a thicker layer of enamel on the cusp tips and marginal ridges relative to the lateral tooth surfaces. Inheritance Schulze and Lenz (1952), Schulze (1957), and others pointed out that one form of amelogenesis imperfecta is X-linked. Mapping In 2 large Swedish families (pedigrees 22 and 41 originally described by Backman and Holmgren, 1988) with X-linked amelogenesis imperfecta, Lagerstrom et al. (1989, 1990) mapped the locus to Xp22 by demonstrating no recombination with DXS85; maximum lod score = 4.45 at theta = 0.00. In 2 of 3 affected families, Aldred et al. (1992) found strong evidence of linkage to an Xp22 marker; the combined maximum lod score for the 2 families was 7.30 for location of AIH1 2 cM distal to DXS16, using multipoint linkage analysis. A third family, however, showed significant evidence against linkage and a strong suggestion of linkage to DXS144E and F9 (300746) with no recombination with either of these markers. The peak lod score in multipoint linkage analysis was 2.84 at theta = 0. This was considered to place the locus, which they referred to as AIH3 (see 301201), at Xq22-q28. Aldred et al. (1992) observed that in the 2 families linked to Xp, clinical manifestations were similar in members of the same sex within each family, whereas in the third, Xq-linked family, the clinical features were more variable in affected members of each sex. Molecular Genetics By Southern blot analysis, Lagerstrom et al. (1991) demonstrated a deletion extending over 5 kb of the amelogenin gene (300391.0001) in males with the hypomineralization form of amelogenesis imperfecta. Carrier females were heterozygous for the molecular defect which appeared to include at least 2 exons of the gene. The extent of the deletion was verified by polymerase chain reaction (PCR) analysis. Segregation of the mutation with the disease was established in 15 members of the kindred analyzed. Lagerstrom-Fermer et al. (1995) stated that affected members of this family had enamel of normal thickness but that it was poorly mineralized and therefore softer than normal. This contrasted with the findings of thin enamel in a patient with a 9-bp deletion (300391.0003). They presented photographs contrasting the appearance of the teeth. Kim et al. (2004) described 2 mutations (300391.0010 and 300391.0011) in the coding region of the AMELX signal peptide. These mutations are predicted to interfere with the secretion of amelogenin. Kim et al. (2004) stated that the common phenotype caused by these signal peptide mutations is enamel hypoplasia with malformed incisal edges on the anterior teeth. The enamel appears to have mineralized normally and contrasts with dentin on radiographs. In affected members of 2 families segregating X-linked amelogenesis imperfecta with a characteristic snow-capped enamel phenotype, Hu et al. (2012) identified deletions of the entire AMELX gene and portions of the ARHGAP6 gene, i.e., the alternative ARHGAP6 promoters 1c and 1d (300391.0012) in a Turkish family and ARHGAP6 promoter 1d and exon 2 in an Eastern European family. By RT-PCR analysis, Hu et al. (2012) showed that the ARHGAP6 promoters are not active in ameloblasts, indicating that their deletion was unlikely to have affected the developing teeth in the Turkish family. The deletion of exon 2 was likely to have precluded expression of ARHGAP6 in the Eastern European family. Although ARHGAP6 was expressed in secretory stage ameloblasts and enamel organ epithelia of mice, Hu et al. (2012) concluded that the phenotype resulted from deletion of AMELX and that loss of ARHGAP6 expression did not appreciably alter the severity of the enamel defects. Animal Model Barron et al. (2010) described a tyr64-to-his missense mutation in the tri-tyrosyl domain of the enamel extracellular matrix protein of mouse Amelx. Affected animals had severe defects of enamel biomineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis, and formation of multicellular masses. Affected ameloblasts expressed but failed to secrete full-length amelogenin, leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Cotransfection of Ambn (601259) and mutant Amelx in a eukaryotic cell line revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wildtype Amelx, mutant Amelx, or Ambn, or cotransfected with both wildtype Amelx and Ambn. Barron et al. (2010) hypothesized that intracellular protein-protein interactions mediated via the amelogenin tri-tyrosyl motif may be a key mechanistic factor underpinning the molecular pathogenesis in this example of AI. INHERITANCE \- X-linked dominant HEAD & NECK Teeth \- Amelogenesis imperfecta \- Hypomineralized enamel \- Soft enamel \- Hard enamel \- Thin enamel \- Pitted enamel \- Wide spacing between teeth \- Discolored teeth (yellow to brown) \- Rough tooth surface \- Vertical ridges on enamel \- Normal dentin \- Anterior open bite \- 'Snow-capped' appearance of teeth MISCELLANEOUS \- Phenotypic variability \- Carrier females exhibit less severe phenotype attributed to random inactivation of the X chromosome MOLECULAR BASIS \- Caused by mutation in the amelogenin gene (AMELX, 300391.0001 ) ▲ 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	AMELOGENESIS IMPERFECTA, TYPE IE	c0399372	5,739	omim	https://www.omim.org/entry/301200	2019-09-22T16:18:48	{"doid": ["0110058"], "mesh": ["C536606"], "omim": ["301200"], "orphanet": ["100033", "88661"], "synonyms": ["Alternative titles", "AMELOGENESIS IMPERFECTA, HYPOPLASTIC/HYPOMATURATION, X-LINKED 1", "AMELOGENESIS IMPERFECTA, HYPOMATURATION TYPE, WITH SNOW-CAPPED TEETH", "AMELOGENESIS IMPERFECTA, X-LINKED 1", "ENAMEL HYPOPLASIA, X-LINKED"]}
A rare inborn error of metabolism characterized by congenital asplenia and childhood or adolescent onset of generalized inflammation, persistent intravascular hemolysis and anemia, severe endothelial injury with abnormal coagulation, bleeding diathesis, and nephropathy. Additional reported manifestations include growth retardation, mild facial dysmorphism, and hepatomegaly. [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	Heme oxygenase-1 deficiency	c1841651	5,740	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=562509	2021-01-23T18:19:07	{"mesh": ["C564200"], "omim": ["614034"], "synonyms": ["HO-1 deficiency"]}
Orofaciodigital syndrome type 14 is a rare subtype of orofaciodigital syndrome, with autosomal recessive inheritance and C2CD3 mutations, characterized by severe microcephaly, trigonocephaly, severe intellectual disability and micropenis, in addition to oral, facial and digital malformations (gingival frenulae, lingual hamartomas, cleft/lobulated tongue, cleft palate, telecanthus, up-slanting palpebral fissures, microretrognathia, postaxial polydactyly of hands and duplication of hallux). Corpus callosum agenesis and vermis hypoplasia with molar tooth sign, on brain imaging, are also 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	Orofaciodigital syndrome type 14	c4014780	5,741	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=434179	2021-01-23T18:17:26	{"omim": ["615948"], "icd-10": ["Q87.0"], "synonyms": ["Microcephaly-cerebral malformation-orofaciodigital syndrome", "OFD14", "Oral-facial-digital syndrome type 14"]}
Familial pityriasis rubra pilaris is a rare genetic condition that affects the skin. The name of the condition reflects its major features: The term "pityriasis" refers to scaling; "rubra" means redness; and "pilaris" suggests the involvement of hair follicles in this disorder. Affected individuals have a salmon-colored skin rash covered in fine scales. This rash occurs in patches all over the body, with distinct areas of unaffected skin between the patches. Affected individuals also develop bumps called follicular keratoses that occur around hair follicles. The skin on the palms of the hands and soles of the feet often becomes thick, hard, and callused, a condition known as palmoplantar keratoderma. Researchers have distinguished six types of pityriasis rubra pilaris based on the features of the disorder and the age at which signs and symptoms appear. The familial form is usually considered part of type V, which is also known as the atypical juvenile type. People with familial pityriasis rubra pilaris typically have skin abnormalities from birth or early childhood, and these skin problems persist throughout life. ## Frequency Familial pityriasis rubra pilaris is a rare condition. Its incidence is unknown, although the familial form appears to be the least common type of pityriasis rubra pilaris. ## Causes In most cases of pityriasis rubra pilaris, the cause of the condition is unknown. However, mutations in the CARD14 gene have been found to cause the familial form of the disorder in a few affected families. The CARD14 gene provides instructions for making a protein that turns on (activates) a group of interacting proteins known as nuclear factor-kappa-B (NF-κB). NF-κB regulates the activity of multiple genes, including genes that control the body's immune responses and inflammatory reactions. It also protects cells from certain signals that would otherwise cause them to self-destruct (undergo apoptosis). The CARD14 protein is found in many of the body's tissues, but it is particularly abundant in the skin. NF-κB signaling appears to play an important role in regulating inflammation in the skin. Mutations in the CARD14 gene lead to overactivation of NF-κB signaling, which triggers an abnormal inflammatory response. Researchers are working to determine how these changes lead to the specific features of familial pityriasis rubra pilaris. ### Learn more about the gene associated with Familial pityriasis rubra pilaris * CARD14 ## Inheritance Pattern Familial pityriasis rubra pilaris usually has an autosomal dominant inheritance pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Affected individuals usually inherit the condition from one affected parent. However, the condition is said to have incomplete penetrance because not everyone who inherits the altered gene from a parent develops the condition's characteristic skin abnormalities. The other types of pityriasis rubra pilaris are sporadic, which means they occur in people with no history of the disorder in their family. [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	Familial pityriasis rubra pilaris	c0032027	5,742	medlineplus	https://medlineplus.gov/genetics/condition/familial-pityriasis-rubra-pilaris/	2021-01-27T08:25:04	{"gard": ["7401"], "mesh": ["D010916"], "omim": ["173200"], "synonyms": []}
Cancer originating in or on the ovary Ovarian cancer Micrograph of a mucinous ovarian carcinoma stained by H&E. SpecialtyOncology, gynecology SymptomsEarly: vague[1] Later: bloating, pelvic pain, abdominal swelling, loss of appetite[1] Usual onsetUsual age of diagnosis 63 years old[2] TypesOvarian carcinoma, germ cell tumor, sex cord stromal tumor[3] Risk factorsNever having children, hormone therapy after menopause, fertility medication, obesity, genetics[4][3][5] Diagnostic methodTissue biopsy[1] TreatmentSurgery, radiation therapy, chemotherapy[1] PrognosisFive-year survival rate c. 49% (US)[6] Frequency1.2 million (2015)[7] Deaths161,100 (2015)[8] Ovarian cancer is a cancer that forms in or on an ovary.[4][9] It results in abnormal cells that have the ability to invade or spread to other parts of the body.[10] When this process begins, there may be no or only vague symptoms.[1] Symptoms become more noticeable as the cancer progresses.[1][11] These symptoms may include bloating, pelvic pain, abdominal swelling, and loss of appetite, among others.[1] Common areas to which the cancer may spread include the lining of the abdomen, lymph nodes, lungs, and liver.[12] The risk of ovarian cancer increases in women who have ovulated more over their lifetime. This includes those who have never had children, those who begin ovulation at a younger age and those who reach menopause at an older age.[3] Other risk factors include hormone therapy after menopause, fertility medication, and obesity.[4][5] Factors that decrease risk include hormonal birth control, tubal ligation, and breast feeding.[5] About 10% of cases are related to inherited genetic risk; women with mutations in the genes BRCA1 or BRCA2 have about a 50% chance of developing the disease.[3] Ovarian carcinoma is the most common type of ovarian cancer, comprising more than 95% of cases.[3] There are five main subtypes of ovarian carcinoma, of which high-grade serous carcinoma (HGSC) is the most common.[3] These ovarian tumors are believed to start in the cells covering the ovaries,[3] though some may form at the Fallopian tubes.[13] Less common types of ovarian cancer include germ cell tumors[14]and sex cord stromal tumors.[3] A diagnosis of ovarian cancer is confirmed through a biopsy of tissue, usually removed during surgery.[1] Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks.[15] Those at very high risk may have their ovaries removed as a preventive measure.[4] If caught and treated in an early stage, ovarian cancer is often curable.[1] Treatment usually includes some combination of surgery, radiation therapy, and chemotherapy.[1] Outcomes depend on the extent of the disease, the subtype of cancer present, and other medical conditions.[16][3] The overall five-year survival rate in the United States is 49%.[6] Outcomes are worse in the developing world.[3] In 2012, new cases occurred in approximately 239,000 women.[3] In 2015 it was present in 1.2 million women and resulted in 161,100 deaths worldwide.[8][7] Among women it is the seventh-most common cancer and the eighth-most common cause of death from cancer.[3] The typical age of diagnosis is 63.[2] Death from ovarian cancer is more common in North America and Europe than in Africa and Asia.[3] ## Contents * 1 Signs and symptoms * 1.1 Early symptoms * 1.2 Later symptoms * 1.3 Children * 2 Risk factors * 2.1 Hormones * 2.2 Genetics * 2.3 Environmental factors * 2.4 Other * 2.5 Protective factors * 3 Pathophysiology * 4 Diagnosis * 4.1 Examination * 4.1.1 Risk scoring * 4.2 Pathology * 4.2.1 Epithelial carcinoma * 4.2.1.1 Serous carcinoma * 4.2.1.2 Small-cell carcinoma * 4.2.1.2.1 Primary peritoneal carcinoma * 4.2.1.3 Clear-cell carcinoma * 4.2.1.4 Clear-cell adenocarcinoma * 4.2.1.5 Endometrioid * 4.2.1.5.1 Malignant mixed müllerian tumor (carcinosarcoma) * 4.2.1.6 Mucinous * 4.2.1.6.1 Mucinous adenocarcinoma * 4.2.1.6.2 Pseudomyxoma peritonei * 4.2.1.7 Undifferentiated epithelial * 4.2.1.7.1 Malignant Brenner tumor * 4.2.1.7.2 Transitional cell carcinoma * 4.2.2 Sex cord-stromal tumor * 4.2.2.1 Granulosa cell tumor * 4.2.2.1.1 Adult granulosa cell tumor * 4.2.2.1.2 Juvenile granulosa cell tumor * 4.2.2.2 Sertoli-Leydig cell tumor * 4.2.2.3 Sclerosing stromal tumors * 4.2.3 Germ cell tumor * 4.2.3.1 Dysgerminoma * 4.2.3.2 Choriocarcinoma * 4.2.3.3 Immature (solid) teratoma * 4.2.3.4 Mature teratoma (dermoid cyst) * 4.2.3.5 Yolk sac tumor/endodermal sinus tumor * 4.2.3.6 Embryonal carcinoma * 4.2.3.7 Polyembryoma * 4.2.4 Squamous cell carcinoma * 4.2.5 Mixed tumors * 4.2.6 Secondary ovarian cancer * 4.2.7 Borderline tumors * 4.3 Staging * 4.3.1 FIGO * 4.3.2 AJCC/TNM * 4.3.3 Grading * 5 Screening * 6 Prevention * 7 Management * 7.1 Surgery * 7.2 Chemotherapy * 7.2.1 Platinum-sensitive or platinum-resistant * 7.3 Radiation therapy * 7.4 Hormonal therapy * 7.5 Immunotherapy * 7.6 Follow-up * 7.7 Palliative care * 7.8 Psychosocial care * 8 Prognosis * 8.1 Prognostic factors * 8.2 Survival rates * 8.3 Recurrence rates * 9 Epidemiology * 9.1 United States * 9.2 United Kingdom * 9.3 Ethnicity * 9.4 Older women * 10 In pregnancy * 11 Other animals * 12 Research * 12.1 Screening * 12.2 Prognosis research * 12.3 Immunotherapy * 12.4 Pharmacology * 12.5 Hormones and radiation * 12.6 Inflammation * 12.7 Clinical trials * 13 References * 14 Further reading * 15 External links ## Signs and symptoms[edit] ### Early symptoms[edit] Site of ovarian cancer Early signs and symptoms of ovarian cancer may be absent or subtle. In most cases, symptoms exist for several months before being recognized and diagnosed.[17][18] Symptoms can be misdiagnosed as irritable bowel syndrome.[19] The early stages of ovarian cancer tend to be painless. Symptoms can vary based on the subtype.[17] Ovarian borderline tumors, also known as low malignant potential (LMP) ovarian tumors, do not cause an increase in CA125 levels and are not identifiable with an ultrasound. The typical symptoms of an LMP tumor can include abdominal distension or pelvic pain. Particularly large masses tend to be benign or borderline.[20][17] The most typical symptoms of ovarian cancer include bloating, abdominal or pelvic pain or discomfort, back pain, irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during sexual intercourse, loss of appetite, fatigue, diarrhea, indigestion, heartburn, constipation, nausea, feeling full, and possibly urinary symptoms (including frequent urination and urgent urination).[18] ### Later symptoms[edit] The growing mass may cause pain if ovarian torsion develops. Symptoms can be caused by a mass pressing on the other abdominopelvic organs or from metastases.[17][21][22] If these symptoms start to occur more often or more severely than usual, especially after no significant history of such symptoms, ovarian cancer is considered.[17][20] Metastases may cause a Sister Mary Joseph nodule.[22] Rarely, teratomas can cause growing teratoma syndrome or peritoneal gliomatosis.[22] Some experience menometrorrhagia and abnormal vaginal bleeding after menopause in most cases. Other common symptoms include hirsutism, abdominal pain, virilization, and an adnexal mass.[23] ### Children[edit] In adolescents or children with ovarian tumors, symptoms can include severe abdominal pain, irritation of the peritoneum, or bleeding.[24] Symptoms of sex cord-stromal tumors produce hormones that can affect the development of secondary sex characteristics. Sex cord-stromal tumors in prepubertal children may be manifested by early puberty; abdominal pain and distension are also common. Adolescents with sex cord-stromal tumors may experience amenorrhea. As the cancer becomes more advanced, it can cause an accumulation of fluid in the abdomen. If the malignancy has not been diagnosed by the time it causes ascites, it is typically diagnosed shortly thereafter.[17] Advanced cancers can also cause abdominal masses, lymph node masses, or pleural effusion.[22] ## Risk factors[edit] Ovarian cancer is related to the amount of time spent ovulating. Thus not having children is a risk factor for ovarian cancer, likely because ovulation is suppressed via pregnancy. During ovulation, cells are constantly stimulated to divide while ovulatory cycles continue. Therefore, people who have not borne children are at twice the risk of ovarian cancer than those who have. A longer period of ovulation caused by early first menstruation and late menopause is also a risk factor.[20][25][26] Both obesity and hormone replacement therapy also raise the risk.[17] The risk of developing ovarian cancer is less for women who have fewer menstrual cycles, no menstrual cycles, breast feeding, take oral contraceptives, have multiple pregnancies, and have a pregnancy at an early age. The risk of developing ovarian cancer is reduced in women who have had tubal ligation (colloquially known as having one's "tubes tied"), both ovaries removed, or hysterectomy (an operation in which the uterus, and sometimes the cervix, is removed).[18] Age is also a risk factor.[17][16] ### Hormones[edit] Use of fertility medication may contribute to ovarian borderline tumor formation, but the link between the two is disputed and difficult to study.[19] Fertility drugs may be associated with a higher risk of borderline tumors.[22] Those who have been treated for infertility but remain nulliparous are at higher risk for epithelial ovarian cancer; however, those who are successfully treated for infertility and subsequently give birth are at no higher risk. This may be due to shedding of precancerous cells during pregnancy but the cause remains unclear.[20] The risk factor may instead be infertility itself, not the treatment.[25] Hormonal conditions such as polycystic ovary syndrome and endometriosis are associated with ovarian cancer, but the link is not completely confirmed.[19] Postmenopausal hormone replacement therapy (HRT) with estrogen likely increases the risk of ovarian cancer. The association has not been confirmed in a large-scale study,[20][27] but notable studies including the Million Women Study have supported this link. Postmenopausal HRT with combined estrogen and progesterone may increase contemporaneous risk if used for over 5 years, but this risk returns to normal after cessation of therapy.[25] Estrogen HRT with or without progestins increases the risk of endometrioid and serous tumors but lowers the risk of mucinous tumors. Higher doses of estrogen increase this risk.[22] Endometriosis is another risk factor for ovarian cancer,[25] as is pain with menstruation. Endometriosis is associated with clear-cell and endometrioid subtypes, low-grade serous tumors, stage I and II tumors, grade 1 tumors, and lower mortality.[22] Before menopause, obesity can increase a person's risk of ovarian cancer, but this risk is not present after menopause. This risk is also relevant in those who are both obese and have never used HRT. A similar association with ovarian cancer appears in taller people.[25] ### Genetics[edit] Further information: Hereditary breast–ovarian cancer syndrome People with ovarian or breast cancer in a pedigree chart of a family A family history of ovarian cancer is a risk factor for ovarian cancer. People with hereditary nonpolyposis colon cancer (Lynch syndrome), and those with BRCA-1 and BRCA-2 genetic abnormalities are at increased risk. The major genetic risk factor for ovarian cancer is a mutation in BRCA1 or BRCA2 genes, or in DNA mismatch repair genes, which is present in 10% of ovarian cancer cases. Only one allele need be mutated to place a person at high risk. The gene can be inherited through either the maternal or paternal line, but has variable penetrance.[17][20] Though mutations in these genes are usually associated with increased risk of breast cancer, they also carry a substantial lifetime risk of ovarian cancer, a risk that peaks in a person's 40s and 50s. The lowest risk cited is 30% and the highest 60%.[19][17][20] Mutations in BRCA1 have a lifetime risk of developing ovarian cancer of 15–45%.[22] Mutations in BRCA2 are less risky than those with BRCA1, with a lifetime risk of 10% (lowest risk cited) to 40% (highest risk cited).[17][22] On average, BRCA-associated cancers develop 15 years before their sporadic counterparts because people who inherit the mutations on one copy of their gene only need one mutation to start the process of carcinogenesis, whereas people with two normal genes would need to acquire two mutations.[20] In the United States, five of 100 women with a first-degree relative with ovarian cancer will eventually get ovarian cancer themselves, placing those with affected family members at triple the risk of women with unaffected family members. Seven of 100 women with two or more relatives with ovarian cancer will eventually get ovarian cancer.[20][28] In general, 5–10% of ovarian cancer cases have a genetic cause.[20] BRCA mutations are associated with high-grade serous nonmucinous epithelial ovarian cancer.[22] A strong family history of endometrial cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (also known as Lynch syndrome), which confers a higher risk for developing a number of cancers, including ovarian cancer. Lynch syndrome is caused by mutations in mismatch repair genes, including MSH2, MLH1, MLH6, PMS1, and PMS2.[17] The risk of ovarian cancer for an individual with Lynch syndrome is between 10 and 12 percent.[17][20] People of Icelandic descent, European Jewish descent/Ashkenazi Jewish descent, and Hungarian descent are at higher risk for epithelial ovarian cancer.[20] Estrogen receptor beta gene (ESR2) seems to be a key to pathogenesis and response to therapy.[29] Other genes that have been associated with ovarian cancer are BRIP1, MSH6, RAD51C and RAD51D.[30] CDH1, CHEK2, PALB2 and RAD50 have also been associated with ovarian cancer.[31] Several rare genetic disorders are associated with specific subtypes of ovarian cancer. Peutz–Jeghers syndrome, a rare genetic disorder, also predisposes people to sex cord tumour with annular tubules.[19][17] Ollier disease and Maffucci syndrome are associated with granulosa cell tumors in children and may also be associated with Sertoli-Leydig tumors. Benign fibromas are associated with nevoid basal cell carcinoma syndrome.[17] ### Environmental factors[edit] Industrialized nations, with the exception of Japan, have high rates of epithelial ovarian cancer, which may be due to diet in those countries. Caucasian are at a 30–40% higher risk for ovarian cancer when compared to Black and Hispanic people, likely due to socioeconomic factors; white women tend to have fewer children and different rates of gynecologic surgeries that affect risk for ovarian cancer.[20] Cohort studies have found a correlation between dairy consumption and ovarian cancer, but case-control studies do not show this correlation. There is mixed evidence regarding the effect of red meat and processed meat in ovarian cancer.[22] Tentative evidence suggests that talc, pesticides, and herbicides increase the risk of ovarian cancer.[32] The American Cancer Society notes that as of now, no study has been able to accurately link any single chemical in the environment, or in the human diet, directly to mutations that cause ovarian cancer.[33] ### Other[edit] Alcohol consumption does not appear to be related to ovarian cancer.[22][34] Other factors that have been investigated, such as smoking, low levels of vitamin D in the blood,[35] presence of inclusion ovarian cysts, and infection with human papilloma virus (the cause of some cases of cervical cancer), have been disproven as risk factors for ovarian cancer.[19][22] The carcinogenicity of perineal talc is controversial, because it can act as an irritant if it travels through the reproductive tract to the ovaries.[22][20][25] Case-control studies have shown that use of perineal talc does increase the risk of ovarian cancer, but using talc more often does not create a greater risk.[22] Use of talc elsewhere on the body is unrelated to ovarian cancer.[25] Sitting regularly for prolonged periods is associated with higher mortality from epithelial ovarian cancer. The risk is not negated by regular exercise, though it is lowered.[36] Increased age (up to the 70s) is a risk factor for epithelial ovarian cancer because more mutations in cells can accumulate and eventually cause cancer. Those over 80 are at slightly lower risk.[20] Smoking tobacco is associated with a higher risk of mucinous ovarian cancer; after smoking cessation, the risk eventually returns to normal. A diet high in animal fats may be associated with ovarian cancer, but the connection is unclear. Diet seems to play a very small role, if any, in ovarian cancer risk.[25] Higher levels of C-reactive protein are associated with a higher risk of developing ovarian cancer.[22] ### Protective factors[edit] Suppression of ovulation, which would otherwise cause damage to the ovarian epithelium and, consequently, inflammation, is generally protective. This effect can be achieved by having children, taking combined oral contraceptives, and breast feeding, all of which are protective factors.[17] A longer period of breastfeeding correlates with a larger decrease in the risk of ovarian cancer.[25] Each birth decreases risk of ovarian cancer more, and this effect is seen with up to five births. Combined oral contraceptives reduce the risk of ovarian cancer by up to 50%, and the protective effect of combined oral contraceptives can last 25–30 years after they are discontinued.[20][25] Regular use of aspirin or acetaminophen (paracetamol) may be associated with a lower risk of ovarian cancer; other NSAIDs do not seem to have a similar protective effect.[22] Tubal ligation is protective because carcinogens are unable to reach the ovary and fimbriae via the vagina, uterus, and Fallopian tubes.[17] Tubal ligation is also protective in women with the BRCA1 mutation, but not the BRCA2 mutation.[22] Hysterectomy reduces the risk, and removal of both Fallopian tubes and ovaries (bilateral salpingo-oophorectomy) dramatically reduces the risk of not only ovarian cancer but breast cancer as well.[19] This is still a topic of research, as the link between hysterectomy and lower ovarian cancer risk is controversial. The reasons that hysterectomy may be protective have not been elucidated as of 2015.[25] A diet that includes large amounts of carotene, fiber, and vitamins with low amounts of fat—specifically, a diet with non-starchy vegetables (e.g. broccoli and onions)—may be protective,[20] though research is still ongoing in this area.[25] Higher caffeine intake and consumption of more than two cups of tea a day have both been associated with lower ovarian cancer risk.[22] Smoking tobacco is protective for sex cord-stromal tumors.[23] ## Pathophysiology[edit] Mutations found in ovarian cancer subtypes[19][22][37] Gene mutated Mutation type Subtype Prevalence AKT1 amplification 3% AKT2 amplification/mutation 6%,[19] 20%[37] ARID1A point mutation endometrioid and clear cell BECN1 deletion BRAF point mutation low-grade serous 0.5% BRCA1 nonsense mutation high-grade serous 5% BRCA2 frameshift mutation high-grade serous 3% CCND1 amplification 4% CCND2 upregulation 15% CCNE1 amplification 20% CDK12 high-grade serous CDKN2A downregulation (30%) and deletion (2%) 32% CTNNB1 clear cell DICER1 missense mutation (somatic) nonepithelial 29% DYNLRB1 (km23) mutation 42% EGFR amplification/overexpression 20% ERBB2 (Her2/neu) amplification/overexpression mucinous and low-grade serous 30% FMS coexpression with CSF-1 50% FOXL2 point mutation (402 C to G) adult granulosa cell ~100% JAG1 amplification 2% JAG2 amplification 3% KRAS amplification mucinous and low-grade serous 11% MAML1 amplification and point mutation 2% MAML2 amplification and point mutation 4% MAML3 amplification 2% MLH1 1% NF1 deletion (8%) and point mutation (4%) high-grade serous 12% NOTCH3 amplification and point mutation 11% NRAS low-grade serous PIK3C3 (PI3K3) amplification/mutation 12–20% PIK3CA amplification endometrioid and clear cell 18% PPP2R1A endometrioid and clear cell PTEN deletion endometrioid and clear cell 7% RB1 deletion (8%) and point mutation (2%) 10% TGF-β mutation/overexpression 12% TP53 mutation/overexpression high-grade serous 20–50% TβRI mutation 33% TβRII mutation 25% USP36 overexpression Ovarian cancer forms when errors in normal ovarian cell growth occur. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called an ovarian tumor or growth. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.[38] When an ovary releases an egg, the egg follicle bursts open and becomes the corpus luteum. This structure needs to be repaired by dividing cells in the ovary.[25] Continuous ovulation for a long time means more repair of the ovary by dividing cells, which can acquire mutations in each division.[20] Overall, the most common gene mutations in ovarian cancer occur in NF1, BRCA1, BRCA2, and CDK12. Type I ovarian cancers, which tend to be less aggressive, tend to have microsatellite instability in several genes, including both oncogenes (most notably BRAF and KRAS) and tumor suppressors (most notably PTEN).[19] The most common mutations in Type I cancers are KRAS, BRAF, ERBB2, PTEN, PIK3CA, and ARID1A.[22] Type II cancers, the more aggressive type, have different genes mutated, including p53, BRCA1, and BRCA2.[19] Low-grade cancers tend to have mutations in KRAS, whereas cancers of any grade that develop from low malignant potential tumors tend to have mutations in p53.[20] Type I cancers tend to develop from precursor lesions, whereas Type II cancers can develop from a serous tubal intraepithelial carcinoma.[22] Serous cancers that have BRCA mutations also inevitably have p53 mutations, indicating that the removal of both functional genes is important for cancer to develop.[20] In 50% of high-grade serous cancers, homologous recombination DNA repair is dysfunctional, as are the notch and FOXM1 signaling pathways. They also almost always have p53 mutations. Other than this, mutations in high-grade serous carcinoma are hard to characterize beyond their high degree of genomic instability. BRCA1 and BRCA2 are essential for homologous recombination DNA repair, and germline mutations in these genes are found in about 15% of people with ovarian cancer.[19] The most common mutations in BRCA1 and BRCA2 are the frameshift mutations that originated in a small founding population of Ashkenazi Jews.[20] Almost 100% of rare mucinous carcinomas have mutations in KRAS and amplifications of ERBB2 (also known as Her2/neu).[19] Overall, 20% of ovarian cancers have mutations in Her2/neu.[17] Serous carcinomas may develop from serous tubal intraepithelial carcinoma, rather than developing spontaneously from ovarian tissue. Other carcinomas develop from cortical inclusion cysts, which are groups of epithelial ovarian cells inside the stroma.[20] ## Diagnosis[edit] ### Examination[edit] A very large ovarian cancer as seen on CT Micrograph of serous carcinoma, a type of ovarian cancer, diagnosed in peritoneal fluid Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound.[17][39] Sometimes a rectovaginal examination is used to help plan a surgery.[20] The diagnosis must be confirmed with surgery to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis), and look for cancer cells in the abdominal fluid. This helps to determine if an ovarian mass is benign or malignant.[17] Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis; as a result, it is rarely diagnosed until it spreads and advances to later stages (III/IV).[40] Additionally, symptoms of ovarian cancer may appear similar to irritable bowel syndrome. In patients in whom pregnancy is a possibility, BHCG level can be measured during the diagnosis process. Serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase can be measured in young girls and adolescents with suspected ovarian tumors as younger patients are more likely to have malignant germ cell tumors.[17][22] A physical examination, including a pelvic examination, and a pelvic ultrasound (transvaginal or otherwise) are both essential for diagnosis: physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity), while pelvic examination may reveal an ovarian or abdominal mass.[19] An adnexal mass is a significant finding that often indicates ovarian cancer, especially if it is fixed, nodular, irregular, solid, and/or bilateral. 13–21% of adnexal masses are caused by malignancy; however, there are other benign causes of adnexal masses, including ovarian follicular cyst, leiomyoma, endometriosis, ectopic pregnancy, hydrosalpinx, tuboovarian abscess, ovarian torsion, dermoid cyst, cystadenoma (serous or mucinous), diverticular or appendiceal abscess, nerve sheath tumor, pelvic kidney, ureteral or bladder diverticulum, benign cystic mesothelioma of the peritoneum, peritoneal tuberculosis, or paraovarian cyst. Ovaries that can be felt are also a sign of ovarian cancer in postmenopausal women. Other parts of a physical examination for suspected ovarian cancer can include a breast examination and a digital rectal exam. Palpation of the supraclavicular, axillary, and inguinal lymph nodes may reveal lymphadenopathy, which can be indicative of metastasis. Another indicator may be the presence of a pleural effusion, which can be noted on auscultation.[22] When an ovarian malignancy is included in a list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count and serum electrolyte test is usually obtained;[41] when an ovarian cancer is present, these tests often show a high number of platelets (20–25% of people) and low blood sodium levels due to chemical signals secreted by the tumor.[20] A positive test for inhibin A and inhibin B can indicate a granulosa cell tumor.[22] A blood test for a marker molecule called CA-125 is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity.[41] CA-125 levels in premenopausal people over 200 U/mL may indicate ovarian cancer, as may any elevation in CA-125 above 35 U/mL in post-menopausal people. CA-125 levels are not accurate in early stage ovarian cancer, as fully half of stage I ovarian cancer patients have a normal CA-125 level.[22][20] CA-125 may also be elevated in benign (non-cancerous) conditions, including endometriosis, pregnancy, uterine fibroids, menstruation, ovarian cysts, systemic lupus erythematosus, liver disease, inflammatory bowel disease, pelvic inflammatory disease, and leiomyoma.[22][42] HE4 is another candidate for ovarian cancer testing, though it has not been extensively tested. Other tumor markers for ovarian cancer include CA19-9, CA72-4, CA15-3, immunosuppressive acidic protein, haptoglobin-alpha, OVX1, mesothelin, lysophosphatidic acid, osteopontin, and fibroblast growth factor 23.[22] Use of blood test panels may help in diagnosis.[22][41] The OVA1 panel includes CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and transthyretin. OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal people indicates a high risk for cancer.[20] A different set of laboratory tests is used for detecting sex cord-stromal tumors. High levels of testosterone or dehydroepiandrosterone sulfate, combined with other symptoms and high levels of inhibin A and inhibin B can be indicative of an SCST of any type.[23] Current research is looking at ways to consider tumor marker proteomics in combination with other indicators of disease (i.e. radiology and/or symptoms) to improve diagnostic accuracy. The challenge in such an approach is that the disparate prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results, which in turn may lead to issues such as performing surgical procedures in which cancer is not found intraoperatively.[citation needed] Genomics approaches have not yet been developed for ovarian cancer.[22] CT scanning is preferred to assess the extent of the tumor in the abdominopelvic cavity, though magnetic resonance imaging can also be used.[19] CT scanning can also be useful for finding omental caking or differentiating fluid from solid tumor in the abdomen, especially in low malignant potential tumors. However, it may not detect smaller tumors. Sometimes, a chest x-ray is used to detect metastases in the chest or pleural effusion. Another test for metastatic disease, though it is infrequently used, is a barium enema, which can show if the rectosigmoid colon is involved in the disease. Positron emission tomography, bone scans, and paracentesis are of limited use; in fact, paracentesis can cause metastases to form at the needle insertion site and may not provide useful results.[20] However, paracentesis can be used in cases where there is no pelvic mass and ascites is still present.[20] A physician suspecting ovarian cancer may also perform mammography or an endometrial biopsy (in the case of abnormal bleeding) to assess the possibility of breast malignancies and endometrial malignancy, respectively. Vaginal ultrasonography is often the first-line imaging study performed when an adnexal mass is found. Several characteristics of an adnexal mass indicate ovarian malignancy; they usually are solid, irregular, multilocular, and/or large; and they typically have papillary features, central vessels, and/or irregular internal septations.[22] However, SCST has no definitive characteristics on radiographic study.[23] To definitively diagnose ovarian cancer, a surgical procedure to inspect the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious tissue is removed and sent for microscopic analysis. Usually, this includes a unilateral salpingo-oophorectomy, removal of a single affected ovary and Fallopian tube. Fluid from the abdominal cavity can also be analyzed for cancerous cells. If cancer is found, this procedure can also be used to determine the extent of its spread (which is a form of tumor staging).[17] #### Risk scoring[edit] A widely recognized method of estimating the risk of malignant ovarian cancer is the risk of malignancy index (RMI), calculated based on an initial workup.[19][43] An RMI score of over 200 or 250 is generally felt to indicate high risk for ovarian cancer.[19][22] The RMI is calculated as: RMI = ultrasound score × menopausal score x CA-125 level in U/ml.[19] Two methods can be used to determine the ultrasound score and menopausal score, with the resultant scores being referred to as RMI 1 and RMI 2, respectively, depending on what method is used. Feature RMI 1[19] RMI 2[22][44] Ultrasound abnormalities: * multilocular cyst * solid areas * ascites * intra-abdominal metastases * 0 = no abnormality * 1 = one abnormality * 3 = two or more abnormalities * 0 = none * 1 = one abnormality * 4 = two or more abnormalities Menopausal score * 1 = premenopausal * 3 = postmenopausal * 1 = premenopausal * 4 = postmenopausal CA-125 Quantity in U/ml Quantity in U/ml Another method for quantifying risk of ovarian cancer is the Risk of Ovarian Cancer Algorithm (ROCA), observes levels over time and determines if they are increasing rapidly enough to warrant transvaginal ultrasound.[20] The Risk of Ovarian Malignancy algorithm uses CA-125 levels and HE4 levels to calculate the risk of ovarian cancer; it may be more effective than RMI. The IOTA models can be used to estimate the probability that an adnexal tumor is malignant.[45] They include LR2 risk model, The Simple Rules risk (SRrisk) calculation and Assessment of Different Neoplasias in the Adnexa (ADNEX) model that can be used to assess risk of malignancy in an adnexal mass, based on its characteristics and risk factors. The QCancer (Ovary) algorithm is used to predict likelihood of ovarian cancer from risk factors.[22] ### Pathology[edit] Ovarian cancers in women aged 20+, with area representing relative incidence and color representing five-year relative survival rate[46] Ovarian cancers are classified according to the microscopic appearance of their structures (histology or histopathology). Histology dictates many aspects of clinical treatment, management, and prognosis. The gross pathology of ovarian cancers is very similar regardless of histologic type: ovarian tumors have solid and cystic masses.[20] According to SEER, the types of ovarian cancers in women age 20 and over are:[46] Percent of ovarian cancers in women age 20+ Percent of ovarian cancers in women age 20+ by subdivision Histology Five-year RSR 89.7 Surface epithelial-stromal tumor (adenocarcinoma) 54.4 26.4 Papillary serous cystadenocarcinoma 21.0 15.9 Borderline adenocarcinoma (underestimated - short data collection interval) 98.2 12.6 Adenocarcinoma, not otherwise specified 18.3 9.8 Endometrioid tumor 70.9 5.8 Serous cystadenocarcinoma 44.2 5.5 Papillary 21.0 4.2 Mucinous cystadenocarcinoma 77.7 4.0 Clear-cell ovarian tumor 61.5 3.4 Mucinous adenocarcinoma 49.1 1.3 Cystadenocarcinoma 50.7 5.5 Carcinoma 4.1 Carcinoma not otherwise specified 26.8 1.1 Sex cord-stromal tumor 87.8 0.3 Other carcinomas, specified 37.3 1.7 Mullerian tumor 29.8 1.5 Germ cell tumor 91.0 0.8 Teratoma 89.1 0.5 Dysgerminoma 96.8 0.3 Other, specified 85.1 0.6 Not otherwise specified 23.0 0.5 Epidermoid (squamous cell carcinoma) 51.3 0.2 Brenner tumor 67.9 0.2 Other, specified 71.7 Ovarian cancers are histologically and genetically divided into type I or type II. Type I cancers are of low histological grade and include endometrioid, mucinous, and clear-cell carcinomas. Type II cancers are of higher histological grade and include serous carcinoma and carcinosarcoma.[19] #### Epithelial carcinoma[edit] A pathological specimen of ovarian carcinoma Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer, representing approximately 90% of ovarian cancers. It includes serous tumor, endometrioid tumor, and mucinous cystadenocarcinoma. Less common tumors are malignant Endometrioid ovarian cancer, Clear cell ovarian cancer, and Brenner tumor (transitional cell carcinoma of the ovary). Epithelial ovarian cancers develop from the epithelium, a layer of cells that covers the ovary.[47] ##### Serous carcinoma[edit] Most people with epithelial ovarian carcinoma, about two-thirds, have a serous carcinoma,[19] though this proportion is estimated as high as 80%.[22][48] Low-grade serous carcinoma is less aggressive than high-grade serous carcinomas, though it does not typically respond well to chemotherapy or hormonal treatments.[19] Serous carcinomas are thought to begin in the Fallopian tube.[47] Histologically, serous adenocarcinomas have psammoma bodies. Low-grade serous adenocarcinomas resemble Fallopian tube epithelium, whereas high-grade serous adenocarcinomas show anaplasia and nuclear atypia.[20] 50% of the time, serous carcinomas are bilateral, and in 85% of cases, they have spread beyond the ovary at the time of diagnosis. Most have a diameter over 15 cm.[48] Serous Tubal Intraepithelial Carcinoma (STIC) is now recognized to be the precursor lesion of most so-called ovarian high-grade serous carcinomas.[49] STIC is characterised by 1. Abnormal p53 staining 2. Ki67 proliferation index in excess of 10% 3. Positive WT1 (to exclude metastases)[50] ##### Small-cell carcinoma[edit] Small-cell ovarian carcinoma is rare and aggressive, with two main subtypes: hypercalcemic and pulmonary. It is typically fatal within 2 years of diagnosis. Hypercalcemic small cell ovarian carcinoma overwhelmingly affects those in their 20s, causes high blood calcium levels, and affects one ovary. Pulmonary small cell ovarian cancer usually affects both ovaries of older women and looks like oat-cell carcinoma of the lung.[20] ###### Primary peritoneal carcinoma[edit] Main article: Primary peritoneal carcinoma Primary peritoneal carcinomas develop from the peritoneum, a membrane that covers the abdominal cavity that has the same embryonic origin as the ovary. They are often discussed and classified with ovarian cancers when they affect the ovary.[47][51] They can develop even after the ovaries have been removed and may appear similar to mesothelioma.[20] ##### Clear-cell carcinoma[edit] Clear-cell ovarian carcinomas do not typically respond well to chemotherapy and may be related to endometriosis.[19] They represent approximately 5% of all endometrial cancers. Japanese women develop clear-cell ovarian cancer more frequently than other groups of women.[22] ##### Clear-cell adenocarcinoma[edit] Hobnail cells seen in a clear cell carcinoma sample Clear-cell adenocarcinomas are histopathologically similar to other clear cell carcinomas, with clear cells and hobnail cells. They represent approximately 5–10% of epithelial ovarian cancers and are associated with endometriosis in the pelvic cavity. They are typically early-stage and therefore curable by surgery, but advanced clear-cell adenocarcinomas (approximately 20%) have a poor prognosis and are often resistant to platinum chemotherapy.[20] ##### Endometrioid[edit] Endometrioid adenocarcinomas make up approximately 15–20% of epithelial ovarian cancers. Because they are typically low-grade, endometrioid adenocarcinomas have a good prognosis. These tumors frequently co-occur with endometriosis or endometrial cancer.[20] ###### Malignant mixed müllerian tumor (carcinosarcoma)[edit] Mixed müllerian tumors make up less than 1% of ovarian cancer. They have epithelial and mesenchymal cells visible and tend to have a poor prognosis.[20] ##### Mucinous[edit] Mucinous tumors include mucinous adenocarcinoma and mucinous cystadenocarcinoma.[20] ###### Mucinous adenocarcinoma[edit] Main article: Mucinous adenocarcinoma Mucinous adenocarcinomas make up 5–10% of epithelial ovarian cancers. Histologically, they are similar to intestinal or cervical adenocarcinomas and are often actually metastases of appendiceal or colon cancers. Advanced mucinous adenocarcinomas have a poor prognosis, generally worse than serous tumors, and are often resistant to platinum chemotherapy, though they are rare.[20] ###### Pseudomyxoma peritonei[edit] Main article: Pseudomyxoma peritonei Pseudomyxoma peritonei refers to a collection of encapsulated mucous or gelatinous material in the abdominopelvic cavity, which is very rarely caused by a primary mucinous ovarian tumor. More commonly, it is associated with ovarian metastases of intestinal cancer.[20] ##### Undifferentiated epithelial[edit] Undifferentiated cancers - those where the cell type cannot be determined - make up about 10% of epithelial ovarian cancers and have a comparatively poor prognosis.[20][47] When examined under the microscope, these tumors have very abnormal cells that are arranged in clumps or sheets. Usually there are recognizable clumps of serous cells inside the tumor.[20] ###### Malignant Brenner tumor[edit] Main article: Brenner tumor Malignant Brenner tumors are rare. Histologically, they have dense fibrous stroma with areas of transitional epithelium, and some squamous differentiation. To be classified as a malignant Brenner tumor, it must have Brenner tumor foci and transitional cell carcinoma. The transitional cell carcinoma component is typically poorly differentiated and resembles urinary tract cancer.[20] ###### Transitional cell carcinoma[edit] Main article: Transitional cell carcinoma Transitional cell carcinomas represent less than 5% of ovarian cancers. Histologically, they appear similar to bladder carcinoma. The prognosis is intermediate - better than most epithelial cancers but worse than malignant Brenner tumors.[20] #### Sex cord-stromal tumor[edit] Main article: Sex cord-stromal tumor Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor, the benign thecoma, and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 7% of ovarian cancers. They occur most frequently in women between 50 and 69 years of age but can occur in women of any age, including young girls. They are not typically aggressive and are usually unilateral;[17] they are therefore usually treated with surgery alone. Sex cord-stromal tumors are the main hormone-producing ovarian tumors.[23] Several different cells from the mesenchyme can give rise to sex-cord or stromal tumors. These include fibroblasts and endocrine cells. The symptoms of a sex-cord or stromal ovarian tumor can differ from other types of ovarian cancer. Common signs and symptoms include ovarian torsion, hemorrhage from or rupture of the tumor, an abdominal mass, and hormonal disruption. In children, isosexual precocious pseudopuberty may occur with granulosa cell tumors since they produce estrogen. These tumors cause abnormalities in menstruation (excessive bleeding, infrequent menstruation, or no menstruation) or postmenopausal bleeding. Because these tumors produce estrogen, they can cause or occur at the same time as endometrial cancer or breast cancer. Other sex-cord/stromal tumors present with distinct symptoms. Sertoli-Leydig cell tumors cause virilization and excessive hair growth due to the production of testosterone and androstenedione, which can also cause Cushing's syndrome in rare cases. Also, sex-cord stromal tumors occur that do not cause a hormonal imbalance, including benign fibromas, which cause ascites and hydrothorax.[17] With germ cell tumors, sex cord-stromal tumors are the most common ovarian cancer diagnosed in women under 20.[23] ##### Granulosa cell tumor[edit] Granulosa cell tumors are the most common sex-cord stromal tumors, making up 70% of cases, and are divided into two histologic subtypes: adult granulosa cell tumors, which develop in women over 50, and juvenile granulosa tumors, which develop before puberty or before the age of 30. Both develop in the ovarian follicle from a population of cells that surrounds germinal cells.[23] ###### Adult granulosa cell tumor[edit] Adult granulosa cell tumors are characterized by later onset (30+ years, 50 on average). These tumors produce high levels of estrogen, which causes its characteristic symptoms: menometrorrhagia; endometrial hyperplasia; tender, enlarged breasts; postmenopausal bleeding; and secondary amenorrhea. The mass of the tumor can cause other symptoms, including abdominal pain and distension, or symptoms similar to an ectopic pregnancy if the tumor bleeds and ruptures.[23] ###### Juvenile granulosa cell tumor[edit] ##### Sertoli-Leydig cell tumor[edit] Sertoli-Leydig tumors are most common in women before the age of 30, and particularly common before puberty.[23] ##### Sclerosing stromal tumors[edit] Sclerosing stromal tumors typically occur in girls before puberty or women before the age of 30.[23] #### Germ cell tumor[edit] Main article: Ovarian germ cell tumors Germ cell tumors of the ovary develop from the ovarian germ cells.[47] Germ cell tumor accounts for about 30% of ovarian tumors, but only 5% of ovarian cancers, because most germ-cell tumors are teratomas and most teratomas are benign. Malignant teratomas tend to occur in older women, when one of the germ layers in the tumor develops into a squamous cell carcinoma.[17] Germ-cell tumors tend to occur in young women (20s–30s) and girls, making up 70% of the ovarian cancer seen in that age group.[24] Germ-cell tumors can include dysgerminomas, teratomas, yolk sac tumors/endodermal sinus tumors, and choriocarcinomas, when they arise in the ovary. Some germ-cell tumors have an isochromosome 12, where one arm of chromosome 12 is deleted and replaced with a duplicate of the other.[17] Most germ-cell cancers have a better prognosis than other subtypes and are more sensitive to chemotherapy. They are more likely to be stage I at diagnosis.[23] Overall, they metastasize more frequently than epithelial ovarian cancers. In addition, the cancer markers used vary with tumor type: choriocarcinomas are monitored with beta-HCG and endodermal sinus tumors with alpha-fetoprotein.[17] Germ-cell tumors are typically discovered when they become large, palpable masses. However, like sex cord tumors, they can cause ovarian torsion or hemorrhage and, in children, isosexual precocious puberty. They frequently metastasize to nearby lymph nodes, especially para-aortic and pelvic lymph nodes.[17] The most common symptom of germ cell tumors is subacute abdominal pain caused by the tumor bleeding, necrotizing, or stretching the ovarian capsule. If the tumor ruptures, causes significant bleeding, or torses the ovary, it can cause acute abdominal pain, which occurs in less than 10% of those with germ-cell tumors. They can also secrete hormones which change the menstrual cycle. In 25% of germ-cell tumors, the cancer is discovered during a routine examination and does not cause symptoms.[23] Diagnosing germ cell tumors may be difficult because the normal menstrual cycle and puberty can cause pain and pelvic symptoms, and a young woman may even believe these symptoms to be those of pregnancy, and not seek treatment due to the stigma of teen pregnancy. Blood tests for alpha-fetoprotein, karyotype, human chorionic gonadotropin, and liver function are used to diagnose germ cell tumor and potential co-occurring gonadal dysgenesis. A germ cell tumor may be initially mistaken for a benign ovarian cyst.[23] ##### Dysgerminoma[edit] Main article: Dysgerminoma Dysgerminoma accounts for 35% of ovarian cancer in young women and is the most likely germ cell tumor to metastasize to the lymph nodes; nodal metastases occur in 25–30% of cases.[24][23] These tumors may have mutations in the KIT gene, a mutation known for its role in gastrointestinal stromal tumor. People with an XY karyotype and ovaries (gonadal dysgenesis) or an X,0 karyotype and ovaries (Turner syndrome) who develop a unilateral dysgerminoma are at risk for a gonadoblastoma in the other ovary, and in this case, both ovaries are usually removed when a unilateral dysgerminoma is discovered to avoid the risk of another malignant tumor. Gonadoblastomas in people with Swyer or Turner syndrome become malignant in approximately 40% of cases. However, in general, dysgerminomas are bilateral 10–20% of the time.[17][23] They are composed of cells that cannot differentiate further and develop directly from germ cells or from gonadoblastomas. Dysgerminomas contain syncytiotrophoblasts in approximately 5% of cases, and can therefore cause elevated hCG levels. On gross appearance, dysgerminomas are typically pink to tan-colored, have multiple lobes, and are solid. Microscopically, they appear identical to seminomas and very close to embryonic primordial germ cells, having large, polyhedral, rounded clear cells. The nuclei are uniform and round or square with prominent nucleoli and the cytoplasm has high levels of glycogen. Inflammation is another prominent histologic feature of dysgerminomas.[23] ##### Choriocarcinoma[edit] Main article: Choriocarcinoma Choriocarcinoma can occur as a primary ovarian tumor developing from a germ cell, though it is usually a gestational disease that metastasizes to the ovary. Primary ovarian choriocarcinoma has a poor prognosis and can occur without a pregnancy. They produce high levels of hCG and can cause early puberty in children or menometrorrhagia (irregular, heavy menstruation) after menarche.[23] ##### Immature (solid) teratoma[edit] Main article: Immature teratoma Immature, or solid, teratomas are the most common type of ovarian germ cell tumor, making up 40–50% of cases. Teratomas are characterized by the presence of disorganized tissues arising from all three embryonic germ layers: ectoderm, mesoderm, and endoderm; immature teratomas also have undifferentiated stem cells that make them more malignant than mature teratomas (dermoid cysts). The different tissues are visible on gross pathology and often include bone, cartilage, hair, mucus, or sebum, but these tissues are not visible from the outside, which appears to be a solid mass with lobes and cysts. Histologically, they have large amounts of neuroectoderm organized into sheets and tubules along with glia; the amount of neural tissue determines the histologic grade. Immature teratomas usually only affect one ovary (10% co-occur with dermoid cysts) and usually metastasize throughout the peritoneum. They can also cause mature teratoma implants to grow throughout the abdomen in a disease called growing teratoma syndrome; these are usually benign but will continue to grow during chemotherapy, and often necessitate further surgery. Unlike mature teratomas, immature teratomas form many adhesions, making them less likely to cause ovarian torsion. There is no specific marker for immature teratomas, but carcinoembryonic antigen (CEA), CA-125, CA19-9, or AFP can sometimes indicate an immature teratoma.[23] Stage I teratomas make up the majority (75%) of cases and have the best prognosis, with 98% of patients surviving 5 years; if a Stage I tumor is also grade 1, it can be treated with unilateral surgery only. Stage II though IV tumors make up the remaining quarter of cases and have a worse prognosis, with 73–88% of patients surviving 5 years.[23] ##### Mature teratoma (dermoid cyst)[edit] Main article: Dermoid cyst Mature teratomas, or dermoid cysts, are rare tumors consisting of mostly benign tissue that develop after menopause. The tumors consist of disorganized tissue with nodules of malignant tissue, which can be of various types. The most common malignancy is squamous cell carcinoma, but adenocarcinoma, basal-cell carcinoma, carcinoid tumor, neuroectodermal tumor, malignant melanoma, sarcoma, sebaceous tumor, and struma ovarii can also be part of the dermoid cyst. They are treated with surgery and adjuvant platinum chemotherapy or radiation.[23] ##### Yolk sac tumor/endodermal sinus tumor[edit] Main article: Yolk sac tumor Yolk sac tumors, formerly called endodermal sinus tumors, make up approximately 10–20% of ovarian germ cell malignancies, and have the worst prognosis of all ovarian germ cell tumors. They occur both before menarche (in one-third of cases) and after menarche (the remaining two-thirds of cases). Half of the people with yolk sac tumors are diagnosed in stage I. Typically, they are unilateral until metastasis, which occurs within the peritoneal cavity and via the bloodstream to the lungs. Yolk sac tumors grow quickly and recur easily, and are not easily treatable once they have recurred. Stage I yolk sac tumors are highly treatable, with a 5-year disease-free survival rate of 93%, but stage II-IV tumors are less treatable, with survival rates of 64–91%.[23] Their gross appearance is solid, friable, and yellow, with necrotic and hemorrhagic areas. They also often contain cysts that can degenerate or rupture. Histologically, yolk sac tumors are characterized by the presence of Schiller-Duval bodies (which are pathognomonic for yolk sac tumors) and a reticular pattern. Yolk sac tumors commonly secrete alpha-fetoprotein and can be immunohistochemically stained for its presence; the level of alpha-fetoprotein in the blood is a useful marker of recurrence.[23] ##### Embryonal carcinoma[edit] Main article: Embryonal carcinoma Embryonal carcinomas, a rare tumor type usually found in mixed tumors, develop directly from germ cells but are not terminally differentiated; in rare cases they may develop in dysgenetic gonads. They can develop further into a variety of other neoplasms, including choriocarcinoma, yolk sac tumor, and teratoma. They occur in younger people, with an average age at diagnosis of 14, and secrete both alpha-fetoprotein (in 75% of cases) and hCG.[23] Histologically, embryonal carcinoma appears similar to the embryonic disc, made up of epithelial, anaplastic cells in disorganized sheets, with gland-like spaces and papillary structures.[23] ##### Polyembryoma[edit] Main article: Polyembryoma Polyembryomas, the most immature form of teratoma and very rare ovarian tumors, are histologically characterized by having several embryo-like bodies with structures resembling a germ disk, yolk sac, and amniotic sac. Syncytiotrophoblast giant cells also occur in polyembryomas.[23] #### Squamous cell carcinoma[edit] Primary ovarian squamous cell carcinomas are rare and have a poor prognosis when advanced. More typically, ovarian squamous cell carcinomas are cervical metastases, areas of differentiation in an endometrioid tumor, or derived from a mature teratoma.[20] #### Mixed tumors[edit] Mixed tumors contain elements of more than one of the above classes of tumor histology. To be classed as a mixed tumor, the minor type must make up more than 10% of the tumor.[22] Though mixed carcinomas can have any combination of cell types, mixed ovarian cancers are typically serous/endometrioid or clear cell/endometrioid.[20] Mixed germ cell tumors make up approximately 25–30% of all germ cell ovarian cancers, with combinations of dysgerminoma, yolk sac tumor, and/or immature teratoma. The prognosis and treatment vary based on the component cell types.[23] #### Secondary ovarian cancer[edit] Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere in the body.[17] About 7% of ovarian cancers are due to metastases, while the rest are primary cancers.[citation needed] Common primary cancers are breast cancer, colon cancer, appendiceal cancer, and stomach cancer (primary gastric cancers that metastasize to the ovary are called Krukenberg tumors).[17] Krukenberg tumors have signet ring cells and mucinous cells.[20] Endometrial cancer and lymphomas can also metastasize to the ovary.[48] #### Borderline tumors[edit] Ovarian borderline tumors, sometimes called low malignant potential (LMP) ovarian tumors, have some benign and some malignant features.[20] LMP tumors make up approximately 10%-15% of all ovarian tumors.[22][47] They develop earlier than epithelial ovarian cancer, around the age of 40–49. They typically do not have extensive invasion; 10% of LMP tumors have areas of stromal microinvasion (<3mm, <5% of tumor). LMP tumors have other abnormal features, including increased mitosis, changes in cell size or nucleus size, abnormal nuclei, cell stratification, and small projections on cells (papillary projections). Serous and/or mucinous characteristics can be seen on histological examination, and serous histology makes up the overwhelming majority of advanced LMP tumors. More than 80% of LMP tumors are Stage I; 15% are stage II and III and less than 5% are stage IV.[20] Implants of LMP tumors are often non-invasive.[47] ### Staging[edit] Ovarian cancer is staged using the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy via midline laparotomy, removal of (usually) both ovaries and Fallopian tubes, (usually) the omentum, pelvic (peritoneal) washings, assessment of retroperitoneal lymph nodes (including the pelvic and para-aortic lymph nodes), appendectomy in suspected mucinous tumors, and pelvic/peritoneal biopsies for cytopathology.[19][17][22][52] Around 30% of ovarian cancers that appear confined to the ovary have metastasized microscopically, which is why even stage-I cancers must be staged completely.[17] 22% of cancers presumed to be stage I are observed to have lymphatic metastases.[22] The AJCC stage is the same as the FIGO stage. The AJCC staging system describes the extent of the primary tumor (T), the absence or presence of metastasis to nearby lymph nodes (N), and the absence or presence of distant metastasis (M).[53] The most common stage at diagnosis is stage IIIc, with over 70% of diagnoses.[17] #### FIGO[edit] Ovarian adenocarcinoma deposit in the mesentery of the small bowel FIGO stages of ovarian cancer[19][52] Stage Description I Cancer is completely limited to the ovary IA involves one ovary, capsule intact, no tumor on ovarian surface, negative washings IB involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings IC tumor involves one or both ovaries IC1 surgical spill IC2 capsule has ruptured or tumor on ovarian surface IC3 positive ascites or washings II pelvic extension of the tumor (must be confined to the pelvis) or primary peritoneal tumor, involves one or both ovaries IIA tumor found on uterus or fallopian tubes IIB tumor elsewhere in the pelvis III cancer found outside the pelvis or in the retroperitoneal lymph nodes, involves one or both ovaries IIIA metastasis in retroperitoneal lymph nodes or microscopic extrapelvic metastasis IIIA1 metastasis in retroperitoneal lymph nodes IIIA1(i) the metastasis is less than 10 mm in diameter IIIA1(ii) the metastasis is greater than 10 mm in diameter IIIA2 microscopic metastasis in the peritoneum, regardless of retroperitoneal lymph node status IIIB metastasis in the peritoneum less than or equal to 2 cm in diameter, regardless of retroperitoneal lymph node status; or metastasis to liver or spleen capsule IIIC metastasis in the peritoneum greater than 2 cm in diameter, regardless of retroperitoneal lymph node status; or metastasis to liver or spleen capsule IV distant metastasis (i.e. outside of the peritoneum) IVA pleural effusion containing cancer cells IVB metastasis to distant organs (including the parenchyma of the spleen or liver), or metastasis to the inguinal and extra-abdominal lymph nodes * Stage 1 ovarian cancer * Stage 2 ovarian cancer * Stage 3 ovarian cancer * Stage 4 ovarian cancer #### AJCC/TNM[edit] The AJCC/TNM staging system indicates where the tumor has developed, spread to lymph nodes, and metastasis.[22] AJCC/TNM stages of ovarian cancer[22] Stage Description T Primary tumor Tx Cannot be assessed T0 No evidence T1 Tumor limited to ovary/ovaries T1a One ovary with intact capsule, no surface tumor, and negative ascites/peritoneal washings T1b Both ovaries with intact capsules, no surface tumor, and negative ascites/peritoneal washings T1c One or both ovaries with ruptured capsule or capsules, surface tumor, positive ascites/peritoneal washings T2 Tumor is in ovaries and pelvis (extension or implantation) T2a Expansion to uterus or Fallopian tubes, negative ascites/peritoneal washings T2b Expansion in other pelvic tissues, negative ascites/peritoneal washings T2c Expansion to any pelvic tissue, positive ascites/peritoneal washings T3 Tumor is in ovaries and has metastasized outside the pelvis to the peritoneum (including the liver capsule) T3a Microscopic metastasis T3b Macroscopic metastasis less than 2 cm diameter T3c Macroscopic metastasis greater than 2 cm diameter N Regional lymph node metastasis Nx Cannot be assessed N0 No metastasis N1 Metastasis present M Distant metastasis M0 No metastasis M1 Metastasis present (excluding liver capsule, including liver parenchyma and cytologically confirmed pleural effusion) The AJCC/TNM stages can be correlated with the FIGO stages:[22] FIGO T N M I T1 N0 M0 IA T1a N0 M0 IB T1b N0 M0 IC T1c N0 M0 II T2 N0 M0 IIA T2a N0 M0 IIB T2b N0 M0 IIC T2c N0 M0 III T3 N0 M0 IIIA T3a N0 M0 IIIB T3b N0 M0 IIIC T3c N0/N1 M0 IV Any Any M1 #### Grading[edit] Grade 1 tumors have well differentiated cells (look very similar to the normal tissue) and are the ones with the best prognosis. Grade 2 tumors are also called moderately well-differentiated and they are made up of cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.[54] Metastasis in ovarian cancer is very common in the abdomen, and occurs via exfoliation, where cancer cells burst through the ovarian capsule and are able to move freely throughout the peritoneal cavity. Ovarian cancer metastases usually grow on the surface of organs rather than the inside; they are also common on the omentum and the peritoneal lining. Cancer cells can also travel through the lymphatic system and metastasize to lymph nodes connected to the ovaries via blood vessels; i.e. the lymph nodes along the infundibulopelvic ligament, the broad ligament, and the round ligament. The most commonly affected groups include the paraaortic, hypogastric, external iliac, obturator, and inguinal lymph nodes. Usually, ovarian cancer does not metastasize to the liver, lung, brain, or kidneys unless it is recurrent disease; this differentiates ovarian cancer from many other forms of cancer.[20] ## Screening[edit] There is no simple and reliable way to test for ovarian cancer in women who do not have any signs or symptoms. Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks.[15] The Pap test does not screen for ovarian cancer.[18] Ovarian cancer is usually only palpable in advanced stages.[20] Screening is not recommended using CA-125 measurements, HE4 levels, ultrasound, or adnexal palpation in women who are at average risk. Risk of developing ovarian cancer in those with genetic factors can be reduced. Those with a genetic predisposition may benefit from screening. This high risk group has benefited with earlier detection.[19][17][55] Ovarian cancer has low prevalence, even in the high-risk group of women from the ages of 50 to 60 (about one in 2000), and screening of women with average risk is more likely to give ambiguous results than detect a problem which requires treatment. Because ambiguous results are more likely than detection of a treatable problem, and because the usual response to ambiguous results is invasive interventions, in women of average risk, the potential harms of having screening without an indication outweigh the potential benefits. The purpose of screening is to diagnose ovarian cancer at an early stage, when it is more likely to be treated successfully.[17][55] Screening with transvaginal ultrasound, pelvic examination, and CA-125 levels can be used instead of preventive surgery in women who have BRCA1 or BRCA2 mutations. This strategy has shown some success.[20] ## Prevention[edit] People with strong genetic risk for ovarian cancer may consider the surgical removal of their ovaries as a preventive measure. This is often done after completion of childbearing years. This reduces the chances of developing both breast cancer (by around 50%) and ovarian cancer (by about 96%) in people at high risk. Women with BRCA gene mutations usually also have their Fallopian tubes removed at the same time (salpingo-oophorectomy), since they also have an increased risk of Fallopian tube cancer. However, these statistics may overestimate the risk reduction because of how they have been studied.[17][55] People with a significant family history for ovarian cancer are often referred to a genetic counselor to see if testing for BRCA mutations would be beneficial.[20] The use of oral contraceptives, the absence of 'periods' during the menstrual cycle, and tubal ligation reduce the risk.[56] There may an association of developing ovarian cancer and ovarian stimulation during infertility treatments. Endometriosis has been linked to ovarian cancers. Human papillomavirus infection, smoking, and talc have not been identified as increasing the risk for developing ovarian cancer.[19] ## Management[edit] Once it is determined that ovarian, fallopian tube, or primary peritoneal cancer is present, treatment is scheduled by a gynecologic oncologist (a physician trained to treat cancers of a woman's reproductive system). Gynecologic oncologists can perform surgery on and give chemotherapy to women with ovarian cancer. A treatment plan is developed.[57] Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy, regardless of the subtype of ovarian cancer.[47][58] Surgical treatment may be sufficient for well-differentiated malignant tumors and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors confined to the ovary. For patients with advanced disease, a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.[59] Second-look surgery and maintenance chemotherapy have not been shown to provide benefit.[20] ### Surgery[edit] Surgery has been the standard of care for decades and may be necessary in obtaining a specimen for diagnosis. The surgery depends upon the extent of nearby invasion of other tissues by the cancer when it is diagnosed. This extent of the cancer is described by assigning it a stage, the presumed type, and the grade of cancer. The gynecological surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy). The Fallopian tubes (salpingectomy), uterus (hysterectomy), and the omentum (omentectomy) may also be removed. Typically, all of these organs are removed.[60] For low-grade, unilateral stage-IA cancers, only the involved ovary (which must be unruptured) and Fallopian tube will be removed. This can be done especially in young people who wish to preserve their fertility. However, a risk of microscopic metastases exists and staging must be completed.[19] If any metastases are found, a second surgery to remove the remaining ovary and uterus is needed.[59] Tranexamic acid can be administered prior to surgery to reduce the need for blood transfusions due to blood loss during the surgery.[22] If a tumor in a premenopausal woman is determined to be a low malignant potential tumor during surgery, and it is clearly stage I cancer, only the affected ovary is removed. For postmenopausal women with low malignant potential tumors, hysterectomy with bilateral salpingo-oophorectomy is still the preferred option. During staging, the appendix can be examined or removed. This is particularly important with mucinous tumors.[20] In children or adolescents with ovarian cancer, surgeons typically attempt to preserve one ovary to allow for the completion of puberty, but if the cancer has spread, this is not always possible. Dysgerminomas, in particular, tend to affect both ovaries: 8–15% of dysgerminomas are present in both ovaries.[24] People with low-grade (well-differentiated) tumors are typically treated only with surgery,[17] which is often curative.[47] In general, germ cell tumors can be treated with unilateral surgery unless the cancer is widespread or fertility is not a factor.[23] In women with surgically staged advanced epithelial ovarian cancer (stages III and IV), studies suggest all attempts should be made to reach complete cytoreduction (surgical efforts to remove the bulk of the tumor).[61] In advanced cancers, where complete removal is not an option, as much tumor as possible is removed in a procedure called debulking surgery. This surgery is not always successful, and is less likely to be successful in women with extensive metastases in the peritoneum, stage- IV disease, cancer in the transverse fissure of the liver, mesentery, or diaphragm, and large areas of ascites. Debulking surgery is usually only done once.[19] Computed tomography (abdominal CT) is often used to assess if primary debulking surgery is possible, but low certainty evidence also suggests fluorodeoxyglucose‐18 (FDG) PET/CT and MRI may be useful as an addition for assessing macroscopic incomplete debulking.[62] More complete debulking is associated with better outcomes: women with no macroscopic evidence of disease after debulking have a median survival of 39 months, as opposed to 17 months with less complete surgery.[17] By removing metastases, many cells that are resistant to chemotherapy are removed, and any clumps of cells that have died are also removed. This allows chemotherapy to better reach the remaining cancer cells, which are more likely to be fast-growing and therefore chemosensitive.[20] Interval debulking surgery is another protocol used, where neoadjuvant chemotherapy is given, debulking surgery is performed, and chemotherapy is finished after debulking.[59] Though no definitive studies have been completed, it is shown to be approximately equivalent to primary debulking surgery in terms of survival, and shows slightly lower morbidity.[20] There are several different surgical procedures that can be employed to treat ovarian cancer. For stage I and II cancer, laparascopic (keyhole) surgery can be used, but metastases may not be found. For advanced cancer, laparoscopy is not used, since debulking metastases requires access to the entire peritoneal cavity. Depending on the extent of the cancer, procedures may include a bilateral salpingo-oophorectomy, biopsies throughout the peritoneum and abdominal lymphatic system, omentectomy, splenectomy, bowel resection, diaphragm stripping or resection, appendectomy, or even a posterior pelvic exenteration.[20] To fully stage ovarian cancer, lymphadenectomy can be included in the surgery, but a significant survival benefit to this practice may not happen.[19] This is particularly important in germ cell tumors because they frequently metastasize to nearby lymph nodes.[17] If ovarian cancer recurs, secondary surgery is sometimes a treatment option. This depends on how easily the tumor can be removed, how much fluid has accumulated in the abdomen, and overall health.[19] Effectivenes of this surgery depends on surgical technique, completeness of cytoreduction, and extent of disease.[63] It also can be helpful in people who had their first surgery done by a generalist and in epithelial ovarian cancer.[22] Secondary surgery can be effective in dysgerminomas and immature teratomas.[23] Evidence suggests surgery in recurrent epithelial ovarian cancer may be associated with prolonging life in some women with platinum-sensitive disease.[64] The major side effect of an oophorectomy in younger women is early menopause, which can cause osteoporosis. After surgery, hormone replacement therapy can be considered, especially in younger women. This therapy can consist of a combination of estrogen and progesterone, or estrogen alone. Estrogen alone is safe after hysterectomy; when the uterus is still present, unopposed estrogen dramatically raises the risk of endometrial cancer.[19] Estrogen therapy after surgery does not change survival rates.[22] People having ovarian cancer surgery are typically hospitalized afterwards for 3–4 days and spend around a month recovering at home.[65] Surgery outcomes are best at hospitals that do a large number of ovarian cancer surgeries.[20] It is unclear if laparoscopy or laparotomy is better or worse for FIGO stage I ovarian cancer.[66] There is also no apparent difference between total abdominal hysterectomy and supracervical hysterectomy for advanced cancers. Approximately 2.8% of people having a first surgery for advanced ovarian cancer die within two weeks of the surgery (2.8% perioperative mortality rate).[22] More aggressive surgeries are associated with better outcomes in advanced (stage III or IV) ovarian cancer.[20] ### Chemotherapy[edit] Chemotherapy has been a general standard of care for ovarian cancer for decades, although with variable protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. In some cases, there may be reason to perform chemotherapy first, followed by surgery. This is called "neoadjuvant chemotherapy", and is common when a tumor cannot be completely removed or optimally debulked via surgery. Though it has not been shown to increase survival, it can reduce the risk of complications after surgery. If a unilateral salpingo-oophorectomy or other surgery is performed, additional chemotherapy, called "adjuvant chemotherapy", can be given.[19][22] Adjuvant chemotherapy is used in stage 1 cancer typically if the tumor is of a high histologic grade (grade 3) or the highest substage (stage 1c), provided the cancer has been optimally staged during surgery.[22][59] Bevacizumab may be used as an adjuvant chemotherapy if the tumor is not completely removed during surgery or if the cancer is stage IV; it can extend progression-free survival but has not been shown to extend overall survival.[22] Chemotherapy is curative in approximately 20% of advanced ovarian cancers;[20] it is more often curative with malignant germ cell tumors than epithelial tumors.[23] Adjuvant chemotherapy has been found to improve survival and reduce the risk of ovarian cancer recurring compared to no adjuvant therapy in women with early stage epithelial ovarian cancer.[67] Chemotherapy in ovarian cancer typically consists of platins, a group of platinum-based drugs, combined with non-platins. Common therapies can include paclitaxel, cisplatin, topotecan, doxorubicin, epirubicin, and gemcitabine. Carboplatin is typically given in combination with either paclitaxel or docetaxel; the typical combination is carboplatin with paclitaxel.[19][22] Carboplatin is superior to cisplatin in that it is less toxic and has fewer side effects, generally allowing for an improved quality of life in comparison, though both are similarly effective.[22] Three-drug regimens have not been found to be more effective,[19] and platins alone or nonplatins alone are less effective than platins and nonplatins in combination.[22] There is a small benefit in platinum‐based chemotherapy compared with non‐platinum therapy.[68] Platinum combinations can offer improved survival over single platinum. In people with relapsed ovarian cancer, evidence suggests topotecan has a similar effect on overall survival as paclitaxel and topotecan plus thalidomide, whilst it is superior to treosulfan and not as effective as pegylated liposomal doxorubicin in platinum-sensitive people.[69] Chemotherapy can be given intravenously or in the peritoneal cavity.[17] Though intraperitoneal chemotherapy is associated with longer progression-free survival and overall survival, it also causes more adverse side effects than intravenous chemotherapy.[22] It is mainly used when the cancer has been optimally debulked. Intraperitoneal chemotherapy can be highly effective because ovarian cancer mainly spreads inside the peritoneal cavity, and higher doses of the drugs can reach the tumors this way.[20] Chemotherapy can cause anemia; intravenous iron has been found to be more effective than oral iron supplements in reducing the need for blood transfusions.[22] Typical cycles of treatment involve one treatment every 3 weeks, repeated for 6 weeks or more.[70] Fewer than 6 weeks (cycles) of treatment is less effective than 6 weeks or more.[22] Germ-cell malignancies are treated differently than other ovarian cancers — a regimen of bleomycin, etoposide, and cisplatin (BEP) is used with 5 days of chemotherapy administered every 3 weeks for 3 to 4 cycles.[17][23] Chemotherapy for germ cell tumors has not been shown to cause amenorrhea, infertility, birth defects, or miscarriage.[23] Maintenance chemotherapy has not been shown to be effective.[22] In people with BRCA mutations, platinum chemotherapy is more effective.[19] Germ-cell tumors and malignant sex-cord/stromal tumors are treated with chemotherapy, though dysgerminomas and sex-cord tumors are not typically very responsive.[17][24] #### Platinum-sensitive or platinum-resistant[edit] If ovarian cancer recurs, it is considered partially platinum-sensitive or platinum-resistant, based on the time since the last recurrence treated with platins: partially platinum-sensitive cancers recurred 6–12 months after last treatment, and platinum-resistant cancers have an interval of less than 6 months. Second-line chemotherapy can be given after the cancer becomes symptomatic, because no difference in survival is seen between treating asymptomatic (elevated CA-125) and symptomatic recurrences.[medical citation needed] For platinum-sensitive tumors, platins are the drugs of choice for second-line chemotherapy, in combination with other cytotoxic agents. Regimens include carboplatin combined with pegylated liposomal doxorubicin, gemcitabine, or paclitaxel.[17] Carboplatin-doublet therapy can be combined with paclitaxel for increased efficacy in some cases. Another potential adjuvant therapy for platinum-sensitive recurrences is olaparib, which may improve progression-free survival but has not been shown to improve overall survival.[22] (Olaparib, a PARP inhibitor, was approved by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy.[71][72]) For recurrent germ cell tumors, an additional 4 cycles of BEP chemotherapy is the first-line treatment for those tho have been treated with surgery or platins. If the tumor is determined to be platinum-resistant, vincristine, dactinomycin, and cyclophosphamide (VAC) or some combination of paclitaxel, gemcitabine, and oxaliplatin may be used as a second-line therapy.[23] For platinum-resistant tumors, there are no high-efficacy chemotherapy options. Single-drug regimens (doxorubicin or topotecan) do not have high response rates,[19] but single-drug regimens of topotecan, pegylated liposomal doxorubicin, or gemcitabine are used in some cases.[17][22] Topotecan cannot be used in people with an intestinal blockage. Paclitaxel used alone is another possible regimen, or it may be combined with liposomal doxorubicin, gemcitabine, cisplatin, topotecan, etoposide, or cyclophosphamide.[70] ( See also Palliative care below.) Novel agents are being developed to inhibit the development of new blood vessels (angiogenesis) for women with ovarian cancer who develop resistance to chemotherapy drugs. As of 2011 only preliminary results are available.[73] ### Radiation therapy[edit] Dysgerminomas are most effectively treated with radiation,[24] though this can cause infertility and is being phased out in favor of chemotherapy.[17] Radiation therapy does not improve survival in people with well-differentiated tumors.[17] In stage 1c and 2 cancers, radiation therapy is used after surgery if there is the possibility of residual disease in the pelvis but the abdomen is cancer-free. Radiotherapy can also be used in palliative care of advanced cancers. A typical course of radiotherapy for ovarian cancer is 5 days a week for 3–4 weeks. Common side effects of radiotherapy include diarrhea, constipation, and frequent urination.[74] ### Hormonal therapy[edit] Despite the fact that 60% of ovarian tumors have estrogen receptors, ovarian cancer is only rarely responsive to hormonal treatments. A Cochrane review found a lack of evidence about the effects of tamoxifen in people with relapsed ovarian cancer.[75]Estrogen alone does not have an effect on the cancer, and tamoxifen and letrozole are rarely effective.[19] "Some women with borderline malignancy ovarian cancer and stromal ovarian cancer may receive hormonal therapy."[60] ### Immunotherapy[edit] Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody drug bevacizumab, though still a topic of active research, is used to treat advanced cancer along with chemotherapy.[59] It has been approved for this use in the European Union.[76] ### Follow-up[edit] Specific follow-up depends on, for example, the type and stage of ovarian cancer, the treatment, and the presence of any symptoms. Usually, a check-up appointment is made about every 2 to 3 months initially, followed by twice per year for up to 5 years.[77] For epithelial ovarian cancers, the most common test upon follow-up is CA-125 level. However, treatment based only on elevated CA-125 levels and not any symptoms can increase side effects without any prolongation of life, so the implication of the outcome of a CA-125 test can be discussed before taking it.[78] The recommendation as of 2014 is recurrent cancer may be present if the CA-125 level is twice normal.[19] Treating a recurrence detected by CA-125 does not improve survival.[22] For women with germ-cell tumors, follow-up tests generally include alpha-fetoprotein (AFP) and/or human chorionic gonadotropin. For women with stromal cancers, tests for hormones like estrogen, testosterone, and inhibin are sometimes helpful.[78] Inhibin can also be useful for monitoring the progress of sex-cord tumors, along with mullerian inhibiting substance. AFP can also be used to monitor Sertoli-Leydig tumors.[17] In dysgerminomas, lactate dehydrogenase and its two isozymes (LDH-1 and LDH-2) are used to test for recurrence.[23] Women with ovarian cancer may not need routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising.[79] Imaging without these indications is discouraged because it is unlikely to detect a recurrence, improve survival, and because it has its own costs and side effects.[79] However, CT imaging can be used if desired, though this is not common.[19] If a tumor is easily imaged, imaging may be used to monitor the progress of treatment.[80] ### Palliative care[edit] Palliative care focuses on relieving symptoms and increasing or maintaining quality of life. This type of treatment's purpose is not to cure the cancer but to make the woman more comfortable while living with cancer that can not be cured. It has been recommended as part of the treatment plan for any person with advanced ovarian cancer or patients with significant symptoms.[81] In platinum-refractory and platinum-resistant cases, other palliative chemotherapy is the main treatment.[20][60] Palliative care can entail treatment of symptoms and complications of the cancer, including pain, nausea, constipation, ascites, bowel obstruction, edema, pleural effusion, and mucositis. Especially if the cancer advances and becomes incurable, treatment of symptoms becomes one of the main goals of therapy. Palliative care can also entail helping with decision-making such as if or when hospice care is appropriate, and the preferred place for the patient at end of life care.[22] Bowel obstruction can be treated with palliative surgery (colostomy, ileostomy, or internal bypass) or medicine, but surgery has been shown to increase survival time.[19][22] Palliative surgery may result in short bowel syndrome, enterocutaneous fistula, or re-obstruction; or may not be possible due to the extent of obstruction.[20] Other treatments of complications can include total parenteral nutrition, a low-residue diet, palliative gastrostomy, and adequate pain control.[19] Bowel obstruction can also be treated with octreotide when palliative surgery is not an option. Cancer can also block the ureters, which can be relieved by a nephrostomy or a ureteric stent. Ascites can be relieved by repeated paracentesis or placement of a drain to increase comfort.[82] Pleural effusions can be treated in a similar manner, with repeated thoracentesis, pleurodesis, or placement of a drain.[20] Radiation therapy can be used as part of the palliative care of advanced ovarian cancer, since it can help to shrink tumors that are causing symptoms.[60] Palliative radiotherapy typically lasts for only a few treatments, a much shorter course of therapy than non-palliative radiotherapy.[74] It is also used for palliation of chemotherapy-resistant germ cell tumors.[23] ### Psychosocial care[edit] Ovarian cancer has a significant effect on quality of life, psychological health and well-being. Interventions are available to help with the needs and social support. Many ovarian cancer survivors report a good quality of life and optimism. Others reported a "spiritual change" that helped them find meaning during their experience. Others have described their loss of faith after their diagnosis with ovarian cancer. Those who have gone through treatment sometimes experience social isolation but benefit from having relationships with other survivors. Frustration and guilt have been described by some who have expressed their inability to care for their family.[83] Self-esteem and body image changes can occur due to hair loss, removal of ovaries and other reproductive structures, and scars. There is some improvement after hair grows in. Sexual issues can develop. The removal of ovaries results in surgically-induced menopause that can result in painful intercourse, vaginal dryness, loss of sexual desire and being tired. Though prognosis is better for younger survivors, the impact on sexuality can still be substantial.[83] Anxiety, depression and distress is present in those surviving ovarian cancer at higher rates than in the general population.[83][84] The same psychosocial problems can develop in family members. Emotional effects can include a fear of death, sadness, memory problems and difficulty in concentrating. When optimism was adopted by those at the beginning of their treatment, they were less likely to develop distress. Those who have fear of the cancer recurring may have difficulty in expressing joy even when disease-free. The more treatments that a woman undergoes, the more likely the loss of hope is expressed. Women often can cope and reduce negative psychosocial effects by a number of strategies. Activities such as traveling, spending additional time with family and friends, ignoring statistics, journaling and increasing involvement in spiritually-based events are adaptive.[83] Women with ovarian cancer may also experience difficulties with their diet and are at risk of malnutrition.[85] ## Prognosis[edit] Relative five-year survival of invasive epithelial ovarian cancer by stage[86] Ovarian cancer usually has a relatively poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning most cases are not diagnosed until they have reached advanced stages.[79][19] Ovarian cancer metastasizes early in its development, often before it has been diagnosed. High-grade tumors metastasize more readily than low-grade tumors. Typically, tumor cells begin to metastasize by growing in the peritoneal cavity.[17] More than 60% of women presenting with ovarian cancer have stage-III or stage-IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, including the uterus, urinary bladder, bowel, lining of the bowel wall, and omentum, forming new tumor growths before cancer is even suspected. The five-year survival rate for all stages of ovarian cancer is 46%; the one-year survival rate is 72% and the ten-year survival rate is 35%.[87] For cases where a diagnosis is made early in the disease, when the cancer is still confined to the primary site, the five-year survival rate is 92.7%.[88] About 70% of women with advanced disease respond to initial treatment, most of whom attain complete remission, but half of these women experience a recurrence 1–4 years after treatment.[17] Brain metastasis is more common in stage III/IV cancer but can still occur in cancers staged at I/II. People with brain metastases survive a median of 8.2 months, though surgery, chemotherapy, and whole brain radiation therapy can improve survival.[22] Ovarian cancer survival varies significantly with subtype. Dysgerminomas have a very favorable prognosis. In early stages, they have a five-year survival rate of 96.9%.[24] Around two-thirds of dysgerminomas are diagnosed at stage I.[23] Stage-III dysgerminomas have a five-year survival of 61%; when treated with BEP chemotherapy after incomplete surgical removal, dysgerminomas have a 95% two-year survival rate. Sex-cord-stromal malignancies also have a favorable prognosis; because they are slow-growing, even those with metastatic disease can survive a decade or more.[17] Low malignant potential tumors usually only have a bad prognosis when there are invasive tumor implants found in the peritoneal cavity.[20] Complications of ovarian cancer can include spread of the cancer to other organs, progressive function loss of various organs, ascites, and intestinal obstructions, which can be fatal. Intestinal obstructions in multiple sites are the most common proximate cause of death.[19] Intestinal obstruction in ovarian cancer can either be a true obstruction, where tumor blocks the intestinal lumen, or a pseudo-obstruction, when tumor prevents normal peristalsis.[89] Continuous accumulation of ascites can be treated by placing a drain that can be self-drained.[19] ### Prognostic factors[edit] There are a number of prognostic factors in ovarian cancer. Positive prognostic factors - those indicating better chances of survival - include no residual disease after surgery (stage III/IV), complete macroscopic resection (stage IV), BRCA2 mutations, young age (under 45 years), nonserous type, low histologic grade, early stage, co-occurrence with endometrial cancer, and low CA-125 levels. There is conflicting evidence for BRCA1 as a prognostic factor. Conversely, negative prognostic factors - those that indicate a worse chance of survival - include rupture of the ovarian capsule during surgery, older age (over 45 years), mucinous type, stage IV, high histologic grade, clear cell type, upper abdominal involvement, high CA-125 levels, the presence of tumor cells in the blood, and elevated cyclooxygenase-2.[22] Expression of various mRNAs can also be prognostic for ovarian cancer. High levels of Drosha and Dicer are associated with improved survival, whereas high levels of let-7b, HIF1A, EphA1, and poly(ADP-ribose) polymerase are associated with worse survival. Cancers that are positive for WT1 carry a worse prognosis; estrogen-receptor positive cancers have a better prognosis.[22] ### Survival rates[edit] Overall five-year survival rates for all types of ovarian cancer are presented below by stage and histologic grade:[17] Stage Survival I 90–95% II 70–80% III 20–50% IV 1–5% Histologic grade Survival Low grade 88% Intermediate grade 58% High grade 27% The survival rates given below are for the different types of ovarian cancer, according to American Cancer Society.[86] They come from the National Cancer Institute, SEER, and are based on patients diagnosed from 2004 to 2010. Invasive epithelial ovarian cancer Stage Relative five-year survival rate I 90% IA 94% IB 92% IC 85% II 70% IIA 78% IIB 73% III 39% IIIA 59% IIIB 52% IIIC 39% IV 17% Ovarian stromal tumors Stage Relative five-year survival rate I 95% II 78% III 65% IV 35% Germ cell tumors of the ovary Stage Relative five-year Survival Rate I 98% II 94% III 87% IV 69% Fallopian tube carcinoma Stage Relative five-year survival rate I 87% II 86% III 52% IV 40% Low malignant potential tumors[20] Stage Relative five-year survival rate I 99% II 98% III 96% IV 77% ### Recurrence rates[edit] Ovarian cancer frequently recurs after treatment. Overall, in a 5-year period, 20% of stage I and II cancers recur. Most recurrences are in the abdomen.[20] If a recurrence occurs in advanced disease, it typically occurs within 18 months of initial treatment (18 months progression-free survival). Recurrences can be treated, but the disease-free interval tends to shorten and chemoresistance increases with each recurrence.[19] When a dysgerminoma recurs, it is most likely to recur within a year of diagnosis, and other malignant germ cell tumors recur within 2 years 90% of the time. Germ cell tumors other than dysgerminomas have a poor prognosis when they relapse, with a 10% long-term survival rate.[23] Low malignant potential tumors rarely relapse, even when fertility-sparing surgery is the treatment of choice. 15% of LMP tumors relapse after unilateral surgery in the previously unaffected ovary, and they are typically easily treated with surgery. More advanced tumors may take up to 20 years to relapse, if they relapse at all, and are only treated with surgery unless the tumor has changed its histological characteristics or grown very quickly. In these cases, and when there is significant ascites, chemotherapy may also be used. Relapse is usually indicated by rising CA-125 levels and then progresses to symptomatic relapse within 2–6 months.[20] Recurrent sex cord-stromal tumors are typically unresponsive to treatment but not aggressive.[23] It is the most deadly gynecologic cancer.[20] ## Epidemiology[edit] Age-standardized death from ovarian cancer per 100,000 inhabitants in 2004[90] no data less than 0.6 0.6–1.2 1.2–1.8 1.8–2.4 2.4–3 3–3.6 3.6–4.2 4.2–4.8 4.8–5.4 5.4–6 6–7 more than 7 In 2014, the number of new cases that occurred in developed countries was about 9.4 per 100,000, compared to 5.0 per 100,000 in developing countries.[19] Globally, about 160,000 people died from ovarian cancer in 2010. This was an increase from 113,000 in 1990.[91] The number of new cases per year in Europe is approximately 5–15 per 100,000 women.[22] In Europe, Lithuania, Latvia, Ireland, Slovakia, and the Czech Republic have the highest incidences of ovarian cancer, whereas Portugal and Cyprus have the lowest incidences.[22] In 2008, the five-year survival rate was 44%. This has increased since 1977 when the survival rate was 36%.[83] ### United States[edit] Ovarian cancer cases diagnosed by age group in the US[88] In 2010, in the United States, an estimated 21,880 new cases were diagnosed and 13,850 women died of ovarian cancer. Around 1,800 of the new diagnoses were sex-cord or stromal tumors.[17] In 2014, over 220,000 diagnoses of epithelial ovarian cancer were made yearly.[19] The overall lifetime risk in the US is around 1.6%[17][22] In the US, ovarian cancer affects 1.3–1.4% and is the cause of death of about 1% of women.[20][92] In the United States, it is also the fifth-most common cancer in women but the fourth-most common cause of cancer death.[22] This decrease made it the ninth-most common cancer in women.[20] The risks from developing specific types of ovarian cancer varies. Germ cell tumors and sex cord-stromal tumors are less common than epithelial tumors. The number of new cases a year in the US is 0.4 per 100,000 women and 0.2 per 100,000 women, respectively. In young people, sex-cord stromal tumors and germ cell tumors total 1% of overall ovarian cancer.[23] Ovarian cancer represents approximately 4% of cancers diagnosed in women.[22] ### United Kingdom[edit] It is the 5th most common cancer in UK women.[22][25] In the UK, the incidence rate over the whole population is 21.6 per 100,000. In the United Kingdom as of 2014, approximately 7,000–7,100 yearly diagnoses with 4,200 deaths.[19][25] The risk in the UK is similar, at 1.7%. Ashkenazi Jewish women carry mutated BRCA alleles five times more often than the rest of the population, giving them a higher risk developing ovarian cancer.[19] Ovarian cancer is the fifth-most common cancer in women in the UK (around 7,100 women were diagnosed with the disease in 2011), and it is the fifth-most common cause of cancer death in women (around 4,300 women died in 2012).[93] ### Ethnicity[edit] Black women have twice the risk for sex cord-stromal tumors compared to non-Black women.[23] ### Older women[edit] In the US, the incidence rate in women over 50 is approximately 33 per 100,000.[94] The rate of ovarian cancer between 1993 and 2008 decreased in women of the 40–49 age cohort and in the 50–64 age cohort.[19] Ovarian cancer is most commonly diagnosed after menopause,[25] between the ages of 60 and 64. Ninety percent of ovarian cancer occurs in women over the age of 45 and 80% in women over 50.[22] Older women are more likely to present with advanced ovarian cancer.[16] ## In pregnancy[edit] Malignant germ cell tumors are the type of ovarian cancer most likely to occur during pregnancy. They are typically diagnosed when an adnexal mass is found on examination (in 1–2% of all pregnancies), a tumor is seen on ultrasound, or the parent's level of alpha-fetoprotein is elevated. Dermoid cysts and dysgerminomas are the most common germ cell tumors during pregnancy. Germ cell tumors diagnosed during pregnancy are unlikely to have metastasized and can be treated by surgery and, in some cases, chemotherapy, which carries the risk of birth defects. Yolk sac tumors and immature teratomas grow particularly quickly and are usually treated with chemotherapy even during pregnancy; however, dysgerminomas that have been optimally debulked may be treated after childbirth.[23] ## Other animals[edit] Ovarian tumors have been reported in equine mares. Reported tumor types include teratoma,[95][96] cystadenocarcinoma,[97] and particularly granulosa cell tumor.[98][99][100][101][102] ## Research[edit] ### Screening[edit] Screening by hysteroscopy to obtain cell samples obtained for histological examination is being developed. This is similar to the current pap smear that is used to detect cervical cancer.[103] The UK Collaborative Trial of Ovarian Cancer Screening is testing a screening technique that combines CA-125 blood tests with transvaginal ultrasound.[19] Other studies suggest that this screening procedure may be effective.[76] Although results published in 2015 were not conclusive, there was some evidence that screening may save lives in the long-term.[104] As a result, the trial has been extended and will publish definitive results at the end of 2019. One major problem with screening is no clear progression of the disease from stage I (noninvasive) to stage III (invasive) is seen, and it may not be possible to find cancers before they reach stage III. Another problem is that screening methods tend to find too many suspicious lesions, most of which are not cancer, but malignancy can only be assessed with surgery.[19] The ROCA method combined with transvaginal ultrasonography is being researched in high-risk women to determine if it is a viable screening method. It is also being investigated in normal-risk women as it has shown promise in the wider population.[20] Studies are also in progress to determine if screening helps detect cancer earlier in people with BRCA mutations.[76] ### Prognosis research[edit] Research into various prognostic factors for ovarian cancer is also going on. Recent research shows that thrombocytosis predicts lower survival and higher stage cancer.[19] Ongoing research is also investigating the benefits of surgery for recurrent ovarian cancer.[76] ### Immunotherapy[edit] While an active area of research, as of 2018 there is no goodevidence that immunotherapy is effective for ovarian cancer.[105] However, trials of the antibody and VEGF inhibitor bevacizumab, which can slow the growth of new blood vessels in the cancer, have shown promising results, especially in combination with pazopanib, which also slows the process of blood vessel growth. Bevacizumab has been particularly effective in preliminary studies on stage-III and -IV cancer[19] and has been cited as having at least a 15% response rate.[17] It is being investigated particularly in mucinous ovarian cancers.[76] ### Pharmacology[edit] mTOR inhibitors were a highly investigated potential treatment in the 2000s and 2010s, but the side effects of these drugs (particularly hyperglycemia and hyperlipidemia) were not well tolerated and the survival benefit not confirmed. PI3 kinase inhibitors have been of interest, but they tend to be highly toxic and cause diarrhea. Another investigated drug is selumetinib, a MAPK inhibitor. It improved survival, but did not correlate with any mutations found in tumors.[19] Bevacizumab can also be combined with platinum chemotherapy, a combination that has had positive preliminary results in PFS, but equivocal results regarding overall survival. One disadvantage to these treatments is the side effect profile, which includes high blood pressure and proteinuria. The drug can also exacerbate bowel disease, leading to fistulae or bowel perforation. Vintafolide, which consists of an antifolate conjugated with vinblastine, is also in clinical trials; it may prove beneficial because folate receptors are overexpressed in many ovarian cancers.[19] Another potential immunotherapy is trastuzumab, which is active against tumors positive for Her2/neu mutations.[17] Other angiogenesis inhibitors are also being investigated as potential ovarian cancer treatments. Combretastatin and pazopanib are being researched in combination for recurrent ovarian cancer. Trebananib and tasquinimod are other angiogenesis inhibitors being investigated. The monoclonal antibody farletuzumab is being researched as an adjuvant to traditional chemotherapy. Another type of immunotherapy involves vaccines, including TroVax.[76] An alternative to BEP chemotherapy, a regimen of 3 cycles of carboplatin and etoposide, is a current topic of research for germ cell malignancies.[23] Intraperitoneal chemotherapy has also been under investigation during the 2000s and 2010s for its potential to deliver higher doses of cytotoxic agent to tumors. Preliminary trials with cisplatin and paclitaxel have shown it is not well tolerated, but does improve survival, and more tolerable regimens are being researched.[19] Cisplatin and paclitaxel are both being researched as intraperitoneal chemotherapy agents. A specific chemotherapy regimen for rare clear-cell cancers is also under investigation: irinotecan combined with cisplatin.[76] PARP inhibitors have also shown promise in early trials, particularly in people with BRCA gene mutations, since the BRCA protein interacts with the PARP pathway. It is also being studied in recurrent ovarian cancer in general, where preliminary studies have shown longer PFS. Specifically, olaparib has shown greater survival compared to doxorubicin, though this treatment is still being investigated. It is not clear yet which biomarkers are predictive of responsiveness to PARP inhibitors.[19] Rucaparib is another PARP inhibitor being researched in BRCA-positive and BRCA-negative recurrent advanced ovarian cancer. Niraparib is a PARP inhibitor being tested in BRCA-positive recurrent ovarian cancer.[76] Tyrosine kinase inhibitors are another investigational drug class that may have applications in ovarian cancer. Angiogenesis inhibitors in the receptor tyrosine kinase inhibitor group, including pazopanib, cediranib, and nintedanib, have also been shown to increase progression free survival (PFS), but their benefit for overall survival has not been investigated as of 2015.[19] Preliminary research showed that cediranib combined with platins in recurrent ovarian cancer increased the time to second recurrence by 3–4 months and increased survival by 3 months.[76] MK-1775 is a tyrosine kinase inhibitor that is being used in combination with paclitaxel and carboplatin in platinum-sensitive cancers with p53 mutations. Nintedanib is being researched as a potential therapy in combination with cyclophosphamide for people with recurrences.[76] Histone deacetylase inhibitors (HDACi) are another area of research. ### Hormones and radiation[edit] Hormone therapies are a topic of current research in ovarian cancer, particularly, the value of certain medications used to treat breast cancer. These include tamoxifen, letrozole, and anastrozole. Preliminary studies have showed a benefit for tamoxifen in a small number of people with advanced ovarian cancer. Letrozole may help to slow or stop growth of estrogen receptor positive ovarian cancer. Anastrozole is being investigated in postmenopausal people with estrogen receptor-positive cancer.[76] Research into mitigating side effects of ovarian cancer treatment is also ongoing. Radiation fibrosis, the formation of scar tissue in an area treated with radiation, may be relieved with hyperbaric oxygen therapy, but research has not been completed in this area. Treatment of ovarian cancer may also cause people to experience psychiatric difficulties, including depression. Research is ongoing to determine how counseling and psychotherapy can help people who have ovarian cancer during treatment.[76] ### Inflammation[edit] There are some indications that pelvic inflammatory disease may be associated with ovarian cancer, especially in non-western countries. It may be due to the inflammatory process present with pelvic inflammatory disease.[106] ### Clinical trials[edit] Clinical trials are monitored and funded by US governmental organizations to test treatment options to see if they are safe and effective. These include NIH Clinical Research Trials and You (National Institutes of Health),[107] Learn About Clinical Trials (National Cancer Institute),[108] Search for Clinical Trials (National Cancer Institute),[109] ClinicalTrials.gov (National Institutes of Health).[110][57] Clinical trials are also conducted in Canada.[111] ## References[edit] 1. ^ a b c d e f g h i j "Ovarian Epithelial Cancer Treatment". NCI. 2014-05-12. Archived from the original on 5 July 2014. Retrieved 1 July 2014. 2. ^ a b "What are the risk factors for ovarian cancer?". www.cancer.org. 2016-02-04. Archived from the original on 17 May 2016. Retrieved 18 May 2016. 3. ^ a b c d e f g h i j k l m World Cancer Report 2014. World Health Organization. 2014. Chapter 5.12. ISBN 978-9283204299. Archived from the original on 2016-09-19. 4. ^ a b c d "Ovarian Cancer Prevention". NCI. December 6, 2013. Archived from the original on 6 July 2014. Retrieved 1 July 2014. 5. ^ a b c "Ovarian Cancer Prevention". NCI. 2014-06-20. Archived from the original on 6 July 2014. Retrieved 1 July 2014. 6. ^ a b "SEER Stat Fact Sheets: Ovary Cancer". NCI. Archived from the original on 6 July 2014. Retrieved 18 June 2014. 7. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 8. ^ a b GBD 2015 Mortality and Causes of Death Collaborators (October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/S0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 9. ^ Seiden, Michael (2015). "Gynecologic Malignancies, Chapter 117". MGraw-Hill Medical. Archived from the original on September 10, 2017. Retrieved June 24, 2017. 10. ^ "Defining Cancer". National Cancer Institute. 2007-09-17. Archived from the original on 25 June 2014. Retrieved 10 June 2014. 11. ^ Ebell MH, Culp MB, Radke TJ (March 2016). "A Systematic Review of Symptoms for the Diagnosis of Ovarian Cancer". American Journal of Preventive Medicine. 50 (3): 384–394. doi:10.1016/j.amepre.2015.09.023. PMID 26541098. 12. ^ Ruddon RW (2007). Cancer Biology (4th ed.). Oxford: Oxford University Press. p. 223. ISBN 9780195175431. Archived from the original on 2015-09-15. 13. ^ Piek JM, van Diest PJ, Verheijen RH (2008). "Ovarian carcinogenesis: an alternative hypothesis". Ovarian Cancer. Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 622. pp. 79–87. doi:10.1007/978-0-387-68969-2_7. ISBN 978-0-387-68966-1. PMID 18546620. 14. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 15. ^ a b Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, Doubeni CA, et al. (February 2018). "Screening for Ovarian Cancer: US Preventive Services Task Force Recommendation Statement". JAMA. 319 (6): 588–594. doi:10.1001/jama.2017.21926. PMID 29450531. 16. ^ a b c Gibson SJ, Fleming GF, Temkin SM, Chase DM (2016). "The Application and Outcome of Standard of Care Treatment in Elderly Women with Ovarian Cancer: A Literature Review over the Last 10 Years". Frontiers in Oncology. 6: 63. doi:10.3389/fonc.2016.00063. PMC 4805611. PMID 27047797. 17. ^ 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 ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd Seiden MV (2012). "Gynecologic Malignancies". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. ISBN 978-0-07-174889-6. 18. ^ a b c d "Ovarian Cancer, Inside Knowledge, Get the Facts about Gynecological Cancer" (PDF). Centers for Disease Control and Prevention. September 2016. Archived (PDF) from the original on June 16, 2017. Retrieved June 17, 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 19. ^ 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 ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh Jayson GC, Kohn EC, Kitchener HC, Ledermann JA (October 2014). "Ovarian cancer". Lancet. 384 (9951): 1376–88. doi:10.1016/S0140-6736(13)62146-7. PMID 24767708. S2CID 205971030. 20. ^ 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 ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG (2012). "Epithelial Ovarian Cancer". Williams Gynecology (2nd ed.). McGraw Hill Medical. pp. 853–878. ISBN 978-0-07-171672-7. 21. ^ "Ovarian cancer symptoms". www.cancerresearchuk.org. Archived from the original on 2015-05-12. Retrieved 2015-05-16. 22. ^ 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 ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt "Ovarian cancer". DynaMed. June 18, 2015. Archived from the original on June 21, 2015. 23. ^ 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 ak al am an ao Williams Gynecology 2012 24. ^ a b c d e f g DeCherney A, Nathan L, Goodwin TM, Laufer N, Roman A (2012). "Pediatric and Adolescent Gynecology". Current Diagnosis & Treatment Obstetrics & Gynecology (11th ed.). ISBN 978-0071638562. 25. ^ a b c d e f g h i j k l m n o p "Ovarian cancer risks and causes". Cancer Research UK. 15 January 2014. Archived from the original on 21 February 2015. Retrieved 29 January 2015. 26. ^ Gong TT, Wu QJ, Vogtmann E, Lin B, Wang YL (June 2013). "Age at menarche and risk of ovarian cancer: a meta-analysis of epidemiological studies". International Journal of Cancer. 132 (12): 2894–900. doi:10.1002/ijc.27952. PMC 3806278. PMID 23175139. 27. ^ Manson JE, Bassuk SS (2012). "The Menopause Transition and Postmenopausal Hormone Therapy". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. ISBN 978-0-07-174889-6. 28. ^ "Ovarian Cancer Prevention (PDQ®)". National Cancer Institute. 2013. Archived from the original on 2013-12-31. Retrieved 2013-12-30. 29. ^ Kyriakidis I, Papaioannidou P (2016). "Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy". Arch Gynecol Oncol. 293 (6): 1161–8. doi:10.1007/s00404-016-4027-8. PMID 26861465. S2CID 25627227. 30. ^ Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, Casadei S, Yi Q, Burger RA, Chan JK, Davidson SA, Mannel RS, DiSilvestro PA, Lankes HA, Ramirez NC, King MC, Swisher EM, Birrer MJ (2015). "Inherited mutations in women With ovarian carcinoma". JAMA Oncol. 30 (4): 1–9. doi:10.1001/jamaoncol.2015.5495. PMC 4845939. PMID 26720728. 31. ^ Kuusisto KM, Bebel A, Vihinen M, Schleutker J, Sallinen SL (2011). "Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals". Breast Cancer Res. 13 (1): R20. doi:10.1186/bcr2832. PMC 3109589. PMID 21356067. 32. ^ Salehi F, Dunfield L, Phillips KP, Krewski D, Vanderhyden BC (March 2008). "Risk factors for ovarian cancer: an overview with emphasis on hormonal factors". Journal of Toxicology and Environmental Health Part B: Critical Reviews. 11 (3–4): 301–21. doi:10.1080/10937400701876095. PMID 18368558. S2CID 5589506. 33. ^ "Do we know what causes ovarian cancer?". www.cancer.org. Archived from the original on 2016-11-10. 34. ^ Hjartåker A, Meo MS, Weiderpass E (January 2010). "Alcohol and gynecological cancers: an overview". European Journal of Cancer Prevention. 19 (1): 1–10. doi:10.1097/CEJ.0b013e328333fb3a. PMID 19926999. S2CID 27570587. 35. ^ Zhang X, Nicosia SV, Bai W (2006). "Vitamin D receptor is a novel drug target for ovarian cancer treatment". Curr Cancer Drug Targets. 6 (3): 229–44. doi:10.2174/156800906776842939. PMID 16712459. 36. ^ Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter DA (2015). "Sedentary Time and Its Association With Risk for Disease Incidence, Mortality, and Hospitalization in Adults: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 162 (2): 123–32. doi:10.7326/M14-1651. PMID 25599350. S2CID 7256176. 37. ^ a b Odunsi K, Pejovic T, Anderson ML (2011). Molecular Biology of Gynecologic Cancers. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. Wolters Kluwer/Lippincott Williams & Wilkins. pp. 1302–1310. ISBN 978-1-4511-0545-2. 38. ^ "Genetics of Breast and Ovarian Cancer (PDQ®)". National Cancer Institute. 2 October 2014. Archived from the original on 22 October 2014. Retrieved 27 October 2014. 39. ^ "Can Ovarian Cancer Be Found Early?". American Cancer Society. 40. ^ Rossing MA, Wicklund KG, Cushing-Haugen KL, Weiss NS (2010-01-28). "Predictive Value of Symptoms for Early Detection of Ovarian Cancer". J Natl Cancer Inst. 102 (4): 222–9. doi:10.1093/jnci/djp500. PMC 2826180. PMID 20110551. 41. ^ a b c Miller RW, Ueland FR (March 2012). "Risk of malignancy in sonographically confirmed ovarian tumors". Clinical Obstetrics and Gynecology. 55 (1): 52–64. doi:10.1097/GRF.0b013e31824970cf. PMID 22343229. 42. ^ "Ovarian cancer tests". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 43. ^ "Guideline CG122. Ovarian cancer: The recognition and initial management of ovarian cancer, Appendix D: Risk of malignancy index (RMI I)". NICE clinical guidelines. April 2011. Archived from the original on 2013-09-22. 44. ^ Geomini P, Kruitwagen R, Bremer GL, Cnossen J, Mol BW (February 2009). "The accuracy of risk scores in predicting ovarian malignancy: a systematic review". Obstetrics and Gynecology. 113 (2 Pt 1): 384–94. doi:10.1097/AOG.0b013e318195ad17. PMID 19155910. S2CID 24585101. 45. ^ Kaijser J, Bourne T, De Rijdt S, Van Holsbeke C, Sayasneh A, Valentin L, et al. (August 2012). "Key findings from the International Ovarian Tumor Analysis (IOTA) study: an approach to the optimal ultrasound based characterisation of adnexal pathology". Australasian Journal of Ultrasound in Medicine. 15 (3): 82–86. doi:10.1002/j.2205-0140.2012.tb00011.x. PMC 5025098. PMID 28191150. 46. ^ a b Kosary CL (2007). "Chapter 16: Cancers of the Ovary" (PDF). In Baguio RN, Young JL, Keel GE, Eisner MP, Lin YD, Horner MJ (eds.). SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988–2001, Patient and Tumor Characteristics. SEER Program. NIH Pub. No. 07-6215. Bethesda, MD: National Cancer Institute. pp. 133–144. Archived from the original on 2013-10-10. 47. ^ a b c d e f g h i "Types of ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 48. ^ a b c Levy G, Purcell, Karen (2013). DeCherney AH, Nathan L, Laufer N, Roman AS (eds.). Premalignant & Malignant Disorders of the Ovaries & Oviducts. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology, 11e. McGraw-Hill. ISBN 978-0-07-163856-2. Archived from the original on 2017-09-10. 49. ^ Nucci, Marisa R. (3 February 2020). Gynecologic pathology : a volume in the series Foundations in diagnostic pathology (Second ed.). p. 946. ISBN 978-0-323-35909-2. 50. ^ Nucci, Marisa R. (3 February 2020). Gynecologic pathology : a volume in the series Foundations in diagnostic pathology (Second ed.). p. 946. ISBN 978-0-323-35909-2. 51. ^ "Primary peritoneal carcinoma". www.cancerresearchuk.org. Archived from the original on 2015-05-20. Retrieved 2015-05-16. 52. ^ a b "Ovarian Cancer Staging" (PDF). Society for Gynecologic Oncology. 1 January 2014. Archived (PDF) from the original on 5 November 2014. 53. ^ "How is ovarian cancer staged?". American Cancer Society. Archived from the original on November 24, 2016. Retrieved June 17, 2017. 54. ^ "Stages of ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 55. ^ a b c Croswell JM, Brawley OW, Kramer BS (2012). "Prevention and Early Detection of Cancer". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. ISBN 978-0-07-174889-6. 56. ^ Cibula D, Widschwendter M, Májek O, Dusek L (2010). "Tubal ligation and the risk of ovarian cancer: review and meta-analysis". Human Reproduction Update. 17 (1): 55–67. doi:10.1093/humupd/dmq030. PMID 20634209. 57. ^ a b "How Is Ovarian Cancer Treated?". Centers for Disease Control and Prevention. February 13, 2017. Archived from the original on June 16, 2017. Retrieved June 17, 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 58. ^ Marchetti C, Pisano C, Facchini G, Bruni GS, Magazzino FP, Losito S, Pignata S (January 2010). "First-line treatment of advanced ovarian cancer: current research and perspectives". Expert Review of Anticancer Therapy. 10 (1): 47–60. doi:10.1586/era.09.167. PMID 20014885. S2CID 40586650. 59. ^ a b c d e "Types of treatment for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-12. Retrieved 2015-05-16. 60. ^ a b c d "Treatment of ovarian cancer". Canadian Cancer Society. Archived from the original on 26 October 2016. Retrieved 17 June 2017. 61. ^ Elattar A, Bryant A, Winter-Roach BA, Hatem M, Naik R (August 2011). "Optimal primary surgical treatment for advanced epithelial ovarian cancer". The Cochrane Database of Systematic Reviews (8): CD007565. doi:10.1002/14651858.cd007565.pub2. PMC 6457688. PMID 21833960. 62. ^ Roze JF, Hoogendam JP, van de Wetering FT, Spijker R, Verleye L, Vlayen J, et al. (October 2018). "Positron emission tomography (PET) and magnetic resonance imaging (MRI) for assessing tumour resectability in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer". The Cochrane Database of Systematic Reviews. 10: CD012567. doi:10.1002/14651858.cd012567.pub2. PMC 6517226. PMID 30298516. 63. ^ Segura-Sampedro, Juan José; Morales-Soriano, Rafael; Arjona-Sánchez, Álvaro; Cascales-Campos, Pedro (11 May 2020). "Secondary surgical cytoreduction needs to be assessed taking into account surgical technique, completeness of cytoreduction, and extent of disease". World Journal of Surgical Oncology. 18 (1): 92. doi:10.1186/s12957-020-01853-4. PMC 7216587. PMID 32393274. 64. ^ Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, Galaal K (February 2013). "Surgical cytoreduction for recurrent epithelial ovarian cancer". The Cochrane Database of Systematic Reviews (2): CD008765. doi:10.1002/14651858.cd008765.pub3. PMC 6457850. PMID 23450588. 65. ^ "Surgery for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 66. ^ Falcetta FS, Lawrie TA, Medeiros LR, da Rosa MI, Edelweiss MI, Stein AT, et al. (October 2016). "Laparoscopy versus laparotomy for FIGO stage I ovarian cancer". The Cochrane Database of Systematic Reviews. 10: CD005344. doi:10.1002/14651858.CD005344.pub4. PMC 6464147. PMID 27737492. 67. ^ Lawrie TA, Winter-Roach BA, Heus P, Kitchener HC (December 2015). "Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer". The Cochrane Database of Systematic Reviews (12): CD004706. doi:10.1002/14651858.cd004706.pub5. PMC 6457737. PMID 26676202. 68. ^ Stewart L (1999-01-25). "Chemotherapy for advanced ovarian cancer. Advanced Ovarian Cancer Trialists Group". The Cochrane Database of Systematic Reviews (2): CD001418. doi:10.1002/14651858.cd001418. PMID 10796788. 69. ^ Lihua P, Chen XY, Wu TX (April 2008). "Topotecan for ovarian cancer". The Cochrane Database of Systematic Reviews (2): CD005589. doi:10.1002/14651858.cd005589.pub2. PMC 6905487. PMID 18425923. 70. ^ a b "Drugs used for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 71. ^ Yao, Stephanie (19 December 2014). "FDA approves Lynparza to treat advanced ovarian cancer: First LDT companion diagnostic test also approved to identify appropriate patients". U.S. Food and Drug Administration. Archived from the original on 14 September 2015. 72. ^ "Innovative treatment for gynaecological cancers approved for Cancer Drugs Fund". Retrieved 2019-08-14. 73. ^ Gaitskell K, Martinek I, Bryant A, Kehoe S, Nicum S, Morrison J (September 2011). "Angiogenesis inhibitors for the treatment of ovarian cancer". The Cochrane Database of Systematic Reviews (9): CD007930. doi:10.1002/14651858.cd007930.pub2. PMC 4167846. PMID 21901715. 74. ^ a b "Radiotherapy for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 75. ^ Williams C, Simera I, Bryant A (March 2010). "Tamoxifen for relapse of ovarian cancer". The Cochrane Database of Systematic Reviews (3): CD001034. doi:10.1002/14651858.cd001034.pub2. PMC 4235755. PMID 20238312. 76. ^ a b c d e f g h i j k l "Ovarian cancer research". www.cancerresearchuk.org. Archived from the original on 2015-05-09. Retrieved 2015-05-16. 77. ^ "Follow up for ovarian cancer". Cancer Research UK. 2017-08-30. Archived from the original on 2014-08-29. 78. ^ a b Follow-up care Archived 2013-12-25 at the Wayback Machine from American Cancer Society. Last Medical Review: 03/21/2013. Last Revised: 02/06/2014 79. ^ a b c Society of Gynecologic Oncology (February 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, Society of Gynecologic Oncology, archived from the original on 1 December 2013, retrieved 19 February 2013, which cites * Bhosale P, Peungjesada S, Wei W, Levenback CF, Schmeler K, Rohren E, Macapinlac HA, Iyer RB (August 2010). "Clinical Utility of Positron Emission Tomography/Computed Tomography in the Evaluation of Suspected Recurrent Ovarian Cancer in the Setting of Normal CA-125 Levels". International Journal of Gynecological Cancer. 20 (6): 936–944. doi:10.1111/IGC.0b013e3181e82a7f. PMID 20683399. S2CID 13542187. 80. ^ "Chemotherapy for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 81. ^ "ASCO Provisional Clinical Opinion: The Integration of Palliative Care into Standard Oncology Care". ASCO. Archived from the original on 21 August 2014. Retrieved 20 August 2014. 82. ^ "Treating advanced ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-19. Retrieved 2015-05-16. 83. ^ a b c d e Roland KB, Rodriguez JL, Patterson JR, Trivers KF (November 2013). "A literature review of the social and psychological needs of ovarian cancer survivors". Psycho-Oncology. 22 (11): 2408–18. doi:10.1002/pon.3322. PMID 23760742. S2CID 30648891. 84. ^ Watts S, Prescott P, Mason J, McLeod N, Lewith G (November 2015). "Depression and anxiety in ovarian cancer: a systematic review and meta-analysis of prevalence rates". BMJ Open. 5 (11): e007618. doi:10.1136/bmjopen-2015-007618. PMC 4679843. PMID 26621509. 85. ^ Billson HA, Holland C, Curwell J, Davey VL, Kinsey L, Lawton LJ, et al. (September 2013). "Perioperative nutrition interventions for women with ovarian cancer". The Cochrane Database of Systematic Reviews (9): CD009884. doi:10.1002/14651858.cd009884.pub2. PMID 24027084. 86. ^ a b "Survival rates for ovarian cancer, by stage". American Cancer Society. Archived from the original on 29 October 2014. Retrieved 29 October 2014. 87. ^ "Statistics and outlook for ovarian cancer". www.cancerresearchuk.org. Archived from the original on 2015-05-18. Retrieved 2015-05-16. 88. ^ a b Survival rates based on SEER incidence and NCHS mortality statistics, as cited by the National Cancer Institute in SEER Stat Fact Sheets — Cancer of the Ovary Archived 2014-07-06 at the Wayback Machine 89. ^ Gucalp R, Dutcher J (2012). "Oncologic Emergencies". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. ISBN 978-0-07-174889-6. 90. ^ "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved June 15, 2017. The statistics are from 2004. This weblink opens up with an automatic Excel file download 91. ^ Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. (December 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. hdl:10536/DRO/DU:30050819. PMID 23245604. S2CID 1541253. 92. ^ Ramirez PT, Gershenson DM (September 2013). "Ovarian Cancer". The Merck Manual for Health Care Professionals. 93. ^ "Ovarian cancer statistics". Cancer Research UK. Archived from the original on 6 October 2014. Retrieved 28 October 2014. 94. ^ Hennessy BT, Suh GK, Markman M (2011). Kantarjian HM, Wolff RA, Koller CA (eds.). Ovarian Cancer. The MD Anderson Manual of Medical Oncology (2nd ed.). McGraw-Hill. ISBN 978-0-07-170106-8. Archived from the original on 2017-09-10. 95. ^ Catone G, Marino G, Mancuso R, Zanghì A (April 2004). "Clinicopathological features of an equine ovarian teratoma". Reprod. Domest. Anim. 39 (2): 65–9. doi:10.1111/j.1439-0531.2003.00476.x. PMID 15065985. 96. ^ Lefebvre R, Theoret C, Doré M, Girard C, Laverty S, Vaillancourt D (November 2005). "Ovarian teratoma and endometritis in a mare". Can. Vet. J. 46 (11): 1029–33. PMC 1259148. PMID 16363331. 97. ^ Son YS, Lee CS, Jeong WI, Hong IH, Park SJ, Kim TH, Cho EM, Park TI, Jeong KS (May 2005). "Cystadenocarcinoma in the ovary of a Thoroughbred mare". Aust. Vet. J. 83 (5): 283–4. doi:10.1111/j.1751-0813.2005.tb12740.x. PMID 15957389. 98. ^ Frederico LM, Gerard MP, Pinto CR, Gradil CM (May 2007). "Bilateral occurrence of granulosa-theca cell tumors in an Arabian mare". Can. Vet. J. 48 (5): 502–5. PMC 1852596. PMID 17542368. 99. ^ Hoque S, Derar RI, Osawa T, Taya K, Watanabe G, Miyake Y (June 2003). "Spontaneous repair of the atrophic contralateral ovary without ovariectomy in the case of a granulosa theca cell tumor (GTCT) affected mare". J. Vet. Med. Sci. 65 (6): 749–51. doi:10.1292/jvms.65.749. PMID 12867740. 100. ^ Sedrish SA, McClure JR, Pinto C, Oliver J, Burba DJ (November 1997). "Ovarian torsion associated with granulosa-theca cell tumor in a mare". J. Am. Vet. Med. Assoc. 211 (9): 1152–4. PMID 9364230. 101. ^ Moll HD, Slone DE, Juzwiak JS, Garrett PD (1987). "Diagonal paramedian approach for removal of ovarian tumors in the mare". Vet Surg. 16 (6): 456–8. doi:10.1111/j.1532-950X.1987.tb00987.x. PMID 3507181. Archived from the original on 2012-10-10. 102. ^ Doran R, Allen D, Gordon B (January 1988). "Use of stapling instruments to aid in the removal of ovarian tumours in mares". Equine Vet. J. 20 (1): 37–40. doi:10.1111/j.2042-3306.1988.tb01450.x. PMID 2835223. 103. ^ Gizzo S, Noventa M, Quaranta M, Vitagliano A, Saccardi C, Litta P, Antona D (February 2017). "A novel hysteroscopic approach for ovarian cancer screening/early diagnosis". Oncology Letters. 13 (2): 549–553. doi:10.3892/ol.2016.5493. PMC 5351187. PMID 28356928. subscription required 104. ^ Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. (March 2016). "Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial". Lancet. 387 (10022): 945–956. doi:10.1016/S0140-6736(15)01224-6. PMC 4779792. PMID 26707054. 105. ^ Paijens ST, Leffers N, Daemen T, Helfrich W, Boezen HM, Cohlen BJ, Melief CJ, de Bruyn M, Nijman HW (September 2018). "Antigen-specific active immunotherapy for ovarian cancer". Cochrane Database Syst Rev. 9: CD007287. doi:10.1002/14651858.CD007287.pub4. PMC 6513204. PMID 30199097. 106. ^ Ingerslev K, Hogdall E, Schnack TH, Skovrider-Ruminski W, Hogdall C, Blaakaer J (2017). "The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis". Infectious Agents and Cancer. 12 (1): 25. doi:10.1186/s13027-017-0134-9. PMC 5437405. PMID 28529540. 107. ^ "NIH Clinical Research Trials and You". Archived from the original on 8 June 2017. Retrieved 17 June 2017. 108. ^ "Clinical Trials Information for Patients and Caregivers". National Cancer Institute. Archived from the original on 16 June 2017. Retrieved 17 June 2017. 109. ^ "Find NCI-Supported Clinical Trials". National Cancer Institute. 2016-06-23. Archived from the original on 1 July 2017. Retrieved 17 June 2017. 110. ^ "Home — ClinicalTrials.gov". www.clinicaltrials.gov. Archived from the original on 16 June 2017. Retrieved 17 June 2017. 111. ^ "Home - Canadian Cancer Trials". www.canadiancancertrials.ca. Archived from the original on 26 June 2017. Retrieved 17 June 2017. ## Further reading[edit] * Cannistra SA (December 2004). "Cancer of the ovary". N. Engl. J. Med. 351 (24): 2519–29. doi:10.1056/NEJMra041842. PMID 15590954. * Petrucelli N, Daly MB, Feldman GL (2013). "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer". BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer. University of Washington, Seattle. PMID 20301425. NBK1247. ## External links[edit] * "Ovarian, Fallopian Tube, and Primary Peritoneal Cancer - Patient Version". National Cancer Institute. Retrieved 30 March 2017. * What is Ovarian Cancer Infographic, information on ovarian cancer \- Mount Sinai Hospital, New York Classification D * ICD-10: C56 * ICD-9-CM: 183, 220 * ICD-O: varied * MeSH: D010051 * DiseasesDB: 9418 * SNOMED CT: 363443007 External resources * MedlinePlus: 000889 * eMedicine: med/1698 * Patient UK: Ovarian cancer * Orphanet: 213500 * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma Authority control * GND: 4013746-6 * LCCN: sh2010104661 * NDL: 00569292 [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	Ovarian cancer	c1140680	5,743	wikipedia	https://en.wikipedia.org/wiki/Ovarian_cancer	2021-01-18T18:41:08	{"gard": ["7295"], "mesh": ["D010051"], "umls": ["C1299247", "C0919267", "C1140680"], "orphanet": ["213517", "213500"], "wikidata": ["Q172341"]}
Breast cancer (BC) is the most common cancer in women, accounting for 25% of all new cases of cancer. Most BC cases are sporadic, while 5-10% are estimated to be due to an inherited predisposition. ## Epidemiology Prevalence of germline BRCA mutations has been estimated to be about 1:1,600 women in the general population. The lifetime risk of developing hereditary BC (HBC) and/or OC can reach 80%. ## Clinical description HBC is not associated with specific phenotypic features. ## Etiology Autosomal dominant alterations in two genes, BRCA1 and BRCA2, are likely to account for most familial cases of early-onset BC and/or ovarian cancer (OC), and for 3-4% of all BC. For a given mutation in the susceptibility gene, disease severity and age at onset show great variability within and between BC families, suggesting the involvement of other genetic as well as non-genetic factors. ## Diagnostic methods HBC diagnosis relies upon the following characteristics: increasing numbers of affected family members through the same bloodline (either maternal or paternal), early onset of disease, an excess of bilateral disease, an association with ovarian cancer (at any age), and occurrence of BC in males. Genetic testing confirms the diagnosis and allows better management of people at high risk of developing BC and/or OC. ## Management and treatment The management strategies include surveillance, surgical options and chemoprevention, and accurate treatment of BC and OC in mutation carriers, but the treatment guidelines are still under debate. Studies of cohorts of BRCA1 and BRCA2 mutation carriers are underway in an effort to develop targeted cancer prevention strategies. [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	Hereditary breast and ovarian cancer syndrome	c0677776	5,744	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=145	2021-01-23T18:02:47	{"mesh": ["D061325"], "omim": ["604370", "612555", "613399", "614291"], "umls": ["C0677776"], "icd-10": ["C50", "C56"]}
## Summary ### Clinical characteristics. Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility. ### Diagnosis/testing. The most sensitive and specific biochemical screening test for any one of the acute porphyrias (including HCP) during an acute attack is a striking increase in urinary porphobilinogen. Quantitative analysis of porphyrins in both urine and feces is essential to distinguish between the different acute porphyrias and establish the diagnosis of HCP. Identification of a heterozygous pathogenic variant in CPOX (encoding the enzyme coproporphyrinogen-III oxidase) confirms the diagnosis and enables family studies. ### Management. Treatment of manifestations: Acute attacks are treated by discontinuation of any medications thought to induce attacks, management of dehydration and/or hyponatremia, administration of carbohydrate, and infusion of hematin (Panhematin®, Recordati Group). Treatment of symptoms and complications, such as seizures, should be with medications known to be safe in acute porphyria (see www.drugs-porphyria.org). A minority of affected individuals experience repeat acute attacks, in which case management strategies include suppression of ovulation in females, prophylactic use of hematin, and liver transplantation when attacks and neurologic complications persist despite multiple courses of hematin. Treatment of chronic (cutaneous) manifestations is through avoidance of sun/light, including wearing protective clothing and using protective tinted glass for cars and windows to prevent exposure to blue light. Prevention of primary manifestations: Agents or circumstances that may trigger an acute attack (including use of oral contraception and progestins in women) are avoided. Suppression of menses using a GnRH agonist (leuprolide, nafarelin, and others) may help CPOX heterozygotes who experience monthly exacerbations. Menopausal symptoms may occur as a side effect of GnRH agonists and can be treated with a low dose of estrogen. In CPOX heterozygotes undergoing surgery, minimize preoperative fasting and provide intravenous glucose in the perioperative period. Anesthesia induction using non-barbiturate agents is recommended. Surveillance: Annual liver and kidney function in those with chronically elevated ALA levels and/or those older than age 60 years; assessment for liver fibrosis (transient elastography [FibroScan®] or a blood-based test [FibroTest® or FibroSure®]); annual screening for hepatocellular carcinoma with abdominal imaging and serum alpha-fetoprotein in those older than age 60. Agents/circumstances to avoid: Fasting, use of oral contraception and progestins in females, and certain drugs including barbiturates and phenytoin. Evaluation of relatives at risk: If the family-specific CPOX pathogenic variant is known, clarification of the genetic status of relatives at risk allows early diagnosis of heterozygotes and education regarding how to avoid risk factors known to be associated with acute attacks. ### Genetic counseling. HCP is inherited in an autosomal dominant manner with low penetrance. Most individuals with HCP have an affected parent; the proportion with a de novo pathogenic variant is unknown. Each child of an individual with HCP has a 50% chance of inheriting the CPOX pathogenic variant. Because of reduced penetrance, many individuals with a CPOX pathogenic variant have no signs or symptoms of HCP. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known. ## Diagnosis Hereditary coproporphyria (HCP) is classified as both an acute (hepatic) porphyria (with neurologic manifestations that occur as discrete, severe episodes) and a chronic (cutaneous) porphyria with long-standing photosensitivity. Diagnostic criteria for HCP have been published [Anderson et al 2005, Whatley et al 2009]. ### Suggestive Findings Acute hepatic porphyria should be suspected in individuals with the following symptoms or findings: * Nausea for at least 48 hours * Abdominal, back, or extremity pain for at least 48 hours * New-onset seizures * Hyponatremia * Family history of porphyria Note: (1) Although CPOX pathogenic variants occur equally in males and females, acute attacks are much more frequent in women, mainly between ages 16 and 45 years (the years of active ovulation). (2) Absence of a known family history of porphyria does not preclude the diagnosis. Chronic cutaneous porphyria is suspected in individuals with bullae and fragility of light-exposed skin that result in depigmented scars; however, the cutaneous signs occur in only a minority of heterozygotes, even during an acute attack. ### Establishing the Diagnosis The diagnosis of HCP is established in a proband by biochemical testing (see Table 1), followed by identification of a heterozygous pathogenic variant in CPOX by molecular genetic testing (see Table 2). #### Biochemical Testing For an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see Differential Diagnosis). Note: Since initial management is the same for all four types of acute porphyria, it is not necessary to determine at the outset of treatment which one of the four types of acute porphyria is present. The most sensitive and specific biochemical diagnostic tests for HCP are detailed in Table 1. Once the diagnosis of an acute porphyria is established by identification of a striking increase in urinary porphobilinogen (PBG), quantitative analysis of porphyrins in both urine and feces may help define the specific type (Figure 1). #### Figure 1. Excretion profile of the hepatic porphyrias Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Pathogenic variants that decrease the function of a particular (more...) * Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal. * The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include ARUP (Salt Lake City, UT) and the Porphyria Center, University of Texas Medical Branch (Galveston, TX). * The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [Kühnel et al 2000]. ### Table 1. Biochemical Characteristics of Hereditary Coproporphyria (HCP) View in own window Deficient EnzymeUrineStool ActiveAsxActiveAsx Coproporphyringen-III oxidase 1, 2↑PBG 3, 4 ↑COPRO 5Normal PBG COPRO 6COPRO >> PROTO 7See footnote 8 Active = symptomatic CPOX heterozygotes; Asx = asymptomatic CPOX heterozygotes; COPRO = coproporphyrin; NormaI PBG = <2 mg (0.85 μmol) per g urine creatinine; PBG = porphobilinogen; PROTO = protoporphyrin 1\. Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase 2\. The enzyme assay is not widely available and is not used for diagnostic purposes. 3\. Active HCP is suggested by a quantitative urine PBG that is at least threefold the upper limit of normal. 4\. Commercial laboratories offer quantitative delta aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary. 5\. See Differential Diagnosis for discussion of nonspecific elevation of COPRO in the urine. 6\. Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see Differential Diagnosis). 7\. 60%-95% of the total COPRO is isomer-III. 8\. Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see Biochemical Testing). #### Molecular Genetic Testing The molecular testing approach typically includes single-gene testing targeting the type of acute porphyria suggested by biochemical testing. * Sequence analysis of CPOX is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * If detailed CPOX testing is normal, PPOX (the gene for variegate porphyria [VP]) is analyzed. The biochemical findings in HCP and VP can overlap, leading to misassignment of diagnosis in some instances. ### Table 2. Molecular Genetic Testing Used in Hereditary Coproporphyria View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method CPOXSequence analysis 332/33 4, 5 Gene-targeted deletion/duplication analysis 6See footnote 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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\. Sequence analysis identified a pathogenic variant in 31 of 32 (97%) individuals with the clinical and biochemical diagnosis of HCP [Whatley et al 2009]. 5\. Grimes et al [2016], Lambie et al [2018] 6\. 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. 7\. A 13-kb deletion extending from exon 4 to the 3'UTR [Whatley et al 2009] and a 1.3-kb deletion spanning exon 5 (found in 4 Swedish families) [Barbaro et al 2012] have been published. ## Clinical Characteristics ### Clinical Description Hereditary coproporphyria (HCP) is classified as both an acute and a chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is long standing (see Table 3). In a German study of 46 individuals with acute HCP, 90% had abdominal pain; only 13% had cutaneous findings despite substantial overproduction of coproporphyrin [Kühnel et al 2000]. An earlier British study of 111 individuals with HCP reported similar findings [Brodie et al 1977]. Symptoms prior to puberty in individuals who are heterozygous for a CPOX pathogenic variant have never been observed. Fertility and longevity do not appear to be reduced in CPOX heterozygotes. #### Acute Attacks The initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake. Typically the pain is not well localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy. Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria. A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups. Neurologic manifestations. Seizures may occur early in an attack and be the problem that brings the affected individual to medical attention. In a young woman with abdominal pain and new-onset seizures, it is critical to consider acute porphyria because of the implications for seizure management (see Management). When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact. In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed. Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system. Of note, when the acute attack is recognized early and treated appropriately (see Management), the outlook for survival and eventual complete recovery is good. Psychosis. The mental status of people presenting with an acute attack of porphyria varies widely and can include psychosis. Commonly the predominant feature is distress (including pain) that may seem hysterical or feigned, given a negative examination, absence of fever, and abdominal imaging showing some ileus only. Incessant demands for relief may be interpreted as drug-seeking behavior. Because of the altered affect in acute porphyria, it has been speculated that mental illness is a long-term consequence of an attack and that mental institutions may house disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary PBG and/or PBG deaminase activity in blood (which diagnoses acute intermittent porphyria) has been performed, with mixed results [Jara-Prado et al 2000]. The experience of those who have monitored affected individuals over many years suggests that heterozygotes who are at risk for one of the acute porphyrias are no more prone to chronic mental illness than individuals in the general population; however, a prospective study is needed. Kidney and liver disease. In people with any type of acute porphyria, the kidneys and liver may develop chronic changes that often are subclinical. One manifestation of the liver problem is excess primary liver cancer (hepatocellular carcinoma). The risk is greatest in women older than age 60 with acute intermittent porphyria (160-fold increased risk above the general population risk); for men there is a 37-fold increase in risk [Sardh et al 2013]. This and the kidney disease may be restricted largely to heterozygotes with chronically elevated plasma or urine delta aminolevulinic acid (ALA). Hypertension may be chronic in those with frequent symptoms and may contribute to renal disease. Inasmuch as ALA and porphobilinogen (PBG) tend to be minimally elevated or normal in HCP heterozygotes, the risk of hepatic and renal complications may be less in HCP than in acute intermittent porphyria. Circumstances commonly associated with acute attacks are caloric deprivation, changes in female reproductive hormones, and use of porphyria-inducing medications or drugs: * Caloric deprivation. Fasting appears to sensitize the heme-synthetic pathway to an inducer, which could be external (i.e., a medication) or internal (ovarian hormones). The sensitizing effect of caloric deprivation was demonstrated in the 1960s in experimental animals and has been confirmed by clinical observation. People who fail to eat because of intercurrent illness or who undertake drastic weight loss are predisposed to an acute attack. First attacks have been reported after reduction gastroplasty for obesity [Bonkovsky et al 2008]. CPOX heterozygotes undergoing surgery are at risk because of the routine preoperative fast. This and other anecdotal experience have led to consensus that the first line of treatment for an acute attack is intravenous glucose, which is occasionally helpful. * Changes in female reproductive hormones. A role for female reproductive hormones can be inferred from the fact that acute attacks are infrequent prior to menarche and after menopause. Some women have monthly attacks that appear a few days before the onset of menstruation (when progestins peak). Attacks have been linked to use of oral contraceptives; the risk may be associated more with the progesterone component than the estrogen component. * Use of porphyria-inducing medications or drugs. See Management, Agents/Circumstances to Avoid. Chronic (cutaneous) manifestations. Photocutaneous damage is present in only a small minority of those with acute attacks. Bullae and fragility of light-exposed skin, in particular the backs of the hands, result in depigmented scars. Facial skin damage also occurs, with excess hair growth on the temples, ears, and cheeks; this is more noticeable in women than in men. The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP). #### Threshold for a Pathogenic Effect of Porphyrins and Their Precursors Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist. * Acute (hepatic) porphyrias. A threshold for acute attacks is suggested by the fact that in virtually all symptomatic individuals, urinary PBG excretion exceeds 25 mg/g creatinine, or more than tenfold the upper limit of normal. Urinary ALA excretion increases roughly in parallel. * In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for CPOX heterozygotes (see Management, Evaluations Following Initial Diagnosis). * Chronic (cutaneous) porphyrias. A threshold has been well defined for porphyria cutanea tarda (PCT), in which photosensitivity occurs at values of urine uroporphyrin (the predominant pathway intermediate) that are more than 20-fold the upper limit of normal. However, the same is not apparent with regard to urine coproporphyrin: only a minority of CPOX heterozygotes exhibit any photosensitivity. Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity. ### Pathophysiology The regulation of heme synthesis differs in liver and in bone marrow, the principal sites of heme production in the body. The liver is the main source of precursors in the acute (hepatic) porphyrias: acute attacks are precipitated when environmental factors stimulate increased hepatic heme synthesis and the genetically altered step in heme production becomes rate limiting (Figure 1). Heme synthesis in the liver largely serves production of the cytochrome P450 family of heme-proteins, which are present in high concentration in the liver and have a relatively high turnover rate. It is estimated that 20%-25% of total heme production normally occurs in the liver [Billing 1978]; however, that proportion increases when the liver is exposed to xenobiotics that undergo oxidative metabolism and stimulate cytochrome production (especially CYP3A4). Acute attacks. The precursors ALA and PBG, unlike porphyrins, are colorless and non-fluorescent and do not contribute to photosensitivity in porphyria. Rather, ALA and PBG are highly associated with the neurologic manifestations of acute porphyria and are probably causal, although the mechanism remains speculative. The currently favored hypothesis implicates ALA (more than PBG), in part because acute neurologic symptoms occur in two other inherited conditions involving overproduction of ALA but not PBG (delta ALA dehydratase deficiency porphyria and tyrosinemia). In addition, lead poisoning causes a similar biochemical derangement by binding the sulfhydryls of ALA dehydratase and reducing enzymatic activity; the symptoms in lead poisoning closely mimic those of acute porphyria [Bissell et al 2015]. Experimental studies indicate that ALA is a pro-oxidant species that is capable of damaging the inner membrane of mitochondria [Vercesi et al 1994]. Liver transplantation has established that this organ is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [Soonawalla et al 2004]. Moreover, transplantation of a porphyric liver into a normal recipient in two cases resulted in high circulating levels of ALA and PBG and symptoms of porphyria [Dowman et al 2011]. Cutaneous manifestations. Porphyrins are energized by blue light (peak wavelength 410 nm). In a test tube, as activated porphyrins relax back to the ground state, the released energy is evident as red fluorescence (ca. 625 nm). In vivo, the cycle of light activation and relaxation back to the ground state causes tissue damage, the nature of which varies with the porphyrin. URO and COPRO give rise to bullae and fragility of light-exposed skin, in particular the backs of the hands. ### Genotype-Phenotype Correlations HCP. CPOX pathogenic variants are not clustered around the enzymatic site. Furthermore, no correlation exists between the clinical phenotype and the residual enzymatic activity measured in vitro for a given pathogenic variant [Lamoril et al 2001]. * Neonatal-onset HCP. In two reported cases, heterozygous (but not biallelic) CPOX variants have been associated with massive elevation of coproporphyrins, cutaneous blistering, and hemolytic anemia with onset in the neonatal period. In one case, the pathogenic variant was in exon 6 causing exon 6 skipping. In the other, it was a four-base-pair deletion in exon 7. The clinical picture resembled harderporphyria (see Genetically Related Disorders), but fecal analysis indicated HCP (markedly increased coproporphyrin and normal harderoporphyrin). Both cases also manifested adrenal insufficiency and hypospadias (with a 46,XY karyotype) [Hasegawa et al 2017]. The syndrome has been termed "neonatal-onset HCP," although the same CPOX variants also give rise to typical adult-onset HCP. The reason for the dramatic difference in presentation is unknown. It has been suggested that adrenal insufficiency is the proximal cause of the neonatal form, perhaps because heme synthesis is regulated by adrenal steroids to a degree that has not been appreciated. * Homozygotes for CPOX pathogenic variants that cause minimal or no symptoms in heterozygotes have very low coproporphyringen-III oxidase activity and a severe phenotype [Schmitt et al 2005, Hasanoglu et al 2011] (see Genetically Related Disorders). Double heterozygosity for pathogenic variants in genes causing two different types of acute (hepatic) porphyria. Double heterozygotes for a pathogenic variant in CPOX and either a pathogenic variant in PPOX (variegate porphyria [VP]) [van Tuyll van Serooskerken et al 2011] or ALAD (ALA dehydratase deficiency porphyria [ADP]) [Akagi et al 2006] have been described. The phenotypes of such double heterozygotes vary but are not necessarily more severe than those associated with heterozygosity for either pathogenic variant alone, suggesting that double heterozygotes for two different types of acute porphyria may not be as rare as has been assumed. ### Penetrance Because population studies to determine the prevalence of HCP heterozygosity have not been done, the penetrance of CPOX pathogenic variants is unknown. Given the rarity of acute attacks of HCP relative to acute intermittent porphyria (AIP), it is suspected that only a small minority of CPOX heterozygotes express the clinical disease. In 32 members of an Australian family, 14 (including 10 adults) were determined to have HCP on the basis of a high fecal COPRO III/I ratio and/or low lymphocyte CPOX enzyme activity; however, only one had clinical symptoms of porphyria [Blake et al 1992]. HCP, along with AIP and VP, are genetic disorders with reduced penetrance. Heme production in most heterozygotes appears to be adequate for physiologic homeostasis. Thus, environmental or physiologic factors play a role in the pathogenesis of acute attacks (see Management, Agents/Circumstances to Avoid). Genetic co-factors may also be involved; none has been identified to date. ### Nomenclature "Coproporphyrinuria" describes urine with an elevated level of coproporphyrin of any cause. Coproporphyria in individuals heterozygous for a CPOX pathogenic variant is referred to as hereditary coproporphyria. ### Prevalence Clinical experience suggests that HCP is the least prevalent of the three principal types of acute porphyria: AIP, VP, and HCP. However, symptoms in HCP may be less frequent than in AIP or VP. Population surveys for CPOX pathogenic variants have not been reported. ## Differential Diagnosis The genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in accumulation of a specific metabolite (Figure 1). In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurovisceral or cutaneous) and the tissue origin of the excess production of pathway intermediates (liver [i.e., hepatic] or bone marrow [i.e., erythropoietic]). * Porphyrias with neurovisceral manifestations are considered acute because the symptoms occur as discrete, severe episodes, which may be spontaneous but frequently are induced by external factors. The four acute porphyrias are: ALA dehydratase-deficiency porphyria (ADP), acute intermittent porphyria (AIP), HCP, and variegate porphyria (VP). Only a few individuals with ADP have been reported in the world literature. * Porphyrias with cutaneous manifestations include either chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and hepatoerythropoietic porphyria [HEP]) or acute non-blistering photosensitivity (i.e., EPP and XLP). ### Table 3. Classification of the Hereditary Porphyrias View in own window Type of PorphyriaFindingsMOI Neurovisceral 1Photocutaneous HepaticADP+0AR AIP+0AD HCP++AD PCT type II0+AD VP++AD ErythropoieticCEP0+AR EPP, AR0\+ 2AR XLP0\+ 2XL 0 = no symptoms; + = mild to severe symptoms; AD = autosomal dominant; ADP = ALA dehydratase-deficiency porphyria; AIP = acute intermittent porphyria; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; HCP = hereditary coproporphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; VP = variegate porphyria; XL = X-linked; XLP = X-Linked protoporphyria 1\. Porphyrias with neurovisceral manifestations have been considered "acute" in part because the most common of these disorders, named "acute intermittent porphyria," is the prototype for the neurovisceral porphyrias in which symptoms can occur acutely as discrete, severe episodes; however, some affected individuals develop chronic manifestations, and a few remain susceptible to exacerbating factors throughout their lives. 2\. Photocutaneous manifestations of EPP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP). While these clinical distinctions are important for the differential diagnosis, biochemical analysis is always necessary; however, biochemical testing may fail to distinguish HCP from VP, in which case molecular genetic testing of CPOX (HCP) and PPOX (VP) may be the only definitive diagnostic test. In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the Guillain-Barré syndrome. However, abdominal pain, constipation, and tachycardia precede the acute neurologic illness in the acute porphyrias but not in Guillain-Barré syndrome. CSF protein is normal in the acute porphyrias, but elevated in Guillain-Barré syndrome. Urinary PBG is markedly elevated in the acute porphyrias when symptoms are present, but normal in Guillain-Barré syndrome. Coproporphyrinuria * Lead intoxication. The predominant elevation of coproporphyrin that is characteristic of HCP can also be seen in lead intoxication, in which the symptoms resemble those of an acute porphyria. The additional diagnostic finding in heavy metal poisoning is elevation of ALA unaccompanied by any increase in PBG. * Rotor syndrome, inherited in an autosomal recessive manner and caused by simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3, is also associated with coproporphyrinuria [van de Steeg et al 2012]. * Nonspecific coproporphyrinuria. The most important differential diagnosis in an individual with elevated urine coproporphyrin is HCP vs nonspecific coproporphyrinuria. Of all the people referred to a porphyria center, the largest subgroup has nonspecific coproporphyrinuria. Elevation of urine coproporphyrin is associated with a wide range of clinical conditions. It is particularly frequent in acquired liver disease (e.g., chronic viral hepatitis), but can also be seen in neurologic or hematologic diseases. Rarely, it is caused by an inherited hepatic transporter defect. Two tests helpful for the differential diagnosis of coproporphyrinuria are: * Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms; * The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [Gibson et al 2000]. For a case example of misdiagnosis of nonspecific coproporphyrinuria, click here. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the evaluations listed in Table 4 are recommended (if they have not already been completed). ### Table 4. Recommended Evaluations Following Initial Diagnosis of Hereditary Coproporphyria View in own window EvaluationComment Review of medications for those thought to induce attacksSee Agents/Circumstances to Avoid. Detailed neurologic examination * For signs of motor neuropathy (indicating a more advanced attack & thus, need for early treatment w/hematin; see Table 5) * Inquiry into possibility of seizures 1 Measurement of serum sodium concentrationHyponatremia is characteristic & may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction w/due regard for risk of central pontine myelinolysis. Quantitation of urinary excretion of PBG on several occasions over a few mos to establish baselineFor future use in determining if a new symptom or drug reaction is due to an acute attack 2 Consultation w/medical geneticist &/or genetic counselor PBG = porphobilinogen 1\. Tran et al [2013] 2\. In an acute attack urinary excretion of PBG is substantially elevated over the baseline. ### Treatment of Manifestations Treatment guidelines for hereditary coproporphyria have been published [Balwani et al 2017] (full text). #### Acute Attacks ### Table 5. Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria View in own window ManifestationTreatmentConsideration/Other Acute abdominal painIdentify & discontinue any medications thought to induce attacks.See Agents/Circumstances to Avoid. Discontinue all nonessential medications.Treat symptoms & complications w/medications known to be safe in acute porphyria (see www.drugs-porphyria.org). Nausea/vomitingAdminister glucose-containing IV solution to reverse fasting state.Some individuals recover w/rehydration & glucose infusion only; those who do not respond in 24-48 hours should receive intravenous hematin. Obtain a serum sodium level. 1In those w/hyponatremia, rehydration w/10% dextrose in 0.5N sodium chloride is recommended. 2 Moderate to severe acute attacksAdminister intravenous hematin. * For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose. * Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin®, Recordati, 1-888-575-8344). 3, 4, 5, 6 * Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia. Motor neuropathyAdminister hematin as soon as possible if signs of motor neuropathy are present.Hematin given at the initial signs of motor neuropathy may halt its progression; however, it has no effect on established motor deficits, which are the result of axonal degeneration. 7 SeizuresAdminister short-acting benzodiazepine (e.g., midazolam) or magnesium. 8A number of commonly used anti-seizure medications, incl phenytoin & sodium valproate, are contraindicated because of the risk of exacerbating an attack. Status epilepticus or refractory seizuresConsider propofol.For more prolonged control of seizures, the combination of gabapentin & propofol is effective & safe. Repeat acute attacks &/or severe diseaseSuppress ovulation in females.Use a GnRH agonist (leuprolide, nafarelin, others). 9 Use hematin prophylactically.Chronic use of hematin can lead to iron overload. 10, 11, 12, 13 Consider liver transplantation in selected cases. * The status of the disease in candidates for liver transplantation must be well documented biochemically. * Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication. 1\. Hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis. 2\. Aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level. 3\. Hematin (350-mg vial) is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (147 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [Anderson et al 2006]. 4\. The infusion is started without delay, as hematin in solution decays rapidly [Goetsch & Bissell 1986]. 5\. The preparation is given into a large peripheral vein or via central line over 10-15 minutes to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals. 6\. An alternative in Europe and elsewhere is heme arginate (Normosang®; not available in the US). 7\. Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop. 8\. This treatment has been used to control eclamptic seizures [Sadeh et al 1991]. 9\. Oral contraceptives and progestins should be avoided. 10\. Treatment of iron overload is indicated when the serum ferritin exceeds 1,500 ng/mL. 11\. An oral chelator, such as deferasirox or deferiprone, is convenient but causes side effects of gastric distress and nausea in some users. 12\. A small phlebotomy can be done with each hematin infusion, provided the hemoglobin is >10 g/dL. Withdrawal of 100 mL of blood is sufficient for maintaining iron balance, relative to the amount of iron in a 250-mg dose of injectable hematin. 13\. For those with a significant iron burden, withdrawal of 200 cc of blood with each hematin infusion will produce net negative iron balance. #### Chronic (Cutaneous) Manifestations ### Table 6. Treatment of Low-Grade Chronic or Seasonal Cutaneous Symptoms in Individuals with Hereditary Coproporphyria View in own window TreatmentConsideration/Other Avoid sun/light.This includes both direct sun/light & through window glass. 1 Wear protective clothing: long sleeves, gloves, & wide-brimmed hats.Topical sunscreens are not helpful because they block UVB light, not the blue light that causes porphyrin-related skin injury. Use protective tinted glass for cars & windows to prevent exposure to blue light.Gray or smoke-colored filters provide only partial protection. 1\. Damage is caused by blue light and long-wave ultraviolet light (UVA), both of which pass through window glass. Note: The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous as well as the neurovisceral symptoms could respond to hematin administration. Indeed, this is the finding of a case report of an individual with severe HCP who was given "maintenance" hematin [Ma et al 2011]. ### Prevention of Primary Manifestations ### Table 7. Prevention of Acute Attacks in COPX Heterozygotes View in own window PrinciplePreventionConsideration/Other Identifying those at risk of attacksSee Evaluation of Relatives at Risk. Education of at-risk individualsEducate regarding circumstances that may trigger an acute attack (see Clinical Description). Selection of appropriate contraception for femalesThe recommended method of birth control for HCP heterozygotes is an IUD plus a barrier (diaphragm &/or condom). 1 * A copper-eluting IUD is theoretically the safest in women w/porphyria. * The hormone-eluting IUD may also be safe because the systemic increase in hormone is quite small; however, little information exists on its use in women w/acute porphyria. Suppress menses using a GnRH agonist. * Leuprolide, nafarelin, & other GnRH agonists may help those who experience monthly exacerbations. * If menopausal side effects occur, they can be treated by adding low-dose estrogen. 2 Prevention of acute attacks in those undergoing surgeryMinimize preoperative fast as much as possible. Provide intravenous glucose (10% dextrose in half-normal saline) in perioperative period. Induce anesthesia using non-barbiturate agents that have little or no P450-inducing activity (e.g., propofol, ketamine, short-acting benzodiazepines).Inhalation agents (isoflurane) & muscle relaxants also appear to be low-risk for triggering an attack. 1\. Oral contraceptives (birth control pills) are risky and not recommended. 2\. Andersson et al [2003] Prevention of acute attacks does not involve the following: * Use of glucose. Because glucose is used to treat acute attacks, its use in preventing attacks has been suggested, and is in fact touted in lay discussions of porphyria; however, there is no evidence that heterozygotes can protect themselves by overeating or adopting a high-carbohydrate diet, and they risk becoming obese. Heterozygotes should adhere to a healthful diet with the usual balance of protein, fat, and carbohydrate. Weight loss is possible but only by incremental restriction of calories combined with exercise. Extreme diets (e.g., all bacon, all brown rice, starvation) are risky and should be avoided. * Liver transplantation. Because the vast majority of attacks respond to hematin and other supportive measures, liver transplantation has no role in prevention of acute attacks in a CPOX heterozygote. ### Surveillance For those who have chronically elevated ALA (which is infrequent in those who are asymptomatic) and/or are older than age 60 years, an annual assessment of liver and kidney function is recommended. Current noninvasive techniques for evaluation of fibrosis in the liver include transient elastography (FibroScan®) and a blood-based test (FibroTest® or FibroSure®) [see Balwani et al 2017]. Note: These assessments have been vetted mainly for people with chronic viral hepatitis or steatohepatitis but may also be useful in porphyria. For affected individuals older than age 60 and anyone with evidence of chronic liver injury, annual screening for hepatocellular carcinoma with abdominal imaging (e.g., ultrasound) and serum alpha-fetoprotein is indicated [Balwani et al 2017]. ### Agents/Circumstances to Avoid Avoid the following: * Extreme caloric deprivation (i.e., total fasting, gastric bypass surgery). A case report of an acute attack occurring in a 23-year-old male who had been taking Hydroxycut®, an over-the-counter weight-loss supplement, has been published [Haimowitz et al 2015]. * Female reproductive hormones. For recommendations regarding contraception, see Prevention of Primary Manifestations. * Medications. Some drugs are clearly unsafe for CPOX heterozygotes. It is important to note, however, that many other drugs are safe. Providers should not regard individuals with acute porphyria as "untreatable." Compilations of safe and unsafe drugs are available online and are updated as new information becomes available. See porphyriafoundation.org, drugs-porphyria.org/, or the smartphone app found at porphyriadrugs.com. In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin. ### Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk for HCP in order to identify as early as possible those who would benefit from education regarding the risk factors associated with acute attacks. * If the CPOX pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. * If the CPOX pathogenic variant in the family is not known, a first-degree relative with symptoms can be evaluated with biochemical tests (see Diagnosis). Note: Although some CPOX heterozygotes have a diagnostic biochemical profile of heme precursors in urine and feces (see Table 1, Active columns), many have normal findings (see Table 1, Asx [asymptomatic] columns) and can only be diagnosed by molecular genetic testing. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management The effect of pregnancy on inducing acute attacks is unpredictable. In general, serious problems during pregnancy are unusual. In fact, some women with recurrent symptoms associated with the menstrual cycle report improvement during pregnancy. Attacks, if they occur, are usually in the first trimester. The women most at risk are those with hyperemesis gravidarum and inadequate caloric intake [Aggarwal et al 2002]. Among antiemetics, ondansetron is not expected to precipitate or exacerbate acute attacks, although several studies have suggested that ondansetron exposure in the first trimester of pregnancy could lead to an increased risk of cleft palate and/or congenital heart defects in the fetus. These suggested risks have not been confirmed. However, metoclopramide should be avoided, as it may precipitate acute attacks [Shenhav et al 1997]. The experience with administration of hematin (or heme arginate, which is not available in the US) during pregnancy is limited. Badminton & Deybach [2006] published an anecdotal report of successful heme arginate treatment (without adverse fetal effect) in several women experiencing attacks of variegate porphyria or other acute porphyrias during pregnancy. Based on the absence of reported adverse effects, use of hematin to control exacerbations of acute intermittent porphyria during pregnancy has been recommended [Isenschmid et al 1992, Farfaras et al 2010]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Hematin for infusion (Panhematin®, Recordati Group) is currently the only approved therapy for symptomatic acute porphyria and is a critical part of management. However, it has shortcomings: poor stability in solution; the need for intravenous administration with the attendant risk of phlebitis; interference with coagulation; and iron overload. Alternatives are under investigation. One is gene therapy in which the normal gene (CPOX in the case of hereditary coproporphyria) is targeted to hepatocytes (ClinicalTrials.gov NCT02082860). Another uses small interfering RNA (siRNA) directed against ALA synthase to downregulate hepatic production of ALA and PBG (Givosiran, Alnylam Pharmaceuticals, Cambridge, MA) (ClinicalTrials.gov NCT02452372). In principle, the latter should be relevant to any of the acute porphyrias. In Phase I-II trials, a single subcutaneous dose of the siRNA reduced ALA synthase and plasma ALA to target levels for a one-month period. Side effects were minor. In affected individuals with recurrent symptoms, the need for hematin infusion was reduced. A Phase III clinical trial is currently under way (August 2018). 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	Hereditary Coproporphyria	c0162531	5,745	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK114807/	2021-01-18T21:21:53	{"mesh": ["D046349"], "synonyms": []}
Distal trisomy of the long arm of chromosome 10 (10q) is characterized by pre- and postnatal growth retardation, a pattern of specific facial features, hypotonia, and developmental and psychomotor delay. ## Epidemiology To date, approximately 40 cases of trisomy 10q have been reported. ## Clinical description Most cases are diagnosed in infancy or in childhood. The range and severity of symptoms and physical findings may vary from case to case, depending upon the exact length and location of the duplicated portion of chromosome 10q. Characteristic craniofacial findings include a flat round face with full cheeks and a large prominent forehead, highly arched eyebrows, short and narrow palpebral fissures (blepharophimosis), widely spaced eyes with telecanthus, a short nose, a bow-shaped mouth with a prominent upper lip, and a small mandible. A few major malformations have also been reported, including renal and cardiac anomalies. Minor defects of the hands and/or feet, bone anomalies and cryptorchidism are frequent signs. ## Etiology The duplicated region almost always includes 10qter, with the most frequent proximal breakpoint at 10q24 (with variation from q22 to q25). Interstitial duplications of 10q have also been reported. Most cases of distal trisomy 10q result from of a parental balanced translocation or pericentric inversion, and may be accompanied by another chromosomal imbalance. Intrachromosomal duplications or de novo translocations are also observed. ## Diagnostic methods Diagnosis is suspected on the basis of the clinical features and is confirmed by karyotyping and fluorescence in situ hybridization (FISH) with specific 10q probes. ## Antenatal diagnosis Prenatal diagnosis is possible using cytogenetic tools. ## Genetic counseling The risk of recurrence for siblings depends on the parental karyotypes. ## Management and treatment Management is multidisciplinary and symptomatic only. Early educational (speech, occupational and physical therapy) and rehabilitation programs should be offered to all patients. ## Prognosis Prognosis is variable. A number of reported patients died in infancy from respiratory 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	Distal trisomy 10q	c2931731	5,746	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96102	2021-01-23T18:15:26	{"mesh": ["C538087"], "umls": ["C2931728", "C2931731"], "icd-10": ["Q92.3"], "synonyms": ["Distal duplication 10q", "Telomeric duplication 10q", "Trisomy 10qter"]}
This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (April 2019) (Learn how and when to remove this template message) Malignant rhabdoid tumour SpecialtyOncology Malignant rhabdoid tumour (MRT) is a very aggressive form of tumour originally described as a variant of Wilms' tumour, which is primarily a kidney tumour that occurs mainly in children. MRT was first described as a variant of Wilms' tumour of the kidney in 1978.[1] MRTs are a rare and highly malignant childhood neoplasm. Rhabdoid tumours outside the kidney were later reported in many tissues including the liver, soft tissue, and the central nervous system. Several cases of primary intracranial MRT have been reported since its recognition as a separate entity in 1978. The term rhabdoid was used due to its similarity with rhabdomyosarcoma under the light microscope. The exact pathogenesis of MRT is unknown. The cerebellum is the most common location for primary intracerebral MRT (i.e., atypical teratoid rhabdoid tumor). Biggs et al. were first to report a primary intracranial MRT around 1987.[2] Although the cell of origin is not known, cytogenetic studies have suggested a common genetic basis for rhabdoid tumours regardless of location with abnormalities in chromosome 22 commonly occurring. ## Contents * 1 Genetics * 1.1 Rhabdoid tumours in kidney and brain * 2 Diagnosis * 3 Prognosis * 4 See also * 5 References * 6 Literature * 7 External links ## Genetics[edit] There have been reported cases of a child having both atypical teratoid rhabdoid tumours in the brain as well as rhabdoid tumours of the kidney. Weeks and associates reported on 111 renal rhabdoid cases of which 13.5% also had a central nervous system malignancy. It has been hypothesized that a germline INI mutation may predispose a child to these tumours. There have been some references in the literature alluding to a new diagnosis called rhabdoid predisposition syndrome related to the gene hSNF5/INI1. These tumours have been associated with mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) located on the long arm of chromosome 22 (22q11) and transcription activator BRG1/ATP-dependent chromatin remodeler (SMARCA4) located on the short arm of chromosome 19 (19p13.2).[3] ### Rhabdoid tumours in kidney and brain[edit] Considerable debate has been focused on whether atypical teratoid rhabdoid tumors are the same as rhabdoid tumours of the kidney (i.e., just extrarenal MRTs). The recent recognition that both CNS atypical teratoid/rhabdoid tumours and MRTs have deletions of the INI1 gene in chromosome 22 indicates that rhabdoid tumours of the kidney and brain are identical or closely related entities, although the CNS variant tends to have its mutations on Taxon 9 and MRTs elsewhere. This observation is not surprising because rhabdoid tumours at both locations possess similar histologic, clinical, and demographic features. Moreover, 10-15% of patients with MRTs have synchronous or metachronous brain tumours, many of which are second primary malignant rhabdoid tumours. This similarity excludes composite rhabdoid tumours, which occur mainly in adults. ## Diagnosis[edit] Rhabdoid tumour The histologic diagnosis of malignant rhabdoid tumour depends on identification of characteristic rhabdoid cells—large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm. However, the histology can be heterogeneous and the diagnosis of MRT can often be difficult. Misclassifications can occur. In MRTs, the INI1 gene (SMARCB1) on chromosome 22q functions as a classic tumour suppressor gene. Inactivation of INI1 can occur via deletion, mutation, or acquired UPD.[4] In a recent study,[4] Single nucleotide polymorphism array karyotyping identified deletions or LOH of 22q in 49/51 rhabdoid tumours. Of these, 14 were copy neutral LOH (or acquired UPD), which is detectable by SNP array karyotyping, but not by FISH, cytogenetics, or array CGH. MLPA detected a single exon homozygous deletion in one sample that was below the resolution of the SNP array. SNP array karyotyping can be used to distinguish, for example, a medulloblastoma with an isochromosome 17q from a primary rhabdoid tumour with loss of 22q11.2. When indicated, molecular analysis of INI1 using MLPA and direct sequencing may then be employed. Once the tumour-associated changes are found, an analysis of germline DNA from the patient and the parents can be done to rule out an inherited or de novo germline mutation or deletion of INI1, so that appropriate recurrence risk assessments can be made.[4] ## Prognosis[edit] Regardless of location, all rhabdoid tumours are highly aggressive, have a poor prognosis, and tend to occur in children less than two years of age. ## See also[edit] * Epithelioid sarcoma * Atypical teratoid rhabdoid tumour ## References[edit] 1. ^ Beckwith JB, Palmer NF (1978). "Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study". Cancer. 41 (5): 1937–48. doi:10.1002/1097-0142(197805)41:5<1937::AID-CNCR2820410538>3.0.CO;2-U. PMID 206343. 2. ^ PJ Biggs; Garen PD; Powers JM; Garvin AJ (1987). "Malignant rhabdoid tumor of the central nervous system". Human Pathology. 18 (4): 332–337. doi:10.1016/S0046-8177(87)80161-2. PMID 3030922. 3. ^ Finetti MA, Grabovska Y, Bailey S, Williamson D (2020) Translational genomics of malignant rhabdoid tumours: Current impact and future possibilities. Semin Cancer Biol 4. ^ a b c Jackson EM, Sievert AJ, Gai X, et al. (March 2009). "Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors". Clin. Cancer Res. 15 (6): 1923–30. doi:10.1158/1078-0432.CCR-08-2091. PMC 2668138. PMID 19276269. ## Literature[edit] * Donner LR, Wainwright LM, Zhang F, Biegel JA (2007). "Mutation of the INI1 gene in composite rhabdoid tumor of the endometrium". Hum. Pathol. 38 (6): 935–9. doi:10.1016/j.humpath.2006.12.003. PMC 1963314. PMID 17376508. * Jeffrey S Dome, MD; D Ashley Hill, MD (January 8, 2007). "Malignant Rhabdoid Tumor". EMedicine from WebMD. * Perry A, Fuller CE, Judkins AR, Dehner LP, Biegel JA (2005). "INI1 expression is retained in composite rhabdoid tumors, including rhabdoid meningiomas". Mod. Pathol. 18 (7): 951–8. doi:10.1038/modpathol.3800375. PMID 15761491. * Biegel JA, Fogelgren B, Wainwright LM, Zhou JY, Bevan H, Rorke LB (2000). "Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor" (abstract page). Genes Chromosomes Cancer. 28 (1): 31–7. doi:10.1002/(SICI)1098-2264(200005)28:1<31::AID-GCC4>3.0.CO;2-Y. PMID 10738300. * Huret J, Sevenet N (2000). "Rhabdoid predispoition syndrome". Atlas of Genetics and Cytogenetics in Oncology and Haematology (1): 31–7. Archived from the original on 2005-12-26. * Weeks DA, Beckwith JB, Mierau GW, Luckey DW (1989). "Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center". American Journal of Surgical Pathology. 13 (6): 439–58. doi:10.1097/00000478-198906000-00001. PMID 2543225. ## External links[edit] Classification D * ICD-O: 8963/3 * OMIM: 609322 * MeSH: D018335 * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Malignant rhabdoid tumour	c0206743	5,747	wikipedia	https://en.wikipedia.org/wiki/Malignant_rhabdoid_tumour	2021-01-18T18:40:03	{"gard": ["7572"], "mesh": ["D018335"], "umls": ["C0206743"], "orphanet": ["69077"], "wikidata": ["Q6743515"]}
A rare, genetic, lethal, neurometabolic malformation syndrome characterized by multiple, variable, congenital cardiac (systolic murmur, atrial septal defect), urinary (duplicated collecting system, vesicoureteral reflux) and central nervous system (thin corpus callosum, cerebellar hypoplasia) malformations associated with neonatal hypotonia, early-onset epileptic encephalopathy, and myoclonic seizures. Craniofacial dysmorphism (prominent occiput, enlarged fontanel, fused metopic suture, upslanted palpebral fissures, overfolded helix, depressed nasal bridge, anteverted nose, malar flattening, microstomy with downturned corners, Pierre-Robin sequence, high arched palate, short neck) and other manifestations (joint contractures, hyperreflexia, dysplastic nails, developmental delay) are also observed. [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	Multiple congenital anomalies-hypotonia-seizures syndrome type 2	c3275508	5,748	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300496	2021-01-23T17:57:04	{"gard": ["12777"], "omim": ["300868"], "icd-10": ["Q87.8"], "synonyms": ["MCAHS type 2"]}
Maternally inherited diabetes and deafness (MIDD) is a form of diabetes that is often accompanied by hearing loss, especially of high tones. The diabetes in MIDD is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin, which regulates the amount of sugar in the blood. In MIDD, the diabetes and hearing loss usually develop in mid-adulthood, although the age that they occur varies from childhood to late adulthood. Typically, hearing loss occurs before diabetes. Some people with MIDD develop an eye disorder called macular retinal dystrophy, which is characterized by colored patches in the light-sensitive tissue that lines the back of the eye (the retina). This disorder does not usually cause vision problems in people with MIDD. Individuals with MIDD also may experience muscle cramps or weakness, particularly during exercise; heart problems; kidney disease; and constipation. Individuals with MIDD are often shorter than their peers. ## Frequency About 1 percent of people with diabetes have MIDD. The condition is most common in the Japanese population and has been found in populations worldwide. ## Causes Mutations in the MT-TL1, MT-TK, or MT-TE gene cause MIDD. These genes are found in mitochondrial DNA, which is part of cellular structures called mitochondria. Although most DNA is packaged in chromosomes within the cell nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). The MT-TL1, MT-TK, and MT-TE genes provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks (amino acids) into functioning proteins. The MT-TL1 gene provides instructions for making a specific form of tRNA that is designated as tRNALeu(UUR). During protein assembly, this molecule attaches to the amino acid leucine (Leu) and inserts it into the appropriate locations in the growing protein. Similarly, the protein produced from the MT-TK gene, called tRNALys, attaches to the amino acid lysine (Lys) and inserts it into proteins being assembled. Also, the protein produced from the MT-TE gene, called tRNAGlu, attaches to the amino acid glutamic acid (Glu) and adds it to growing proteins. These tRNA molecules are present only in mitochondria, and they help assemble proteins that are involved in producing energy for cells. In certain cells in the pancreas called beta cells, mitochondria also play a role in controlling the amount of sugar (glucose) in the bloodstream. In response to high glucose levels, mitochondria help trigger the release of insulin, which stimulates cells to take up glucose from the blood. Mutations in the MT-TL1, MT-TK, or MT-TE gene reduce the ability of tRNA to add amino acids to growing proteins, which slows protein production in mitochondria and impairs their functioning. Researchers believe that the disruption of mitochondrial function lessens the ability of mitochondria to help trigger insulin release. In people with this condition, diabetes results when the beta cells do not produce enough insulin to regulate blood sugar effectively. Researchers have not determined how the mutations lead to hearing loss or the other features of MIDD. ### Learn more about the genes and chromosome associated with Maternally inherited diabetes and deafness * MT-TE * MT-TK * MT-TL1 * mitochondrial dna ## Inheritance Pattern MIDD is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children. Most of the body's cells contain thousands of mitochondria, each with one or more copies of mtDNA. These cells can have a mix of mitochondria containing mutated and unmutated DNA (heteroplasmy). The severity of MIDD is thought to be associated with the percentage of mitochondria with the mtDNA mutation. [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	Maternally inherited diabetes and deafness	c0342289	5,749	medlineplus	https://medlineplus.gov/genetics/condition/maternally-inherited-diabetes-and-deafness/	2021-01-27T08:25:49	{"gard": ["4003"], "mesh": ["C536246"], "omim": ["520000"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that the Ogna type of epidermolysis bullosa simplex (EBSOG) is caused by heterozygous mutation in the PLEC1 gene (601282) on chromosome 8q24. Clinical Features This form of EBS was identified by Gedde-Dahl (1971) in a large Norwegian kindred living in the town of Ogna. It was differentiated from the more generalized form of Koebner (131900) and the localized form of Weber and Cockayne (131800) by the occurrence of skin bruising in the Ogna type. Gedde-Dahl (1977) identified 97 cases in the Norwegian kindred. He suggested that the first family of Cockayne (see 131800) may have had the Ogna form. Koss-Harnes et al. (2002) characterized the ultrastructural characteristics of EBS Ogna skin and found that blisters do not start via cytolysis of subnuclear central portions of the basal cell cytoplasm as in EBS Koebner and EBS Weber-Cockayne, but originate in the deepest areas of the basal cell cytoplasm, immediately above (but not within) hemidesmosomes. In unseparated perilesional and preblistering skin, keratin filaments are inconspicuous and normal for basal cells, but their insertion into the hemidesmosome attachment plates is impaired. Clumped basal keratins as in the Dowling-Meara type (131760) were not found in any of the skin samples. The hemidesmosomes themselves are normally structured with regard to their extracellular portions, but their intracellular attachment plates are mostly thin, their thickness being about half that of normal hemidesmosome attachment plates. This specific ultrastructure is significantly different from classical cases of EBS Koebner, EBS Weber-Cockayne, and EBS Dowling-Meara, all of which form entirely normal hemidesmosomes. Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several affected members of the Norwegian kindred showed normal staining patterns using antibodies to plectin. Mapping Olaisen and Gedde-Dahl (1973) concluded that the locus for this disorder is closely linked (about 3 cM) to that for red cell soluble glutamate-pyruvate transaminase (GPT; 138200). Inasmuch as GPT has been localized to 8q24, EBS1 must be located there as well. Molecular Genetics Koss-Harnes et al. (2002) reported that the EBS Ogna phenotype is due to a site-specific heterozygous missense mutation within the rod domain of plectin (601282.0005). Mutations in plectin also cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (226670). Koss-Harnes et al. (2002) showed that EBS Ogna is not restricted to a single Norwegian kindred as theretofore believed. A German family with the phenotypic hallmarks of EBS Ogna carried an identical de novo mutation. Koss-Harnes et al. (2002) concluded that these 2 mutations arose about 200 years apart. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Generalized bruising tendency \- Skin fragility with non-scarring blistering \- Small hemorrhagic blisters on hands Electron Microscopy \- Blisters originating in basal cells above hemidesmosomes \- Impaired keratin filament insertion into hemidesmosomes \- Abnormal hemidesmosome intracellular attachment plates Nails \- Onychogryphosis of large toenails (occasional) MOLECULAR BASIS \- Caused by mutations in the plectin 1 gene (PLEC1, 601282.0005 ) ▲ 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	EPIDERMOLYSIS BULLOSA SIMPLEX, OGNA TYPE	c0432317	5,750	omim	https://www.omim.org/entry/131950	2019-09-22T16:41:32	{"doid": ["0060736"], "mesh": ["C535962"], "omim": ["131950"], "orphanet": ["79401"]}
Paroxysmal dyskinesia Other namesParoxysmal dystonic choreoathetosis SpecialtyNeurology The paroxysmal dyskinesias (PD) are a group of movement disorders characterized by attacks of hyperkinesia with intact consciousness.[1] Paroxysmal dyskinesia is a rare disorder, however the number of individuals it affects remains unclear. There are three different subtypes of PD that include paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). Other neurological diseases have similar symptoms to PD, such as epilepsy and Parkinson's. The different subtypes make accurate and quick diagnosis of PD challenging. Thus, PD is often under reported and misdiagnosed, making it difficult to accurately study its prevalence in human populations. Onset of PD is usually in late childhood to early adolescence. New drug regimens help treat symptoms of PD, but no cure for the disorder is known. ## Contents * 1 Types * 1.1 Paroxysmal kinesigenic dyskinesia (PKD) * 1.2 Paroxysmal non-kinesogenic dyskinesia (PNKD) * 1.3 Paroxysmal exercise-induced dyskinesia (PED) * 2 Signs and symptoms * 2.1 PKD * 2.2 PNKD * 2.3 PED * 3 Causes * 3.1 PKD * 3.2 PNKD * 3.3 PED * 4 Diagnosis * 4.1 PKD * 4.2 PNKD * 4.3 PED * 5 Management * 5.1 PKD * 5.2 PNKD * 5.3 PED * 6 Prognosis * 7 References * 8 External links ## Types[edit] These movement disorders are classified into three main types based on their triggers and the duration and frequency of the attacks. ### Paroxysmal kinesigenic dyskinesia (PKD)[edit] This is characterized by attacks of involuntary movements (dystonia, chorea, or ballism), which are typically triggered by sudden voluntary movements, but can also be triggered by involuntary movements as well (for example, hyperventilating). These voluntary movements usually involve whole body activity such as standing, walking, and running. The age of onset is typically in childhood or early adolescence with most cases reporting improvement or complete remission with aging.[2] Attacks last from seconds to minutes and are known to be at higher risk of occurring during stress, fear, cold, heat, or menstruation. ### Paroxysmal non-kinesogenic dyskinesia (PNKD)[edit] This is similar to PKD, characterizing as an episodic movement disorder, but is not triggered by voluntary movements. The attacks for PNKD are spontaneous and last from hours to days. It is an autosomal dominant disorder passing to nearly 50% of the offspring. Some predisposing factors include stress, excitement, alcoholic beverages, tea, and beverages with caffeine. ### Paroxysmal exercise-induced dyskinesia (PED)[edit] This is an extremely rare type of paroxysmal dyskinesia characterized by sudden, involuntary, dystonic movements, often including repetitive twisting motions and painful posturing. The attacks are triggered by exercise and other physical exertion, and usually last from minutes to an hour. Attacks usually appear in the body part that is being exercised or exerted over a period of time, perhaps 10 to 15 minutes.[2] ## Signs and symptoms[edit] ### PKD[edit] The symptoms for PKD are varied from case to case, however, typically they consist of involuntary movements. Such contractile movements include dystonia, chorea, athetosis, and ballism. For example, “Her attacks were characterized as sudden unilateral stiffness of upper and lower limbs followed by an involuntary extrarotation of the arm and leg.” [3] Another frequently occurring symptom is the presence of an aura before the attack. These sensations manifest in several forms, usually described as a tingling in the target limb.[3] A single limb is the most frequently affected area; however it is possible for an attack to affect more than one limb. When more than one limb is affected, the two limbs are usually unilateral (same side), even though cases of bilateral (opposite sides) symptoms have also been observed.[3] Another frequently affected area is the torso, with some PKD patients twisting their body.[4] Attacks experienced by PKD patients typically last less than a minute,[5] however longer attack can occur. To further distinguish between PKD and epilepsy, patients typically retain consciousness during their attacks, and are able to recall the attacks even after they have ended. Despite retaining consciousness, patients are usually incapable of speech during the attack and may experience great pain in the affected area.[4] The frequency of attacks vary greatly. Some patients have been noted as having hundreds of attacks per day, while others go months without an attack.[3] ### PNKD[edit] The attacks consist of dystonia, chorea, and athetosis just like PKD. They are mostly of the limbs, and are usually unilateral or asymmetric. What sets PNKD apart from PKD is that the attacks can last anywhere from four minutes to four hours, but shorter and longer attacks have been reported as well. The attacks also affect the limbs, usually unilaterally, but bilateral symptoms have also been experienced. PNKD patients usually report the presence of an aura before an attack as well; however they are usually different from those of PKD patients. Once again the aura varies, but is typically felt in the target limb. Another frequently noted aura is dizziness [3] PNKD patients experience attacks that last much longer than those of PKD. These attacks vary in length and can last anywhere between four minutes and four hours. Similar to the difference between length of attacks, the intervals between attacks are much longer. The Interval between PNKD patients’ attacks is from one day to several months.[3] ### PED[edit] PED attacks are characterized in multiple ways. One distinguishing characteristic of PED patients is that they typically experience longer durations of dystonia during their attacks. The most frequent target of attacks are both legs bilaterally, rather than unilateral symptoms.[3] The attacks have also been known to affect the upper half of the body as well. In some cases, patients have had attacks that affected the posturing of their neck and shoulder.[6] Usually there is not an indicative aura symptom prior to a PED attack, which has to do with the nature of the onset of attacks. The duration and frequency of PED attacks fall between those of PKD and PNKD. The attacks can be relieved with rest, typically taking about 10 minutes from cessation of the exercise.[6] Attacks usually do not last longer than 30 minutes.[3] Attacks typically occur at intervals of between a day and a month, however, there is a great deal of variability here. This variability can be contributed to the nature of the onset of attacks. ## Causes[edit] All PD associated subtypes have genetic contributions and are likely to run in a families genetic history due to dominant allele mutations. Mutations of identified genes have been leading areas of research in the study and treatment of paroxysmal dyskinesia. PKD, PNKD, and PED are classified as separate subtypes because they all have different presentations of symptoms, but also, because they are believed to have different pathologies. Studies on diseases that are similar in nature to PD have revealed insights into the causes of movement disorders. Hypnogenic paroxysmal dyskinesia is a form of epilepsy affecting the frontal lobe. Single genes have been identified on chromosomes 15, 20, and 21, which contribute to the pathology of these epilepsy disorders.[4] Utilizing new knowledge about pathologies of related and similar disease can shed insight on the causal relationships in paroxysmal dyskinesia. ### PKD[edit] Numerous causes have been proposed for PKD, such as genetic mutations, multiple sclerosis, brain trauma, and endocrine dysfunction. This is not an exhaustive list; many other causes are being proposed and studied. Until causal genes can be identified, the pathology of PKD will not be fully understood. Researchers have identified specific loci in chromosomes 16 and 22, which have been reported to have a genotype-phenotype correlation.[4] ### PNKD[edit] Research on the pathology for PNKD suggests that mutations to specific nucleotide sequences in chromosome 2, MR-1 (myofibrililogenesis regulator - 1) may be linked to PNKD.[4] Studies on MR-1 reveal that it serves as a detoxifying agent. PNKD is sometimes induced by the consumption of alcohol or coffee. Individuals with a mutation in the MR-1 gene sequence may have problems detoxifying the body when alcohol or caffeine is ingested, perhaps resulting in the onset of PNKD. Other studies have revealed a possible mutation on the calcium sensitive potassium (BK) channel.[4] A mutation affecting the influx and efflux of potassium and calcium can cause large scale changes in a neuron. This specific mutation leads to increased excitability of the neuron, often inducing rapid depolarization eliciting numerous action potentials. The pathogenesis of PKND is partially defined by the identification of mutations in the myofibrillogenesis regulator 1 (MR-1), whose gene product is an enzyme involved in the detoxification of methylglyoxal (a compound present in coffee, cola, and alcoholic beverages).[2] ### PED[edit] Long periods of continuous physical exercise is often considered the causal factor involved in a PED diagnosis. It is important to note that PED a is sometimes co-diagnosed with epilepsy and young-onset Parkinson's disease. Correlations between the causes of young-onset Parkinson's disease and PED may be due to a similar problem, specifically a mutation of a potassium channel gene on chromosome 1.[4] The pathogenesis of PED has also been linked to mutations in the GLUT1 glucose transporter which can result in transient energy deficits in the basal ganglia.[2] ## Diagnosis[edit] Diagnosis is similar, but slightly different for each type of PD. Some types are more understood than others, and therefore have more criteria for diagnosis. ### PKD[edit] The guidelines for diagnosing PKD were reviewed and confirmed by Unterberger and Trinka.[3] PKD consists of unexpected forms of involuntary movements of the body. The patient is usually diagnosed sometime before their 20s, and is more likely diagnosed during childhood than early adulthood. Almost all PKD's are idiopathic, but there have been examples of autosomal dominant inheritance as well.[3] Physical examination and brain imaging examinations show normal results, and an EEG shows no specific abnormalities as well. However, the negative synchronous EEG results can be used to prove that PKD is not a sort of reflex epilepsy, but a different disease.[4] PKD is the most prevalent subtype of paroxysmal dyskinesia, encompassing over 80% of all given PD diagnosis. PKD is more prevalent in boys, usually as high as 3.75:1.[4] ### PNKD[edit] PNKD has a set guideline for diagnosis that is slightly different from PKD. PNKD usually occurs unexpectedly, and is not brought on by sudden movements or exercise. Instead the attacks are brought on by stresses such as emotional stress, fatigue, alcohol, or caffeine consumption.[3] Just like PKD, PNKD also shows autosomal dominance in family history.[3] Physical examination and brain imaging examinations show normal results, and EEG shows no specific abnormalities as well.[4] PNKD is more prevalent in boys, with ratios of 1.4:1.[4] ### PED[edit] PED has a set guideline for diagnosis that is similar, but slightly different from both PKD and PNKD. PED attacks consist of dystonic and bilateral movements usually in the lower limbs of the body.[3] These attacks are usually brought about only by exercise and physical exhaustion. PED patients do not feel an aura-like sensation before an attack occurs, unlike PKD and PNKD. These attacks usually last from 5 to 30 minutes, and can occur once a day or once a month.[3] Physical examination and brain imaging examinations show normal results, and EEG shows no specific abnormalities as well.[4] PED is the rarest paraoxysmal dyskinesia subtype. ## Management[edit] ### PKD[edit] PKD patients usually show a good response to anticonvulsants. Most commonly used medications are sodium blockers, carbamazepine and phenytoin. During a drug-testing study, patients reported a decreasing response to the latter use of anticonvulsants and switched to carbamazepine or phenytoin.[2] Refraining from established triggers such as sudden movement has been shown to lessen attacks occurrences. Avoidance of predisposing factors such as stress, excitement, and fatigue also help manage attacks. ### PNKD[edit] Treatment for PKND is more difficult than other Paroxysmal Dyskinesias. The majority of patients experience some relief from low dosages of clonazepam, a muscle relaxant and anticonvulsant. Similar to PKD, avoidance of stress, excitement, and fatigue will lower the frequency of PNKD attacks. Many patients also avoid known methyglyoxal containing foods and beverages such as alcohol, coffee, tea, and chocolate. ### PED[edit] PED patients usually avoid prolonged, continuous exertion to prevent occurrence of attacks. Use of anticonvulsants such as benzodiazepines show little to no success in PED patients. A few cases have shown that patients were able to lessen their attacks with a high carbohydrate snack. A new approach to managing PED is the ketogenic diet, which alters the primary cerebral energy metabolism from glucose to ketone bodies. Reports have shown that the ketonic diet protects against seizures in epilepsy.[2] In PED, it is probable that ketones will provide sufficient energy for the basal ganglia, which is normally deficient in patients with PED.[2] ## Prognosis[edit] Paroxysmal Dyskinesia is not a fatal disease. Life can be extremely difficult with this disease depending on the severity. The prognosis of PD is extremely difficult to determine because the disease varies from person to person. The attacks for PKD can be reduced and managed with proper anticonvulsants, but there is no particular end in sight for any of the PD diseases. PKD has been described to cease for some patients after the age of 20, and two patients have reported to have a family history of the disease where PKD went into complete remission after the age of 23.[7] With PNKD and PED, at this time, there is no proper way to determine an accurate prognosis. ## References[edit] 1. ^ Blueprints Neurology, 2nd ed. 2. ^ a b c d e f g Strzelczyk, A.; Bürk, K.; Oertel, W. H. (2011). "Treatment of paroxysmal dyskinesias". Expert Opinion on Pharmacotherapy. 12 (1): 63–72. doi:10.1517/14656566.2010.513971. PMID 21108579. 3. ^ a b c d e f g h i j k l m n Unterberger, I.; Trinka, E. (2008). "Review: Diagnosis and treatment of paroxysmal dyskinesias revisited". Therapeutic Advances in Neurological Disorders. 1 (2): 4–11. doi:10.1177/1756285608095119. PMC 3002546. PMID 21180566. 4. ^ a b c d e f g h i j k l Zhou, J. Q.; Zhou, L. M.; Fang, Z. Y.; Wang, Q.; Chen, Z. Y.; Yang, L. B.; Chen, S. D.; Cai, X. D. (2011). "Analyzing clinical and electrophysiological characteristics of Paroxysmal Dyskinesia". Journal of Research in Medical Sciences. 16 (1): 110–114. PMC 3063430. PMID 21448393. 5. ^ Demirkiran, M.; Jankovic, J. (1995). "Paroxysmal dyskinesias: Clinical features and classification". Annals of Neurology. 38 (4): 571–579. doi:10.1002/ana.410380405. PMID 7574453. 6. ^ a b Bhattacharyya, K. B.; Basu, S.; Ray, A. D.; Bhattacharya, S. (2000). "Sporadic paroxysmal exercise induced dystonia: Report of a case and review of the literature". Neurology India. 48 (4): 401–402. PMID 11146614. 7. ^ Choi, I. S.; Kim, J. H.; Jung, W. Y. (1996). "Paroxysmal kinesigenic choreoathetosis". Yonsei Medical Journal. 37 (1): 68–71. doi:10.3349/ymj.1996.37.1.68. PMID 8967112. ## External links[edit] Classification D * ICD-10: G24.8 External resources * Orphanet: 1431 [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	Paroxysmal dyskinesia	c0752210	5,751	wikipedia	https://en.wikipedia.org/wiki/Paroxysmal_dyskinesia	2021-01-18T18:39:08	{"mesh": ["D002819"], "umls": ["C0752210"], "orphanet": ["1431"], "wikidata": ["Q7139584"]}
Seizures-scoliosis-macrocephaly syndrome is a rare, genetic neurometabolic disorder characterized by seizures, macrocephaly, delayed motor milestones, moderate intellectual disability, scoliosis with no exostoses, muscular hypotonia present since birth, as well as renal dysfunction. Coarse facial features (including hypertelorism and long hypoplastic philtrum) and bilateral cryptorchidism (in males) are also commonly reported. Additional manifestations include abnormal gastrointestinal motility (resulting in constipation, diarrhea, gastroesophageal reflux and dysphagia), gait disturbances, strabismus and ventricular septal defects. [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	Seizures-scoliosis-macrocephaly syndrome	c4225248	5,752	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=466926	2021-01-23T17:14:52	{"omim": ["616682"], "synonyms": ["SSM syndrome"]}
Abortion in Armenia is legal on request up to 12 weeks of pregnancy, and in special circumstances between 12 weeks and 22 weeks.[1] Abortion has been legal since November 23, 1955, when Armenia was a republic of the Soviet Union.[2][3] Pregnancies may be ended on request by the mother until the twelfth week and for medical and social reasons until the twenty-second week with a doctor's approval.[4] Since 2016, when a law banning sex-selective abortion was passed, mandatory counseling is required before abortion along with a 3-day waiting period. The law has been criticized as using sex-selective abortion as a pretext to restrict access to abortion, although the government denied this, and claimed that it did not intend to question women's right to access safe abortion.[5] Abortion was used as a manner of birth control in Armenia[6] and the number of maternal deaths from abortion complications used to be very high (between 10 and 20% in 2000).[2] After massive reforms, the number of deaths declined to 5% in 2005.[2] In 2014, 21.77% of pregnancies in Armenia ended in abortion, a slight rise from the all-time low recorded in 2010 (21.52%).[7] The United Nations reported an abortion rate (expressed as the number of abortions per 1000 women aged 15–44) of 13.9 in 2004[8] and 16.9 as of 2010[update].[9] ## Sex-selective abortion[edit] Armenia, together with other countries, notably China and India, has a problem with sex-selective abortion.[10][11][12] This has caused major political debates, both internationally and nationally. Nevertheless, the policies that Armenia has adopted to deal with this issue have been controversial and subject to criticism.[13][14] In 2016, the country adopted regulations to curb this practice. Sex-selective abortion was explicitly outlawed in 2016.[15] However, even before 2016, sex-selective abortion was implicitly banned, since Armenia, ever since its legalization of abortion in 1955 under Soviet law, has always restricted abortion after the first trimester, when sex-selective abortions happen, the only thing that has changed several times throughout the years being the reasons laid down by the government in order for an abortion after 12 weeks to be approved.[3] Since sex-selection was never an approved legal reason, such abortions were always technically illegal.[16] As such, the 2016 law explicitly banning an abortion for reasons of sex-selection was seen as redundant and unenforceable, and it came with a major controversy: the requirement of a 3 days waiting period.[14] There has been concern that poor women from rural areas will not be able to afford to travel several times to cities to have safe abortions, thus increasing the rate of unsafe abortion in the country, especially given the high rate of abortion in general.[14] A criticism of Armenia's policies that deal with sex-selection is that they do not focus on the culture which sees women as inferior, and which fuels sex-selection due to the way girls are devalued.[17] ## See also[edit] * Health in Armenia * Women in Armenia ## References[edit] 1. ^ "Armenia: Abortion Law". 2. ^ a b c National Statistical Service [Armenia]; Ministry of Health [Armenia]; ORC Macro (December 2006). "Abortion" (PDF). Armenia Demographic and Health Survey 2005 (Report). p. 73. Retrieved 14 March 2017. 3. ^ a b "Armenia". Abortion Policies: A Global Review (DOC). Country Profiles. United Nations Population Division. 2002. Retrieved 14 March 2017. 4. ^ International Planned Parenthood Foundation European Network (January 2009). Abortion Legislation in Europe (PDF) (Report). pp. 6–7. Retrieved 14 March 2017. 5. ^ "Restrictions in the law on abortion in Armenia". ASTRA Central and Eastern European Women’s Network for Sexual and Reproductive Rights and Health. Archived from the original on 27 September 2017. Retrieved 22 December 2018. 6. ^ International Planned Parenthood Foundation European Network (February 2004). Abortion Legislation in Europe (PDF) (Report). p. 5. Retrieved 14 March 2017. 7. ^ Johnston, Wm. Robert (25 February 2017). "Historical abortion statistics, Armenia". Johnston's Archive. Retrieved 14 March 2017. 8. ^ "World Abortion Policies 2007". United Nations. 2007. Retrieved 14 March 2017. 9. ^ "World Abortion Policies 2013". United Nations. 2013. Retrieved 14 March 2017. 10. ^ Moore, Suzanne (22 February 2018). "'We lose 1,400 girls a year. Who will our boys marry?': Armenia's quandary". The Guardian. Retrieved 22 December 2018. 11. ^ "Gendercide in the Caucasus". The Economist. 21 September 2013. Retrieved 22 December 2018. 12. ^ Michael, Marc; King, Lawrence; Guo, Liang; McKee, Martin; Richardson, Erica; Stuckler, David (2013). "The Mystery of Missing Female Children in the Caucasus: An Analysis of Sex Ratios by Birth Order". International Perspectives on Sexual and Reproductive Health. 39 (2): 97–102. doi:10.1363/3909713. PMID 23895886. 13. ^ "Network of advocates for women's reproductive rights launched in Armenia". International Campaign for Women's Right to Safe Abortion. Retrieved 22 December 2018. 14. ^ a b c Low, Florence (21 October 2016). "Law to cut sex-selective abortions in Armenia 'putting lives at risk'". The Guardian. Retrieved 22 December 2018. 15. ^ "ARMENIA – Sex selection banned". International Campaign for Women's Right to Safe Abortion. Retrieved 22 December 2018. 16. ^ Nanore, Barsoumian (23 November 2011). "The Baby Doom: Selective Abortions in Armenia". The Armenian Weekly. Retrieved 22 December 2018. 17. ^ Pujol-Mazzini, Anna (8 October 2017). "Armenians urged to value their women as abortions of girls skew population". Reuters. Retrieved 22 December 2018. * v * t * e Abortion in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e Abortion in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom * England * Northern Ireland * Scotland * Wales * Vatican City States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Abortion in Armenia	None	5,753	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Armenia	2021-01-18T18:34:02	{"wikidata": ["Q625835"]}
Phaeohyphomycosis refers to fungal infections caused by dematiaceous (darkly pigmented) fungi. It can be associated with a variety of clinical syndromes including invasive sinusitis; nodules or abscesses beneath the skin; keratitis; lung masses; osteomyelitis; mycotic arthritis; endocarditis; brain abscess; and wide-spread infection. Although the condition can affect anyone, it is most commonly diagnosed in people with suppressed immune systems (like those who have undergone an organ transplant) and can even be life-threatening in these populations. Treatment depends on the signs and symptoms present in each person but may include surgery and/or various antifungal medications. [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	Phaeohyphomycosis	c0276721	5,754	gard	https://rarediseases.info.nih.gov/diseases/12803/phaeohyphomycosis	2021-01-18T17:58:21	{"mesh": ["D060446"], "synonyms": []}
Pulmonary heart disease Other namesCor pulmonale Right ventricular hypertrophy SpecialtyPulmonology SymptomsCyanosis, wheezing[1] CausesPrimary pulmonary hypertension[2] Diagnostic methodEKG, Thrombophilia screen [1] TreatmentVasodilators, Diuretics[3] Pulmonary heart disease, also known as cor pulmonale, is the enlargement and failure of the right ventricle of the heart as a response to increased vascular resistance (such as from pulmonic stenosis) or high blood pressure in the lungs.[2] Chronic pulmonary heart disease usually results in right ventricular hypertrophy (RVH),[4] whereas acute pulmonary heart disease usually results in dilatation.[5] Hypertrophy is an adaptive response to a long-term increase in pressure. Individual muscle cells grow larger (in thickness) and change to drive the increased contractile force required to move the blood against greater resistance. Dilatation is a stretching (in length) of the ventricle in response to acute increased pressure.[6] To be classified as pulmonary heart disease, the cause must originate in the pulmonary circulation system; RVH due to a systemic defect is not classified as pulmonary heart disease. Two causes are vascular changes as a result of tissue damage (e.g. disease, hypoxic injury), and chronic hypoxic pulmonary vasoconstriction. If left untreated, then death may result. The heart and lungs are intricately related; whenever the heart is affected by a disease, the lungs risk following and vice versa.[citation needed] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Wheezing The sound of wheezing as heard with a stethoscope. * * * Problems playing this file? See media help. The symptoms/signs of pulmonary heart disease (cor pulmonale) can be non-specific and depend on the stage of the disorder, and can include blood backing up into the systemic venous system, including the hepatic vein.[7][8] As pulmonary heart disease progresses, most individuals will develop symptoms like:[1] * Shortness of breath * Wheezing * Cyanosis * Ascites * Jaundice * Enlargement of the liver * Raised jugular venous pressure (JVP) * Third heart sound * Intercostal recession * Presence of abnormal heart sounds ## Causes[edit] Blood clot[9] The causes of pulmonary heart disease (cor pulmonale) are the following: * Acute respiratory distress syndrome (ARDS)[10] * COPD[2] * Primary pulmonary hypertension[2] * Blood clots in lungs[2] * Kyphoscoliosis[2] * Interstitial lung disease[2] * Cystic fibrosis[2] * Sarcoidosis[11] * Obstructive sleep apnea (untreated)[2] * Sickle cell anemia[12] * Bronchopulmonary dysplasia (in infants)[13] ## Pathophysiology[edit] The pathophysiology of pulmonary heart disease (cor pulmonale) has always indicated that an increase in right ventricular afterload causes RV failure (pulmonary vasoconstriction, anatomic disruption/pulmonary vascular bed and increased blood viscosity are usually involved [1]), however most of the time, the right ventricle adjusts to an overload in chronic pressure. According to Voelkel, et al., pressure overload is the initial step for changes in RV, other factors include:[14] * Ischemia * Inflammation * Oxidative damage * Epigenetics * Abnormal cardiac energetics ## Diagnosis[edit] Normal heart (left) and right ventricular hypertrophy (right) Investigations available to determine the cause of cor pulmonale include the following:[1] * Chest x-ray – right ventricular hypertrophy, right atrial dilatation, prominent pulmonary artery * ECG – right ventricular hypertrophy, dysrhythmia, P pulmonale (characteristic peaked P wave) * Thrombophilia screen- to detect chronic venous thromboembolism (proteins C and S, antithrombin III, homocysteine levels) P pulmonale ### Differential diagnosis[edit] The diagnosis of pulmonary heart disease is not easy as both lung and heart disease can produce similar symptoms. Therefore, the differential diagnosis should assess:[15] * Atrial myxoma * Congestive heart failure * Constrictive pericarditis * Infiltrative cardiomyopathies * Right heart failure (right ventricular infarction) * Ventricular septal defect ## Treatment[edit] The treatment for cor pulmonale can include the following: antibiotics, expectorants, oxygen therapy, diuretics, digitalis, vasodilators, and anticoagulants. Some studies have indicated that Shenmai injection with conventional treatment is safe and effective for cor pulmonale (chronic).[3] Treatment requires diuretics (to decrease strain on the heart).[1] Oxygen is often required to resolve the shortness of breath. Additionally, oxygen to the lungs also helps relax the blood vessels and eases right heart failure.[16] When wheezing is present, the majority of individuals require a bronchodilator.[1] A variety of medications have been developed to relax the blood vessels in the lung, calcium channel blockers are used[17] but only work in few cases and according to NICE are not recommended for use at all.[18] Anticoagulants are used when venous thromboembolism is present. Venesection is used in severe secondary polycythemia (because of hypoxia), which improves symptoms though survival rate has not been proven to increase. Finally, transplantation of single/double lung in extreme cases of cor pulmonale is also an option.[1] ## Epidemiology[edit] The epidemiology of pulmonary heart disease (cor pulmonale) accounts for 7% of all heart disease in the U.S [15] According to Weitzenblum, et al., the mortality that is related to cor pulmonale is not easy to ascertain, as it is a complication of COPD.[19] ## See also[edit] * Bilharzial cor pulmonale. ## References[edit] 1. ^ a b c d e f g h "Cor Pulmonale. Pulmonary heart disease information. Patient \| Patient". Patient. Retrieved 2015-12-22. 2. ^ a b c d e f g h i "Cor pulmonale: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-12-21. 3. ^ a b Shi, Liwei; Xie, Yanming; Liao, Xing; Chai, Yan; Luo, Yanhua (2015-11-24). "Shenmai injection as an adjuvant treatment for chronic cor pulmonale heart failure: a systematic review and meta-analysis of randomized controlled trials". BMC Complementary and Alternative Medicine. 15: 418. doi:10.1186/s12906-015-0939-2. ISSN 1472-6882. PMC 4659214. PMID 26603978. 4. ^ Voelkel, Norbert F.; Quaife, Robert A.; Leinwand, Leslie A.; Barst, Robyn J.; McGoon, Michael D.; Meldrum, Daniel R.; Dupuis, Jocelyn; Long, Carlin S.; Rubin, Lewis J. (2006-10-24). "Right Ventricular Function and Failure Report of a National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure". Circulation. 114 (17): 1883–1891. doi:10.1161/CIRCULATIONAHA.106.632208. ISSN 0009-7322. PMID 17060398. 5. ^ Matthews, Jennifer Cowger; McLaughlin, Vallerie (2008-02-01). "Acute Right Ventricular Failure in the Setting of Acute Pulmonary Embolism or Chronic Pulmonary Hypertension: A Detailed Review of the Pathophysiology, Diagnosis, and Management". Current Cardiology Reviews. 4 (1): 49–59. doi:10.2174/157340308783565384. ISSN 1573-403X. PMC 2774585. PMID 19924277. 6. ^ "Types of Cardiomyopathy - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2015-12-22. 7. ^ George, Ronald B. (2005-01-01). Chest Medicine: Essentials of Pulmonary and Critical Care Medicine. Lippincott Williams & Wilkins. p. 226. ISBN 9780781752732. 8. ^ "Cor Pulmonale". 9. ^ "Blood clots: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-12-22. 10. ^ Nixon, J. V. (2010-10-18). The AHA Clinical Cardiac Consult. Lippincott Williams & Wilkins. p. 136. ISBN 9781608316229. 11. ^ Wilkins, Lippincott Williams & (2009-01-01). Professional Guide to Diseases. Lippincott Williams & Wilkins. p. 139. ISBN 9780781778992. 12. ^ O'Malley, Paul D. (2006-01-01). New Developments in Sickle Cell Disease Research. Nova Publishers. p. 214. ISBN 9781594547928. 13. ^ MacDonald, Mhairi G.; Seshia, Mary M. K.; Mullett, Martha D. (2005-01-01). Avery's Neonatology: Pathophysiology & Management of the Newborn. Lippincott Williams & Wilkins. p. 699. ISBN 9780781746434. 14. ^ Voelkel, Norbert F.; Gomez-Arroyo, Jose; Abbate, Antonio; Bogaard, Harm J. (2013-01-01). "Mechanisms of right heart failure—A work in progress and a plea for failure prevention". Pulmonary Circulation. 3 (1): 137–143. doi:10.4103/2045-8932.109957. ISSN 2045-8932. PMC 3641721. PMID 23662190. 15. ^ a b "Cor Pulmonale: Introduction to Cor Pulmonale, Etiology and Pathophysiology of Cor Pulmonale, Epidemiology of Cor Pulmonale". 2018-11-16. Cite journal requires `\|journal=` (help) 16. ^ George, Ronald B. (2005-01-01). Chest Medicine: Essentials of Pulmonary and Critical Care Medicine. Lippincott Williams & Wilkins. p. 227. ISBN 9780781752732. 17. ^ "Calcium Channel Blockers". livertox.nih.gov. Retrieved 2015-12-22. 18. ^ "Calcium channel blockers are not recommended for the treatment of cor pulmonale. \| NICE". www.nice.org.uk. Retrieved 2015-12-22. 19. ^ Weitzenblum, Emmanuel (2003-02-01). "Chronic Cor Pulmonale". Heart. 89 (2): 225–230. doi:10.1136/heart.89.2.225. ISSN 1355-6037. PMC 1767533. PMID 12527688. ## Further reading[edit] * Forfia, Paul R.; Vaidya, Anjali; Wiegers, Susan E. (2013-01-01). "Pulmonary heart disease: The heart-lung interaction and its impact on patient phenotypes". Pulmonary Circulation. 3 (1): 5–19. doi:10.4103/2045-8932.109910. ISSN 2045-8932. PMC 3641739. PMID 23662171. * Taussig, Lynn M.; Landau, Louis I. (2008-04-09). Pediatric Respiratory Medicine. Elsevier Health Sciences. ISBN 978-0323070720. * Jamal, K.; Fleetham, J. A.; Thurlbeck, W. M. (1990-05-01). "Cor Pulmonale: Correlation with Central Airway Lesions, Peripheral Airway Lesions, Emphysema, and Control of Breathing". American Review of Respiratory Disease. 141 (5_pt_1): 1172–1177. doi:10.1164/ajrccm/141.5_Pt_1.1172. ISSN 0003-0805. PMID 2339840. ## External links[edit] Classification D * ICD-10: I26, I27 * ICD-9-CM: 415.0 * MeSH: D011660 External resources * MedlinePlus: 000129 Scholia has a topic profile for Pulmonary heart disease. * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline Authority control * NDL: 00562815 [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	Pulmonary heart disease	c0034072	5,755	wikipedia	https://en.wikipedia.org/wiki/Pulmonary_heart_disease	2021-01-18T18:53:34	{"mesh": ["D011660"], "umls": ["C0034072"], "icd-9": ["415.0"], "wikidata": ["Q1131786"]}
A number sign (#) is used with this entry because type III GM1-gangliosidosis is caused by mutation in the gene encoding beta-galactosidase-1 (GLB1; 611458). For a general discussion of classification and phenotypic heterogeneity of GM1-gangliosidosis, see type I (230500). Description GM1-gangliosidosis type III is an autosomal recessive lysosomal storage disorder characterized by neurodegeneration and mild skeletal changes. Age at onset ranges from 3 to 30 years. The disorder is less severe than GM1-gangliosidosis types I and II (230600). Type III shows extreme clinical variability, with some patients having only focal neurologic signs, such as dystonia, and others having more severe involvement with extrapyramidal signs and mental retardation. GLB1 enzymatic activity usually ranges from approximately 4 to 10% of control values (Suzuki et al., 2001). Clinical Features Wenger et al. (1974) described beta-galactosidase deficiency in young adults. Loonen et al. (1974) reported a patient with type III GM1-gangliosidosis who had angiokeratoma beginning at age 8 years, cerebellar dysfunction and diminishing vision beginning at age 16, and myoclonic fits, intellectual deterioration and coarsening of the face beginning at age 22. Suzuki et al. (1977) reported 2 Japanese sibs, aged 34 and 30 years, respectively, with the adult form of GM1-gangliosidosis. They had progressive pyramidal and extrapyramidal disease with generalized muscle atrophy without dysmorphism or macular cherry-red spots. Suzuki et al. (1978) found increased GM1 accumulation in cultured skin fibroblasts from these patients. However, the accumulation was less than that observed in patients with type I infantile disease, indicating a correlation of storage material with disease severity. By cell complementation studies, Suzuki et al. (1979) confirmed that the Japanese adults had a variant form of beta-galactosidase deficiency. Stevenson et al. (1978) reported 3 patients from 2 families with type III GM1-gangliosidosis. All had onset by age 4 years, but showed survival into adulthood. One affected boy had early signs of stuttering, overactivity, mental retardation, spasticity, and ataxia. Radiographic examination at age 19 years showed scoliosis, irregularity of the vertebral plates, flattened vertebral bodies, and dysplastic femoral heads. Another child developed walking difficulties at age 3 and showed progressive deterioration with loss of speech and the development of choreic movements and progressive spasticity. The third patient began deteriorating at age 3 years. He never learned to speak clearly, developed abnormal hand movements, and showed mental retardation. He had generalized spasticity, athetoid movements, and rigidity. None of the patients had visceromegaly or macular red spots. Stevenson et al. (1978) stated that these patients had a more severe phenotype than usually seen in type III, but less severe than in types I and II. Wenger et al. (1980) described a brother and sister, aged 19 and 25 years, respectively, with ataxia, mild intellectual deterioration, slurred speech, mild vertebral changes and little, if any, visceromegaly. A primary defect in beta-galactosidase was indicated by the half-normal values in many relatives, including both parents, and by the normal levels of sialidase. Complementation with infantile type I GM1-gangliosidosis did not occur, indicating that it was a variant form of that disorder. Chakraborty et al. (1994) provided follow-up of the family reported by Wenger et al. (1980). The 38-year-old sister and 32-year-old brother had normal childhood development but delayed or defective speech development. Neurologic workup of the sister at age 19 showed a defect in articulation and impairment of upper and lower limb coordination. At age 38, she showed a severe and progressive stutter, hyperactive deep tendon reflexes, especially in the legs, and pes cavus. Intelligence, cranial nerve function, and funduscopic examination were all normal. Bilateral total hip replacement had been required at the age of 33 years. The brother showed progressive dysarthria, moderate ataxia, and intention tremor, but cranial nerve funduscopic examinations were normal. Flattening of vertebral bodies, progressive kyphosis, and subluxation of the right hip were features. Both sides of the family originated from a small town in western Denmark. Goldman et al. (1981) and Kobayashi and Suzuki (1981) reported a 27-year-old man with GM1-gangliosidosis who experienced a slowly progressive dystonia that began at about age 4 years. Dystonia primarily affected the face and limbs and eventually became incapacitating. Myoclonus, seizures, and macular cherry-red spots were never observed. Postmortem examination revealed intraneuronal storage, localized predominantly to the basal ganglia, in which neurons contained round, multilamellated inclusions. Other areas of the central nervous system appeared relatively unaffected, although small basilar dilatations were observed in scattered cortical pyramidal neurons and Purkinje cell dendrites showed focal swellings. Vacuolated cells of the reticuloendothelial system were observed, including Kupffer cells and histiocytes in the spleen, marrow, and intestinal tract. Biochemical analysis revealed a generalized beta-galactosidase deficiency with specific accumulation of GM1 ganglioside in the basal ganglia. Uyama et al. (1992) described 3 Japanese brothers with type III GM1-gangliosidosis presenting as dystonia. The patients were examined at ages 28, 31, and 33 years. They had developed dysarthria with facial grimacing in early childhood. As adults, all had generalized dystonia that did not disappear when the patients were lying or sitting relaxed. Brain imaging showed bilaterally symmetric high density lesions only in the putamen. Yoshida et al. (1992) reported 16 Japanese patients with adult GM1-gangliosidosis from 10 unrelated families. Age at onset ranged from 3 to 30 years. The main clinical manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic posturing, facial grimacing, and parkinsonism were commonly seen. Dysmorphism, visceromegaly, and severe mental impairment were not observed. Chakraborty et al. (1994) reported a 21-year-old patient with type III GM1-gangliosidosis who presented at age 3 years with speech difficulties that continued as a severe stutter. Neurologic examination demonstrated spastic quadriparesis, especially in the legs, with a scissoring gait. The patient had a history of urinary incontinence. Cranial nerve and funduscopic examinations, as well as intellect, were normal. Magnetic resonance imaging showed mild ventricular enlargement. The patient was also described as having short stature and scoliosis. Biochemical Features Early complementation studies on cells from patients with types I, II, and III GM1-gangliosidosis yielded conflicting results. Although mutant beta-galactosidase-1 in the different types is due to allelic mutations at the same locus, some studies showed complementation between the different types (see, e.g. Galjaard et al. (1975, 1975) and Koster et al., 1976; Reuser et al., 1979). However, in a detailed review, O'Brien and Norden (1977) discussed several possible explanations for the finding of complementation between different types of GM1-gangliosidosis, including alterations of tertiary structure and protein-protein interaction between different mutant monomers. O'Brien and Norden (1977) argued that the findings of complementation did not necessarily imply that the different types of GM1-gangliosidosis were nonallelic. Taylor et al. (1980) reported biochemical studies of 2 of the patients reported by Stevenson et al. (1978). Beta-galactosidase differed in pH optima, heat denaturation, NaCl kinetics, and electrophoretic mobility from each other and from the normal. No complementation was found in cell fusion studies. The authors concluded that the 2 patients had different primary mutations at the beta-galactosidase locus that were likely structural in nature. Mutoh et al. (1988) demonstrated altered properties of the mutant enzyme and altered apparent molecular weights of the enzyme isolated from the liver of a patient with the adult form of GM1-gangliosidosis. The findings suggested that some patients with the adult form have a structurally altered enzyme. Hoogeveen et al. (1986) showed that the mutations in some cases of infantile and adult forms of GM1-gangliosidosis interfere with the phosphorylation of precursor beta-galactosidase. As a result, the precursor is secreted instead of being compartmentalized into the lysosomes and further processed. Molecular Genetics In the affected sibs reported by Wenger et al. (1980), Chakraborty et al. (1994) identified compound heterozygosity for 2 mutations in the GLB1 gene (611458.0013; 611458.0022). In 6 Japanese patients with the adult/chronic form of GM1-gangliosidosis, Nishimoto et al. (1991) identified a mutation in the GLB1 gene (I51T; 611458.0004). Yoshida et al. (1991, 1992) also found the I51T mutation in Japanese patients with adult GM1-gangliosidosis. All patients except 1 were homozygotes. One patient was a compound heterozygote with an R457Q mutation (611458.0008). Clinically, the compound heterozygous patient showed more severe neurologic manifestations and a more rapid clinical course than did the homozygotes. The I51T allele showed 5.28 to 7.28% residual enzyme activity, whereas the compound heterozygous patient had 4.24% residual activity. The mutations causing residual enzyme activity appeared to be related to severity of clinical manifestations, but other genetic or environmental factors likely also contributed to the phenotype since there was considerable variation in age of onset and clinical course among I51T homozygotes. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Face \- Normal facies Eyes \- No cherry red spots \- Corneal clouding ABDOMEN Liver \- No hepatomegaly Spleen \- No splenomegaly SKELETAL Spine \- Mild platyspondyly \- Mild anterior beaking of lumbar vertebrae \- Kyphosis \- Scoliosis Pelvis \- Hypoplastic acetabulae \- Flat femoral heads \- Flared iliac wings MUSCLE, SOFT TISSUES \- Muscle atrophy NEUROLOGIC Central Nervous System \- Normal early development \- Mental retardation, mild \- Cerebral atrophy, mild, diffuse \- No myoclonus \- No seizures \- Dystonia VOICE \- Slurred speech HEMATOLOGY \- Foam cells (bone marrow) LABORATORY ABNORMALITIES \- Decreased beta-galactosidase activity (leukocyte, fibroblast, plasma) MISCELLANEOUS \- Onset of disease 3-30 years MOLECULAR BASIS \- Caused by mutation in the beta-1-galactosidase gene (GLB1, 230500.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	GM1-GANGLIOSIDOSIS, TYPE III	c0085131	5,756	omim	https://www.omim.org/entry/230650	2019-09-22T16:27:39	{"doid": ["0080489"], "mesh": ["D016537"], "omim": ["230650"], "orphanet": ["354", "79257"], "synonyms": ["Alternative titles", "GANGLIOSIDOSIS, GENERALIZED GM1, ADULT TYPE", "GANGLIOSIDOSIS, GENERALIZED GM1, CHRONIC TYPE", "GANGLIOSIDOSIS, GENERALIZED GM1, TYPE III", "GANGLIOSIDOSIS, GENERALIZED GM1, TYPE 3"], "genereviews": ["NBK164500"]}
A rare hepatic disease characterized by immune-mediated, acute or chronic liver inflammation, clinically presenting as cryptogenic hepatitis, with interface hepatitis on histological examination, elevated serum aminotransferase levels, and hypergammaglobulinemia, in the presence or absence of specific circulating autoantibodies. Patients may be asymptomatic, chronically ill, or present with acute liver failure. All ages and both genders may be affected, although there is a clear female preponderance. Concurrent autoimmune diseases are frequently observed. [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	Autoimmune hepatitis	c0241910	5,757	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2137	2021-01-23T18:04:46	{"gard": ["5871"], "mesh": ["D019693"], "umls": ["C0241910"], "icd-10": ["K75.4"], "synonyms": ["AIH"]}
Linear lichen planus (LLP) is a rare form of lichen planus, which is a condition that affects the skin and/or mouth. In LLP, specifically, affected people develop itchy, purple, flat-topped papules (bumps) in a linear distribution along the lines of Blaschko. Although these papules can be found anywhere on the body, they most commonly affect the limbs (arms and legs). The exact underlying cause of LLP is unknown; however, it has been associated with metastatic cancer, HIV infection and hepatitis C infection. Treatment is not always necessary as some cases of LLP resolve on their own. Mild cases can often be managed with topical steroids, while more intensive therapies may be required for severe 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	Linear lichen planus	c0023650	5,758	gard	https://rarediseases.info.nih.gov/diseases/11898/linear-lichen-planus	2021-01-18T17:59:22	{"orphanet": ["254379"], "synonyms": ["Blaschkoid LP", "Blaschkoid lichen planus", "Linear LP", "LLP"]}
Progressive sensorineural hearing loss - hypertrophic cardiomyopathy is an extremely rare disorder described in one family to date that is characterized by progressive, late onset, autosomal dominant sensorineural hearing loss, QT interval prolongation, and mild cardiac hypertrophy. [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	Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome	c2931767	5,759	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228012	2021-01-23T16:55:32	{"mesh": ["C538197"], "omim": ["606346"], "synonyms": ["Progressive neurosensory deafness-hypertrophic cardiomyopathy syndrome", "Progressive neurosensory hearing loss-hypertrophic cardiomyopathy syndrome", "Progressive sensorineural deafness-hypertrophic cardiomyopathy syndrome"]}
## Summary ### Clinical characteristics. Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high. ### Diagnosis/testing. The diagnosis of MHS is established with in vitro muscle contracture testing by measuring the contracture responses of biopsied muscle samples to halothane and graded concentrations of caffeine. The diagnosis of MHS can also be established by identification of a pathogenic variant in CACNA1S, RYR1, or STAC3 on molecular genetic testing. ### Management. Treatment of manifestations: Early diagnosis of an MH episode is essential. Successful treatment of an acute episode of MH includes: discontinuation of potent inhalation agents and succinylcholine; increase in minute ventilation to lower end-tidal CO2; use of MHAUS helpline; administration of dantrolene sodium intravenously; cooling measures if body temperature is >38.5° C; treatment of cardiac arrhythmias if needed (do not use calcium channel blockers); monitoring blood gases, serum concentrations of electrolytes and CK, blood and urine for myoglobin, and coagulation profile; treatment of metabolic abnormalities. Prevention of primary manifestations: Individuals with MHS should not be exposed to potent volatile agents and succinylcholine. Individuals undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Individuals with MHS should carry proper identification as to their susceptibility. Agents/circumstances to avoid: Avoid potent inhalation anesthetics and succinylcholine. Calcium channel blockers should not be given together with dantrolene due to a potential cardiac depressant effect. Serotonin antagonist (5HT3-antagonist) antiemetics should be used cautiously. Individuals with MHS should avoid extremes of heat, but not restrict athletic activity unless there is a history of overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution. In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH. Evaluation of relatives at risk: If the MHS-causative pathogenic variant in the family is known, molecular genetic testing can be used to established increased risk of MH in a heterozygous individual; molecular genetic testing alone cannot be used to identify family members who are not at increased risk for MH due to other possible genetic risk factors. If the pathogenic variant in the family is not known or if an at-risk relative is found to be negative for a familial pathogenic variant, muscle contracture testing can be used to assess susceptibility to MH. Pregnancy management: If a pregnant woman with MHS requires a non-emergent surgery, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Continuous epidural analgesia is highly recommended for labor and delivery. If a cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended (if not otherwise contraindicated). If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an MH-susceptible individual. ### Genetic counseling. Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder. Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH. The proportion of individuals with MHS caused by a de novo pathogenic variant is unknown. Each child of an individual with MHS has a 50% chance of inheriting a causative pathogenic variant. Prenatal teesting for a pregnancy at increased risk is possible if there is a known MH pathogenic variant in the family. ## Diagnosis Consensus guidelines for the diagnosis and management of malignant hyperthermia susceptibility (MHS) have been published [Glahn et al 2010, Larach et al 2012, Hopkins et al 2015, Riazi et al 2018]. ### Suggestive Findings MHS should be suspected in individuals presenting with clinical findings summarized in Table 1. The findings relate to signs occurring during or shortly after general anesthesia. Each clinical finding is weighted as to significance in being associated with MHS as determined by malignant hyperthermia (MH) experts using a Delphi method. Points are assigned according to weight and are then totaled to produce a raw score, which translates to a likelihood of MH score, ranging from a raw score of 0 (MH rank 1: almost never/very unlikely) to a raw score ≥50 (MH rank 6: almost certain) [Larach et al 1994]. The more criteria an individual fulfills, the more likely that an MH episode has occurred. For example, with only temperature elevation during anesthesia, an individual is not likely to be susceptible to MH. A limitation of the scoring system is that not every clinical finding may be measured (e.g., arterial blood gas); MH may also recognized very quickly and treated before all the signs appear. ### Table 1. Criteria Used in the Clinical Grading Scale for Malignant Hyperthermia View in own window Clinical Finding (Maximum Score) 1Manifestation 2 Respiratory acidosis (15)End-tidal CO2 >55 mmHg, PaCO2 >60 mmHg Cardiac involvement (3)Unexplained sinus tachycardia, ventricular tachycardia, or ventricular fibrillation Metabolic acidosis (10)Base deficit >8 mEq/L, pH <7.25 Muscle rigidity (15)Generalized rigidity, severe masseter muscle rigidity Muscle breakdown (15)Serum creatine kinase concentration >20,000/L units, cola-colored urine, excess myoglobin in urine or serum, plasma [K+] >6 mEq/L Temperature increase (15)Rapidly increasing temperature, T >38.8° C OtherRapid reversal of MH signs with dantrolene (score=5), elevated resting serum creatine kinase concentration (score=10) Family history (15)Consistent with autosomal dominant inheritance From Larach et al [1994], Rosenberg et al [2015] 1\. Clinical findings (except family history) are in order of relative importance. 2\. Signs occurring during or shortly after general anesthesia in the untreated individual #### Indications for Muscle Biopsy and Contracture Testing to Confirm the Diagnosis in a Proband * Definite indications * Proband with a suspected clinical history of MH * First-degree relative of a proband with a clinical history of MH, if the proband cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available) * At-risk family members when the MH-causing variant is not known * Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents * Isolated masseter muscle rigidity with succinylcholine * Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia) * Military service. The military requires determination of MH susceptibility by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service. Possible indications. Debate exists as to other indications for diagnostic MH muscle biopsy. Some experts believe that individuals who experience any one of the following signs should undergo biopsy, following careful discussion of the pros and cons of the test: * Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH * Exercise-related rhabdomyolysis in the absence of a known myopathy Not recommended * Weight less than about 20 kg or age younger than five years * Diagnosis of neuroleptic malignant syndrome or serotonin syndrome * Because contracture testing is available on a limited basis, some physicians consider all individuals with a suspected history of MH as MH susceptible and avoid anesthetic agents known to trigger MH. Although this strategy is useful, it does not provide guidance and specific answers to family members and limits the anesthetic options for the individual and family. Details regarding MH muscle biopsy centers can be obtained from the Malignant Hyperthermia Association of the US website (www.mhaus.org). #### Indications for Molecular Genetic Testing (See Establishing the Diagnosis, Note.) * Confirmed clinical episode of MH * Positive caffeine/halothane contracture test * High likelihood of having experienced an MH episode, as determined by biopsy center/hotline consultants, and/or likely MH based on the Clinical Grading Scale (see Table 1) * Relative with a positive contracture test or a known MH-causing variant * Unexplained death with signs of MH during or immediately after anesthesia * Exercise-related rhabdomyolysis and/or heat stroke ### Establishing the Diagnosis The diagnosis of MHS is established in a proband with: * A positive diagnostic contracture test OR * A heterozygous pathogenic variant in one of the genes listed in Table 3 identified by molecular genetic testing. Note: (1) Molecular genetic testing is not 100% sensitive; MHS cannot be excluded based on failure to identify a pathogenic variant in one of the genes listed in Table 3. In such cases contracture testing should be performed at an MH muscle biopsy center. (2) A variant is established as pathogenic through variant assessment that includes functional analysis (see Molecular Genetics). #### Contracture Test Since the mid-1970s, the standard diagnostic test for MHS has been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. The test is referred to as the caffeine/halothane contracture test (CHCT) in North America and the in vitro contracture test (IVCT) in Europe and elsewhere. (Note: The calcium-induced calcium release test is used only in Japan, and no international standards exist.) * The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center in order to undergo testing. * The individual is anesthetized with general anesthesia, spinal anesthetic or with a femoral nerve block or one of its variants: * Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability. * In all cases, the anesthetic drugs used must be safe for MH-susceptible individuals. * The surgeon must not use electrocautery or stretch the muscle. Muscle bundles weighing 100-150 mg are mounted in a chamber containing buffered solution and, after a period of stabilization, are caused to contract with supramaximal electrical stimuli. The isometric contracture that develops following exposure to pharmacologic agents that cause sarcoplasmic reticulum calcium release (e.g., halothane, caffeine, and ryanodine) is measured. The two versions of the testing protocol with international standards of test performance and interpretation are the North American [Litman & Rosenberg 2005] and the European versions [Hopkins et al 2015]. The essential differences are: (1) the North American protocol utilizes exposure to 3% halothane, while the European version utilizes incremental exposure to halothane; and (2) the North American version requires testing of three muscle bundles for each drug, whereas the European version requires testing of two muscle bundles for each drug (see Table 2). ### Table 2. Testing Protocols for Malignant Hyperthermia View in own window DesignationNorth American Protocol 1DesignationEuropean Protocol 2 MHS * Contracture of ≥0.7 g to 3% halothane; OR * Contracture of ≥0.3 g to 2.0 mmol/L caffeine MHShc * Contracture of ≥0.2 g to ≤2% halothane; AND * Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine MHSContracture to: * Halothane only; OR * Caffeine only MHSh 3 or MHSc 3Contracture to: * Halothane only; OR * Caffeine only MHN * No contracture; OR * Contracture of <0.7 g to halothane; OR * Contracture of <0.3 g to 2.0 mmol/L caffeine MHNNo significant contractures to either agent MHN = malignant hyperthermia negative; MHS = malignant hyperthermia susceptible; MHSc = malignant hyperthermia susceptible with contracture after caffeine exposure; MHSh = malignant hyperthermia susceptible with contracture after halothane exposure; MHShc = malignant hyperthermia susceptible with contracture after halothane exposure and after caffeine exposure Note: (1) Studies to determine the sensitivity and specificity of the contracture test show that both protocols have a sensitivity of about 100%. Specificity is generally between 80% and 97%, according to several studies with these protocols [Allen et al 1998]. (2) Some laboratories employ 1.0 or 2.0 μmol/L ryanodine or 4-chloro-m-chlorocresol in addition to halothane and caffeine to clarify equivocal results. 1\. In the North American protocol, most centers report results as MHS or MHN. 2\. Hopkins et al [2015] 3\. MHSc, and MHSh are both considered MHS. #### Molecular Genetic Testing: Recommended Tier 1 When the clinical and laboratory findings suggest the diagnosis of MHS, molecular genetic testing approaches should include use of a multigene panel. A MHS multigene panel that includes CACNA1S, RYR1, STAC3, 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. #### Molecular Genetic Testing: Tier 2 Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if gene-targeted testing did not identify a pathogenic variant in an individual with a positive contracture test. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 3. Molecular Genetic Testing Used in Malignant Hyperthermia Susceptibility (MHS) View in own window Gene 1, 2Proportion of MHS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 CACNA1S~1% 6~100%Unknown 7 RYR150%-60% 8~100%2 families 9 STAC3<1% 10~100%Unknown 7 Unknown 11Up to 40%NA 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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\. Monnier et al [1997], Stewart et al [2001] 7\. No data on detection rate of gene-targeted deletion/duplication analysis are available. 8\. Sambuughin et al [2005], Galli et al [2006], Robinson et al [2006], Kraeva et al [2011] 9\. Sambuughin et al [2001a] 10\. Horstick et al [2013], Zaharieva et al [2018] 11\. Up to 30% of individuals with MHS do not have an identified pathogenic variant in any of the genes in Table 1. MHS has been linked to 17q11.2-q24, 3q13.1, 5p, and 7q21-q22; however, no additional MH-related candidate genes have been identified. ## Clinical Characteristics ### Clinical Description The manifestations of malignant hyperthermia (MH) result from exposure to certain volatile anesthetic agents (i.e., halothane, isoflurane, sevoflurane, desflurane, and enflurane) that act as triggers either alone or in conjunction with succinylcholine, a depolarizing muscle relaxant. MH is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism [Rosenberg et al 2015] with variable clinical presentations (depending on the triggering agents and environmental factors, such as metabolic state and body temperature) at the beginning of anesthesia. The triggering substances initiate uncontrolled release of calcium from the sarcoplasmic reticulum via the skeletal muscle calcium release channel (RyR1), and also may promote entry of extracellular calcium into the myoplasm leading to the sustained pathologic increase in cytosolic calcium in skeletal muscle cells [Yang et al 2007, Duke et al 2010, Riazi et al 2018]. Increased myoplasmic calcium causes contracture of skeletal muscles and activates glycogenolysis and cell metabolism, resulting in excessive production of heat and excess lactate. Activation of the oxidative cycle leads to high oxygen consumption and high carbon dioxide production. MH clinical manifestations are variable; with prompt and rapid clinical response, some signs may not appear. Hypercapnia is common, as is tachycardia. Hyperthermia may be one of the early signs of MH. However, failure to monitor core temperature may lead to a delay in detecting hyperthermia. Skin temperature measurement is often misleading during MH crises [Larach et al 2010]. Acidosis may be mild if the syndrome is recognized and treated promptly. HyperCKemia and rhabdomyolysis are more common when succinylcholine has been used but may be mild or not appear at all in some individuals, for reasons that are not clear. In some instances rhabdomyolysis does not appear for several hours. Hyperkalemia, leading to cardiac arrhythmia and even arrest, is uncommon if the syndrome is detected and treated promptly but may develop with remarkable rapidity. In survivors, normalization of edematous muscle and serum CK concentration occurs within ten to 15 days, but symptom resolution may take longer (Figure 1) [Jurkat-Rott et al 2000]. #### Figure 1. Clinical features of malignant hyperthermia susceptibility Note: Early diagnosis and rapid therapy are both life saving and lead to a reduction of clinical symptoms. MH may appear at any point during anesthetization or within an hour or so after termination of anesthesia. If succinylcholine is used during induction of anesthesia, an acceleration of the manifestations of MH may occur; tachycardia, elevation of end-tidal carbon dioxide levels, hypertension, marked temperature elevation, and arrhythmias are seen over the course of five to ten minutes. However, a completely normal response to succinylcholine may be present in some individuals susceptible to MH; in these individuals, a potent inhalation agent is apparently necessary to trigger the syndrome. In almost all instances, the first manifestations of MH occur in the operating room. In classic MH, the initial signs are tachycardia, rapidly rising end-tidal C02, and tachypnea. Tachypnea is usually not recognized because most individuals receiving general anesthesia are paralyzed. Shortly after the heart rate increases, the blood pressure may increase, often associated with ventricular arrhythmias induced by sympathetic nervous system stimulation from hypercarbia, hyperkalemia, and catecholamine release. Thereafter, muscle rigidity or increased muscle tone may become apparent; and body temperature increases at a rate of 1°-2° C every five minutes. At the same time, the CO2 absorbent used in general anesthesia becomes activated and warm to the touch from the exothermic reaction with the CO2 exhaled by the affected individual. The individual may display peripheral mottling, on occasion sweating, and in rare cases cyanosis. Blood gas analysis usually reveals hypercarbia (PCO2>60 mmHg) and respiratory and metabolic acidosis without oxygen desaturation. Elevation of end-tidal CO2 greater than 55 mmHg is one of the earliest signs of MH; however, vigorous mechanical hyperventilation may prevent hypercarbia and delay the diagnosis [Karan et al 1994]. A mixed venous blood sample shows even more evidence of CO2 retention and metabolic acidosis. Hyperkalemia, hypercalcemia, lactacidemia, and myoglobinuria are characteristic but not always present. Increase in serum CK concentration often exceeds 20,000 units/L in the first 12-24 hours. Death results unless the individual is promptly treated (see Management). Even with treatment and survival, the individual is at risk for life-threatening myoglobinuric renal failure, disseminated intravascular coagulation (DIC), compartment syndrome, and recrudescence of the syndrome within the first 24-36 hours following the episode. A study of MH using a North American MH registry containing information about affected individuals reported between 1987 and 2006 showed that nonfatal complications occurred in 35% of these individuals. Twelve of these complications included cardiac, renal, or hepatic dysfunction; coma or change in consciousness level; pulmonary edema; and DIC [Larach et al 2010]. Early diagnosis and rapid therapy are life saving and also lead to a reduction of clinical symptoms. It should be noted that modern anesthetic care and monitoring often allow early detection of MH. Treatment with dantrolene results in much lower morbidity and mortality than first reported when MH was recognized in the 1960s [Larach et al 2008]; however, mortality may be as high as 11% [Rosero et al 2009]. The likelihood of any complication increased 2.9 times per 2° C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene administration [Larach et al 2010]. The most frequent complications associated with dantrolene administration are muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). There is a 25% increase in the risk for any of the above complications when the total dose of dantrolene as required by clinical indications is twice the recommended initial treatment dose of 2.5 mg/kg [Brandom et al 2011]. The presentation of MH outside a hospital setting may pose special problems. Several deaths from MH have occurred when the episode began in an ambulatory surgery setting. Probable causes include inadequate preparation for treating MH (including absence of dantrolene), insufficient and unprepared personnel, and problems in stabilizing an affected individual prior to transfer to a hospital. It is suggested that all facilities have a plan to deal with MH and hold practice drills at regular intervals (see Larach et al [2012] for transfer-of-care protocols). MH may also occur in the early postoperative period, usually within the first hour of recovery from anesthesia. Characteristic tachycardia, tachypnea, hypertension, and arrhythmias presage an episode of MH. Isolated myoglobinuria without an obvious increase in metabolism in the postoperative period (≤24 hours) should alert the anesthesiologist to the possibility of MH. Of note, an MH episode may not occur with every exposure to "trigger" agents; clinical manifestations depend on genetic predisposition, dose of trigger agents, and duration of trigger exposure. Signs of MH have also been reported without exposure to anesthetic agents. In some cases signs follow overdose of MDMA agonists; in other cases MH may be associated with heat and exercise. #### Environmental/Exertional Heat Stress Recent clinical, genetic, and laboratory studies using animal models provide evidence for a relationship between environmental or exertional heat stress (EHS) and MHS [Chelu et al 2006, Yang et al 2006, Durham et al 2008, Lanner et al 2012]. Some individuals who have experienced exertional heat illness have been found to be MH susceptible based on contracture testing [Capacchione & Muldoon 2009]. In one study, one third of young military recruits who experienced exercise-induced heat illness had an abnormal contracture response. Evidence of a relation between EHS and MHS is presented by Tobin et al [2001] in the case report of a boy age 12 years who died from an MH-like event following participation in a football game. The boy had recovered from a previous clinical MH episode during general anesthesia with sevoflurane; sequence analysis revealed that both the boy and his father had a common RYR1 pathogenic variant (p.Arg163Cys). A more recent study found that two unrelated children who experienced fatal non-anesthetic awake episodes triggered by either a viral prodrome or exposure to environmental heat stress possessed an identical RYR1 variant (p.Arg3983Cys), while one of the children also had a second variant (p.Asp4505His) [Groom et al 2011]. #### MHS Phenotypes Several distinct RYR1-related myopathies can predispose to classic MH: * Central core disease (OMIM 117000) and multiminicore disease (OMIM 255320) are myopathies caused by mutation of RYR1. Muscle weakness can range from mild to severe. Most affected individuals have mild disease with symmetric proximal muscle weakness & variable involvement of facial & neck muscles. Motor development is usually delayed, but most affected individuals acquire independent ambulation. Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, and respiratory insufficiency requiring assisted ventilation. Multiminocore disease is broadly classified into four groups: classic form, moderate form with hand involvement, antenatal form with arthrogryposis multiplex congenita, and ophthalmoplegic form. About 75% of affected individuals have classic symptoms characterized by neonatal hypotonia, delayed motor development, and axial muscle weakness, which leads to development of scoliosis and significant respiratory involvement; varying severity of spinal rigidity is present. Each of the other three forms is seen in fewer than 10% of individuals. * King or King-Denborough syndrome (OMIM 145600) is characterized by: distinctive facies, ptosis, downslanted palpebral fissures, widely spaced eyes, epicanthal folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, single palmar crease, pectus excavatum, winging of the scapulae, lumbar lordosis, and mild thoracic scoliosis. Individuals present with hypotonia at birth, slightly delayed motor development, diffuse joint hyperextensibility, and mild proximal muscle weakness. Muscle biopsy reveals minimal but identifiable changes represented by fiber size variability, type I fiber predominance and atrophy, perimysial fibrous infiltration, and some disarray of the intermyofibrillary network. Pathogenic variants in RYR1 have been found in some individuals with King-Denborough syndrome. * STAC3 disorder (Native American myopathy), caused by biallelic pathogenic variants in STAC3, is characterized by congenital myopathy and musculoskeletal involvement of the trunk and extremities. Most children have weakness with myopathic facies, progressive kyphoscoliosis, and contractures. Other common findings are palatal anomalies (including cleft palate) and short stature. Risks for MHS and restrictive lung disease are increased. Intellect is typically normal. Other RYR1 allelic conditions associated with MH susceptibility: * Vladutiu et al [2011] revealed that variants in RYR1 may contribute to the underlying genetic risk for non-anesthesia-induced myopathies, such as statin-induced myopathy. * In a study of 12 young men with exercise-induced rhabdomyolysis (ER), ten were determined to be MH susceptible on contracture testing and three had known MHS RYR1 pathogenic variants [Wappler et al 2001]. In addition, the two RYR1 pathogenic variants p.Arg401Cys and p.Arg614Cys are associated with MHS, EHS, and ER [Davis et al 2002]. * RYR1 variants have also been found to underlie ER in African American men [Sambuughin et al 2009]. This study identified three novel RYR1 variants: p.Ala933Thr, p.Gly2160Ser, and p.Thr4294Met, in individuals with ER. * Retrospective data on Canadian individuals with MHS and ER showed that an RYR1 or CACNA1S pathogenic variant was identified in three of 17 individuals [Kraeva et al 2017]. ### Genotype-Phenotype Correlations Genotype-phenotype correlations in MHS are difficult to study. No correlation between genotype and clinical phenotype is apparent because caffeine/halothane contracture test / in vitro contracture test results are variable among diagnostic laboratories, and clinical episodes of MHS that fulfill all criteria are rare because of successful intervention during anesthetic complications. A limited number of studies have addressed genotype-phenotype correlations in individuals with RYR1-related MHS [Robinson et al 2002, Robinson et al 2003, Carpenter et al 2009]. Stronger contractures and shorter response times in the response to caffeine have been reported in individuals with an RYR1 pathogenic variant [Carpenter et al 2009]. No genotype-phenotype correlations for STAC3 have been identified. No genotype-phenotype correlations for CACNA1S have been identified. ### Penetrance In a multicenter case-control study, the overall penetrance for RYR1-related MHS was 40.6%. The probability of developing MH on exposure to triggers was 0.25 among all individuals with an RYR1 pathogenic variant and 0.76 in survivors of MH reactions (95% CI of the difference 0.41 to 0.59) [Ibarra Moreno et al 2019]. ### Prevalence The incidence of MH is best described by the reported incidence per anesthetic. The estimates of the incidence range from one in 3,000 anesthetics to one in 50,000 anesthetics, with most estimating an incidence in children of about one in 10,000 anesthetics and in adults of one in 50,000 anesthetics. The prevalence of MH in individuals undergoing surgery in New York state hospitals was estimated at 1:100,000 for adults [Brady et al 2009] and 3:100,000 for children [Li et al 2011]. Because many individuals who experience marked hyperthermia while undergoing surgery may be coded as being MH susceptible, the exact incidence and prevalence has been difficult to clarify. It appears certain that there are more than 1,000 cases of MH in the US each year [Brandom & Muldoon 2004]. The incidence varies depending on the routine use of trigger anesthetics. Gonsalves et al [2013] identified a prevalence of 0.46% (4/870) for MHS-related RYR1 pathogenic variants. Based on genetic variation data of more than 60,000 individuals (gnomad.broadinstitute.org; accessed 9-19-2019), the combined prevalence of MHS-related RYR1 pathogenic variants was estimated at 1:2750 [Riazi et al 2018]. Using RYR1 and CACNA1S genomic databases, the estimated prevalence of an MHS-related pathogenic variant was 1:1556 [Mungunsukh et al 2019]. ## Differential Diagnosis Malignant hyperthermia (MH). The combination of hypercarbia, muscle rigidity, tachycardia, hyperthermia, metabolic acidosis, and rhabdomyolysis during or shortly after anesthesia is distinctive for MH. Some conditions share elements of MH (see Tables 5a and 5b). ### Table 5a. Acquired Conditions to Consider in the Differential Diagnosis of Malignant Hyperthermia (MH) View in own window ConditionFeaturesComment SepsisHyperthermia, hypercarbia, & acidosisRigidity & marked ↑ of serum CK concentration are uncommon; leukocytosis (typically present w/sepsis) is uncommon in MH. Overheating from aggressive heating measures used w/anesthesia (esp in pediatric population)Hyperthermia, tachycardia, & sometimes acidosis Pheochromocytoma crisisHypertension, tachycardia, & sometimes fever; may be mistaken for MH, esp in postoperative periodHeart failure may result from unopposed alpha activity if beta blockade is used to treat tachycardia. Ischemic encephalopathyManifests by failure to awaken from anesthesia, muscle rigidity sometimes progressing to opisthotonus, hyperthermia, & tachycardiaSeizures are common in ischemic encephalopathy but not in MH. Ascending tonic-clonic syndromeAscending tonic-clonic activity occurs when agent ascends into the cerebral ventricles leading to frank seizures, rigidity accompanied by fever, & acidosis if respiration is compromisedFollows intrathecal injection of a water-soluble, high ionic radiologic contrast agent ThyrotoxicosisHyperthermia, hypercarbia, & tachycardiaNot assoc w/muscle rigidity Neuroleptic malignant syndrome (NMS)Shares all features of MH incl muscle rigidity, rhabdomyolysis, acidosis, & feverManifests after administration of neuroleptic agents such as atypical antipsychotics, haloperidol, & drugs used in treatment of schizophrenia 1; occurs in the non-anesthetized individual Serotonin syndromeSigns similar to NMSRare reaction from serotonin uptake inhibitor drugs; occurs in the non-anesthetized individual 1\. Postmortem high-resolution melting followed by sequencing of selected exons of RYR1 in 11 individuals who died of NMS revealed two pathogenic variants, one of which had previously been reported in individuals with MH [Sato et al 2010]. ### Table 5b. Heritable Myopathies to Consider in the Differential Diagnosis of Malignant Hyperthermia View in own window ConditionGeneMOIComment Dystrophinopathy (Duchenne or Becker muscular dystrophy)DMDXLFollowing administration of succinylcholine or potent volatile anesthetics, affected individuals are at ↑ risk for rhabdomyolysis & life-threatening hyperkalemia w/cardiac arrest. 1 Myotonic dystrophy type 1DMPKADFollowing succinylcholine administration, can be assoc w/muscle rigidity mimicking MH Myotonic dystrophy type 2CNBPAD Myotonia congenitaCLCN1AR AD AD = autosomal dominant; AR = autosomal recessive; MH = malignant hyperthermia; MOI = mode of inheritance; XL = X-linked 1\. Although these adverse events were first believed to represent a form of MH, it now appears that the pathophysiology of the hyperkalemic episodes differs from that of MH in many respects, although elevation of intracellular calcium concentration is probably common to both syndromes [Hayes et al 2008, Betzenhauser & Marks 2010]. Rhabdomyolysis * Succinylcholine may cause rhabdomyolysis that is not obvious on cursory physical examination in individuals who have any of the myotonic syndromes or dystrophinopathy. * Rhabdomyolysis may occur in the perioperative period in some individuals taking inhibitors of cholesterol formation [Turan et al 2011]. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with malignant hyperthermia susceptibility (MHS), the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 6. Recommended Evaluations Following Initial Diagnosis in Individuals with Malignant Hyperthermia Susceptibility View in own window System/ConcernEvaluation MH acute episode * Arterial blood gas analysis * Measurement of serum electrolytes (Na, K, Cl) * Lactate * Measurement of serum CK concentrations until normalized * Coagulation studies (INR, PTT, D-dimer) * Urine myoglobin * Serum myoglobin concentration * Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) * Continuous core temperature monitoring until episode resolves NeuromuscularNeurologic assessment for evidence of muscle damage OtherConsultation w/clinical geneticist &/or genetic counselor ### Treatment of Manifestations For management guidelines, see Guidelines / Consensus Statements and Figure 2 [Litman & Rosenberg 2005, Glahn et al 2010, Hopkins et al 2015, Hopkins et al 2018, Riazi et al 2018]. #### Figure 2. MHAUS treatment guide for malignant hyperthermia Copyright, The Malignant Hyperthermia Association of the United States (MHAUS) Early diagnosis of MH, together with the administration of dantrolene sodium, is essential in the successful treatment of an acute episode of MH: * Discontinue use of potent inhalation agents and succinylcholine. * Increase minute ventilation to lower end-tidal CO2. * Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil. * Prepare and administer dantrolene: 2.5 mg/kg initial dose. Tachycardia, hypercarbia, and muscle rigidity respond rapidly; multiple doses of dantrolene may be needed. The suggested upper limit is 10 mg/kg; however, more may be given as needed. Continue dantrolene at 1.0 mg/kg every four to eight hours for 24-48 hours, titrating to the desired effect (resolution of hyperthermia, acidosis, and myoglobinemia). Dantrolene sodium is a hydantoin molecule that binds to a specific region of the ryanodine receptor 1 channel. It decreases the uncontrolled release of intracellular calcium [Paul-Pletzer et al 2002]. The toxicity profile of dantrolene, when administered acutely, is extremely benign. Calcium channel blocking agents should not be administered with dantrolene because life-threatening hyperkalemia may result. Dantrolene may aggravate previously existing muscle weakness. * Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5° C. * Treat cardiac arrhythmias as needed. Do not use calcium channel blockers. * Obtain blood gases, serum concentration of electrolytes and CK, blood and urine for myoglobin, and coagulation profile (INR, PTT, D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal. * Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes. * Ensure urine output of 2.0 mL/kg/hr with mannitol, furosemide, and fluids as needed. * Evaluate need for invasive monitoring and continued mechanical ventilation. * Observe the individual in an ICU for at least 36 hours because of the 25% chance of recrudescence following initial treatment. Dantrolene should be continued for at least 36 hours following successful treatment in a dose of about 1.0 mg/kg every six hours or more depending on whether signs of MH are present. * Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH. * Refer the affected individual to the Malignant Hyperthermia Association of the US (MHAUS) for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry. * Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS. Myoglobinuria. The presence of myoglobinuria mandates referral to a neurologist for further investigation. ### Prevention of Primary Manifestations Preventive measures for individuals known to be susceptible to MH: * For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents (i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine). * In general, individuals undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during MH events. * Individuals with any form of myotonia (see Differential Diagnosis) should not receive succinylcholine. * Individuals with central core disease (OMIM 117000), multiminicore disease (OMIM 255320), nemaline myopathy, congenital fiber-type disproportion, or Duchenne or Becker muscular dystrophy should not receive trigger anesthetics. * Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the Medic Alert Foundation. ### Agents/Circumstances to Avoid Individuals who are MH susceptible should avoid potent inhalation anesthetics and succinylcholine. Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result. Serotonin antagonist (5HT3-antagonist) antiemetics should be used cautiously, as sudden death has been reported in a child with multiminicore disease caused by a pathogenic variant in RYR1 (p.Arg3983His) after receiving a therapeutic dose of ondansetron [Gener et al 2010]. Individuals with MH are generally advised to avoid extremes of heat but not to restrict athletic activity or lifestyle unless they have experienced overt rhabdomyolysis or heat stroke. In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH [Metterlein et al 2011b]. ### Evaluation of Relatives at Risk It is appropriate to clarify the status of at-risk relatives of an affected individual in order to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include the following: * If the MHS-causative pathogenic variant in the family is known, molecular genetic testing can be used to established increased risk of MH in a heterozygous individual; molecular genetic testing alone cannot be used to identify family members who are not at increased risk for MH due to other possible genetic risk factors [Hopkins et al 2015]. * If the pathogenic variant in the family is not known or if an at-risk relative is found to be negative for the familial pathogenic variant, muscle contracture testing can be used to assess susceptibility to MH. Note: Molecular genetic testing can only be used to assess inherited risk of MH if the familial variant has been established as pathogenic through variant assessment that includes functional analysis, and assessment of co-segregation. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management If a pregnant woman with MHS requires non-emergent surgery during the pregnancy, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Standard American Society of Anesthesiologists mandated monitoring should be used, along with core temperature monitoring. Fetal monitoring should follow standard guidelines. Dantrolene should not be administered in preparation for surgery or labor and delivery. Continuous epidural analgesia is highly recommended for labor and delivery. If a cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an individual with MHS. In the case of a fetus whose father has MHS but whose mother is not known to have MHS, regional anesthesia or general anesthesia without trigger agents is recommended. For further information regarding the management of pregnant women with MHS, see 2009 guidelines developed by the Malignant Hyperthermia Association of the United States and Hopkins et al [2015]. ### Therapies Under Investigations Preliminary investigation by Lanner et al [2012] has shown that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in a knockout mouse model of MH. This finding is suggestive of possible effectiveness of AICAR in the prophylactic treatment of humans with enhanced susceptibility to exercise- or heat-induced sudden death associated with RYR1 pathogenic variants. 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	Malignant Hyperthermia Susceptibility	c0024591	5,760	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1146/	2021-01-18T21:12:52	{"mesh": ["D008305"], "synonyms": ["Malignant Hyperpyrexia"]}
Episodic ataxia type 4 (EA4) is a very rare form of Hereditary episodic ataxia (see this term) characterized by late-onset episodic ataxia, recurrent attacks of vertigo, and diplopia. [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	Episodic ataxia type 4	c1847843	5,761	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79136	2021-01-23T18:41:06	{"mesh": ["C564698"], "omim": ["606552"], "umls": ["C1847843"], "icd-10": ["G11.8"], "synonyms": ["PATX", "Periodic vestibulocerebellar ataxia"]}
Gould (1854) described 2 sibs with this combination. [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	ICHTHYOSIS CONGENITA WITH BILIARY ATRESIA	c0400974	5,762	omim	https://www.omim.org/entry/242400	2019-09-22T16:26:33	{"mesh": ["C562886"], "omim": ["242400"]}
HIV/AIDS has been a public health concern for Latin America due to a remaining prevalence of the disease.[1] In 2018 an estimated 2.2 million people had HIV in Latin America and the Caribbean, making the HIV prevalence rate approximately 0.4% in Latin America.[1] Some demographic groups in Latin America have higher prevalence rates for HIV/ AIDS including men who have sex with men having a prevalence rate of 10.6%, and transgender women having one of the highest rates within the population with a prevalence rate of 17.7%.[2] Female sex workers and drug users also have higher prevalence for the disease than the general population (4.9% and 1%-49.7% respectively).[2] One aspect that has contributed to the higher prevalence of HIV/AIDS in LGBTQIA+ groups in Latin America is the concept of homophobia.[1] Homophobia in Latin America has historically affected HIV service provision through under reported data and less priority through government programs.[3] Antiretroviral treatment coverage has been high, with AIDS related deaths decreasing between 2007 to 2017 by 12%, although the rate of new infections has not seen a large decrease.[1] The cost of antiretroviral medicines remain a barrier for some in Latin America, as well as country wide shortages of medicines and condoms.[4] In 2017 77% of Latin Americans with HIV were aware of their HIV status.[4] The prevention of HIV/AIDS in Latin America among groups with a higher prevalence such as men who have sex with men and transgender women, has been aided with educational outreach, condom distribution, and LGBTQIA+ friendly clinics.[5] Other main prevention methods include condom availability, education and outreach, HIV awareness, and mother-to-child transmission prevention.[1] ## Contents * 1 Origin and epidemiology of HIV/AIDS in Latin America * 2 Prevention of HIV/AIDS infections * 2.1 Prevention practices and methods * 2.2 Public health initiatives * 3 See also * 4 References * 5 External links ## Origin and epidemiology of HIV/AIDS in Latin America[edit] The first documented reporting of what would come to be known as HIV/AIDS happened in June 1981.[6] In September of 1982, AIDS is given its name and a case definition for the very first time.[7] Specific details on the origin of HIV/AIDS in Latin America are lacking, but in 1983, the first known HIV cases in Latin America were confirmed in Mexico and Haiti in the form of the HIV-1.[8] Blood screening in Mexico was scare in the early 1990s, which contributed to 63% of female AIDS cases stemming from blood transfusions.[9] Currently, the prevalence rate of HIV/AIDS in Latin America is highest in Belize (2%), Honduras (1.9%), Panama (1.54%) and Guatemala (1.4%).[10] Since 2000, the prevalence of HIV/AIDS in the Caribbean has been highest in Haiti (5.2%), the Bahamas (4.1%), and the Dominican Republic (2.8%).[10] ## Prevention of HIV/AIDS infections[edit] In order to prevent and slow the transmission rates within the Latin American population public health initiatives need to target vulnerable populations.[11] Providing treatment, education, and health services that are stigma-free and accessible to vulnerable populations is key to combating the prevalence of HIV/AIDS in Latin America.[1] Another common barrier in accessing health services among transgender women is a mistrust of the health system as a whole from past discrimination towards this community within the health system.[2] ### Prevention practices and methods[edit] To prevent transmission between individuals, safe sex practices and treatment using antiretroviral treatment is a necessary public health intervention. Within Latin America as of 2018, 62% of those that are aware of their positive HIV status are currently on antiretroviral therapy, and of those individuals only 55% of them are virally suppressed, and carry an undetectable load. This accounts for 29% of the entire HIV positive community in Latin America.[1] Practices to prevent transmission of HIV/AIDS * Engaging in less risky sexual behavior[12] * Correctly using barrier methods (male condoms and dental damns)[12] * Getting tested for HIV/AIDS and getting treated with antiretroviral therapy[12] * Taking preventative medicines for high risk populations, like post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) [12] * Not using or injecting drugs [12] These safe sex practices reduce the risk of contracting HIV/AIDS. Many of these treatments are not widely available and accessible to vulnerable populations within Latin America.[11] In order to successfully implement these prevention methods the stigma and discrimination surrounding vulnerable populations needs to be addressed within the present health systems in Latin America.[11] ### Public health initiatives[edit] Within Latin America there are many barriers to prevention methods, including late diagnostic testing of patients, lack of testing centers in rural communities, and the stigma/discrimination within the HIV positive population.[11] In 2009, the Elimination Initiative was launched in partnership with UNICEF, the Pan American Health Organization, the Latin American Center for Perinatology (CLAP) and other organizations. It aimed to integrate the services of prevention and diagnosis of both HIV and syphilis within the framework of primary care services, prenatal, sexual, reproductive and family health.[13] Recently in Bahamas, Brazil, El Salvador, Jamaica, Peru, and Trinidad and Tobago self tests were made available, and have the potential to increase testing in at-risk populations.[14] However the accessibility and affordability of the tests is under scrutiny from public health professionals.[1] Other public health initiatives include education regarding safe sex practice use and condom availability. Programs in Mexico and Brazil that aimed to prevent mother-to-child transmission (PMTCT) is an important initiative that has been relatively successful at reducing the prevalence of HIV/AIDS in this population from 16.7% in 2010 to 10.4% in 2017.[15][1] ## See also[edit] * HIV/AIDS in North America * HIV/AIDS in South America * HIV/AIDS in the Caribbean * AIDS pandemic * HIV/AIDS in Argentina * HIV/AIDS in Brazil ## References[edit] 1. ^ a b c d e f g h i "HIV and AIDS in Latin America the Caribbean regional overview". Avert. 2015-07-21. Retrieved 2019-11-17. 2. ^ a b c García, Patricia J; Bayer, Angela; Cárcamo, César P (June 2014). "The Changing Face of HIV in Latin America and the Caribbean". Current HIV/AIDS Reports. 11 (2): 146–157. doi:10.1007/s11904-014-0204-1. ISSN 1548-3568. PMC 4136548. PMID 24824881. 3. ^ "Homophobia and HIV". Avert. 2015-07-20. Retrieved 2019-11-17. 4. ^ a b "Miles to go—closing gaps, breaking barriers, righting injustices". www.unaids.org. Retrieved 2019-11-17. 5. ^ Silva-Santisteban, Alfonso; Eng, Shirley; de la Iglesia, Gabriela; Falistocco, Carlos; Mazin, Rafael (2016-07-17). "HIV prevention among transgender women in Latin America: implementation, gaps and challenges". Journal of the International AIDS Society. 19 (3Suppl 2): 20799. doi:10.7448/IAS.19.3.20799. ISSN 1758-2652. PMC 4949309. PMID 27431470. 6. ^ "A Timeline of HIV and AIDS". HIV.gov. 2016-05-11. Retrieved 2019-11-18. 7. ^ "Current Trends Update on Acquired Immune Deficiency Syndrome (AIDS) --United States". www.cdc.gov. Retrieved 2019-11-18. 8. ^ del Rio, Carlos; Sepúlveda, Jaime (Summer 2002). "AIDS in Mexico: lessons learned and implications for developing countries". AIDS. 16 (11): 1445–1447. doi:10.1097/00002030-200207260-00001. PMID 12131182. 9. ^ Kimball, A M; Berkley, S; Ngugi, E; Gayle, H (May 1995). "International Aspects of the AIDS/HIV Epidemic". Annual Review of Public Health. 16 (1): 253–282. doi:10.1146/annurev.pu.16.050195.001345. ISSN 0163-7525. PMID 7639874. 10. ^ a b Morison, Linda (2001-09-01). "The global epidemiology of HIV/AIDS". British Medical Bulletin. 58 (1): 7–18. doi:10.1093/bmb/58.1.7. ISSN 0007-1420. 11. ^ a b c d dos Santos, Monika ML; Kruger, Pieter; Mellors, Shaun E.; Wolvaardt, Gustaaf; van der Ryst, Elna (2014-01-27). "An exploratory survey measuring stigma and discrimination experienced by people living with HIV/AIDS in South Africa: the People Living with HIV Stigma Index". BMC Public Health. 14 (1): 80. doi:10.1186/1471-2458-14-80. ISSN 1471-2458. PMC 3909177. PMID 24461042. 12. ^ a b c d e "Prevention \| HIV Basics \| HIV/AIDS \| CDC". www.cdc.gov. 2019-12-02. Retrieved 2019-12-05. 13. ^ Organización Panamericana de la Salud. Iniciativa regional para la eliminación de la transmisión maternoinfantil de VIH y de la sífilis congénita en América Latina y el Caribe: documento conceptual. Montevideo: CLAP/SMR; set. 2009 14. ^ Volk, Jonathan E; Lippman, Sheri A; Grinsztejn, Beatriz; Lama, Javier R; Fernandes, Nilo M; Gonzales, Pedro; Hessol, Nancy A; Buchbinder, Susan (2016-06-01). "Acceptability and feasibility of HIV self-testing among men who have sex with men in Peru and Brazil". International Journal of STD & AIDS. 27 (7): 531–536. doi:10.1177/0956462415586676. ISSN 0956-4624. PMC 4643427. PMID 25971262. 15. ^ Rely, Kely; Bertozzi, Stefano M.; Avila-Figueroa, Carlos; Guijarro, Maria Teresa (2003-09-01). "Cost-effectiveness of strategies to reduce mother-to-child HIV transmission in Mexico, a low-prevalence setting". Health Policy and Planning. 18 (3): 290–298. doi:10.1093/heapol/czg035. ISSN 0268-1080. PMID 12917270. ## External links[edit] * AIDS epidemic update 2005 (PDF) * Specific country data from UNAIDS * AIDSPortal Latin America page Latest research, case studies and news stories * 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 * t * e Latin America articles History By period * Spanish colonization * Portuguese colonization * French colonization * Decolonization * Latin American integration * World War II * Debt crisis By topic * Catholic * Jewish * Libraries * Military * Slavery Foreign relations * Canada * China * Italy * Japan * League of Nations * United Kingdom * United States Geography * Regions Politics Governance * Drug legalization * Falangism * International peacekeeping * Liberalism and conservatism Economy * Agriculture * Agroecology * Central banks and currencies * Stock exchanges * Tourism * Water and sanitation * Wealth inequality Society * Crime * Illegal drug trade * Education * Latin American studies * Etiquette * Feminism * HIV/AIDS * Race and ethnicity Culture * Art * Cinema * Films * Cuisine * Dance * Literature * Media * Music * Religion * Television * Companies * Telenovela * Video games Demographics * Countries by population * Cities * Ethnic groups * Spanish language * Latin Americans * List * Category * 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	HIV/AIDS in Latin America	None	5,763	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Latin_America	2021-01-18T18:31:40	{"wikidata": ["Q5629856"]}
Encephalocraniocutaneous lipomatosis (ECCL) is a rare condition that primarily affects the brain, eyes, and skin of the head and face. Most of this condition's signs and symptoms are present from birth, and they vary widely among affected individuals. A hallmark feature of ECCL is a noncancerous tumor under the scalp covered by a smooth, hairless patch of skin. This type of tumor, called a nevus psiloliparus, is made up of fatty tissue. Some people with ECCL also have noncancerous tumors under the skin elsewhere on the head or face. Many have small flaps of skin called skin tags on the eyelids and around the eyes. Hair loss (alopecia), thin or missing patches of skin on the scalp (dermal hypoplasia or aplasia), and changes in skin coloring (pigmentation) are also possible. The most common eye abnormality in ECCL is a noncancerous growth called a choristoma. These growths can be present in one or both eyes and may affect vision. About two-thirds of people with ECCL have noncancerous fatty tumors inside the brain or around the spinal cord. These tumors are called intracranial lipomas and intraspinal lipomas, respectively. Affected individuals also have an increased risk of developing a type of brain cancer called a glioma. The brain and spinal cord abnormalities associated with ECCL can cause seizures, abnormal tensing of the muscles, and intellectual disability ranging from mild to profound. However, about one-third of affected individuals have normal intelligence. Other kinds of growths may also occur in people with ECCL, including noncancerous jaw tumors. ## Frequency ECCL is a rare disorder. Fewer than 60 cases have been reported in the medical literature. ## Causes ECCL can result from mutations in the FGFR1 gene, which provides instructions for making a protein called fibroblast growth factor receptor 1 (FGFR1). This receptor interacts with proteins called fibroblast growth factors (FGFs) to trigger signaling within cells. Signaling via the FGFR1 protein is involved in many critical processes, such as cell division and the regulation of cell growth and maturation. This signaling is important for the normal development and growth of several parts of the body, including the brain. The FGFR1 gene mutations that cause ECCL arise randomly in one cell during the early stages of development before birth. As cells continue to grow and divide, some cells will have the mutation and others will not. This mixture of cells with and without a genetic mutation is known as mosaicism. In cells with an altered FGFR1 gene, the resulting FGFR1 protein is overactive, triggering abnormal signaling that affects cell growth and division. Researchers are studying how these changes in signaling lead to the growth of noncancerous tumors and the other features of ECCL. In some people with ECCL, no FGFR1 gene mutation has been identified, and the cause of the disease is unknown. Other genetic changes are under study as possible causes of this condition. ### Learn more about the gene associated with Encephalocraniocutaneous lipomatosis * FGFR1 ## Inheritance Pattern This condition is described as sporadic because it occurs in people without a history of the disorder in their family. Because ECCL results from mosaic gene mutations, which occur after conception, individuals do not inherit the condition from their parents. [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	Encephalocraniocutaneous lipomatosis	c0406612	5,764	medlineplus	https://medlineplus.gov/genetics/condition/encephalocraniocutaneous-lipomatosis/	2021-01-27T08:25:53	{"gard": ["2108"], "mesh": ["C535736"], "omim": ["613001"], "synonyms": []}
Neurological condition Dysgraphia SpecialtyPsychiatry, Pediatrics SymptomsPoor handwriting and spelling Dysgraphia is a deficiency in the ability to write, primarily handwriting, but also coherence.[1] Dysgraphia is a transcription disability, meaning that it is a writing disorder associated with impaired handwriting, orthographic coding, and finger sequencing (the movement of muscles required to write).[2] It often overlaps with other learning disabilities such as speech impairment, attention deficit hyperactivity disorder, or developmental coordination disorder.[3] In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysgraphia is characterized as a learning disability in the category of written expression when one's writing skills are below those expected given a person's age measured through intelligence and age-appropriate education. The DSM is not clear in whether or not writing refers only to the motor skills involved in writing, or if it also includes orthographic skills and spelling.[3] The word dysgraphia comes from the Greek words dys meaning "impaired" and γραφία graphía meaning "writing by hand".[2] There are at least two stages in the act of writing: the linguistic stage and the motor-expressive-praxic stage. The linguistic stage involves the encoding of auditory and visual information into symbols for letters and written words. This is mediated through the angular gyrus, which provides the linguistic rules which guide writing. The motor stage is where the expression of written words or graphemes is articulated. This stage is mediated by Exner's writing area of the frontal lobe.[4] People with dysgraphia can often write on some level and may experience difficulty with other fine motor skills, such as tying shoes. However, dysgraphia does not affect all fine motor skills. People with dysgraphia often have unusual difficulty with handwriting and spelling[2] which in turn can cause writing fatigue.[3] They may lack basic grammar and spelling skills (for example, having difficulties with the letters p, q, b, and d), and often will write the wrong word when trying to formulate their thoughts on paper. The disorder generally emerges when the child is first introduced to writing.[2] Adults, teenagers, and children alike are all subject to dysgraphia.[5] Dysgraphia should be distinguished from agraphia, which is an acquired loss of the ability to write resulting from brain injury, stroke, or progressive illness.[6] ## Contents * 1 Classification * 1.1 Dyslexic * 1.2 Motor * 1.3 Spatial * 2 Signs and symptoms * 2.1 Associated conditions * 3 Causes * 4 Diagnosis * 5 Treatment * 6 School * 7 See also * 8 References * 9 Further reading * 10 External links ## Classification[edit] Dysgraphia is nearly always accompanied by other learning disabilities such as dyslexia or attention deficit disorder,[2][7][8] and this can impact the type of dysgraphia a person might have. Tourette’s syndrome and ASD are other common problems among dysgraphic individuals.[9]There are three principal subtypes of dysgraphia that are recognized. There is little information available about different types of dysgraphia and there are likely more subtypes than the ones listed below. Some people may have a combination of two or more of these, and individual symptoms may vary in presentation from what is described here. Most common presentation is a motor dysgraphia/agraphia resulting from damage to some part of the motor cortex in the parietal lobes.[citation needed] ### Dyslexic[edit] People with dyslexic dysgraphia have illegible spontaneously written work. Their copied work is fairly good, but their spelling is usually poor. Their finger tapping speed (a method for identifying fine motor problems) is normal, indicating that the deficit does not likely stem from cerebellar damage. A Dyslexic Dysgraphic does not necessarily have dyslexia (dyslexia and dysgraphia appear to be unrelated).[citation needed] ### Motor[edit] Dysgraphia can be difficult to diagnose because the handwriting starts out clear and slowly degrades, making the writer appear lazy. Motor dysgraphia is due to deficient fine motor skills, poor dexterity, poor muscle tone, or unspecified motor clumsiness. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and it cannot be sustained for a significant length of time, as it can cause arthritis-like tensing of the hand. Overall, their written work is poor to illegible even if copied by sight from another document, and drawing is difficult. Oral spelling for these individuals is normal, and their finger tapping speed is below normal. This shows that there are problems within the fine motor skills of these individuals. People with developmental coordination disorder may be dysgraphic. Writing is often slanted due to holding a pen or pencil incorrectly.[2] ### Spatial[edit] A person with spatial dysgraphia has a defect in the understanding of space. They will have illegible spontaneously written work, illegible copied work, and problems with drawing abilities. They have normal spelling and normal finger tapping speed, suggesting that this subtype is not fine motor based. Symptoms in actuality may vary in presentation from what is listed here.[citation needed] ## Signs and symptoms[edit] The symptoms to dysgraphia are often overlooked or attributed to the student being lazy, unmotivated, not caring, or having delayed visual-motor processing. In order to be diagnosed with dysgraphia, one must have a cluster, but not necessarily all, of the following symptoms:[2] * Odd wrist, arm, body, or paper orientations such as bending an arm into an L shape * Excessive erasures * Mixed upper case and lower case letters * Inconsistent form and size of letters, or unfinished letters * Misuse of lines and margins * Inefficient speed of copying * Inattentiveness over details when writing * Frequent need of verbal cues * Relies heavily on vision to write * Difficulty visualizing letter formation beforehand * Poor legibility * Poor spatial planning on paper * Difficulty writing and thinking at the same time (creative writing, taking notes) * Handwriting abilities that may interfere with spelling and written composition * Difficulty understanding homophones and what spelling to use[10] * Having a hard time translating ideas to writing, sometimes using the wrong words altogether * May feel pain while writing (cramps in fingers, wrist and palms)[2] Dysgraphia may cause students emotional trauma often due to the fact that no one can read their writing, and they are aware that they are not performing to the same level as their peers. Emotional problems that may occur alongside dysgraphia include impaired self-esteem, lowered self-efficacy, heightened anxiety, and depression.[2][7] They may put in extra efforts in order to have the same achievements as their peers, but often get frustrated because they feel that their hard work does not pay off.[7] Dysgraphia is a hard disorder to detect as it does not affect specific ages, gender, or intelligence.[7] The main concern in trying to detect dysgraphia is that people hide their disability behind their verbal fluency because they are ashamed that they cannot achieve the same goals as their peers.[7] Having dysgraphia is not related to a lack of cognitive ability,[2] and it is not uncommon in intellectually gifted individuals, but due to dysgraphia their intellectual abilities are often not identified.[7] ### Associated conditions[edit] There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing specially on plain paper (and spelling); younger children may cry, pout, or refuse to complete written assignments. This frustration can cause the child (or adult) a great deal of stress and can lead to stress-related illnesses. This can be a result of any symptom of dysgraphia.[5][7] ## Causes[edit] Dysgraphia is a biologically based disorder with genetic and brain bases.[2] More specifically, it is a working memory problem.[7] In dysgraphia, individuals fail to develop normal connections among different brain regions needed for writing.[7] People with dysgraphia have difficulty in automatically remembering and mastering the sequence of motor movements required to write letters or numbers.[2] Dysgraphia is also in part due to underlying problems in orthographic coding, the orthographic loop, and graphmotor output (the movements that result in writing) by one's hands, fingers and executive functions involved in letter writing.[2] The orthographic loop is when written words are stored in the mind's eye, connected through sequential finger movement for motor output through the hand with feedback from the eye.[7] ## Diagnosis[edit] Several tests exist to diagnose dysgraphia like Ajuriaguerra scale, BHK for children or teenagers, DASH and HHE scale.[11] With devices like drawing tablets, it is now possible to measure the position, tilt, and pressure in real time. From these features, it is possible to compute automatic features like speed and shaking and train a classifier to diagnose automatically children with atypical writing.[11][12] The features extracted have different importances in the classification through development and allow to characterize different subtypes of dysgraphia that could have different origins, outcomes and could require different remediation strategies.[13] ## Treatment[edit] Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. The use of occupational therapy can be effective in the school setting, and teachers should be well informed about dysgraphia to aid in carry-over of the occupational therapist's interventions. Treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting. Dysgraphia can sometimes be partially overcome with appropriate and conscious effort and training.[2] The International Dyslexia Association suggests the use of kinesthetic memory through early training by having the child overlearn how to write letters and to later practice writing with their eyes closed or averted to reinforce the feel of the letters being written. They also suggest teaching the students cursive writing as it has fewer reversible letters and can help lessen spacing problems, at least within words, because cursive letters are generally attached within a word.[citation needed] ## School[edit] There is no special education category for students with dysgraphia;[2] in the United States, The National Center for Learning Disabilities suggests that children with dysgraphia be handled in a case-by-case manner with an Individualized Education Program, or provided individual accommodation to provide alternative ways of submitting work and modify tasks to avoid the area of weakness.[5] Students with dysgraphia often cannot complete written assignments that are legible, appropriate in length and content, or within given time.[2] It is suggested that students with dysgraphia receive specialized instructions that are appropriate for them. Children will mostly benefit from explicit and comprehensive instructions, help translating across multiple levels of language, and review and revision of assignments or writing methods.[7] Direct, explicit instruction on letter formation and guided practice will help students achieve automatic handwriting performance before they use letters to write words, phrases, and sentences.[2] Some older children may benefit from the use of a personal computer or a laptop in class so that they do not have to deal with the frustration of falling behind their peers.[7] It is also suggested by Berninger that teachers with dysgraphic students decide if their focus will be on manuscript writing (printing) or keyboarding. In either case, it is beneficial that students are taught how to read cursive writing as it is used daily in classrooms by some teachers.[2] It may also be beneficial for the teacher to come up with other methods of assessing a child's knowledge other than written tests; an example would be oral testing. This causes less frustration for the child as they are able to get their knowledge across to the teacher without worrying about how to write their thoughts.[5] The number of students with dysgraphia may increase from 4 percent of students in primary grades, due to the overall difficulty of handwriting, and up to 20 percent in middle school because written compositions become more complex. With this in mind, there are no exact numbers of how many individuals have dysgraphia due to its difficulty to diagnose.[2] There are slight gender differences in association with written disabilities; overall it is found that males are more likely to be impaired with handwriting, composing, spelling, and orthographic abilities than females.[7] The Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) doesn't use the term dysgraphia but uses the phrase "an impairment in written expression" under the category of "specific learning disorder". This is the term used by most doctors and psychologists.[14] To qualify for special education services, a child must have an issue named or described in the Individuals with Disabilities Education Act (IDEA). While IDEA doesn't use the term "dysgraphia", it describes it under the category of "specific learning disability". This includes issues with understanding or using language (spoken or written) that make it difficult to listen, think, speak, read, write, spell or to do mathematical calculations.[citation needed] ## See also[edit] * Agraphia * Character amnesia * Dyscravia * Learning disability * Lists of language disorders ## References[edit] 1. ^ Chivers, M. (1991). "Definition of Dysgraphia (Handwriting Difficulty). Dyslexia A2Z. Retrieved from http://www.dyslexiaa2z.com/learning_difficulties/dysgraphia/dysgraphia_definition.html Archived 2011-02-19 at the Wayback Machine 2. ^ a b c d e f g h i j k l m n o p q r s Berninger, Virginia W.; Wolf, Beverly J. (2009). Teaching Students with Dyslexia and Dysgraphia: Lessons from Teaching and Science. Baltimore, Maryland: Paul H. Brooks Publishing Co. ISBN 978-1-55766-934-6. 3. ^ a b c Nicolson, Roderick I.; Fawcett, Angela J. (January 2011). "Dyslexia, dysgraphia, procedural learning and the cerebellum". Cortex. 47 (1): 117–27. doi:10.1016/j.cortex.2009.08.016. PMID 19818437. S2CID 32228208. 4. ^ Roux, Franck-Emmanuel; Dufor, Olivier; Giussani, Carlo; et al. (October 2009). "The graphemic/motor frontal area Exner's area revisited". Annals of Neurology. 66 (4): 537–45. doi:10.1002/ana.21804. PMID 19847902. S2CID 205341904. 5. ^ a b c d "What is Dysgraphia?". National Center for Learning Disabilities. December 9, 2010. Archived from the original on August 7, 2012. 6. ^ "agraphia". the Free Dictionary by Farlex. Retrieved 7 July 2013. 7. ^ a b c d e f g h i j k l m Berninger, Virginia W.; O'Malley May, Maggie (2011). "Evidence-Based Diagnosis and Treatment for Specific Learning Disabilities Involving Impairments in Written and/or Oral Language". Journal of Learning Disabilities. 44 (2): 167–83. doi:10.1177/0022219410391189. PMID 21383108. S2CID 44786460. 8. ^ "Bright Solutions - Free On-Line Videos". www.dys-add.com. Retrieved 23 March 2018. 9. ^ "Fact sheet: Dysgraphia, a co-morbid disorder associated with Autism Spectrum Disorders". www.autism-help.org. 10. ^ Faust, Miriam (2012-02-13). The Handbook of the Neuropsychology of Language. Wiley - Blackwell. p. 912. ISBN 9781444330403. Retrieved 16 February 2016. 11. ^ a b Asselborn, Thibault; Gargot, Thomas; Kidziński, Łukasz; Johal, Wafa; Cohen, David; Jolly, Caroline; Dillenbourg, Pierre (August 31, 2018). "Automated human-level diagnosis of dysgraphia using a consumer tablet" (PDF). NPJ Digital Medicine. 1 (1): 42. doi:10.1038/s41746-018-0049-x. ISSN 2398-6352. PMID 31304322. S2CID 52244820. 12. ^ Perrin, Sarah (September 28, 2018). "New software helps analyze writing disabilities". Medical Xpress. 13. ^ Gargot, Thomas; Asselborn, Thibault; Pellerin, Hugues; Zammouri, Ingrid; Anzalone, Salvatore M.; Casteran, Laurence; Johal, Wafa; Dillenbourg, Pierre; Cohen, David; Jolly, Caroline (2020-09-11). "Acquisition of handwriting in children with and without dysgraphia: A computational approach". PLOS ONE. 15 (9): –0237575. doi:10.1371/journal.pone.0237575. ISSN 1932-6203. Retrieved 2020-12-30. 14. ^ Patino, Erica. "Understanding Dysgraphia". Understood.org. Retrieved September 22, 2016. ## Further reading[edit] * Costa V, Fischer-Baum S, Capasso R, Miceli G, Rapp B (July 2011). "Temporal stability and representational distinctiveness: key functions of orthographic working memory". Cogn Neuropsychol. 28 (5): 338–62. doi:10.1080/02643294.2011.648921. PMC 3427759. PMID 22248210. * Gergely K, Lakos R (February 2013). "[Role of pediatricians in the diagnosis and therapy of dyslexia, dysgraphia and dyscalculia]". Orv Hetil (in Hungarian). 154 (6): 209–18. doi:10.1556/OH.2013.29526. PMID 23376688. * Martins MR, Bastos JA, Cecato AT, Araujo Mde L, Magro RR, Alaminos V (2013). "Screening for motor dysgraphia in public schools". J Pediatr (Rio J). 89 (1): 70–4. doi:10.1016/j.jped.2013.02.011. PMID 23544813. * Purcell JJ, Turkeltaub PE, Eden GF, Rapp B (2011). "Examining the central and peripheral processes of written word production through meta-analysis". Front Psychol. 2: 239. doi:10.3389/fpsyg.2011.00239. PMC 3190188. PMID 22013427. ## External links[edit] Classification D * ICD-10: F81.1, R48.8, R27.8 * ICD-9-CM: 315.2, 784.61, 784.69 * MeSH: D000381 Look up dysgraphia in Wiktionary, the free dictionary. * NINDS Dysgraphia Information Page * v * t * e Dyslexia and related specific developmental disorders Conditions Speech, language, and communication * Expressive language disorder * Infantile speech * Landau–Kleffner syndrome * Language disorder * Lisp * Mixed receptive-expressive language disorder * Specific language impairment * Speech and language impairment * Speech disorder * Speech error * Speech sound disorder * Stuttering * Tip of the tongue Learning disability * Dyslexia * Dyscalculia * Dysgraphia * Disorder of written expression Motor * Developmental coordination disorder * Developmental verbal dyspraxia Sensory * Auditory processing disorder * Sensory processing disorder Related topics * Dyslexia research * Irlen filters * Learning Ally * Learning problems in childhood cancer * Literacy * Management of dyslexia * Multisensory integration * Neuropsychology * Reading acquisition * Spelling * Writing system Lists * Dyslexia in fiction * Languages by Writing System * People with dyslexia [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	Dysgraphia	c0234144	5,765	wikipedia	https://en.wikipedia.org/wiki/Dysgraphia	2021-01-18T19:10:05	{"mesh": ["D000381"], "umls": ["C0001825", "C0234144"], "icd-9": ["784.69", "315.2", "784.61"], "wikidata": ["Q584560"]}
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. (December 2012) Diffuse unilateral subacute neuroretinitis Left eye retina photograph shows moving nematode larva at the macular area [1] Diffuse unilateral subacute neuroretinitis (DUSN) is a rare condition that occurs in otherwise healthy, often young patients and is due to the presence of a subretinal nematode.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] The clinical findings in this disease can be divided into acute and end-stage manifestations: In the acute phase, patients often present with decreased visual acuity, vitritis, papillitis, and crops of gray-white or yellow-white outer retinal lesions. The clustering of the retinal lesions is important because this often helps to localize the causative nematode. If left untreated, patients ultimately develop late sequel, which may include optic atrophy, retinal arterial narrowing, diffuse retinal pigment epithelial changes, and an abnormal electroretinogram. The late findings of this condition are often misinterpreted as unilateral retinitis pigmentosa. ## Cause[edit] DUSN may be caused by a helminthic infection with Toxocara canis, Baylisascaris procyonis, or Ancylostoma caninum. The characteristic lesions are believed to result from a single nematode migrating within the subretinal space. Although previously thought to be endemic in some areas, that belief was likely due to under awareness. DUSN has been diagnosed in patients in many countries and climates including America, Brazil, China and India.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] If the nematode can be seen by an ophthalmologist, which occurs in less than half of cases, it should be treated with photocoagulation for extramacular location and surgical removal in case the larva is lying in the macula. After the worm is killed, visual acuity loss usually does not progress. Alternatively, Antihelminthic treatment such as high dose oral Albendazole and prednisolone may be used.[1] Laser photocoagulation is the treatment of choice in cases of DUSN where the worm is seen clinically or to the outer retinal crops as the worm might be in the vicinity of these lesions.[1] The worm is identifiable in only 30% of the cases. This case may be an early stage of the disease since no optic atrophy or vascular attenuation was present. We used a PSLP for the treatment of the worm instead of a conventional laser as multiple spots of laser in a grid pattern can be administered within a faster time frame. The speed of performing the laser is important as to avoid the migration of the worm to the fovea. In case of a large worm, the first step could be targeting the ends of the worm since laser to the head end would immobilize the worm and prevent its migration.[2] ## References[edit] 1. ^ a b c Yusoff, M; Alwi, AA; Said, MM; Zakariah, S; Ghani, ZA; Zunaina, E (Jun 16, 2011). "Intraocular nematode with diffuse unilateral subacute neuroretinitis: case report". BMC Ophthalmology. 11: 15. doi:10.1186/1471-2415-11-15. PMC 3127854. PMID 21679403. 2. ^ American Academy of Ophthalmology (2012). Retina and vitreous (2011-2012 ed.). ISBN 9781615251193. [1] Relhan N, Pathengay A, Raval V, Nayak S, Choudhury H, Flynn HW Jr. Clinical experience in treatment of diffuse unilateral subretinal neuroretinitis. Clin Ophthalmol 2015;9:1799‑805 [2] Cherukuri N, Panchal B, Kaza H, Doshi S, Pathengay A. Role of PASCAL and optical coherence tomography angiograpgy in the treatment of diffuse unilateral subacute neuroretinitis caused by large live motile worm. Indian J Ophthalmol 2019;67:1494-6. ## External links[edit] Classification D External resources * eMedicine: article/1226931 [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	Diffuse unilateral subacute neuroretinitis	c0339404	5,766	wikipedia	https://en.wikipedia.org/wiki/Diffuse_unilateral_subacute_neuroretinitis	2021-01-18T19:04:54	{"umls": ["C0339404"], "wikidata": ["Q5275425"]}
Benign partial epilepsy with secondarily generalized seizures in infancy is a rare infantile epilepsy syndrome characterized by seizures presenting with motion arrest and staring. They are followed by generalized tonic-clonic convulsions with normal interictal EEG and focal paroxysmal discharges, followed by generalization in ictal EEG. Seizures usually occur in clusters and are responsive to treatment. Psychomotor development is normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Benign partial epilepsy with secondarily generalized seizures in infancy	None	5,767	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166302	2021-01-23T19:01:42	{"icd-10": ["G40.1"]}
Hernandez et al. (1996) described an 8-year-old boy with generalized osteoporosis and oculocutaneous hypopigmentation syndrome (OOCH) without cerebral defects. The child was born of a 47-year-old father and 20-year-old mother, both of Mexican extraction, who denied consanguinity. There was no family history of albinism or hearing difficulties. Psychomotor development was normal. Differences from the Cross syndrome (257800) and Preus syndrome (257790) were the lack of cerebral abnormality and the presence of osteoporosis. Skel \- Generalized osteoporosis Eyes \- Oculocutaneous hypopigmentation syndrome (OOCH) Neuro \- No cerebral defects Inheritance \- ? Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	OSTEOPOROSIS AND OCULOCUTANEOUS HYPOPIGMENTATION SYNDROME	c1832592	5,768	omim	https://www.omim.org/entry/601220	2019-09-22T16:15:13	{"mesh": ["C536062"], "omim": ["601220"], "orphanet": ["2786"]}
A rare autosomal recessive primary immunodeficiency characterized by severe reduction in the cell surface expression of HLA class I molecules, typically resulting in childhood-onset of chronic bacterial infections of the respiratory tract evolving to widespread bronchiectasis and respiratory insufficiency. Sterile necrotizing granulomatous skin lesions mainly involving the extremities and the mid-face may be observed in some patients. Severe viral infections do not occur as part of the condition. Atypical variants without respiratory or cutaneous manifestations, as well as asymptomatic individuals have 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	Immunodeficiency by defective expression of MHC class I	c1858266	5,769	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=34592	2021-01-23T19:08:44	{"gard": ["8427"], "mesh": ["C565759"], "omim": ["241600", "604571"], "umls": ["C1858266"], "icd-10": ["D81.6"], "synonyms": ["Bare lymphocyte syndrome type 1", "MHC class I deficiency"]}
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 2, a form of MRKH syndrome (see this term), is characterized by congenital aplasia of the uterus and upper 2/3 of the vagina that is associated with at least one other malformation such as renal, vertebral, or, less commonly, auditory and cardiac defects. The acronym MURCS (MÜllerian duct aplasia, Renal dysplasia, Cervical Somite anomalies) is also used. ## Epidemiology MRKH syndrome has an estimated worldwide incidence of 1/4500 live female births. The prevalence of MRKH syndrome type 2 is unknown. ## Clinical description MRKH syndrome type 2 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include upper urinary tract malformations (40% of cases), unilateral renal agenesis (23-28%; see this term), ectopia of one or both kidneys (17%; see this term), renal hypoplasia (4%), horseshoe kidney and hydronephrosis. Skeletal abnormalities, mainly of the spine and less frequently in the face and limbs, are also reported. Spinal malformations encountered include scoliosis, isolated vertebral anomalies (asymmetric, fused or wedged vertebrae), isolated Klippel-Feil syndrome and/or Sprengel deformity (see these terms), rib malformation or agenesis, and spina bifida (see this term). Face and limb malformations are mainly brachymesophalangy, ectrodactyly, duplicated thumb, absent radius, atrio-digital dysplasia (Holt-Oram-like syndrome) and facial asymmetry. Hearing impairment, due to middle ear malformations or sensorineural defects, is seen in 10-25% of cases. Heart malformations are very rare but include valvular pulmonary stenosis, Tetralogy of Fallot (see these terms) Holt-Oram or velocardiofacial-like syndromes, aorto-pulmonary window or atrial septal defects. ## Etiology The exact etiology of MRKH syndrome remains largely unknown, even if the spectrum of malformation encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as HNF1B (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 ( 16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, cannot be established. ## Genetic counseling MRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial 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	Mayer-Rokitansky-Küster-Hauser syndrome type 2	c1832817	5,770	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2578	2021-01-23T17:57:15	{"gard": ["5513"], "mesh": ["C537371"], "omim": ["601076"], "umls": ["C1832817"], "icd-10": ["Q87.8"], "synonyms": ["Atypical MRKH syndrome", "MRKH syndrome type 2", "MURCS association", "Müllerian duct aplasia-renal dysplasia-cervical somite anomalies syndrome"]}
Tetrasomy 9p is a rare autosomal anomaly characterized by pre- and postnatal growth retardation, psychomotor delay, mild to moderate intellectual disability, hypotonia, microcephaly, dysmorphic features (ocular hypertelorism, low-set, malformed ears, bulbous/beaked nose, microretrognathia, enophthalmos/micropthalmia, epicanthus, strabismus), cleft lip/palate, skeletal abnormalities (hypoplastic nails/distal phalanges, short stature, short neck, contractures), congenital heart defects, renal and urogenital malformations (renal hypoplasia, genital hypoplasia, cryptorchidism). [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	Tetrasomy 9p	c0795832	5,771	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3310	2021-01-23T17:42:23	{"gard": ["42"], "mesh": ["C538027"], "umls": ["C0795832"], "icd-10": ["Q99.8"], "synonyms": ["Isochromosome 9p"]}
A rare developmental defect of the eye characterized by usually bilateral absence of the normal protrusion of the cornea from the sclera, the corneal curvature being the same as that of the adjacent sclera. Most patients develop hyperopia, hazy corneal limbus, and arcus lipoides at an early age. The condition may present as an autosomal dominant or an autosomal recessive form, with the latter showing more severe signs and symptoms (such as a round and opaque thickening located centrally in the cornea) and more frequent association with other ocular anomalies. [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	Congenital cornea plana	c1852557	5,772	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=53691	2021-01-23T17:09:00	{"mesh": ["C565158"], "omim": ["121400", "217300"], "icd-10": ["Q13.4"]}
Cutaneous amoebiasis Other namesAoebiasis cutis,[1] SpecialtyInfectious disease Cutaneous amoebiasis, refers to a form of amoebiasis that presents primarily in the skin. It can be caused by Acanthamoeba[2][3] or Entamoeba histolytica.[4]:421[5] When associated with Acanthamoeba, it is also known as "cutaneous acanthamoebiasis".[6] Balamuthia mandrillaris can also cause cutaneous amoebiasis, but can prove fatal if the amoeba enters the bloodstream [7][8] ## Contents * 1 Diagnosis * 2 See also * 3 References * 4 External links ## Diagnosis[edit] It is characterized by ulcers. Diagnosis of amebiasis cutis calls for high degree of clinical suspicion. This needs to be backed with demonstration of trophozoites from lesions. Unless an early diagnosis can be made such patients can suffer from significant morbidity.[9] ## See also[edit] * Skin lesion ## References[edit] 1. ^ Bumb RA, Mehta RD (2006). "Amoebiasis cutis in HIV positive patient". Indian J Dermatol Venereol Leprol. 72 (3): 224–6. doi:10.4103/0378-6323.25786. PMID 16766840. 2. ^ "EyeRounds.org:Acanthamoeba Keratitis: 39-year-old contact lens wearer with persisting keratitis & pain". Retrieved 2009-01-17. 3. ^ Walia R, Montoya JG, Visvesvera GS, Booton GC, Doyle RL (March 2007). "A case of successful treatment of cutaneous Acanthamoeba infection in a lung transplant recipient". Transpl Infect Dis. 9 (1): 51–4. doi:10.1111/j.1399-3062.2006.00159.x. PMID 17313473. 4. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 5. ^ Kenner BM, Rosen T (2006). "Cutaneous amebiasis in a child and review of the literature". Pediatr Dermatol. 23 (3): 231–4. doi:10.1111/j.1525-1470.2006.00223.x. PMID 16780468. 6. ^ Da Rocha-Azevedo, B.; Tanowitz, H.; Marciano-Cabral, F. (2009). "Diagnosis of infections caused by pathogenic free-living amoebae". Interdisciplinary Perspectives on Infectious Diseases. 2009: 251406. doi:10.1155/2009/251406. PMC 2719787. PMID 19657454. 7. ^ Rocha-Azevedo B, Jamerson M, Cabral GA, Silva-Filho FC, Marciano-Cabral F (January 2007). "The interaction between the amoeba Balamuthia mandrillaris and extracellular matrix glycoproteins in vitro". Parasitology. 134 (Pt 1): 51–8. doi:10.1017/S0031182006001272. PMID 17032481. 8. ^ Pritzker AS, Kim BK, Agrawal D, Southern PM, Pandya AG (February 2004). "Fatal granulomatous amebic encephalitis caused by Balamuthia mandrillaris presenting as a skin lesion". J. Am. Acad. Dermatol. 50 (2 Suppl): S38–41. doi:10.1016/s0190-9622(03)02090-5. PMID 14726864. 9. ^ Verma, Ghanshyam K; Sharma, Nand Lal; Shanker, Vinay; Mahajan, Vikram K; Kaushik, Rajani; Verma, Santwana; Jindal, Nidhi (February 2010). "Amoebiasis cutis: Clinical suspicion is the key to early diagnosis". Australasian Journal of Dermatology. 51 (1): 52–55. doi:10.1111/j.1440-0960.2009.00594.x. PMID 20148845. ## External links[edit] Classification D * ICD-10: A06.7 * ICD-9-CM: 006.6 * v * t * e Amoebozoal diseases Lobosea (free-living) Centramoebida * Acanthamoeba * Acanthamoeba keratitis * Cutaneous acanthamoebiasis * Granulomatous amoebic encephalitis * Acanthamoeba infection * Balamuthia mandrillaris * Balamuthia amoebic encephalitis * Balamuthia infection Flabellinia * Sappinia diploidea/Sappinia pedata * Sappinia amoebic encephalitis Conosa/Archamoebae * Entamoeba histolytica * Amoebiasis * Amoebic dysentery * Amoebic liver abscess * Cutaneous amoebiasis * Amoebic brain abscess * Amebiasis cutis * Entamoeba gingivalis * v * t * e Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji 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	Cutaneous amoebiasis	c0002441	5,773	wikipedia	https://en.wikipedia.org/wiki/Cutaneous_amoebiasis	2021-01-18T18:53:28	{"umls": ["C0002441"], "icd-9": ["006.6"], "icd-10": ["A06.7"], "wikidata": ["Q5196686"]}
Not to be confused with Sudden arrhythmic death syndrome. Sudden Death Syndrome (SDS), a disease in soybean plants, quickly spread across the southern United States in the 1970s, eventually reaching most agricultural areas of the US. SDS is caused by a Fusarium fungi, more specifically the soil-borne root pathogen Fusarium virguliforme, formerly known as Fusarium solani f. sp. glycines.[1] Losses could exceed hundreds of millions of dollars in US soybean markets alone making it one of the most important diseases found in Soybeans across the US.[1] ## Contents * 1 Importance * 2 Symptoms and signs * 3 Disease cycle * 4 Environmental factors * 5 Disease development * 6 Management * 7 References ## Importance[edit] Sudden Death Syndrome (SDS) has become one of the most impactful yield-reducing diseases in North American soybeans. After making its first appearance in Arkansas in 1971 SDS soon spread to the surrounding states of Tennessee and Mississippi, and then traveled up the Mississippi River to Midwestern states.[2] Currently, the disease affects an area stretching from South Dakota to North Carolina, putting the majority of American soybean producers at risk. The disease has the potential to cause up to 80% yield loss, making it a devastating disease for producers if not detected early and managed correctly.[2] Its presence is currently increasing in northern Midwest states and western Corn Belt states including Minnesota, Nebraska, and Wisconsin, and may coincide with the spread of the Soybean Cyst Nematode (SCN).[2] ## Symptoms and signs[edit] Most of the SDS symptoms can be confused with other factors like nutrient deficiencies and some other diseases like brown stem rot and stem canker.[3] Usually the first symptom seen is interveinal chlorosis, which is the yellowing of the plant material between the leaf veins.[4] When leaves begin to die, puckering and mottling can also be observed along with the chlorosis.[5] As severity increases, necrosis (death of cells) occurs and eventually these leaves will fall off, leaving only petioles left on the stem.[6] If the conditions are right (cool and wet), these symptoms can appear suddenly, causing large yield reductions. Normally, this is seen in mid or late July around the time of flowering and pod production.[7] In addition to foliar symptoms, the stem of the soybean plant can show symptoms as well. If a soybean stem with SDS is split, the pith will be visibly white while the cortical tissue around the pith will be tan to light brown in color.[3][1] If the pith is brown in color (or if the whole stem looks brown on the inside), it is likely that the plant has brown stem rot, rather than SDS.[3] Along with the above-ground foliar and stem symptoms, the roots usually show some kind of rotting and decrease in vigor compared to other healthy soybean roots.[1] If soil conditions are moist, roots are also likely to show blue masses of spores (macroconidia) around the taproot just below the soil surface.[1] Blue fungal masses, found along with the foliar and stem symptoms, are strong diagnostic indicators for SDS.[1] ## Disease cycle[edit] F. virguliforme overwinters as asexual macroconidium and chlamydospores and currently, no research has found a successful sexual stage with this pathogen.[1] When conditions are favorable, these spores germinate on seedling roots and infect the plant. From the V1 to R1 stages (seedling to first flower) of soybean growth, the fungus colonizes within the plant cortex and only goes up the stem a few inches above the soil surface.[1] Toxins are produced when the pathogen colonizes the lower parts of the soybean cortex. These toxins travel up the xylem to the leaves, causing leaf chlorosis and necrosis, eventually leading to leaf and pod drop.[4][1] Blue Fungal spore masses are produced on the roots of the plant where macroconidia are formed. Macroconidia are one of the overwintering phases of the pathogen and can persist in the soil and plant residue for many years.[1] Between growing seasons, F. virguliforme is also found in the form of chlamydospores in the crop residue and freely in the soil.[1] These thick-walled overwintering structures can withstand large temperature fluctuations within the soil and even resist desiccation.[1] ## Environmental factors[edit] Cool and wet soil is the most ideal condition for F. virguliforme, the pathogen that causes SDS.[8][2][9][10] The presence of the disease is often able to be tracked with storm fronts moving across the country. Symptoms of SDS are usually common 10–14 days after heavy rains. While the disease prefers cool soil, symptoms often do not manifest themselves until July or August after a soaking rain saturates the soil. Early planting can leave seeds susceptible to SDS, as can planting vulnerable varieties. SCN infection of a population of plants also creates a favorable environment for SDS, as the roots of the plants are already under stress from the nematode, leaving them vulnerable to infection from F. virguliforme. In addition to cool wet soils, the presence of SCN is one of the most important environmental factors for SDS. Limiting soybean exposure to SCN is much easier in comparison to SDS, so limiting a field's vulnerability to SCN is vital to preventing the introduction of SDS. Environmental factors are some of the largest variables that will determine both the presence and severity of an SDS infection. The ability to control and react to as many of these factors as possible is key to protecting a soybean crop from SDS. ## Disease development[edit] F. virguliforme is a soil-borne pathogen that starts by infecting the roots of soybean seedlings after germination. The fungus then moves up the plant and infects the vascular tissue, causing a brown color within the cortex around the pith of the plant a few inches above the soil surface.[1] Toxins are produced by the fungus when it colonizes the cortex and are sent up the stem to the leaves, causing the above-ground symptoms around first flower during mid-summer.[1] While infection occurs early in the season, symptoms do not normally appear until mid-summer.[11] SDS also has a synergistic relationship with Soybean Cyst Nematode (SCN). Fields that have SCN presence have more severe SDS symptoms.[4] While it is not known exactly how the two interact, it is known that symptoms of SDS are more severe when SCN are present in the field and that F. virguliforme can be isolated from an SCN that is found in the same area as this pathogen.[1] ## Management[edit] -Plant resistant cultivars: Planting SDS resistant cultivars is likely the most reliable way to prevent SDS infection of a soybean crop.[11][9][8] Previously, finding SDS resistant soybean varieties had been fairly difficult to find, and were fairly expensive. However, as the prevalence of SDS in high soybean production areas has increased, seed companies have begun to develop more varieties resistant to F. veruguliforme and SDS. Both resistant and moderately resistant varieties are available. In an informal survey of seed companies showed that about 57% of cultivars are labeled as at least moderately resistant. Individual company lines had a range of 40%-60% of their cultivars labeled as at least moderately resistant.[11] It is important to note that not all seed companies give information regarding the impacts that SDS has on their soybean varieties. It is also recommended to plant a variety that is also resistant to SCN, as the presence of this pathogen can impact the response that a plant has to F. vurguliforme. Because of the symbiotic relationship between these two pathogens, it is important to collect information regarding both when selecting a soybean variety. Most seed companies will release information regarding SCN. -Plant a week or two later: This is a practice that works well in theory but is hard to put into practice in the field. Due to tight schedules and unpredictable spring weather patterns in the Midwest and Great Plains, it can be hard to not plant soybeans as soon as possible. However, when possible, growers should consider waiting one or two weeks after typical early planting dates to allow soil to warm and dry, which will help protect the seedlings from being infected by F. virugliforme. The pathogen does not prefer to infect seedlings in warmer and drier soil. If planting later is not an option, an extra pass over the field with a soil finisher or other shallow tillage implement will also help to expose soil and dry it out. -Take active measures to decrease Soybean Cyst Nematode populations: A good way to help prevent and at least slow the spread and onset of F. virugliforme and SDS is to limit the spread and population of SCN. SCN and F. virugliforme have a symbiotic relationship that helps both to spread throughout fields. Limiting the spread of SCN can be a tedious task, as this requires the prevention of soil transferring from field to field. This means washing equipment and tires between fields. While this can be unrealistic for large growers, a recommendation is a quick rinsing of tires and equipment when moving to different areas or farms. While this is still tedious, it is not as time consuming as doing it after every field, and may save growers some yield down the road. -Limit compaction: While this will not prevent SDS and its spread entirely, limiting soil compaction can help to lessen the severity and yield impact of SDS. When soil becomes compacted, it has less porosity and holds more water. This is very favorable to SDS infection and makes it very hard to control and lessen its severity. Practices that can help to limit compaction include using GPS to run in the same tracks every time you run a pass across the field (tillage, planting, spraying, etc.), using tracks or LSW flotation tires on equipment whenever possible, avoiding driving loaded grain trucks on the field whenever possible, and limiting the travel of loaded grain carts across the field as much as possible. -Keeping an ideal soil pH: SDS thrives in soils with pH exceeding 7.0.[12] SCN also thrives in high pH and can be controlled by lowering soil pH.[12] It is important to note that lowering soil pH below 6.5 leaves soybeans more vulnerable to brown stem rot. Regular soil sampling and the application of gypsum, lime and sulfur are good practices to help control soil pH. -Tillage: No-till systems are particularly vulnerable to SDS,[13][10] as the soil remains cooler and wetter due to not being tilled. While there are benefits to no-till systems, it may be beneficial to consider light tillage prior to planting in cooler and wetter years to help open-up soil to the wind and sun. This will help to dry and warm the soil slightly. Generally, this will require some form of disc or soil finisher, as the coulters on a no-till grain drill generally do not provide enough disturbance to make a measurable difference on soil temperature and moisture by the time of seedling germination. Corn and soybean residue that is left on the field and not tilled under has also been found to maintain inoculum levels of the fungus, which could possibly cause an SDS infection in the next soybean crop.[8] For this reason, a deep tillage that disrupts surface soil is recommended in fields that have been known to have SDS problems in the past. Chisel plows, moldboard plows, field cultivators with v-shoes, and rippers are all effective tillage tools for this type of situation. ## References[edit] 1. ^ a b c d e f g h i j k l m n o "Sudden death syndrome of soybean". www.apsnet.org. Retrieved 2016-11-16. 2. ^ a b c d "Sudden Death Syndrome". WISCONSIN FIELD CROPS PATHOLOGY. Retrieved 2020-12-10. 3. ^ a b c "Sudden Death Syndrome" (PDF). www.iasoybeans.com. Iowa Soybean Association. 2010. 4. ^ a b c "SDS - Crop Protection Network". Crop Protection Network. Retrieved 2016-11-15. 5. ^ "Foliar symptom expression in association with Fusarium virguliforme, causal agent of soybean sudden death syndrome". www.plantmanagementnetwork.org. Retrieved 2016-11-15. 6. ^ Corn and Soybean Field Guide. 2013. p. 172. 7. ^ "Wanted for Yield Robbery: Sudden Death Syndrome". United Soybean Board. Retrieved 2016-11-16. 8. ^ a b c Hartman, G. L.; Chang, H. -X.; Leandro, L. F. (2015-07-01). "Research advances and management of soybean sudden death syndrome". Crop Protection. Ecology and management of Fusarium diseases. 73: 60–66. doi:10.1016/j.cropro.2015.01.017. ISSN 0261-2194. 9. ^ a b "Sudden Death Syndrome of Soybean \| Minnesota Department of Agriculture". www.mda.state.mn.us. Retrieved 2020-12-10. 10. ^ a b "Sudden Death Syndrome of Soybean". cropprotectionnetwork.org. Retrieved 2020-12-10. 11. ^ a b c "Crop Focus: Sudden Death Syndrome of Soybeans" (PDF). www.pioneer.com. Pioneer Agronomy Services. 2010. 12. ^ a b "Sudden Death Syndrome - Soybean Disease". Soybean Research & Information Network. Retrieved 2020-12-10. 13. ^ "Sudden death syndrome on soybean". extension.umn.edu. Retrieved 2020-12-10. [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	Sudden Death Syndrome	None	5,774	wikipedia	https://en.wikipedia.org/wiki/Sudden_Death_Syndrome	2021-01-18T18:39:22	{"wikidata": ["Q30314063"]}
A number sign (#) is used with this entry because hereditary sensory neuropathy type IIC (HSN2C) is caused by homozygous or compound heterozygous mutation in the KIF1A gene (601255) on chromosome 2q37. Mutation in the KIF1A gene can also cause hereditary spastic paraplegia-30 (SPG30; 610357). Description HSN2C is an autosomal recessive disorder characterized by onset in the first decade of progressive distal sensory loss leading to ulceration and amputation of the fingers and toes. Affected individuals also develop distal muscle weakness, primarily affecting the lower limbs (summary by Riviere et al., 2011). For a discussion of genetic heterogeneity of HSN, see HSAN1 (162400). Clinical Features Riviere et al. (2011) reported 3 sibs, born of consanguineous Afghan parents, with childhood-onset of hereditary sensory neuropathy. Age at onset ranged between 6 and 10 years. The disorder was characterized by distal numbness of the hands and feet, resulting in ulcerative and mutilated lesions and amputation. There was also mild distal muscle weakness mainly in the lower limbs, associated with wasting of muscles in the lower leg. Vibration and position sense were absent in the feet and hands, but pinprick and touch were normal. Deep tendon reflexes were generally absent. Electrophysiologic studies showed decreased or absent sural, median, and ulnar nerve sensory potentials. Tibial and peroneal motor potentials were decreased or absent. A second family, of Turkish origin, had 2 affected sibs. Both had painless ulcerations, with amputations in 1. Both had distal weakness in the lower limb with milder weakness in the upper limbs. In a third family, 2 Belgian sibs, aged 61 years, had panmodal distal sensory loss with distal ulcerations and amputations of the fingers and toes. Each of these sibs had complete motor paralysis of 1 lower limb. In another Belgian family, an 8-year-old boy had a more severe disorder with panmodal sensory loss and additional features, including low IQ, slowed speech development, short stature, equinus deformities, and was wheelchair-bound. Inheritance The transmission pattern of hereditary sensory neuropathy in the families reported by Riviere et al. (2011) was consistent with autosomal recessive inheritance. Molecular Genetics By genomewide homozygosity mapping followed by candidate gene analysis in a consanguineous Afghan family with HSN2C, Riviere et al. (2011) identified a homozygous truncating mutation in the KIF1A gene (601255.0002). Screening of this gene in 112 unrelated patients with HSAN identified 2 additional families with the same mutation and 1 patient who was compound heterozygous for 2 mutations (601255.0002 and 601255.0003). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (1 patient) SKELETAL Hands \- Ulceration and amputation of the fingers due to sensory loss Feet \- Ulceration and amputation of the toes due to sensory loss \- Equinus deformities (1 patient) MUSCLE, SOFT TISSUES \- Distal leg muscle atrophy \- Distal weakness, upper and lower limbs (variable) \- Paralysis of the lower limbs (later) NEUROLOGIC Central Nervous System \- Delayed psychomotor development (1 patient) Peripheral Nervous System \- Distal sensory loss, panmodal (retained in some patients) \- Hyporeflexia \- Areflexia \- Spontaneous pain (1 patient) \- Decreased or absent sensory potentials in the sural, ulnar and median nerves \- Decreased or absent motor potentials in the tibial and peroneal nerves MISCELLANEOUS \- Onset in childhood \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the kinesin family member 1A gene (KIF1A, 601255.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	NEUROPATHY, HEREDITARY SENSORY, TYPE IIC	c0020072	5,775	omim	https://www.omim.org/entry/614213	2019-09-22T15:56:06	{"doid": ["0070147"], "mesh": ["D009477"], "omim": ["614213"], "orphanet": ["970"], "genereviews": ["NBK49247"]}
Pityriasis rubra pilaris (PRP) refers to a group of skin conditions that cause constant inflammation and scaling of the skin. People with PRP have reddish, scaly patches that may occur everywhere on the body, or only on certain areas. Some people with PRP also develop thickened skin on the underside of the hands and feet (palmoplantar keratoderma), various nail abnormalities, and/or thinning of the hair. There are several types of PRP classified by age when symptoms begin, body areas involved, and whether other conditions are present. This condition occurs in adults (adult onset PRP) as well as children (juvenile onset PRP). In most cases, PRP is not inherited and the cause is not known. In some people, particularly some with type V (the “atypical juvenile type”), PRP has autosomal dominant inheritance and may be caused by mutations in the CARD14 gene. Treatment options vary based on symptoms and severity. No one treatment works for all people with PRP. Examples of treatment options include topical emollients or medications, oral retinoids, and/or immunosuppressants. [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	Pityriasis rubra pilaris	c0032027	5,776	gard	https://rarediseases.info.nih.gov/diseases/7401/pityriasis-rubra-pilaris	2021-01-18T17:58:18	{"mesh": ["D010916"], "omim": ["173200"], "orphanet": ["2897"], "synonyms": []}
Obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome is characterised by precocious obesity, congenital hypothyroidism, neonatal colitis, cardiac hypertrophy, craniosynostosis and developmental delay. It has been described in two brothers, one of whom died within the first month of life. The parents of the two children were nonconsanguineous and in good health, however, the pregnancies were complicated by a maternal HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelets). The mode of inheritance has not yet been clearly established. [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	Obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome	None	5,777	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88643	2021-01-23T18:28:11	{}
A number sign (#) is used with this entry because of evidence that hereditary megaloblastic anemia-1 can be caused by mutation in the gene encoding cubilin (CUBN; 602997) or the AMN (605799) gene. The CUBN and AMN gene products form a complex that acts as a receptor for vitamin B12 and gastric intrinsic factor (GIF; 609342). Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN. Description Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor. See also congenital pernicious anemia due to a defect in intrinsic factor (261000). Adult pernicious anemia (170900) is a distinct autoimmune disorder associated with plasma autoantibodies to gastric parietal cells or gastric intrinsic factor. In these cases, there is gastric atrophy and a relatively high frequency of associated thyroiditis and myxedema. Clinical Features Waters and Murphy (1963) reported 3 affected brothers. Both parents and 5 other sibs had subnormal or borderline vitamin B12 absorption. See also Lambert et al. (1961). Mollin et al. (1955) reported juvenile pernicious anemia in the offspring of a first-cousin marriage. The father developed classic pernicious anemia in middle age. These may have been cases of congenital pernicious anemia due to a defect in intrinsic factor (261000). Grasbeck (1960) described pernicious anemia in association with proteinuria. Whereas a defect in production of intrinsic factor was postulated by the authors cited above, Grasbeck (1960) favored a selective defect in intestinal absorption of vitamin B12 in this disorder which was uninfluenced by administration of intrinsic factor. Proteinuria and malformation of the urinary tract were also present. Imerslund and Bjornstad (1963) and Lamy et al. (1961) reported on the syndrome of chronic relapsing megaloblastic anemia and permanent proteinuria. Mohamed et al. (1966) reported sisters with selective malabsorption of vitamin B12 with adequate gastric secretion of functionally competent intrinsic factor and hydrochloric acid. Persistent proteinuria appears to be an integral part of the syndrome (Mohamed et al., 1966). The latter authors gave a genetic analysis of published cases. In the oldest known patient, Goldberg and Fudenberg (1968) found normal amounts of biologically active intrinsic factor in the gastric juice and found neither antibodies to intrinsic factor nor inhibitors of intrinsic factor. The mechanism of defective absorption was unknown. MacKenzie et al. (1972) studied 3 brothers and found no morphologic abnormality of the ileal mucosa. There seems to be no defect in ileal receptors for the complex between intrinsic factor and B12; the defect appears to be located between the attachment of B12 to the surface of the ileal cell and the binding to transcobalamin II. On the other hand, Burman et al. (1985) described absence of functional receptor. It was inferred that there may be more than one nonallelic form of this disorder--a not surprising finding in light of the complexity of cobalamin absorption. In 1972 Grasbeck stated that 47 cases were known, of which 21 had been diagnosed in Finland. Nevanlinna (1980) stated that in Finland 27 cases in 17 sibships had been identified. Spurling et al. (1964) described 2 Baltimore sisters with this syndrome who had proteinuria. Their parents were fourth cousins. Urban et al. (1981) described 3 cases from 2 families with congenital B12 malabsorption without proteinuria. The defect in intestinal absorption may have been partial. Broch et al. (1984) described a long-term follow-up on 14 patients, aged 6 to 46 years at the time of report. Those with proteinuria in childhood continued to excrete protein (an average of 750 mg/24 hrs), but it seemed that no progression of the renal lesion had occurred. Lin et al. (1994) described 2 affected brothers in a Chinese family. An unusual feature was widespread mottled skin pigmentation, termed poikiloderma, which, unlike the hyperpigmentation sometimes seen with vitamin B12 deficiency, did not respond to treatment. The skin changes in these young adults had been present since the age of 3 or 4 years. Al Essa et al. (1998) described 2 Saudi sisters with this disorder. In children, early anemia usually leads to the diagnosis. In this case, however, the presence of hemoglobinopathy that required frequent transfusions masked the usual macrocytosis, and the older sister was not diagnosed until the age of 12 years when neurologic changes became apparent. Dementia and paralysis responded remarkably to treatment, despite the late diagnosis. Rossler et al. (2003) reported a Lebanese family in which 2 sisters and their 2 first cousins all had Imerslund-Grasbeck syndrome without proteinuria. All presented with classic symptoms of anemia between age 6 and 11 years, and all responded well to treatment with cobalamin. In 2 patients, Schilling test showed 18 to 27% ileal uptake of intrinsic factor/cobalamin, consistent with partial function. Partial function of cobalamin uptake may explain the absence of proteinuria in affected members of this family. Mapping ### Linkage to Chromosome 10 Working with Ralph Grasbeck, an original discoverer of this disorder (Grasbeck and Kantero, 1959; Grasbeck, 1960; Grasbeck, 1972), Aminoff et al. (1995) reported linkage of a recessive gene locus for malabsorption of vitamin B12 to chromosome 10 in multiplex families from Finland and Norway. The locus was assigned to the 6-cM interval between markers D10S548 and D10S466, with a multipoint maximum lod score of 5.36 near marker D10S1477. By haplotype analysis, the healthy sibs in these families did not appear to constitute examples of nonpenetrance, i.e., they appeared not to be homozygotes. A phenomenon awaiting explanation had been the observation that in Finland and Norway, within a few years of the initial description of the condition in 1959 and 1960, many cases were diagnosed, but 30 years later almost no new cases were recognized. Aminoff et al. (1995) hypothesized that the paucity of new cases in these populations was due either to a dietary effect on the gene penetrance that changed with time, or to a drop in the birth rate in subpopulations showing enrichment of the mutation, or to both of these causes. They symbolized the disease locus MGA1 (megaloblastic anemia-1) and localized it to 10p12.1. Kozyraki et al. (1998) used fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones to map the human cubilin gene (602997) to the same region where the MGA1 locus maps. Thus, cubilin was a strong candidate for the molecule whose impaired synthesis, processing, or ligand binding is the basis of this hereditary form of megaloblastic anemia. ### Linkage to Chromosome 14 Aminoff et al. (1999) demonstrated that most cases of this disorder in Finland, where it is relatively frequent, are the result of homozygosity for a missense mutation in the gene encoding cubilin. Unexpectedly, however, Norwegian individuals showing the MGA1 phenotype, as described by Imerslund (1960) (the Norwegian partner in the double eponym), did not have mutations in CUBN. Tanner et al. (2003) used these families to carry out a genomewide search for linkage and established linkage to 14q. They reasoned that candidate genes might have an expression pattern similar to that of CUBN, and previous work indicated high expression in the kidney and small intestine. In searching the database for ESTs, amnionless (AMN; 605799) emerged as a strong candidate. Cytogenetics Celep et al. (1996) described Imerslund-Grasbeck syndrome in 3 Turkish sibs with first-cousin parents. One of the sibs was found to have a deletion of the 2 terminal bands of chromosome 21, q22.2 and q22.3. No other members of the family had a cytogenetic abnormality; 2 affected sibs had previously died. The authors stated that 'the syndrome has not been mapped to a particular chromosome,' and suggested that there might be an etiologic connection between the chromosome deletion and IGS in this case. In fact, it was probably coincidence. Pathogenesis Fyfe et al. (2004) showed that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and form a tightly bound complex early in the biosynthetic pathway that is essential for apical membrane localization and endocytic functions previously ascribed to cubilin alone. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubilin/AMN (cubam) complex and cause Imerslund-Grasbeck syndrome. Diagnosis In 7 families previously diagnosed with Imerslund-Grasbeck syndrome due to inconclusive results on radiocobalamin absorption tests, but who were negative for mutations in the CUBN or the AMN gene, Tanner et al. (2005) identified homozygosity for 6 different mutations in the GIF gene (609342.0002-609342.0007). Tanner et al. (2005) proposed that rather than radiocobalamin absorption tests, mutation analysis of the CUBN, AMN, and GIF genes may be the diagnostic method of choice for cobalamin absorption disorders. Molecular Genetics Tanner et al. (2003) identified 3 different mutations in the AMN gene in homozygosity among 11 affected individuals from 5 families, with heterozygosity found in the 5 parents available for study. Tanner et al. (2004) studied 42 sibships with MGA1, 24 of which were from Scandinavia and 15 from the Middle East. They found that all cases in Finland were caused by mutation in the CUBN gene (3 different mutations were identified), and all cases in Norway were caused by mutation in the AMN gene (2 different mutations were identified); in Turkey, Israel, and Saudi Arabia, there were 2 different AMN mutations and 3 different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in 5 families and tentatively in 3 families, suggesting the presence of at least 1 more gene locus that can cause MGA1. Tanner et al. (2004) concluded that the Scandinavian cases were typical examples of enrichment by founder effects, whereas in the Mediterranean region, high degrees of consanguinity exposed rare mutations in both genes. They suggested that in both regions, physicians' awareness of this disease causes it to be more readily diagnosed than elsewhere. Bouchlaka et al. (2007) reported 9 patients with MGA1 from 6 unrelated consanguineous Tunisian families. Linkage analysis and homozygosity mapping showed that 4 of the families likely had mutations in the CUBN gene, although screening for known mutations in the CUBN gene was negative. Affected members of 1 of the other families had a mutation in the AMN gene (605799.0003) that had been previously reported in a Jewish Israeli family of Tunisian origin and in Turkish families, suggesting a founder effect. The sixth family was excluded from both loci, suggesting further genetic heterogeneity. Animal Model He et al. (2003) demonstrated that Imerslund-Grasbeck syndrome in the dog maps to a region that is orthologous to human 14q and contains the AMN gene, and is presumably caused by mutation in that gene. INHERITANCE \- Autosomal recessive ABDOMEN Gastrointestinal \- Malabsorption of vitamin B12 (cyanocobalamin) \- Normal intrinsic factor protein NEUROLOGIC Central Nervous System \- Confusion \- Dementia Peripheral Nervous System \- Paresthesias \- Sensory impairment \- Peripheral neuropathy HEMATOLOGY \- Megaloblastic anemia, chronic, relapsing \- Pernicious anemia, not influenced by intrinsic factor IMMUNOLOGY \- No antibodies to intrinsic factor LABORATORY ABNORMALITIES \- Proteinuria \- Decreased levels of serum vitamin B12 \- Normal serum folate levels MISCELLANEOUS \- Early childhood onset (before age 5 years) MOLECULAR BASIS \- Caused by mutation in the intrinsic factor-vitamin B12 receptor gene (CUBN, 602997.0001 ) \- Caused by mutation in the amnion associated transmembrane protein gene (AMN, 605799.0001 ) ▲ 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	MEGALOBLASTIC ANEMIA 1	c1306856	5,778	omim	https://www.omim.org/entry/261100	2019-09-22T16:23:35	{"doid": ["13382"], "omim": ["261100"], "icd-10": ["D51.1"], "orphanet": ["35858"], "synonyms": ["Alternative titles", "MGA1", "IMERSLUND-GRASBECK SYNDROME", "PERNICIOUS ANEMIA, JUVENILE, DUE TO SELECTIVE INTESTINAL MALABSORPTION OF VITAMIN B12, WITH PROTEINURIA", "ENTEROCYTE COBALAMIN MALABSORPTION", "ENTEROCYTE INTRINSIC FACTOR RECEPTOR, DEFECT OF"]}
Pigmented wart SpecialtyDermatology Pigmented warts are a cutaneous condition commonly reported in Japan, most often occurring on the hands or feet.[1]:404 ## See also[edit] * Skin lesion * 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 0-7216-2921-0. * v * t * e Skin infections, symptoms and signs related to viruses DNA virus Herpesviridae Alpha HSV * Herpes simplex * Herpetic whitlow * Herpes gladiatorum * Herpes simplex keratitis * Herpetic sycosis * Neonatal herpes simplex * Herpes genitalis * Herpes labialis * Eczema herpeticum * Herpetiform esophagitis Herpes B virus * B virus infection VZV * Chickenpox * Herpes zoster * Herpes zoster oticus * Ophthalmic zoster * Disseminated herpes zoster * Zoster-associated pain * Modified varicella-like syndrome Beta * Human herpesvirus 6/Roseolovirus * Exanthema subitum * Roseola vaccinia * Cytomegalic inclusion disease Gamma * KSHV * Kaposi's sarcoma Poxviridae Ortho * Variola * Smallpox * Alastrim * MoxV * Monkeypox * CPXV * Cowpox * VV * Vaccinia * Generalized vaccinia * Eczema vaccinatum * Progressive vaccinia * Buffalopox Para * Farmyard pox: Milker's nodule * Bovine papular stomatitis * Pseudocowpox * Orf * Sealpox Other * Yatapoxvirus: Tanapox * Yaba monkey tumor virus * MCV * Molluscum contagiosum Papillomaviridae HPV * Wart/plantar wart * Heck's disease * Genital wart * giant * Laryngeal papillomatosis * Butcher's wart * Bowenoid papulosis * Epidermodysplasia verruciformis * Verruca plana * Pigmented wart * Verrucae palmares et plantares * BPV * Equine sarcoid Parvoviridae * Parvovirus B19 * Erythema infectiosum * Reticulocytopenia * Papular purpuric gloves and socks syndrome Polyomaviridae * Merkel cell polyomavirus * Merkel cell carcinoma RNA virus Paramyxoviridae * MeV * Measles Togaviridae * Rubella virus * Rubella * Congenital rubella syndrome ("German measles" ) * Alphavirus infection * Chikungunya fever Picornaviridae * CAV * Hand, foot, and mouth disease * Herpangina * FMDV * Foot-and-mouth disease * Boston exanthem disease Ungrouped * Asymmetric periflexural exanthem of childhood * Post-vaccination follicular eruption * Lipschütz ulcer * Eruptive pseudoangiomatosis * Viral-associated trichodysplasia * Gianotti–Crosti syndrome 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	Pigmented wart	None	5,779	wikipedia	https://en.wikipedia.org/wiki/Pigmented_wart	2021-01-18T18:48:44	{"wikidata": ["Q7193413"]}
Pseudopseudohypoparathyroid SpecialtyRheumatology, medical genetics, endocrinology Usual onsetBefore birth DurationLifetime Differential diagnosisPseudohypoparathyroidism, hypoparathyroidism, Albright's hereditary osteodystrophy TreatmentTreatments to reduce symptoms, genetic counseling Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder,[1] named for its similarity to pseudohypoparathyroidism in presentation. It is more properly Albright hereditary osteodystrophy although without resistance of parathyroid hormone frequently seen in that affliction. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but has (unexpected for the phenotype) normal labs including calcium and PTH.[2] It can be considered a variant of Albright hereditary osteodystrophy,[3] or pseudohypoparathyroidism type 1A, as they present with the same constellation of signs and symptoms, including short stature, brachydactyly, subcutaneous calcification, and obesity. ## Contents * 1 Presentation * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 History * 7 See also * 8 References * 9 External links ## Presentation[edit] Pseudopseudohypoparathyroidism can be best understood by comparing it to other conditions: Condition Appearance PTH levels Calcitriol Calcium Phosphates Imprinting Hypoparathyroidism Normal Low Low Low High Not applicable Pseudohypoparathyroidism Type 1A Skeletal defects High Low Low High Gene defect from mother (GNAS1) Type 1B Normal High Low Low High Gene defect from mother (GNAS1 and STX16) Type 2 Normal High Low Low High ? Pseudopseudohypoparathyroidism Skeletal defects Normal Normal Normal[4] Normal Gene defect from father Hormone resistance is not present in pseudopseudohypoparathyroidism.[5] Short stature may be present. Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism.[6] Osteoma cutis may be present.[7] ## Genetics[edit] Protein GNAS A male with pseudohypoparathyroidism has a 50% chance of passing on the defective GNAS gene to his children, although in an imprinted, inactive form. Any of his children receiving this gene will have pseudopseudohypoparathyroidism. Any of his daughters that have pseudopseudohypoparathyroidism may in turn pass along pseudohypoparathyroidism 1A to her children as the imprinting pattern on the inherited paternal gene will be changed to the maternal pattern in the mother's ovum during meiosis. The gene will be reactivated in any children who inherit it.[citation needed] Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene,[8] but pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney.[9] ## Pathophysiology[edit] The GNAS1 gene involved in both pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism is greatly affected by imprinting. When a father who has pseudohypoparathyroidism undergoes spermatogenesis, imprinting of the GNAS1 gene inactivates both copies of his genes: one will be Functional and the other will be defective. Tissues in the body will re-activate different copies of the GNAS1 gene selectively; the kidneys will selectively activate the (functional) maternal copy while keeping the (defective) paternally-derived gene imprinted and inactive, even in normal individuals. Since the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained in pseudopseudohypoparathyroidism. However, the rest of the tissues will instead selectively display the defective gene, resulting in haploinsufficiency of the GNAS1 product in most tissues, and giving the phenotype of pseudohypoparathyroidism type 1a. As a result, there is also a normal response of urinary cAMP to PTH, and normal serum PTH.[citation needed] ## Diagnosis[edit] The diagnosis is based on the presence of the Albright hereditary osteodystrophy pseudotype but without the PTH resistance. Blood tests including calcium, phosphate, and PTH will exclude other forms of pseudohypoparathyroidism. X-rays may reveal a short fourth metacarpal. Genetic testing can confirm the diagnosis by showing GNAS gene mutation.[1] ## Treatment[edit] Treatments focuses on symptoms, with genetic counseling recommended.[10] ## History[edit] It was characterized in 1952 by Fuller Albright as "pseudo-pseudohypoparathyroidism" (with hyphen).[11][12] ## See also[edit] * GNAS1 * Parathyroid hormone * Longest word in English ## References[edit] 1. ^ a b "Pseudopseudohypoparathyroidism \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-01-31. 2. ^ Tafaj, O.; Jüppner, H. (April 2017). "Pseudohypoparathyroidism: one gene, several syndromes". Journal of Endocrinological Investigation. 40 (4): 347–356. doi:10.1007/s40618-016-0588-4. ISSN 1720-8386. PMID 27995443. S2CID 20811779. 3. ^ Solomon SS, Kerlan RM, King LE, Jones GM, Hashimoto K (January 1975). "Pseudopseudohypoparathyroidism with fibrous dysplasia". Arch Dermatol. 111 (1): 90–3. doi:10.1001/archderm.111.1.90. PMID 1119829. 4. ^ Shahid Hussain; Sharif Aaron Latif; Adrian Hall (1 July 2010). Rapid Review of Radiology. Manson Publishing. pp. 262–. ISBN 978-1-84076-120-7. Retrieved 30 October 2010. 5. ^ Mouallem M, Shaharabany M, Weintrob N, et al. (February 2008). "Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha". Clin. Endocrinol. 68 (2): 233–9. doi:10.1111/j.1365-2265.2007.03025.x. PMID 17803690. S2CID 23654317. 6. ^ Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL (March 2007). "Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity". J. Clin. Endocrinol. Metab. 92 (3): 1073–9. doi:10.1210/jc.2006-1497. PMID 17164301. 7. ^ Jeong KH, Lew BL, Sim WY (May 2009). "Osteoma cutis as the presenting feature of albright hereditary osteodystrophy associated with pseudopseudohypoparathyroidism". Ann Dermatol. 21 (2): 154–8. doi:10.5021/ad.2009.21.2.154. PMC 2861203. PMID 20523775. Archived from the original on 2012-03-15. Retrieved 2010-10-30. 8. ^ Lebrun M, Richard N, Abeguilé G, et al. (June 2010). "Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans". J. Clin. Endocrinol. Metab. 95 (6): 3028–38. doi:10.1210/jc.2009-1451. PMID 20427508. 9. ^ David Terris; Christine G. Gourin (15 November 2008). Thyroid and Parathyroid Diseases: Medical and Surgical Management. Thieme. pp. 193–. ISBN 978-1-58890-518-5. Retrieved 30 October 2010. 10. ^ Simpson, Catherine (21 March 2015). "Pseudopseudohypothyroidism" (PDF). The Lancet. 385 (9973): 1123. doi:10.1016/s0140-6736(14)61640-8. PMID 25484027. S2CID 208793989. 11. ^ Philip R. Beales; I. Sadaf Farooqi; Stephen O'Rahilly (12 September 2008). The genetics of obesity syndromes. Oxford University Press US. pp. 91–. ISBN 978-0-19-530016-1. Retrieved 30 October 2010. 12. ^ ALBRIGHT F, FORBES AP, HENNEMAN PH (1952). "Pseudo-pseudohypoparathyroidism". Trans. Assoc. Am. Physicians. 65: 337–50. PMID 13005676. ## External links[edit] Classification D * ICD-9-CM: 275.49 * OMIM: 612463 * MeSH: D011556 * DiseasesDB: 29783 Look up pseudopseudohypoparathyroidism in Wiktionary, the free dictionary. * v * t * e Parathyroid disease Hypoparathyroidism * Pseudohypoparathyroidism * Pseudopseudohypoparathyroidism Hyperparathyroidism * Primary * Secondary * Tertiary * Osteitis fibrosa cystica Other * Parathyroiditis * v * t * e Disorders due to genomic imprinting Chromosome 15 * Angelman syndrome ♀ / Prader-Willi syndrome ♂ Chromosome 11 * Beckwith–Wiedemann syndrome ♀ / Silver–Russell syndrome ♂ * Myoclonic dystonia Chromosome 20 * Pseudohypoparathyroidism ♀ / Pseudopseudohypoparathyroidism ♂ Chromosome 6 * Transient neonatal diabetes mellitus * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and 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	Pseudopseudohypoparathyroidism	c0033835	5,780	wikipedia	https://en.wikipedia.org/wiki/Pseudopseudohypoparathyroidism	2021-01-18T18:28:21	{"gard": ["7860"], "mesh": ["D011556"], "umls": ["C0033835"], "icd-9": ["275.49"], "orphanet": ["665", "79445"], "wikidata": ["Q1477265"]}
Xeroderma pigmentosum Other namesDeSanctis-Cacchione syndrome[1][2] XP1 / XP2 / XP3 / XP4 / XP5 / XP6 / XP7 [3] Xeroderma pigmentosum I/II/III/IV/V/VI/VII [3] Xeroderma pigmentosum complementation group A/B/C/D/E/F/G [3] xeroderma pigmentosum group A/B/C/D/E/F/G [3] An eight-year-old girl from Guatemala with xeroderma pigmentosum[4] SpecialtyMedical genetics SymptomsSevere sunburn after only a few seconds in the sun, freckling in sun-exposed areas, dry skin, changes in skin pigmentation[1] ComplicationsSkin cancer, brain cancer, cataracts[1] Usual onsetBecomes visible ~6 months of age[2] DurationLifelong CausesGenetic disorder (autosomal recessive)[1] Diagnostic methodBased on symptoms and confirmed by genetic testing[5] Differential diagnosisTrichothiodystrophy, Cockayne syndrome, cerebrooculofacioskeletal syndrome, erythropoietic protoporphyria[6] PreventionNo cure available TreatmentCompletely avoiding sun or UV rays, retinoid creams, vitamin D[5][6] PrognosisLife expectancy is shortened by about 30 years.[7] Frequency• 1 in 100,000 (worldwide)[3] • 1 in 370 (India) [8] • 1 in 22,000 (Japan)[3] • 1 in 250,000 (USA)[9] • 1 in 430,000 (Europe) • 1 in 1,000,000 (UK)[3] Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light.[1] Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun exposed areas, dry skin and changes in skin pigmentation.[1] Nervous system problems, such as hearing loss, poor coordination, loss of intellectual function and seizures, may also occur.[1] Complications include a high risk of skin cancer, with about half having skin cancer by age 10 without preventive efforts, and cataracts.[1] There may be a higher risk of other cancers such as brain cancers.[1] XP is autosomal recessive, with at least nine specific mutations able to result in the condition.[1][6] Normally, the damage to DNA which occurs in skin cells from exposure to UV light is repaired by nucleotide excision repair.[1] In people with xeroderma pigmentosum, this damage is not repaired.[1] As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die.[1] Diagnosis is typically suspected based on symptoms and confirmed by genetic testing.[5] There is no cure for XP.[6] Treatment involves completely avoiding the sun.[6] This includes protective clothing, sunscreen and dark sunglasses when out in the sun.[6] Retinoid creams may help decrease the risk of skin cancer.[6] Vitamin D supplementation is generally required.[5] If skin cancer occurs, it is treated in the usual way.[6] The life expectancy of those with the condition is about 30 years less than normal.[7] The disease affects about 1 in 100,000 worldwide.[3] By region, it affects about 1 in 370 in India,[8] 1 in 20,000 in Japan, 1 in 250,000 people in the United States and 1 in 430,000 in Europe.[9] It occurs equally commonly in males and females.[10] Xeroderma pigmentosum was first described in the 1870s by Moritz Kaposi.[5][10] In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin.[10] Individuals with the disease have been referred to as "children of the night" or "moon children".[11][12] ## Contents * 1 Signs and symptoms * 2 Genetics * 2.1 XP repair proteins * 3 Diagnosis * 3.1 Types * 4 Treatment * 5 Prognosis * 6 History * 7 Culture * 8 Research directions * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Child with xeroderma pigmentosum in Nepal Signs and symptoms of xeroderma pigmentosum may include:[citation needed] * Severe sunburn when exposed to only small amounts of sunlight. These often occur during a child's first exposure to sunlight. * Development of many freckles at an early age * Rough-surfaced growths (solar keratoses), and skin cancers * Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot and clouded * Blistering or freckling on minimum sun exposure * Telangiectasia (spider veins) * Limited growth of hair on chest and legs * Scaly skin * Xeroderma (dry skin) * Irregular dark spots on the skin * Corneal ulcerations ## Genetics[edit] Xeroderma pigmentosum has an autosomal recessive pattern of inheritance. One of the most frequent defects in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER.[13] If left unchecked, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The causes of the neurological abnormalities are poorly understood and are not connected with exposure to ultraviolet light. The most current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER.[14] Since DNA repair is under genetic control, it can mutate. Many genetic disorders such as xeroderma pigmentosum (XP; MIM 278700) are caused by mutations in genes that repair damaged DNA. XP affects the mechanism that repairs UV damage in skin cell DNA. Those affected with the autosomal recessive disorder XP are extremely sensitive to UV light produced by the sun and develop pigmented spots, tumors, and skin cancer with minimal exposure. Individuals with XP are about 1,000 times more likely to develop skin cancer than individuals without the disorder.[citation needed] The molecular defects in XP cells result in a greatly elevated induction of mutations in sun-exposed skin of affected individuals. This increased mutation frequency probably accounts for the pigmentation changes and the skin cancers. Examination of mutations in the p53 gene in tumors from XP patients reveal p53 mutations characteristic of UV exposure in the majority of tumors[15] As with all genetic disorders, genetic counseling and psychological support is appropriate for the families to discuss probability of occurrence in future pregnancies, feelings of isolation and concern about career prospects. There is no cure for xeroderma pigmentosum. The most common fate for individuals with XP is early death from cancer. ### XP repair proteins[edit] The XPA protein acts during NER as a scaffold for assembly of other DNA repair proteins at sites of DNA damage to ensure appropriate excision of the damage.[16] The XPB (ERCC3) protein is employed in unwinding the DNA double helix after DNA damage is initially recognized. Mutations in the XPB(ERCC3) gene can lead to XP or XP combined with Cockayne syndrome.[17] The XPC protein forms a complex with RAD23B protein to form the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER).[18] This complex recognizes a wide variety of damages that thermodynamically destabilize DNA duplexes.[citation needed] The XPD (ERCC2) protein, in combination with the XPB helicase-containing transcription/repair complex TFIIH, is employed in unwinding the DNA duplex after damage is initially recognized. Mutations in the XPD(ERCC2) gene cause a variety of syndromes; XP, trichothiodystrophy (TTD), or a combination of XP and Cockayne syndrome (XPCS).[19][20] Both trichothiodystrophy and Cockayne syndrome display features of premature aging, suggesting an association between deficient DNA repair and premature aging (see DNA damage theory of aging). XPE is a heterodimeric protein composed of two subunits. The larger subunit DDB1 primarily functions as a core component of CUL4A\- and CUL4B-based E3 ubiquitin ligase complexes. Substrates that are ubiquitinnated by these complexes include proteins employed in DNA repair.[21] The XPF (ERCC4) protein together with the ERCC1 protein forms a complex usually designated ERCC1-XPF. This complex separates the DNA helix for a short distance on either side of the site of damage. It then acts as an endonuclease to incise the damaged DNA strand on the 5’ side of the damaged site.[22] Mutant cells with deficient ERCC1-XPF are not only defective in NER, but also in the repair of double-strand breaks and inter-strand crosslinks. The XPG protein is an endonuclease that incises DNA during NER at the 3’ side of the damaged nucleotide. Mutations in the XPG (ERCC5) gene can lead to XP alone, or in combination with Cockayne syndrome (CS), or in combination with infantile lethal cerebro-oculo-facio-skeletal syndrome.[23] ## Diagnosis[edit] ### Types[edit] There are seven complementation groups, plus one variant form: Type Diseases Database OMIM Gene Locus Also known as / description Type A, I, XPA 29877 278700 XPA 9q22.3 Xeroderma pigmentosum group A - the classical form of XP Type B, II, XPB 29878 133510 XPB 2q21 Xeroderma pigmentosum group B Type C, III, XPC 29879 278720 XPC 3p25 Xeroderma pigmentosum group C Type D, IV, XPD 29880 278730 278800 XPD ERCC6 19q13.2-q13.3, 10q11 Xeroderma pigmentosum group D or De Sanctis-Cacchione syndrome (can be considered a subtype of XPD) Type E, V, XPE 29881 278740 DDB2 11p12-p11 Xeroderma pigmentosum group E Type F, VI, XPF 29882 278760 ERCC4 16p13.3-p13.13 Xeroderma pigmentosum group F Type G, VII, XPG 29883 278780 133530 RAD2 ERCC5 13q33 Xeroderma pigmentosum group G and COFS syndrome type 3 Type V, XPV 278750 POLH 6p21.1-p12 Xeroderma pigmentosum variant - these patients have mutation in a gene that codes for a specialized DNA polymerase called polymerase-η (eta). Polymerase-η can replicate over the damage and is needed when cells enter S-phase in the presence of a DNA-replication. ## Treatment[edit] Child in UV-protective clothing during initial stages of XP There is no cure for the disorder; all treatment is symptomatic or preventative. Symptoms can be avoided or controlled by completely avoiding exposure to sunlight, either by staying indoors or wearing protective clothing and using sunscreen when outdoors.[24] Keratosis can also be treated by using cryotherapy or fluorouracil.[4] In more severe cases of XP, even minuscule amounts of UV light, for example, from covered windows or fluorescent bulbs, can be very dangerous and trigger symptoms.[25] On September 10, 2020, Clinuvel Pharmaceuticals announced that it was investigating the use of its FDA-approved flagship drug Scenesse as a potential treatment to increase pain-free light exposure for patients with xeroderma pigmentosum.[26][27][28] ## Prognosis[edit] The average life expectancy of an individual with any type of XP and no neurological symptoms is approximately 37 years, and 29 years if neurological symptoms are present.[3] In the United States, the probability for individuals with the disorder to survive until 40 years of age may be as high as 70% if they have never been exposed to sunlight in their life.[29] In India, many patients with XP die at an early age from skin cancers. However, if a person is diagnosed early, does not have severe neurological symptoms, and takes precautionary measures to completely avoid any exposure to UV light and sunlight, they may be able to survive until middle age.[30] ## History[edit] Xeroderma pigmentosum was first described in 1874 by Hebra and Moritz Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin.[citation needed] The 1968 paper about XP by James Cleaver demonstrated the link between UV-induced DNA damage, faulty DNA repair and cancer.[31] ## Culture[edit] Because people with XP need to strictly avoid sunlight, but can go outside at night, they have been called children of the dark, children of the night, and vampire children. These terms can be considered derogatory.[32] XP has been a plot element in several fictional works. One of the common themes in films about XP is whether teens with XP will risk sun exposure in pursuit of a romantic partner.[33] Film series like Children of Darkness, a German silent-drama film which was released in two parts in the year of 1921 and 1922 respectively, was among some of the initially popular movies that was made about XP. Other films, like the 1964 American drama film Della, starring Joan Crawford, Paul Burke, Charles Bickford and Diane Baker, directed by Robert Gist, which was originally produced by Four Star Television as a television pilot for a proposed NBC series named Royal Bay, was also based on this skin disease. The Dark Side of the Sun, a 1988 American-Yugoslavian drama film, was directed by Božidar Nikolić and stars Brad Pitt for his first ever leading role as a young man in search of a cure for his disorder. The Others (2001 film), a 2001 American psychological horror film starring Nicole Kidman, features two children, Anne and Nicholas, who must avoid all sunlight because of a rare disease characterized by photosensitivity. A CBS television movie aired in 1994, Children of the Dark, was based on the story of the real-life couple Jim and Kim Harrison, whose two daughters have XP.[34][35] Lurlene McDaniel's young adult book How I Do Love Thee features the story "Night Vision", in which the protagonist, leukemia survivor Brett, falls in love with a girl named Shayla that has XP. Christopher Snow, the protagonist of Dean Koontz's Moonlight Bay Trilogy, has XP and therefore must live most of his life during the night. The first two entries of the trilogy, Fear Nothing and Seize the Night, were both published in 1998. The final entry in the trilogy, tentatively titled Ride the Storm, has yet to be published as of August 2020.[36][37] The 2011 French drama film The Moon Child is based on a 13 year old child with XP, which prevents him from exposing himself to daylight. The 2012 documentary Sun Kissed explores the XP problem on the Navajo Indian Reservation, and links it to the genetic legacy of the Long Walk of the Navajo, when the Navajo people were forced to move to a new location.[38][39][40] The 2018 romance film Midnight Sun, based on a 2006 Japanese film, A Song to the Sun, tells the story of a girl named Katie Price, who has a life-threatening sensitivity towards sunlight because of XP, and the impact of her sickness on her normal life, which eventually claims her life as she is accidentally momentarily exposed to sunlight while watching a sunrise. ## Research directions[edit] Research into XP has had two main results: better understanding the disease itself, and also better understanding the normal biological mechanisms involved in DNA repair.[31] Research into XP has produced insights that have been translated into treatments and prevention for cancer.[31] ## See also[edit] * DeSanctis–Cacchione syndrome * Genetic disorder * Biogerontology * Cockayne syndrome * List of cutaneous conditions * List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer * Photophobia * Senescence ## References[edit] 1. ^ a b c d e f g h i j k l m "Xeroderma pigmentosum". Genetics Home Reference. U.S. Library of Medicine. 26 June 2018. Retrieved 28 June 2018. 2. ^ a b "Xeroderma pigmentosum". dermnetnz.org. Retrieved 25 February 2020. 3. ^ a b c d e f g h i "https://myriadwomenshealth.com/2014/05/hello-world/". Myriad Women's Health. Retrieved 2020-07-05. External link in `\|title=` (help) 4. ^ a b Halpern J, Hopping B, Brostoff JM (October 2008). "Photosensitivity, corneal scarring and developmental delay: Xeroderma Pigmentosum in a tropical country". Cases Journal. 1 (1): 254. doi:10.1186/1757-1626-1-254. PMC 2577106. PMID 18937855. 5. ^ a b c d e "Xeroderma Pigmentosum". NORD (National Organization for Rare Disorders). 2017. Retrieved 28 June 2018. 6. ^ a b c d e f g h "Xeroderma pigmentosum". Genetic and Rare Diseases Information Center (GARD). U.S. Department of Health and Human Services. 2018. Retrieved 28 June 2018. 7. ^ a b Ahmad S, Hanaoka F (2008). Molecular Mechanisms of Xeroderma Pigmentosum. Springer Science & Business Media. p. 17. ISBN 9780387095998. 8. ^ a b "When daylight kills: India's XP children". The Telegraph. 2019-06-26. ISSN 0307-1235. Retrieved 2020-07-05. 9. ^ a b Lehmann AR, McGibbon D, Stefanini M (November 2011). "Xeroderma pigmentosum". Orphanet Journal of Rare Diseases. 6: 70. doi:10.1186/1750-1172-6-70. PMC 3221642. PMID 22044607. 10. ^ a b c Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D (2016). Rook's Textbook of Dermatology, 4 Volume Set. John Wiley & Sons. ISBN 9781118441190. 11. ^ Salway JG (2011). Medical Biochemistry at a Glance. John Wiley & Sons. p. 313. ISBN 9781118292402. 12. ^ "Moon children". The Guardian. 1999. 13. ^ Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1-55581-319-2. 14. ^ Brooks PJ (July 2008). "The 8,5'-cyclopurine-2'-deoxynucleosides: candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair". DNA Repair. 7 (7): 1168–79. doi:10.1016/j.dnarep.2008.03.016. PMC 2797313. PMID 18495558. 15. ^ Daya-Grosjean L, Sarasin A (April 2005). "The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors". Mutation Research. 571 (1–2): 43–56. doi:10.1016/j.mrfmmm.2004.11.013. PMID 15748637. 16. ^ Sugitani N, Sivley RM, Perry KE, Capra JA, Chazin WJ (August 2016). "XPA: A key scaffold for human nucleotide excision repair". DNA Repair. 44: 123–135. doi:10.1016/j.dnarep.2016.05.018. PMC 4958585. PMID 27247238. 17. ^ Oh KS, Khan SG, Jaspers NG, Raams A, Ueda T, Lehmann A, Friedmann PS, Emmert S, Gratchev A, Lachlan K, Lucassan A, Baker CC, Kraemer KH (November 2006). "Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome". Human Mutation. 27 (11): 1092–103. doi:10.1002/humu.20392. PMID 16947863. S2CID 22852219. 18. ^ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH (August 1998). "Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair". Molecular Cell. 2 (2): 223–32. doi:10.1016/s1097-2765(00)80132-x. PMID 9734359. 19. ^ Andressoo JO, Hoeijmakers JH, Mitchell JR (December 2006). "Nucleotide excision repair disorders and the balance between cancer and aging". Cell Cycle. 5 (24): 2886–8. doi:10.4161/cc.5.24.3565. PMID 17172862. 20. ^ van de Ven M, Andressoo JO, van der Horst GT, Hoeijmakers JH, Mitchell JR (November 2012). "Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models". DNA Repair. 11 (11): 874–83. doi:10.1016/j.dnarep.2012.08.003. PMID 23046824. 21. ^ Iovine B, Iannella ML, Bevilacqua MA (December 2011). "Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions". The International Journal of Biochemistry & Cell Biology. 43 (12): 1664–7. doi:10.1016/j.biocel.2011.09.001. PMID 21959250. 22. ^ Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, Carter KC, Shell BK, Evans E, de Jong MC, Rademakers S, de Rooij J, Jaspers NG, Hoeijmakers JH, Wood RD (September 1996). "Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease". Cell. 86 (5): 811–22. doi:10.1016/s0092-8674(00)80155-5. hdl:1765/3110. PMID 8797827. S2CID 12957716. 23. ^ Barnhoorn S, Uittenboogaard LM, Jaarsma D, Vermeij WP, Tresini M, Weymaere M, Menoni H, Brandt RM, de Waard MC, Botter SM, Sarker AH, Jaspers NG, van der Horst GT, Cooper PK, Hoeijmakers JH, van der Pluijm I (October 2014). "Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency". PLOS Genetics. 10 (10): e1004686. doi:10.1371/journal.pgen.1004686. PMC 4191938. PMID 25299392. 24. ^ Nussbaum R, McInnes R, Willard H (2016-01-01). Genetics in Medicine. Elsevier. ISBN 978-14377-0696-3. 25. ^ DelhiSeptember 24, india today digital New; September 24, 2014UPDATED; Ist, 2014 09:56. "Xeroderma pigmentosum". India Today. Retrieved 2020-07-05.CS1 maint: numeric names: authors list (link) 26. ^ "SCENESSE® (afamelanotide 16mg) – Welcome to CLINUVEL". Retrieved 2020-09-24. 27. ^ Commissioner, Office of the (2020-03-24). "FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder". FDA. Retrieved 2020-09-24. 28. ^ "Scenesse (afamelanotide) for adults with a history of phototoxic reactions from EPP". SCENESSE® (Afamelanotide). Retrieved 2020-09-24. 29. ^ Kraemer, Kenneth H. (1 February 1987). "Xeroderma Pigmentosum". Archives of Dermatology. 123 (2): 241. doi:10.1001/archderm.1987.01660260111026. Retrieved 21 June 2020. 30. ^ "Xeroderma Pigmentosum \| Skin Disorder \| Skin Cancer \| Treatment in Mumbai \| India". www.theestheticclinic.com. Retrieved 2020-07-05. 31. ^ a b c Kraemer KH, DiGiovanna JJ (March 2015). "Forty years of research on xeroderma pigmentosum at the US National Institutes of Health". Photochemistry and Photobiology. 91 (2): 452–9. doi:10.1111/php.12345. PMC 4355260. PMID 25220021. 32. ^ Almeida, Craig A.; Barry, Sheila A. (2011-08-26). Cancer: Basic Science and Clinical Aspects. John Wiley & Sons. ISBN 9781444357394. 33. ^ Walsh, Katie (23 March 2018). "No spark in sick teen romance - Baltimore Sun". Baltimore Sun. Tribune New Service. Retrieved 2018-07-08. 34. ^ Holder K (1994-05-01). "Family in Twilight for Sun-Sensitive Girls : Health: Two daughters have a rare genetic intolerance that leaves victims vulnerable to skin cancers, blindness and neurological damage after exposure to sunlight". Associated Press. Retrieved 2017-09-14. 35. ^ Voros D (1994-04-15). "Review: 'Children of the Dark'". Variety. Retrieved 2017-09-14. 36. ^ 2017 Interview, capradio.org, 2017. 37. ^ "Frequently Asked Questions". Dean Koontz. Retrieved 24 August 2018. 38. ^ "A Rare Genetic Disorder Is Stalking the Children of the Navajo Nation In POV's 'Sun Kissed,' Premiering Thursday, Oct. 18, 2012, on PBS". 7 June 2012. Retrieved 2018-06-29. 39. ^ Ziff D. "Hiding From the Sun". The Alberquerque Journal. Retrieved 2018-06-29. 40. ^ Bender A (2013-03-06). "Rare disease suddenly arises on Navajo Reservation". People's World. Retrieved 2018-06-29. ## External links[edit] Wikimedia Commons has media related to Xeroderma pigmentosum. * GeneReviews/NCBI/NIH/UW entry on xeroderma pigmentosum Classification D * ICD-10: Q82.1 * ICD-9-CM: 757.33 * OMIM: 278700 * MeSH: D014983 * DiseasesDB: 14198 External resources * MedlinePlus: 001467 * eMedicine: derm/462 neuro/399 * Patient UK: Xeroderma pigmentosum * GeneReviews: Xeroderma Pigmentosum * Orphanet: 910 * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark * v * t * e Metabolic disease: DNA replication and DNA repair-deficiency disorder DNA replication * Separation/initiation: RNASEH2A * Aicardi–Goutières syndrome 4 * Termination/telomerase: DKC1 * Dyskeratosis congenita DNA repair Nucleotide excision repair * Cockayne syndrome/DeSanctis–Cacchione syndrome * Thymine dimer * Xeroderma pigmentosum * IBIDS syndrome MSI/DNA mismatch repair * Hereditary nonpolyposis colorectal cancer * Muir–Torre syndrome * Mismatch repair cancer syndrome MRN complex * Ataxia telangiectasia * Nijmegen breakage syndrome Other * RecQ helicase * Bloom syndrome * Werner syndrome * Rothmund–Thomson syndrome/Rapadilino syndrome * Fanconi anemia * Li-Fraumeni syndrome * Severe combined immunodeficiency * v * t * e Progeroid syndromes DNA repair RecQ-associated * Werner syndrome * Bloom syndrome * Rothmund–Thomson syndrome NER protein-associated * Cockayne syndrome * Xeroderma pigmentosum * Trichothiodystrophy Lamin A/C * Hutchinson–Gilford progeria syndrome * Restrictive dermopathy Other/related disorders * Li–Fraumeni syndrome * Rapadilino syndrome * Baller–Gerold syndrome * DeSanctis–Cacchione syndrome * Nijmegen breakage syndrome * Fanconi anemia * Dyskeratosis congenita * Ataxia telangiectasia * De Barsy syndrome * PIBI(D)S syndrome * BIDS syndrome * Marfanoid–progeroid–lipodystrophy syndrome See also: DNA replication and repair-deficiency 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	Xeroderma pigmentosum	c0043346	5,781	wikipedia	https://en.wikipedia.org/wiki/Xeroderma_pigmentosum	2021-01-18T18:57:55	{"gard": ["7910"], "mesh": ["D014983"], "umls": ["C0043346"], "icd-9": ["757.33"], "orphanet": ["910"], "wikidata": ["Q612693"]}
This article needs attention from an expert in medicine. Please add a reason or a talk parameter to this template to explain the issue with the article. WikiProject Medicine may be able to help recruit an expert. (March 2009) FACES syndrome Other namesFriedman-Goodman syndrome FACES syndrome is a syndrome of unique facial features, anorexia, cachexia, eye and skin anomalies.[1] It is a rare disease and estimated to occur in less than 1 in 1 million people.[2] ## References[edit] 1. ^ Friedman E, Goodman RM (1984). "The "FACES" syndrome: a new syndrome with unique facies, anorexia, cachexia, and eye and skin lesions". J. Craniofac. Genet. Dev. Biol. 4 (3): 227–31. PMID 6438152. 2. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Facial dysmorphism anorexia cachexia eye and skin anomalies syndrome". www.orpha.net. ## External links[edit] Classification D * ICD-10: Q87.0 * MeSH: C536384 External resources * Orphanet: 1969 This article about a congenital malformation 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	FACES syndrome	c2931183	5,782	wikipedia	https://en.wikipedia.org/wiki/FACES_syndrome	2021-01-18T18:30:14	{"gard": ["2387", "2221"], "mesh": ["C536384"], "umls": ["C2931183"], "orphanet": ["1969"], "wikidata": ["Q5424297"]}
Auditory fatigue is defined as a temporary loss of hearing after exposure to sound. This results in a temporary shift of the auditory threshold known as a temporary threshold shift (TTS). The damage can become permanent (permanent threshold shift, PTS) if sufficient recovery time is not allowed before continued sound exposure.[1] When the hearing loss is rooted from a traumatic occurrence, it may be classified as noise-induced hearing loss, or NIHL. There are two main types of auditory fatigue, short-term and long-term.[2] These are distinguished from each other by several characteristics listed individually below. Short-term fatigue * full recovery from TTS can be achieved in approximately two minutes * the TTS is relatively independent of exposure duration[2][3] * TTS is maximal at the exposure frequency of the sound Long-term fatigue * recovery requires a minimum of several minutes but can take up to several days * dependent on exposure duration and noise level[2][3] ## Contents * 1 Physiology * 1.1 Affected anatomy * 1.2 Affected mechanisms * 1.2.1 Traveling wave theory * 1.2.1.1 Classical passive system * 1.2.1.2 Active process * 1.2.2 Excessive vibrations * 1.2.3 Recovery * 1.3 Protective measures * 1.3.1 Toughening and energy spread * 1.3.2 Substances * 1.3.2.1 Furosemide * 1.3.2.2 Salicylic acid * 1.3.2.3 Antioxidants * 1.3.2.4 Limitations * 2 Risk increasing factors * 3 Experimental studies * 4 References ## Physiology[edit] ### Affected anatomy[edit] Human ear anatomy. Brown is outer ear. Red is middle ear. Purple is inner ear. Note: The complete anatomy of the human ear is extensive, and can be divided into the inner ear and outer ear. The remainder of this article mainly references the cochlea, outer hair cells, and organ of Corti. In general, structural damages to any anatomical part of the human ear can cause hearing-related problems. Usually, minor bending of the stereocilia of the inner ear is associated with temporary hearing loss and is involved in auditory fatigue. Complete loss of the stereocilia causes permanent hearing damage and is more associated with noise-induced hearing loss and other auditory diseases. The outer hair cells, or OHCs, can be thought of as microamplifiers that provide stimulation to the inner hair cells. The OHCs are the most fragile of the hair cells, hence their involvement in auditory fatigue and other hearing impairments. The hearing organ in fish is called an otolith, which is sensitive to particle motion, not sound pressure. Some fish also have a lateral line. Location of anatomical parts Inner ear showing cochlea Cochlea showing organ of Corti Organ of Corti showing hair cells ### Affected mechanisms[edit] #### Traveling wave theory[edit] Temporary threshold shifts related to auditory fatigue are related to the amplitude of a stimulus-driven traveling wave.[4] This is believed to be true because the vibration propagated by the active process is not usually at the center of the maximum amplitude of this wave. Instead, it is located much further down and the differences associated between them explain the shift in threshold.[2] The TTS that is experienced is the exhaustion of the active system located at the locus of the traveling wave driven by the cochlear amplifier described below.[4] Auditory fatigue can be explained by the relative activity of the active process at low-level stimulation (<30 dB).[2] ##### Classical passive system[edit] There are two different systems associated with the mechanics of the cochlea: the classical passive system and an active process. The passive system works to stimulate the inner hair cells directly and works at levels above 40 dB.[4] At stimulation levels that prevent the excitation of the passive system, prolonged noise exposure results in a decrease in the loudness heard over time, even when the actual intensity of the noise has not changed.[2] This is caused by the exhaustion of the active process. ##### Active process[edit] The active process is also known as the cochlear amplifier. This amplification increases vibrations of the basilar membrane through energy obtained from the Organ of Corti.[4] As the stimulation increases, it is assumed that basilar membrane displacement, caused by the traveling wave, becomes continually more basal in regards to the cochlea.[5] A sustained low-level stimulus can cause an energetic exhaustion of the active system which in turn prevents the passive system from activating. #### Excessive vibrations[edit] Currently it is believed that auditory fatigue and NIHL are related to excessive vibrations of the inner ear which may cause structural damages.[6][7][8] Metabolic activity is required in order to maintain the electrochemical gradients used in mechano-electrical and electro-mechanical transduction during noise exposure and sound recognition.[6] The metabolic activity is associated with active displacements which are components of the sound-induced vibration involving prestin, a motor protein that causes OHC motility.[6] Excess vibrations require increased metabolic energy. In addition, these extra vibrations can cause the formation of free radicals known as reactive oxygen species or ROS.[9][10] Elevated levels of ROS continue to increase the metabolic demands of the system. These increasing demands fatigue the system and eventually lead to structural damages to the Organ of Corti.[6][11] #### Recovery[edit] In all cases of auditory fatigue, sufficient recovery time should allow full correction of the hearing impairment and return threshold levels to their baseline values.[2] There is currently no way to estimate the amount of time needed to recover from auditory fatigue because it is not usually detectable until after the injury has already occurred. Studies that measured recovery time have noted that the time required is related to the magnitude of the initial hearing loss.[12] The most significant recovery was found to occur during the first 15 minutes following cessation of the noise exposure.[13][14] When sufficient recovery time is not allotted, the effects become permanent, resulting in acquired noise-induced hearing loss.[12] Up to 120 minutes of recovery time can be required of noises of only 95 dB.[12] For comparison, common items that can produce noise at this level are motorcycles and subways.[15] ### Protective measures[edit] #### Toughening and energy spread[edit] Two protective measures have been investigated related to the amount of noise exposure and the duration of that exposure. Although these would be hard to regulate in spontaneous occurrences, they could have a positive effect on work conditions if guidelines could be set for machining times or for other systems that produce loud noises over a long period of time. The toughening effect is put in place by increasing the system's resistance to noise over time.[16] Currently, the specific mechanisms that cause the cochlear toughening are not known. However, the OHCs and related processes are known to play a role.[17] The other toughening measure is to spread a given amount of energy to the system over a longer amount of time. This would allow recovery processes to take place during the quiet interludes that are gained by increasing the exposure duration.[16] So far, studies have not shown a direct correlation between the amount of toughening and the amount of threshold shift experienced.[16] This suggests that even a toughened cochlea may not be completely protected. #### Substances[edit] Both furosemide and salicylic acid are considered ototoxic at certain doses. Research has been done to determine their ability to protect against auditory fatigue and permanent damage through toughening phenomena, a state described by reduced active cochlear displacements. Although limited research has been done with these two substances in terms of protective drug regimes because of their associated risks, both have shown positive results in reducing auditory fatigue by the decrease in ROS formation through individual mechanisms described below.[6][18] ##### Furosemide[edit] Furosemide injections prior to noise exposure have been shown to decrease the endocochlear potential.[19] This decrease results in a reduction of active cochlear displacements and it is believed that the protection by furosemide stems from the limitation of excessive vibrations while the cochlear amplifier is depressed.[20] ##### Salicylic acid[edit] Salicylic acid competitively interferes with anion binding to OHC prestin which thereby reduces motility. This reduction in active displacement is again associated with depression of the cochlear amplifier which decreases the excessive vibrations experienced during noise-exposure.[7][8][9][11] ##### Antioxidants[edit] Vitamins A, C and E have been shown to be 'free radical scavengers' by studies looking for protective tendencies of antioxidants.[21] In addition, NAC, or N-acetyl-L-cysteine (acetylcysteine), has been shown to reduce ROS formation associated with the excessive vibrations induced by the noise exposure.[10][22][23] ##### Limitations[edit] Although auditory fatigue and NIHL protective measures would be helpful for those who are constantly exposed to long and loud noises, current research is limited due to the negative associations with the substances.[6] Furosemide is used in congestive heart failure treatments because of its diuretic properties. Salicylic acid is a compound most frequently used in anti-acne washes, but is also an anticoagulant. Further uses of these substances would need to be personalized to the individual and only under close monitoring. Antioxidants do not have these negative effects and therefore are the most commonly researched substance for the purpose of protecting against auditory fatigue.[6] However, at this time there has been no marketed application. In addition, no synergistic relationships between the drugs on the degree of reduction of auditory fatigue have been discovered at this time.[24] ## Risk increasing factors[edit] * Physical exercise * Heat exposure * Workload * Ototoxic chemicals There are several factors that may not be harmful to the auditory system by themselves, but when paired with an extended noise exposure duration have been shown to increase the risk of auditory fatigue. This is important because humans will remove themselves from a noisy environment if it passes their pain threshold.[12] However, when paired with other factors that may not physically recognizable as damaging, TTS may be greater even with less noise exposure. One such factor is physical exercise. Although this is generally good for the body, combined noise exposure during highly physical activities was shown to produce a greater TTS than just the noise exposure alone.[25][26] This could be related to the amount of ROS being produced by the excessive vibrations further increasing the metabolic activity required, which is already increased during physical exercise. However, a person can decrease their susceptibility to TTS by improving their cardiovascular fitness overall.[12] Heat exposure is another risk factor. As blood temperature rises, TTS increases when paired with high-frequency noise exposure.[12] It is hypothesized that hair cells for high-frequency transduction require a greater oxygen supply than others, and the two simultaneous metabolic processes can deplete any oxygen reserves of the cochlea.[27] In this case, the auditory system undergoes temporary changes caused by a decrease in the oxygen tension of the cochlear endolymph that leads to vasoconstriction of the local vessels.[28] Further research could be done to see if this is a reason for the increased TTS during physical exercise that is during continued noise-exposure as well. Another factor that may not show signs of being harmful is the current workload of a person. Exposure to noise greater than 95 dB in individuals with heavy workloads was shown to cause severe TTS.[12] In addition, the workload was a driving factor in the amount of recovery time required to return threshold levels to their baselines.[12] There are some factors that are known to directly affect the auditory system. Contact with ototoxic chemicals such as styrene, toluene and carbon disulfide heighten the risk of auditory damages.[12] Those individuals in work environments are more likely to experience the noise and chemical combination that can increase the likelihood of auditory fatigue.[10][29] Individually, styrene is known to cause structural damages of the cochlea without actually interfering with functional capabilities.[10] This explains the synergistic interaction between noise and styrene because the cochlea will be increasingly damaged with the excessive vibrations of the noise plus the damage caused by the chemical itself. Specifically, noise damage typically damages the first layer of the outer hair cells. The combined effects of styrene and noise exposure shows damages to all three rows instead, reinforcing previous results.[10] Also, the combined effects of these chemicals and the noise produce greater auditory fatigue than when an individual is exposed to one factor immediately followed by the next.[10] It is important to understand that noise exposure itself is the main influential factor in threshold shifts and auditory fatigue, but that individuals may be at greater risk when synergistic effects take place during interactions with the above factors.[12] ## Experimental studies[edit] Studies have been carried out in humans,[30][31] marine mammals (dolphins,[32] harbour porpoises[33] and harbour seals[33]) rodents (mice,[34][35] rats,[10] guinea pigs[36][37][38][39] and chinchillas[16]) and fish.[40] ## References[edit] 1. ^ Barbara A. Bohne; Gary W. Harding (June 14, 1999). "Noise & Its Effects on the Ear". Noise-induced Hearing Loss. Dept. of Otolaryngology, Washington University School of Medicine, St. Louis, MO. Archived from the original on 2016-07-01. Retrieved July 5, 2016. "Parameters of Noise Which Affect Its Damage Potential" 2. ^ a b c d e f g Charron, S., & Botte, M. C. (1988). Frequency-selectivity in loudness adaptation and auditory fatigue. [Article]. Journal of the Acoustical Society of America, 83(1), 178-187. 3. ^ a b Hirsh IJ, Bilger RC, Burns W. Auditory-Threshold Recovery after Exposures to Pure Tones. The Journal of the Acoustical Society of America. 1955;27(5):1013-1013. 4. ^ a b c d Davis H. An active process in cochlear mechanics. Hearing Research. 1983;9(1):79-90. 5. ^ McFadden D, Plattsmier H. Exposure-induced loudness shifts and threshold shifts. New Perspectives in Noise-induced Hearing Loss. 1982:363-374. 6. ^ a b c d e f g Adelman, C., Perez, R., Nazarian, Y., Freeman, S., Weinberger, J., & Sohmer, H. (2010). Furosemide Administered Before Noise Exposure Can Protect the Ear. [Article]. Annals of Otology Rhinology and Laryngology, 119(5), 342-349. 7. ^ a b Ou HC, Bohne BA, Harding GW. Noise damage in the C57BL/CBA mouse cochlea. Hearing Research. 2000;145(1-2):111-122. 8. ^ a b Wang Y, Hirose K, Liberman MC. Dynamics of Noise-Induced Cellular Injury and Repair in the Mouse Cochlea. JARO - Journal of the Association for Research in Otolaryngology. 2002;3(3):248-268. 9. ^ a b Ohlemiller KK, Wright JS, Dugan LL. Early Elevation of Cochlear Reactive Oxygen Species following Noise Exposure. Audiology and Neurotology. 1999;4(5):229-236. 10. ^ a b c d e f g Chen GD, Henderson D (2009). "Cochlear injuries induced by the combined exposure to noise and styrene". Hearing Research. 254 (1–2): 25–33. doi:10.1016/j.heares.2009.04.005. ISSN 0378-5955. PMID 19371775. 11. ^ a b Henderson D, Bielefeld E, Harris K, Hu B. The role of oxidative stress in noise-induced hearing loss. Ear Hear. 2006;27:1 - 19. 12. ^ a b c d e f g h i j Chen C-J, Dai Y-T, Sun Y-M, Lin Y-C, Juang Y-J. Evaluation of Auditory Fatigue in Combined Noise, Heat and Workload Exposure. Industrial Health. 2007;45(4):527-534. 13. ^ Ward WD. Temporary threshold shift and damage-risk criteria for intermittent noise exposures. Journal of the Acoustical Society of America. 1970(48):561-574. 14. ^ Ward WD. Recovery from high values of temporary threshold shift. Journal of the Acoustical Society of America. 1970(32):497-500. 15. ^ <"Archived copy". Archived from the original on 2010-12-14. Retrieved 2010-12-05.CS1 maint: archived copy as title (link)> 16. ^ a b c d <Hamernik RP, Ahroon WA. Interrupted noise exposures: Threshold shift dynamics and permanent effects. The Journal of the Acoustical Society of America. 1998;103(6):3478-3488. 17. ^ Zheng X-Y, Henderson D, McFadden SL, Hu B-H. The role of the cochlear efferent system in acquired resistance to noise-induced hearing loss. Hearing Research. 1997;104(1-2):191-203. 18. ^ Adelman C, Freeman S, Paz Z, Sohmer H. Salicylic acid injection before noise exposure reduces permanent threshold shift. Audiol Neurootol. 2008;13:266 - 272. 19. ^ Ruggero M, Rich N. Furosemide alters organ of corti mechanics: evidence for feedback of outer hair cells upon the basilar membrane. J Neurosci. 1991;11:1057 - 1067. 20. ^ Ikeda K, Morizono T. Effect of albumin-bound furosemide on the endocochlear potential of the chinchilla. Alleviation of furosemide-induced ototoxicity. Arch Otolaryngol Head Neck Surg. 1989;115:500 - 502. 21. ^ Le Prell CG, Hughes LF, Miller JM. Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma. Free Radical Biology and Medicine. 2007;42(9):1454-1463. 22. ^ Bielefeld E, Kopke R, Jackson R, Coleman J, Liu J, Henderson D. Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration. Acta Otolaryngol. 2007;127:914 - 919. 23. ^ Kopke RD, Jackson RL, Coleman JKM, Liu J, Bielefeld EC, Balough BJ. NAC for noise: From the bench top to the clinic. Hearing Research. 2007;226(1-2):114-125. 24. ^ Tamir S, Adelman C, Weinberger J, Sohmer H. Uniform comparison of several drugs which provide protection from noise induced hearing loss. Journal of Occupational Medicine and Toxicology. 2010;5(1):26. 25. ^ Lindgren F, Axelsson A. The Influence of Physical Exercise on Susceptibility to Noise-Induced Temporary Threshold Shift. Scandinavian Audiology. 1988;17(1):11-17 26. ^ <Miani C, Bertino G, Francescato M, di Prampero P, Staffieri A. Temporary Threshold Shift Induced by Physical Exercise. Scandinavian Audiology. 1996;25(3):179-186. 27. ^ Miller J, Ren T, Dengerink H, Nuttall A. Cochlear blood flow changes with short sound stimulation. Scientific Basis of Noise-Induced Hearing Loss. 1996:95-109. 28. ^ Axelsson A, Vertes D, Miller J. Immediate Noise Effects on Cochlear Vasculature in the Guinea Pig. Acta Oto-Laryngol. 1981;91(1-6):237-246. 29. ^ Mizoue T, Miyamoto T, Simizu T. Combined effect of smoking and occupational exposure to noise on hearing loss in steel factory workers. Occupational and Environmental Medicine. 2003; 60:56-59. 30. ^ Lin, C. Y., Wu, J. L., Shih, T. S., Tsai, P. J., Sun, Y. M., & Guo, Y. L. (2009). Glutathione S-transferase M1, T1, and P1 polymorphisms as susceptibility factors for noise-induced temporary threshold shift. Hearing Research, 257(1-2), 8-15. doi:10.1016/j.heares.2009.07.008 31. ^ Melnick, W. (1991). HUMAN TEMPORARY THRESHOLD SHIFT (TTS) AND DAMAGE RISK. Journal of the Acoustical Society of America, 90(1), 147-154. 32. ^ Finneran, J. J., & Schlundt, C. E. (2010). Frequency-dependent and longitudinal changes in noise-induced hearing loss in a bottlenose dolphin (Tursiops truncatus) (L). Journal of the Acoustical Society of America, 128(2), 567-570. doi:10.1121/1.3458814 33. ^ a b Kastelein, R., Gransier, R., van Mierlo, R., Hoek, L., & de Jong, C. (2011). Temporary hearing threshold shifts and recovery in a harbor porpoise (Phocoena phocoena) and harbor seals (Phoca vitulina) exposed to white noise in a 1/1‐octave band around 4 kHz. The Journal of the Acoustical Society of America, 129, 2432. 34. ^ Groschel, M., Gotze, R., Ernst, A., & Basta, D. (2010). Differential Impact of Temporary and Permanent Noise-Induced Hearing Loss on Neuronal Cell Density in the Mouse Central Auditory Pathway. [Article]. Journal of Neurotrauma, 27(8), 1499-1507. doi:10.1089/neu.2009.1246 35. ^ Housley GD et al., "ATP-gated ion channels mediate adaptation to elevated sound levels" Proc Natl Acad Sci U S A 2013 Apr 30; 110(18):79=494-9 . 36. ^ Fetoni, A. R., Mancuso, C., Eramo, S. L. M., Ralli, M., Piacentini, R., Barone, E., et al. (2010). IN VIVO PROTECTIVE EFFECT OF FERULIC ACID AGAINST NOISE-INDUCED HEARING LOSS IN THE GUINEA-PIG. Neuroscience, 169(4), 1575-1588. doi:10.1016/j.neuroscience.2010.06.022 37. ^ Gourevitch, B., Doisy, T., Avillac, M., & Edeline, J. M. (2009). Follow-up of latency and threshold shifts of auditory brainstem responses after single and interrupted acoustic trauma in guinea pig. Brain Research, 1304, 66-79. doi:10.1016/j.brainres.2009.09.041 38. ^ Chen, Y. S., Tseng, F. Y., Lin, K. N., Yang, T. H., Lin-Shiau, S. Y., & Hsu, C. J. (2008). Chronologic Changes of Nitric Oxide Concentration in the Cochlear Lateral Wall and Its Role in Noise-Induced Permanent Threshold Shift. Laryngoscope, 118(5), 832-836. doi:10.1097/MLG.0b013e3181651c24 39. ^ Yamashita, D., Minami, S. B., Kanzaki, S., Ogawa, K., & Miller, J. M. (2008). Bcl-2 genes regulate noise-induced hearing loss. Journal of Neuroscience Research, 86(4), 920-928. doi:10.1002/jnr.21533 40. ^ Popper, A. N., Halvorsen, M. B., Miller, D., Smith, M. E., Song, J., Wysocki, L. E., ... & Stein, P. (2005). Effects of surveillance towed array sensor system (SURTASS) low frequency active sonar on fish. The Journal of the Acoustical Society of America, 117, 2440. [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	Auditory fatigue	c0039491	5,783	wikipedia	https://en.wikipedia.org/wiki/Auditory_fatigue	2021-01-18T19:07:01	{"mesh": ["D001305"], "wikidata": ["Q4820025"]}
Peutz-Jeghers syndrome Micrograph of Peutz-Jeghers type colonic polyp. H&E stain. SpecialtyMedical genetics Peutz–Jeghers syndrome (often abbreviated PJS) is an autosomal dominant genetic disorder characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa (melanosis).[1] This syndrome can be classed as one of various hereditary intestinal polyposis syndromes[2] and one of various hamartomatous polyposis syndromes.[3] It has an incidence of approximately 1 in 25,000 to 300,000 births.[4] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 2.1 Genetics * 3 Diagnosis * 4 Management * 5 Prognosis * 5.1 Monitoring * 6 Eponym * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] The risks associated with this syndrome include a strong tendency of developing cancer in a number of parts of the body.[5] While the hamartomatous polyps themselves only have a small malignant potential (< 3% per OHCM), patients with the syndrome have an increased risk of developing carcinomas of the liver, lungs, breast, ovaries, uterus, testes and other organs. Specifically, it is associated with an increased risk of sex-cord stromal tumor with annular tubules in the ovaries.[6] The average age of first diagnosis is 23, but the lesions can be identified at birth by an astute pediatrician or family physician. Prior to puberty, the mucocutaneous lesions can be found on the palms and soles. Often the first presentation is a bowel obstruction from an intussusception which is a common cause of mortality; an intussusception is a telescoping of one loop of bowel into another segment. ## Pathophysiology[edit] ### Genetics[edit] In 1998, a gene was found to be associated with the mutation. On chromosome 19, the gene known as STK11 (LKB1)[7] is a possible tumor suppressor gene. It is inherited in an autosomal dominant pattern, which means that anyone who has PJS has a 50% chance of passing the disease on to their offspring.[citation needed] Peutz–Jeghers syndrome is rare and studies typically include only a small number of patients. Even in those few studies that do contain a large number of patients, the quality of the evidence is limited due to pooling patients from many centers, selection bias (only patients with health problems coming from treatment are included), and historical bias (the patients reported are from a time before advances in the diagnosis of treatment of Peutz–Jeghers syndrome were made). Probably due to this limited evidence base, cancer risk estimates for Peutz–Jeghers syndrome vary from study to study.[8] There is an estimated 18–21% risk of ovarian cancer, 9% risk of endometrial cancer, and 10% risk of cervical cancer, specifically adenoma malignum.[6] ## Diagnosis[edit] The main criteria for clinical diagnosis are: * Family history * Mucocutaneous lesions causing patches of hyperpigmentation in the mouth and on the hands and feet. The oral pigmentations are the first on the body to appear, and thus play an important part in early diagnosis. Intraorally, they are most frequently seen on the gingiva, hard palate and inside of the cheek. The mucosa of the lower lip is almost invariably involved as well. * Hamartomatous polyps in the gastrointestinal tract. These are benign polyps with an extraordinarily low potential for malignancy. Having 2 of the 3 listed clinical criteria indicates a positive diagnosis. The oral findings are consistent with other conditions, such as Addison's disease and McCune–Albright syndrome, and these should be included in the differential diagnosis. 90–100% of patients with a clinical diagnosis of PJS have a mutation in the STK11/LKB1 gene. Molecular genetic testing for this mutation is available clinically.[9] ## Management[edit] Resection of the polyps is required only if serious bleeding or intussusception occurs. Enterotomy is performed for removing large, single nodules. Short lengths of heavily involved intestinal segments can be resected. Colonoscopy can be used to snare the polyps if they are within reach.[citation needed] ## Prognosis[edit] Most people with Peutz-Jeghers syndrome will have developed some form of neoplastic disease by age 60 Most patients will develop flat, brownish spots (melanotic macules) on the skin, especially on the lips and oral mucosa, during the first year of life, and a patient's first bowel obstruction due to intussusception usually occurs between the ages of six and 18 years. The cumulative lifetime cancer risk begins to rise in middle age. Cumulative risks by age 70 for all cancers, gastrointestinal (GI) cancers, and pancreatic cancer are 85%, 57%, and 11%, respectively.[10] A 2011 Dutch study followed 133 patients for 14 years. The cumulative risk for cancer was 40% and 76% at ages 40 and 70, respectively. 42 (32%) of the patients died during the study, of which 28 (67%) were cancer related. They died at a median age of 45. Mortality was increased compared with the general population.[11] A family with sinonasal polyposis were followed up for 28 years. Two cases of sinonasal type adenocarcinoma developed. This is a rare cancer. This report suggested that follow up of sinus polyps in this syndrome may be indicated.[12] ### Monitoring[edit] Barium enema radiograph showing multiple polyps (mostly pedunculated) and at least one large mass at the hepatic flexure coated with contrast in a patient with Peutz–Jeghers syndrome. Some suggestions for surveillance for cancer include the following: * Small intestine with small bowel radiography every 2 years, * Esophagogastroduodenoscopy and colonoscopy every 2 years, * CT scan or MRI of the pancreas yearly, * Ultrasound of the pelvis and testes yearly[6] * Mammography from age 25 annually[9] * Papanicolaou smear (Pap smear) annually beginning at age 18-20[6] Follow-up care should be supervised by a physician familiar with Peutz–Jeghers syndrome. Genetic consultation and counseling as well as urological and gynecological consultations are often needed.[citation needed] ## Eponym[edit] First described in a published case report in 1921 by Jan Peutz (1886–1957), a Dutch Internist, it was later formalized into the syndrome by American physicians at Boston City Hospital, Harold Joseph Jeghers (1904–1990) and Kermit Harry Katz (1914–2003), and Victor Almon McKusick (1921–2008) in 1949 and published in the New England Journal of Medicine.[13] ## See also[edit] * List of cutaneous conditions * Sex cord tumour with annular tubules ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 857. ISBN 0-7216-2921-0. 2. ^ Dean, PA (1996), "Hereditary intestinal polyposis syndromes", Rev Gastroenterol Mex, 61 (2): 100–111, PMID 8927912. 3. ^ Jelsig, AM; et al. (2014), "Hamartomatous polyposis syndromes: a review", Orphanet J Rare Dis, 9 (1): 101–111, doi:10.1186/1750-1172-9-101, PMC 4112971, PMID 25022750. 4. ^ Bouquot, Jerry E.; Neville, Brad W.; Damm, Douglas D.; Allen, Carl P. (2008). Oral and Maxillofacial Pathology. Philadelphia: Saunders. p. 16.11. ISBN 978-1-4160-3435-3. 5. ^ Boardman, Lisa A.; Thibodeau, Stephen N.; Schaid, Daniel J.; Lindor, Noralane M.; McDonnell, Shannon K.; Burgart, Lawrence J.; Ahlquist, David A.; Podratz, Karl C.; Pittelkow, Mark; Hartmann, Lynn C. (1998). "Increased Risk for Cancer in Patients with the Peutz-Jeghers Syndrome". Annals of Internal Medicine. 128 (11): 896–9. doi:10.7326/0003-4819-128-11-199806010-00004. PMID 9634427. S2CID 11373591. 6. ^ a b c d Ring, Kari L.; Garcia, Christine; Thomas, Martha H.; Modesitt, Susan C. (November 2017). "Current and future role of genetic screening in gynecologic malignancies". American Journal of Obstetrics and Gynecology. 217 (5): 512–521. doi:10.1016/j.ajog.2017.04.011. ISSN 1097-6868. PMID 28411145. S2CID 29024566. 7. ^ Universal protein resource accession number Q15831 for "Serine/threonine-protein kinase STK11" at UniProt. 8. ^ Riegert-Johnson, Douglas; Gleeson, Ferga C.; Westra, Wytske; Hefferon, Timothy; Song, Louis M. Wong Kee; Spurck, Lauren; Boardman, Lisa A. (August 9, 2008). "Peutz-Jeghers Syndrome". In Riegert-Johnson, Douglas L; Boardman, Lisa A; Hefferon, Timothy; Roberts, Maegan (eds.). Cancer Syndromes. 9. ^ a b McGarrity, Thomas J; Amos, Christopher I; Frazier, Marsha L; Wei, Chongjuan (July 25, 2013). "Peutz-Jeghers Syndrome". In Pagon, Roberta A; Adam, Margaret P; Bird, Thomas D; Dolan, Cynthia R; Fong, Chin-To; Smith, Richard JH; Stephens, Karen (eds.). GeneReviews. Seattle: University of Washington. PMID 20301443. 10. ^ Riegert-Johnson D, Gleeson FC, Westra W, et al. Peutz-Jeghers Syndrome. 2008 Jul 18 [Updated 2008 Aug 9]. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1826/ 11. ^ van Lier, Margot G. F.; Westerman, Anne Marie; Wagner, Anja; Looman, Caspar W. N.; Wilson, J. H. Paul; de Rooij, Felix W. M.; Lemmens, Valery E. P. P.; Kuipers, Ernst J.; Mathus-Vliegen, Elisabeth M. H. (2011-02-01). "High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome". Gut. 60 (2): 141–147. doi:10.1136/gut.2010.223750. ISSN 1468-3288. PMID 21205875. S2CID 11627842. 12. ^ Chiang JM, Chen TC (2017) A Peutz-Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report. Fam Cancer doi: 10.1007/s10689-017-9983-z. 13. ^ Familial Cancer 2002; 1:181–185) ## External links[edit] Classification D * ICD-10: Q85.8 * ICD-9-CM: 759.6 * OMIM: 175200 * MeSH: D010580 * DiseasesDB: 9905 External resources * MedlinePlus: 000244 * eMedicine: med/1807 article/182006article/1664349 * GeneReviews: Peutz-Jeghers Syndrome * Orphanet: 2869 Wikimedia Commons has media related to Peutz–Jeghers syndrome. * GeneReviews/NCBI/NIH/UW entry on Peutz-Jeghers syndrome * Peutz-Jeghers syndrome – Genetics Home Reference * v * t * e Phakomatosis Angiomatosis * Sturge–Weber syndrome * Von Hippel–Lindau disease Hamartoma * Tuberous sclerosis * Hypothalamic hamartoma (Pallister–Hall syndrome) * Multiple hamartoma syndrome * Proteus syndrome * Cowden syndrome * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease Neurofibromatosis * Type I * Type II Other * Abdallat–Davis–Farrage syndrome * Ataxia telangiectasia * Incontinentia pigmenti * Peutz–Jeghers syndrome * Encephalocraniocutaneous lipomatosis * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and 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	Peutz–Jeghers syndrome	c0031269	5,784	wikipedia	https://en.wikipedia.org/wiki/Peutz%E2%80%93Jeghers_syndrome	2021-01-18T18:45:13	{"gard": ["7378"], "mesh": ["D010580"], "umls": ["C0456487", "C0031269", "C0265323"], "icd-9": ["759.6"], "orphanet": ["2869"], "wikidata": ["Q1544989"]}
A number sign (#) is used with this entry because of evidence that focal segmental glomerulosclerosis-7 (FSGS7) is caused by heterozygous mutation in the PAX2 gene (167409) on chromosome 10q24. Mutation in the PAX2 gene can also cause papillorenal syndrome (PAPRS; 120330), a more severe disorder with some overlapping features. Description Focal segmental glomerulosclerosis is a form of kidney injury defined by partial sclerosis of some but not all glomeruli. It is characterized clinically by significant proteinuria with or without features of nephrotic syndrome. Some patients develop end-stage renal disease (summary by Barua et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278). Clinical Features Barua et al. (2014) reported 24 patients from 7 unrelated families with focal segmental glomerulosclerosis. FSGS was defined as having a history of proteinuria, nephrotic syndrome, or biopsy-proven FSGS. The age at onset ranged from 8 to 68 years, but most patients had onset in the second to fourth decades. No ocular or auditory abnormalities were documented. Nine patients developed end-stage renal disease. Ultrasound performed in some patients showed variable subtle abnormalities, including increased echogenicity, dilated renal pelvis, small kidneys, and calyceal diverticulum. Renal biopsy of 1 patient was described in detail: in addition to FSGS, electron microscopy showed diffuse podocytopathy with degenerative changes and focal foot process effacement. Reevaluation of 1 of the families revealed a more severe phenotype, compatible with undiagnosed papillorenal syndrome; this family carried a nonsense mutation. The findings expanded the phenotypic spectrum associated with PAX2 mutations. Inheritance The transmission pattern of FSGS7 in the families reported by Barua et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance. Molecular Genetics In affected members of 7 unrelated families with FSGS, Barua et al. (2014) identified 7 different heterozygous mutations in the PAX2 gene (see, e.g., 167409.0013 and 167409.0014). Six families carried a missense mutation, and 1 with a more severe phenotype carried a nonsense mutation. The mutation in the first family was found by whole-exome sequencing, and the subsequent mutations were found by sequencing this gene in a cohort of 175 patients with familial disease. PAX2 mutations were found in 4% of the total cohort. In vitro functional expression studies of some of the mutations showed that some perturbed protein function by affecting proper binding to DNA causing reduced transactivation activity or by enhancing the repressor activity of PAX2. The findings indicated that PAX2 mutations can cause disease through haploinsufficiency or a dominant-negative effect. INHERITANCE \- Autosomal dominant GENITOURINARY Kidneys \- Focal segmental glomerulosclerosis \- Nephrotic syndrome \- End-stage renal disease (in some patients) \- Biopsy shows effacement of foot processes \- Small kidneys (in some patients) LABORATORY ABNORMALITIES \- Proteinuria MISCELLANEOUS \- Variable age at onset (late childhood to adult) \- Incomplete penetrance \- Variable severity MOLECULAR BASIS \- Caused by mutation in the paired box gene 2 gene (PAX2, 167409.0013 ) ▲ 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	FOCAL SEGMENTAL GLOMERULOSCLEROSIS 7	c1868672	5,785	omim	https://www.omim.org/entry/616002	2019-09-22T15:50:16	{"doid": ["0111132"], "mesh": ["C536404"], "omim": ["616002"], "orphanet": ["656"], "synonyms": ["Alternative titles", "GLOMERULOSCLEROSIS, FOCAL SEGMENTAL, 7"]}
Chromophobe renal cell carcinoma is a rare subtype of the most common form of kidney cancer called renal cell carcinoma (RCC). This type of cancer forms in the cells lining the small tubules in the kidney. These tubules help filter waste from the blood, making urine. Chromophobe RCC accounts for about 5% of all RCC cases, and it is frequently diagnosed between ages 40 and 50. It is typically diagnosed in stage I or stage II, and has an overall better prognosis than other types of RCC. Treatment generally involves surgery. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	Chromophobe renal cell carcinoma	c1266042	5,786	gard	https://rarediseases.info.nih.gov/diseases/6064/chromophobe-renal-cell-carcinoma	2021-01-18T18:01:26	{"mesh": ["D002292"], "umls": ["C1266042"], "synonyms": ["CRCC", "ChRCC"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-42 (RP42) is caused by heterozygous mutation in the KLHL7 gene (611119) on chromosome 7p15. For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Andreasson (1991) studied 26 affected and 6 unaffected members of 4 families from central Norway and Sweden segregating autosomal dominant retinitis pigmentosa. Although fundus examination was similar in patients from all 4 families, showing narrowed vessels and bone spicule pigment, 2 different types of RP could be distinguished by electroretinography (ERG) based on cone b-wave implicit times, which were normal in 1 family ('family 59') but prolonged in the other 3 families. ERG recordings from 10 RP patients in different age groups from a 6-generation family ('family 72') revealed that cone b-wave amplitude decreased with age but implicit time did not, suggesting that amplitude is useful for monitoring the progression of disease whereas implicit time is more suitable for distinguishing different types of disease. Andreasson (1991) found a correlation between age and the log of the amplitude in family 72, with a progression rate of 7.7% per year, corresponding to a half-life of 8.7 years; this was substantially slower than the previously reported average for all RP cases (18%; Berson et al., 1985). Genetic screening failed to detect mutations in the RHO gene (180380). Wen et al. (2011) performed a comprehensive assessment of patients from 3 families with RP42 (RFS073, RFS038, and RFS061), previously studied by Friedman et al. (2009) and found to have 3 different heterozygous mutations in the KLHL7 gene (611119.0001-611119.0003, respectively). All fundi showed the characteristic signs of RP, with clear loss of retinal tissue in the periphery, bone spicule pigmentation, arteriolar attenuation, and waxy optic pallor. In general, visual acuity reduction did not manifest until 50 years of age, and best-corrected visual acuity was 20/50 or better in at least 1 eye, up to age 65 years. Visual field restriction was the initial motivation for all 3 probands to seek medical attention. Static and kinetic visual fields showed concentric constriction to central 10 degrees to 20 degrees by age 65 years. Two patients exhibited bilateral visual field retention in the far periphery on Goldmann perimetry testing. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years. Wen et al. (2011) concluded that mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors, and suggested that strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing might guide mutation screening in autosomal dominant RP. Mapping Friedman et al. (2009) performed a whole-genome scan of 23 members of a large 6-generation Scandinavian family with a slow-progressing retinopathy, previously studied by Andreasson (1991) ('family 72'), and obtained a peak multipoint lod score of 5.0 on chromosome 7p15. They designated the locus RP42. Haplotype analysis defined an approximately 3-Mb critical interval between rs4719697 and rs2188993, a region containing 30 annotated or predicted genes. Friedman et al. (2009) noted that the RP42 locus is distinct from the previously reported RP9 locus on chromosome 7p14.2 (180104). Molecular Genetics In a large 6-generation Scandinavian family with a slow-progressing retinopathy mapping to chromosome 7p15, previously studied by Andreasson (1991) (family 72), Friedman et al. (2009) screened several candidate genes and identified a heterozygous mutation in the KLHL7 gene (S150N; 611119.0001) that segregated completely with disease in the 24 family members who were examined. The mutation was not found in 470 controls, including 183 from Scandinavia. Friedman et al. (2009) then screened the KLHL7 gene in 504 unrelated probands with autosomal dominant RP and identified the S150N mutation in a North American family; 2 additional heterozygous missense mutations (611119.0002 and 611119.0003) were identified in 3 families and 1 proband, respectively. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Retinitis pigmentosa, late-onset form \- Loss of peripheral retinal tissue \- Bone spicule pigmentation \- Arteriolar attenuation \- Waxy optic pallor \- Strong retention of foveal function \- Concentric constriction of visual fields bilaterally \- Sparing of far periphery MISCELLANEOUS \- Late-onset, slowly progressing form of retinitis pigmentosa MOLECULAR BASIS \- Caused by mutation in the kelch-like 7 gene (KLHL7, 611119.0001 ) ▲ 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	RETINITIS PIGMENTOSA 42	c0035334	5,787	omim	https://www.omim.org/entry/612943	2019-09-22T16:00:13	{"doid": ["0110386"], "mesh": ["D012174"], "omim": ["612943"], "orphanet": ["791"], "genereviews": ["NBK1417"]}
Erythema ab igne Other namesFire stains,[1] laptop thigh, granny's tartan, Koruda erythema, toasted skin syndrome[1] Erythema ab igne in a person with chronic abdominal pain who found some relief from the application of heat. SpecialtyDermatology Erythema ab igne (EAI), also known as hot water bottle rash,[2] is a skin condition caused by long-term exposure to heat (infrared radiation).[3] Prolonged thermal radiation exposure to the skin can lead to the development of reticulated erythema, hyperpigmentation, scaling and telangiectasias in the affected area. Some people may complain of mild itchiness and a burning sensation, but often, unless a change in pigmentation is seen, it can go unnoticed. ## Contents * 1 Causes * 2 Pathogenesis * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 Epidemiology * 6 References * 7 External links ## Causes[edit] Reticulated, interlacing, hyperpigmented patches with a few, scattered, erythematous macules at junctions on the medial aspects of the lower legs Different types of heat sources can cause this condition such as: * Repeated application of hot water bottles, heating blankets or heat pads to treat chronic pain—e.g., chronic backache.[4] * Repeated exposure to heated car seats, space heaters, or fireplaces. Repeated or prolonged exposure to a heater is a common cause of this condition in elderly individuals. * Occupational hazards of silversmiths and jewellers (face exposed to heat), bakers and chefs (arms, face) * Resting a laptop computer on the thigh (laptop computer-induced erythema ab igne). In a 2012 review, Riahi and Cohen describe the characteristics of laptop computer-induced erythema ab igne.[5] Temperatures between 43-47 °C can cause this skin condition; modern laptops can generate temperatures in this range. Indeed, laptops with powerful processors can reach temperatures of 50 °C and be associated with burns. Positioning of the laptop on the thighs can allow for direct exposure to the heating elements of the laptop, which include the central processing unit (CPU) and the graphics processing unit (GPU).[5] At least 15 cases have been reported by 2012 with the condition usually affecting the left anterior thigh.[5] In these reports, 9 of the 15 patients were women (60%) with an average age of 25 years at diagnosis. * In Kashmir, due to the use of a kanger which also causes kangri cancer. * It is a classic finding in chronic pancreatitis and may also be seen in people with hypothyroidism or lymphoedema ## Pathogenesis[edit] The pathogenesis of erythema ab igne remains unknown. It has been proposed that thermal radiation exposure can induce damage to superficial blood vessels that subsequently leads to epidermal vascular dilation. The dilation of vessels presents morphologically as the initially observed erythema.[4] Red blood cell extravasion and deposition of hemosiderin that follows clinically appears as hyperpigmentation, which can occur in a reticular distribution. It has also been proposed that the distribution of affected blood vessels — predominantly in the superficial subcutaneous plexus (found in the papillary dermis)— results in the net-like pattern of erythema ab igne skin lesions. ## Diagnosis[edit] ### Differential diagnosis[edit] * Livedo reticularis * Vasculitis ## Treatment[edit] Discontinuing contact with the heat source is the initial treatment of erythema ab igne.[5] If the area is only mildly affected with slight redness, the condition may resolve itself in a few months. If the condition is severe and the skin pigmented and atrophic, resolution is unlikely. In this case, there is a possibility that a squamous cell carcinoma or a neuroendocrine carcinoma such as a Merkel cell carcinoma may form.[6] If there is a persistent sore that does not heal or a growing lump within the rash, a skin biopsy should be performed to rule out the possibility of skin cancer. If the erythema ab igne lesions demonstrate pre-cancerous changes, the use of 5-fluorouracil cream has been recommended.[medical citation needed] Abnormally pigmented skin may persist for years. Treatment with topical tretinoin or laser treatment may improve the appearance.[medical citation needed] ## Epidemiology[edit] Erythema ab igne was once commonly seen in the elderly who stood or sat closely to open fires or electric heaters; however, erythema ab igne has been reported in both young and elderly individuals.[4] Women have a higher incidence of erythema ab igne than men. Although wide use of central heating has reduced the overall incidence of erythema ab igne, it is still sometimes found in people exposed to heat from other sources such as heating pads, space heaters, hot water bottles, and electronic devices. ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. Chapter87. ISBN 978-1-4160-2999-1. 2. ^ Rudolph CM, Soyer HP, Wolf P, Kerl H (February 1998). "Hot-water-bottle rash: not only a sign of chronic pancreatitis". Lancet. 351 (9103): 677. doi:10.1016/S0140-6736(05)78465-8. PMID 9500360. 3. ^ Riahi RR, Cohen PR, Robinson FW, Gray JM (Nov 2010). "Erythema ab igne mimicking livedo reticularis". International Journal of Dermatology. 49 (11): 1314–7. doi:10.1111/j.1365-4632.2009.04433.x. PMID 20964656. 4. ^ a b c "What Caused This Hyperpigmented Reticulated Rash On This Man's Back?". The Dermatologist. Jan 14, 2013. 5. ^ a b c d Cohen, Philip R.; Riahi, Ryan R. (June 2012). "Laptop-induced erythema ab igne: Report and review of literature". Dermatology Online Journal. 18 (6): 5. PMID 22747929. Retrieved 21 January 2013. 6. ^ Tan, S; Bertucci, V (2000). "Erythema ab igne: an old condition new again". Canadian Medical Association Journal. 162 (1): 77–78. PMC 1232235. PMID 11216204. ## External links[edit] Classification D * ICD-10: L59.0 * ICD-9-CM: 692.82 * DiseasesDB: 4438 External resources * eMedicine: derm/130 * DermNet vascular/erythema-ab-igne * New England Journal of Medicine Image Challenge * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Radiation-related disorders / Photodermatoses Ultraviolet/ionizing * Sunburn * Phytophotodermatitis * Solar urticaria * Polymorphous light eruption * Benign summer light eruption * Juvenile spring eruption * Acne aestivalis * Hydroa vacciniforme * Solar erythema Non-ionizing Actinic rays * Actinic keratosis * Atrophic actinic keratosis * Hyperkeratotic actinic keratosis * Lichenoid actinic keratosis * Pigmented actinic keratosis * Actinic cheilitis * Actinic granuloma * Actinic prurigo * Chronic actinic dermatitis Infrared/heat * Erythema ab igne (Kangri ulcer * Kairo cancer * Kang cancer * Peat fire cancer) * Cutis rhomboidalis nuchae * Poikiloderma of Civatte Other * Radiation dermatitis * Acute * Chronic radiodermatitis) * Favre–Racouchot syndrome * Photoaging * Photosensitivity with HIV infection * Phototoxic tar dermatitis [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	Erythema ab igne	c0494853	5,788	wikipedia	https://en.wikipedia.org/wiki/Erythema_ab_igne	2021-01-18T18:53:38	{"icd-9": ["692.82"], "icd-10": ["L59.0"], "wikidata": ["Q2161683"]}
A number sign (#) is used with this entry because of evidence that orofacial cleft-11 (OFC11) is caused by heterozygous mutation in the BMP4 gene (112262) on chromosome 14q22. For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic cleft lip with or without cleft palate, see OFC1 (119530). Description Congenital 'healed' cleft lip (CHCL) is an unusual anomaly consisting of a paramedian 'scar' of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero. The CHCL is frequently associated with an ipsilateral notch in the vermilion border and a 'collapsed' nostril (Castilla and Martinez-Frias, 1995). Clinical Features Castilla and Martinez-Frias (1995) presented 25 CHCL cases, 18 of which represented an isolated malformation found among the 3,950,715 births examined in 2 similar birth defect registries, 1 in Spain and 1 in Latin America. Like open cleft lip, of which it seems to be a variant, CHCL is most frequently seen among males (14/18 isolated cases), and preferentially affects the left side (10/18 cases). CHCL segregated with cleft lip in 1 family. The 5 CHCL cases with other congenital anomalies included 2 cases with hydrocephalus, 2 cases of the VACTERL association, and 1 infant with an atypical oblique facial cleft with single umbilical artery. CHCL may result from a defective fusion of the frontal nasal and maxillary processes (before week 7 of embryonic life), or from a spontaneously repaired open cleft lip, later on. In either way, these cases heal with a visual scar, and the pre-occurrence of CHCL in 2 families suggests a familial predisposition to this phenomenon. Neiswanger et al. (2007) noted that the spectrum of severity in visible CL/P is broad, ranging from notches of the vermilion and/or grooves in the philtrum to complete unilateral and bilateral clefts of the lip and palate. Minimal or microform expressions of the CL/P phenotype, typically involving subtle defects of the lip, alveolar arch, and/or inferior nasal region, are at the mild end of the spectrum. Using high-resolution ultrasonography to examine the orbicularis oris muscle, Neiswanger et al. (2007) found that 10.3% of 525 noncleft relatives of patients with nonsyndromic cleft lip had discontinuity of the orbicularis oris muscle compared to 5.8% of 257 controls (p = 0.04). Male relatives had a significantly higher rate of discontinuity than male controls (12.0% vs 3.2%; p = 0.01); female relatives also had a higher rate of discontinuity than female controls, but the increase was not statistically significant. These data confirm the hypothesis that subepithelial defects in the orbicularis oris are a mild manifestation of the cleft lip phenotype. Molecular Genetics Suzuki et al. (2009) identified mutations in the BMP4 gene (see, e.g., 112262.0003-112262.0005) in children with cleft lip and cleft palate. The parents, who also carried the mutation, only had subtle defects in the orbicularis oris muscle on ultrasound. Overall, BMP4 mutations were identified in 1 of 30 patients with microform clefts, 2 of 87 patients with subepithelial defects in the orbicularis oris muscle, and 5 of 968 patients with overt cleft lip/palate. These results indicated that microforms and subepithelial defects in the orbicularis oris muscle are part of the spectrum of CL/P and should be considered during the clinical evaluation of families with clefts. Animal Model In mice, Liu et al. (2005) demonstrated that conditional inactivation of the Bmp4 gene (112262) in the facial primordia resulted in delayed fusion of the medial nasal process to form the lip, resulting in isolated cleft lip in all mouse embryos at 12 days after conception. However, cleft lip was only present in 22% of mouse embryos at 14.5 days after conception, indicating spontaneous repair or healing of cleft lip in utero. Misc \- Most often in males \- Preferentially left sided Mouth \- Congenital 'healed' cleft lip (CHCL) \- Paramedian upper lip 'scar' \- Ipsilateral notch of vermilion border Nose \- Collapsed nostril Inheritance \- ? Familial predisposition ▲ 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	OROFACIAL CLEFT 11	c0158646	5,789	omim	https://www.omim.org/entry/600625	2019-09-22T16:16:02	{"doid": ["0080404"], "omim": ["600625"], "orphanet": ["199306"], "synonyms": ["Alternative titles", "CLEFT LIP WITH OR WITHOUT CLEFT PALATE, NONSYNDROMIC, 11"], "genereviews": ["NBK1378"]}
A number sign (#) is used with this entry because of evidence that spermatogenic failure-25 (SPGF25) is caused by homozygous or compound heterozygous mutation in the TEX15 gene (605795) on chromosome 8p12. Description Spermatogenic failure-25 is characterized by small testes and infertility, with severe oligozoospermia or azoospermia due to maturation arrest at the primary spermatocyte stage (Okutman et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). Clinical Features Okutman et al. (2015) studied 3 infertile Turkish brothers, born of first-cousin parents. The 2 older brothers were diagnosed with nonobstructive azoospermia, whereas their younger brother was initially diagnosed with severe oligozoospermia. All 3 brothers showed marked reduction in testicular size, with testes that were more than 50% smaller than normal. Histopathology of the proband showed maturation arrest at the primary spermatocyte stage. Testicular sperm extraction (TESE) in the 2 older brothers yielded a limited number of spermatozoa, and intracytoplasmic sperm injection (ICSI) was performed with transfer of 1 embryo each, but the transferred embryos were of poor quality and no pregnancy was obtained. The youngest brother achieved pregnancy using ejaculated sperm, resulting in a healthy child. However, 4 years after his initial evaluation, semen analysis revealed azoospermia, with no spermatozoa detected even after concentration. Colombo et al. (2017) reported 2 Italian brothers, ages 33 and 31 years, with small testes and nonobstructive azoospermia. Hormone evaluation revealed elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), low testosterone, and low inhibin B (see 147290). One brother also had a unilateral Sarteschi grade II varicocele. Wang et al. (2018) described a 33-year-old Chinese man who was infertile and had very small testes. Semen analysis revealed cryptozoospermia, with a sperm count of 0 to 2 cells on centrifugal sediment smear, and very few active spermatozoa were observed. Hormone analysis showed elevated FSH and LH, with low testosterone levels. Molecular Genetics In a consanguineous Turkish family with 3 infertile brothers who had small testes and nonobstructive azoospermia or severe oligozoospermia, Okutman et al. (2015) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the TEX15 gene (Y710X; 605795.0001). The mutation was present in heterozygosity in their unaffected first-cousin parents and in 2 fertile brothers, and was also detected in homozygosity in a fourth brother, who was the youngest of the family and was of unknown fertility status. The mutation was not found in 107 fertile males of Turkish origin, and sequencing TEX15 in 85 unrelated azoospermic men or 13 men with severe oligozoospermia did not reveal any additional mutations. One of the infertile Turkish brothers was initially diagnosed as having severe oligozoospermia and became azoospermic over time; the authors suggested that mutations in TEX15 might correlate with a decrease in sperm count over time. In 2 infertile Italian brothers with small testes and nonobstructive azoospermia, Colombo et al. (2017) performed whole-exome sequencing and identified compound heterozygosity for mutations in the TEX15 gene (605795.0002; 605795.0003). Their unaffected parents were each heterozygous for 1 of the mutations, as were a fertile maternal and paternal uncle, and a male cousin. The heterozygous male relatives had normal testicular volumes and sperm concentrations. By exome sequencing in a 33-year-old infertile Chinese man with small testes and cryptozoospermia, who had a normal karyotype and was negative for Y-chromosome microdeletion, Wang et al. (2018) identified homozygosity for a nonsense mutation in the TEX15 gene (R2312X; 605795.0004), for which his first-cousin parents were heterozygous. INHERITANCE \- Autosomal recessive GENITOURINARY Internal Genitalia (Male) \- Small testes \- Azoospermia, nonobstructive \- Oligozoospermia, severe \- Cryptozoospermia ENDOCRINE FEATURES \- Increased follicle-stimulating hormone (FSH) levels \- Increased luteinizing hormone (LH) levels \- Reduced testosterone levels \- Reduced inhibin B levels MISCELLANEOUS \- Heterozygous males are fertile, with normal testicular volumes and sperm concentrations MOLECULAR BASIS \- Caused by mutation in testis expressed 15 gene (TEX15, 605795.0001 ) ▲ 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	SPERMATOGENIC FAILURE 25	c4693765	5,790	omim	https://www.omim.org/entry/617960	2019-09-22T15:44:13	{"omim": ["617960"], "orphanet": ["399805"], "synonyms": []}
Acromicric dysplasia Other namesAcromicric skeletal dysplasia [1] Acromicric dysplasia is an extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short stature.[2] Most cases have occurred randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out. According to the disease database, Acromicric dysplasia is synonymous with Geleophysic dysplasia (or Geleophysic Dwarfism) and Focal mucopolysaccharidosis. ## Contents * 1 Genetics * 2 References * 3 External links ## Genetics[edit] This condition has been associated with mutations in the Fibrillin 1 (FBN1) gene.[3] Mutations in this gene have also been associated with stiff skin syndrome, Marfan syndrome and its variant Marfanoid–progeroid–lipodystrophy syndrome, autosomal dominant Weill-Marchesani syndrome, isolated ectopia lentis, MASS phenotype, and Shprintzen-Goldberg syndrome.[4][5] ## References[edit] 1. ^ "Acromicric dysplasia \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 18 March 2019. 2. ^ "OMIM Entry - # 102370 - ACROMICRIC DYSPLASIA; ACMICD". omim.org. Retrieved 2017-07-01. 3. ^ Wang T, Yang Y, Dong Q, Zhu H, Liu Y (2020) Acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation in an 8-year-old boy with a missense FBN1 mutation: Case report and literature review. Mol Genet Genomic Med 4. ^ "FBN1 fibrillin 1". Entrez Gene. 5. ^ Online Mendelian Inheritance in Man (OMIM): FIBRILLIN 1; FBN1 - 134797 ## External links[edit] * GeneReview/NIH/UW entry on Geleophysic Dysplasia Classification D * ICD-10: Q77.8 * OMIM: 102370 * MeSH: C535662 * DiseasesDB: 32737 External resources * GeneReviews: Geleophysic Dysplasia * Orphanet: 969 [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	Acromicric dysplasia	c0265287	5,791	wikipedia	https://en.wikipedia.org/wiki/Acromicric_dysplasia	2021-01-18T19:06:29	{"gard": ["7"], "mesh": ["C535662"], "umls": ["C0265287"], "orphanet": ["969"], "wikidata": ["Q4676182"]}
Sex chromosome anomalies, also called Sex chromosome anomalies belong to a group of genetic conditions that are caused or affected by the loss, damage or addition of one or both sex chromosomes (also called gonosomes). In humans this may refer to: * 45, X, also known as Turner syndrome * 45,X/46,XY mosaicism * 46, XX/XY * 47, XXX, also known as Triple X syndrome and trisomy X * 47, XXY, also known as Klinefelter syndrome * 47, XYY, has normal phenotype * 48, XXXX * 48, XXXY * 48, XXYY * 49, XXXXY * 49, XXXXX * XX gonadal dysgenesis * XY gonadal dysgenesis * XX male syndrome 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	Sex chromosome anomalies	c0949683	5,792	wikipedia	https://en.wikipedia.org/wiki/Sex_chromosome_anomalies	2021-01-18T18:44:10	{"mesh": ["D025064"], "orphanet": ["263749"], "synonyms": [], "wikidata": ["Q7458487"]}
A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young-13 (MODY13) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. For a phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391. Clinical Features Bonnefond et al. (2012) described a 4-generation French family with 12 members affected with MODY. Age at diagnosis ranged from 13 to 59 years of age. In addition, 1 member had impaired fasting glucose and another had impaired glucose tolerance. No member of the family had neonatal diabetes mellitus (NDM). Yorifuji et al. (2005) described a 4-generation Japanese family with diabetes mellitus. Age at onset of the 4 affected individuals ranged from 3 years to 26 years. One individual had childhood-onset diabetes; 2 had adult-onset of type 2 diabetes; and one had transient neonatal diabetes. Molecular Genetics In affected members of a 4-generation Japanese family with diabetes, Yorifuji et al. (2005) identified heterozygosity for a cys42-to-arg mutation in the KCNJ11 gene (C42R; 600937.0012). Two nonobese individuals had onset of type 2 diabetes in their twenties. Two of the 4 affected individuals maintained control of diabetes with sulfonylurea therapy alone. Bonnefond et al. (2012) performed whole-exome sequencing in 3 affected and 1 unaffected individuals from a family with MODY and confirmed all mutations by Sanger sequencing. Only 1 mutation (E227K; 600937.0024) in the KCNJ11 gene cosegregated with disease in the family (lod score of 3.68). No other KCNJ11 mutations were found in 25 other subjects with MODY of unknown etiology. Affected individuals were effectively treated with oral sulfonylureas, thus confirming the phenotype as MODY13. The family described by Bonnefond et al. (2012) had 3 generations that could be molecularly characterized; age at diagnosis of diabetes in affected individuals ranged from 13 years to 59 years. Five affected individuals had onset of diabetes at less than 25 years of age. INHERITANCE \- Autosomal dominant GROWTH Other \- Normal BMI ENDOCRINE FEATURES \- Gestational diabetes \- Maturity onset diabetes MISCELLANEOUS \- Intrafamilial phenotypic variability ranging from transient or permanent neonatal diabetes ( 610582 ) to MODY ( 616329 ) to impaired fasting glucose or impaired glucose tolerance \- Treatment with sulfonylurea can be effective MOLECULAR BASIS \- Caused by mutation in the potassium inwardly-rectifying channel, subfamily J, member 11 gene (KCNJ11, 600937.0012 ) ▲ 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	MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13	c0342276	5,793	omim	https://www.omim.org/entry/616329	2019-09-22T15:49:11	{"doid": ["0111110"], "mesh": ["C562772"], "omim": ["616329"], "orphanet": ["552"], "synonyms": ["Alternative titles", "MODY, TYPE 13"], "genereviews": ["NBK500456"]}
Levine et al. (1972) found that clinical ragweed pollenosis (hay fever) and IgE antibody production specific for antigen E (the major purified protein antigen from ragweed pollen extract) correlated closely with HLA haplotypes in successive generations of 7 families. The correlation was thought to be based on the existence of an Ir locus closely linked to the HLA locus (142800). Blumenthal et al. (1974) extensively studied 3 generations of a kindred for skin sensitivity to antigen E of ragweed and for HLA type (142800). They concluded that a locus controlling sensitivity to antigen E (IrE) is linked to the HLA complex on chromosome 6 and that the order is: first locus (LA), second locus (FOUR), IrE. They designated the complex HL-1. Ragweed sensitivity is a specific form of atopy (147050). Because of the distribution of the offending agent, it is a disorder primarily of the eastern United States. Studies by Cookson et al. (1989, 1992), performed in England, concern other allergens since ragweed is not found in that country. Immunology \- Ragweed hay fever \- HLA linkage Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) *[a.k.a.]: also known as	RAGWEED SENSITIVITY	c1867394	5,794	omim	https://www.omim.org/entry/179450	2019-09-22T16:35:19	{"mesh": ["C566725"], "omim": ["179450"]}
Musical hallucinations (also known as auditory hallucinations, auditory Charles Bonnet Syndrome, and Oliver Sacks' syndrome[1]) describes a neurological disorder in which the patient will hallucinate songs, tunes, instruments and melodies. The source of these hallucinations are derived from underlying psychotic illness or hearing impairment. These hallucinations are often rare and are followed by mental decline.[2] Majority of patients who suffer from symptoms of musical hallucinations are older and have onset conditions predisposing them to the disease. While there is no set form of treatment, research has discovered medications and alternative therapies to be successful in alleviating the hallucinations. ## Contents * 1 Description * 2 Causes * 2.1 Hypoacusis * 2.2 Psychiatric disorders * 2.3 Focal brain lesions * 2.4 Epilepsy * 2.5 Intoxication * 2.6 Other Risk Factors * 3 Imaging * 4 Treatment * 5 History * 6 References ## Description[edit] In 73 individual cases reviewed by Evers and Ellger, 57 patients heard tunes that were familiar, while 5 heard unfamiliar tunes. These tunes ranged from religious pieces to childhood favorites, and also included popular songs from the radio. Vocal and instrumental forms of classical music were also identified in most patients. Keshavan found that the consistent feature of musical hallucinations was that it represented a personal memory trace. Memory traces refer to anything that may seem familiar to the patient, which indicate why certain childhood or familiar songs were heard.[3][4] For the case of an 84 year old widow who complained of hearing sounds, she described her symptoms as pleasant, but also sought for treatment because she felt distracted. The music that played over her head was similar to the hymns and songs sung at her own wedding. Moreover, had been widowed for a while and had no signs of psychiatric disorders. However, she did suffer from hypertension, hyperthyroidism, and osteoporosis. From these diagnosis it was theorized that the distress from the illnesses manifested the hallucinations. Through further analysis, researchers found that due the unexpected origin of the hallucinations, there is no clear diagnosis or treatments to carry out. Another case, which studies a 74-year-old woman, described her symptoms as music that would play in short verses of patriotic and children's songs.[5] These symptoms would occur when the patient was alone and much more frequently when driving. Researchers suspected her hearing loss as a factor for developing the hallucinations. Moreover, through further analysis the patient had a medical history of hypertension, hyperlipidemia, and atrial fibrillations. Oftentimes, cases are commonly found in the elderly, but a 29-year-old female reported hearing music for one week. Prior to her hallucinations, the patient had undergone surgery for intraventricular and intracranial hemorrhages, following her recover, she mentioned the onset of hallucinations followed by headaches.[6] Through scans, doctors found no neurological impairments, but prescribed her with medication. For her, the symptoms only lasted a year due to the treatment of quetiapine, which she responded well to. ## Causes[edit] Musical hallucinations can occur in people who are physically and mentally healthy, and for them, there is no known cause.[7] Most people find their musical hallucinations obtrusive, and wish to be rid of them, while others welcome them. In addition, investigators have pointed to factors that are associated with musical hallucinations. Evers and Ellgers compiled a significant portion of musical hallucination articles, case studies etc. and were able to categorize five major etiologies: * Hypoacusis * Psychiatric disorders * Focal brain lesion * Epilepsy * Intoxication ### Hypoacusis[edit] Hypoacusis is defined as impairment in hearing or deafness. Hypoacusis is one of five etiologies of musical hallucinations, and is the most common in the case studies reviewed by Evers and Ellgers.[3] According to Sanchez et al. 2011, there have been suggestions that pontine lesions could alter the central auditory system's function causing hypoacusis and musical hallucinations.[8][9] ### Psychiatric disorders[edit] A case study by Janakiraman et al. 2006, revealed a 93‑year‑old woman with major depressive disorder who experienced musical hallucinations while treated with electroconvulsive therapy (ECT). Investigators found that the patient's depression symptoms were inversely related to her hallucinations and primarily stemmed from the ECT treatment. The patient had no known abnormalities in hearing, suggesting that musical hallucinations could arise from a variety of sources including psychiatric illnesses. After a complete course of ECT, her hallucinations dissipated, also suggesting that they can be acute.[10] According to Evers and Ellgers, some other major psychiatric disorders that contribute to musical hallucinations include schizophrenia and depression. Some patients who have schizophrenia experience musical hallucinations due to their ongoing psychosis, but there are some cases that do so without psychosis. There are also a very small percentage of musical hallucination cases due to obsessive-compulsive disorder (OCD).[3] Several different types of psychiatric disorders can be precursors for Musical Hallucinations. according to Blom and Coebergh, Bipolar Disorder and personality disorders can increase the chances of musical hallucinations. Likewise, cocaine dependence can elevate the symptoms. ### Focal brain lesions[edit] Among the handful of cases that Evers and Ellgers studied, major lesion sites included the temporal cortex; however, the specific location and laterality (left vs. right temporal cortex) was variable. Many cases of focal brain lesions had comorbidity with hearing impairment (see hypoacusis), epileptic activity and intoxication.[3] There have also been several findings of acute musical hallucinations in patients with dorsal pons lesions post-stroke and encephalitis potentially due to disruption of connections between the sensory cortex and reticular formation.[11] Also, any kind of traumatic lesion imposed on the brain can be a risk factor for Musical Hallucinations. ### Epilepsy[edit] Epileptic brain activity in musical hallucinations originates in the left or right temporal lobe.[3] In a specific case studied by Williams et al. 2008, a patient who received a left temporal lobectomy in order to treat epilepsy was diagnosed with musical hallucinations post-surgery. The patient also had multiple additional risk factors that could have accounted for the hallucinations including mild neuropsychiatric dysfunction and tinnitus.[12] The causation of hallucination through epilepsy is linked to seizure episodes. Through experiments, researchers have found that patients with epilepsy and hallucinations will respond to antiepileptics and surgery[13] ### Intoxication[edit] Intoxication accounts for a small percentage of musical hallucination cases. Intoxication leads to either withdrawal or inflammatory encephalopathy, which are major contributors to musical hallucinations. Some of the drugs that have been found to relate to musical hallucinations include salicylates, benzodiazepines, pentoxifylline, propranolol, clomipramine, amphetamine, quinine, imipramine, a phenothiazine, carbamazepine, marijuana, paracetamol, phenytoin, procaine, and alcohol. General anesthesia has also been associated with musical hallucinations.[3] In a case study by Gondim et al. 2010, a seventy–seven-year-old woman with Parkinson's disease (PD) was administered amantadine after a year of various other antiparkinsonian treatments. Two days into her treatment, she started to experience musical hallucinations, which consisted of four musical pieces. The music persisted until three days after cessation of the drug. Although the patient was taking other medications at the same time, the timing of onset and offset suggested that amantadine either had a synergistic effect with the other drugs or simply caused the hallucinations. Although the case wasn't specific to intoxication, it leads to the idea that persons with PD who are treated with certain drugs can experience musical hallucinations.[14] ### Other Risk Factors[edit] In summary, musical hallucinations can be separated into five categories according to their cause: Hyperacusis, psychiatric disorders, brain lesions, epilepsy, and substance use. However, certain factors can trigger hallucinations, these factors include, old age, social isolation and even gender.[15] Many cases highlight female patients who suffer from the disease. Overall, psychiatric disorders and neurological disease lead to hallucinations, but certain factors, such as age and gender play a role in heightening the causation. ## Imaging[edit] Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) show that musical hallucinations activate a wide variety of areas in the brain including the following: auditory areas, motor cortex, visual areas, basal ganglia, brainstem, pons, tegmentum, cerebellum, hippocampi, amygdala, and peripheral auditory system.[16] ## Treatment[edit] To date, there is no successful method of treatment that "cures" musical hallucinations. There have been successful therapies in single cases that have ameliorated the hallucinations. Some of these successes include drugs such as neuroleptics, antidepressants, and certain anticonvulsive drugs. A musical hallucination was alleviated, for example, by antidepressant medications given to patients with depression.[3] Sanchez reported that some authors have suggested that the use of hearing aids may improve musical hallucination symptoms.[9] They believed that the external environment influences the auditory hallucinations, showing worsening of symptoms in quieter environments than in noisier ones.[8][17][18] Oliver Sacks' patient, Mrs. O'C, reported being in an "ocean of sound" despite being in a quiet room due to a small thrombosis or infarction in her right temporal lobe. After treatment, Mrs. O'C was relinquished of her musical experience but said that, "I do miss the old songs. Now, with lots of them, I can't even recall them. It was like being given back a forgotten bit of my childhood again." Sacks also reported another elderly woman, Mrs. O'M, who had a mild case of deafness and reported hearing musical pieces. When she was treated with anticonvulsive medications, her musical hallucinations ceased but when asked if she missed them, she said "Not on your life."[19] Another, potential treatment for hallucinations is donepezil. Researchers found that patients respond well to the drug. The main use of the drug is to treat dementia in patients, but is primarily a cholinesterase inhibitor. The goal of this medication is provide patients with a better quality of life. This includes inhibiting the loss of function or improving the ability to think.[20] For patients of Musial Hallucinations, the medication keeps them more aware and stimulated to control the onset symptoms of hallucinations. Overall, with few adverse effects, research has found that donepezil is an effective and safe choice of treatment.[21] ## History[edit] According to Oliver Sacks' Hallucinations, the first known medical report of musical hallucinations was published in 1846, by French alienist Jules Baillarger.[16] However, the first scientific description of the disorder was reported in the early 1900s. In the last three decades, Berrios has reported case studies in 1990 and 1991 along with Keshavan et al. in 1992. Berrios concluded that confirmed diagnoses of deafness, ear disease, brain disease, advanced age and drug use are all important factors in the development of musical hallucinations. After analyzing 46 cases, Berrios found a female predominance of 80% in women over the age of 60. The study concluded that musical hallucinations were more likely to be seen in elderly women affected by deafness or brain disease than in individuals with no psychiatric illness at all.[22][4] Keshevan and Berrios were the first authors to identify classes of musical hallucinations. These classes consisted of hearing loss, coarse brain disease (i.e. tumors), epileptic disorder, stroke, and psychiatric disorder. Although no statistical analyses were performed, the authors stated that deafness was the most strongly related factor in musical hallucinations and that there was a female predominance, which could entail a genetic component.[3][22][4] ## References[edit] 1. ^ Blom, Jan Dirk; Coebergh, Jan Adriaan F.; Lauw, René; Sommer, Iris E. C. (2015). "Musical Hallucinations Treated with Acetylcholinesterase Inhibitors". Frontiers in Psychiatry. 6. doi:10.3389/fpsyt.2015.00046. ISSN 1664-0640. 2. ^ Golden, Erin C.; Josephs, Keith A. (December 2015). "Minds on replay: musical hallucinations and their relationship to neurological disease". Brain: A Journal of Neurology. 138 (Pt 12): 3793–3802. doi:10.1093/brain/awv286. ISSN 1460-2156. PMID 26446167. 3. ^ a b c d e f g h Evers, S; Ellger, T (2004). "The clinical spectrum of musical hallucinations". Journal of the Neurological Sciences. 227 (1): 55–65. doi:10.1016/j.jns.2004.08.004. PMID 15546592. S2CID 23786425. 4. ^ a b c Keshavan, M.S.; David, A.S.; Steingard, S.; Lishman, W.A. (1992). "Musical hallucinations: a review and synthesis". Cognitive and Behavioral Neurology. 3 (3): 211–23. 5. ^ Brunner, Jacob P.; Amedee, Ronald G. (2015). "Musical Hallucinations in a Patient with Presbycusis: A Case Report". The Ochsner Journal. 15 (1): 89–91. ISSN 1524-5012. PMC 4365855. PMID 25829887. 6. ^ Doluweera, Yasira; Suraweera, Chathurie (2018-06-27). "Those Who Hear Music: Three Cases on Musical Hallucinations". Case Reports in Psychiatry. Retrieved 2020-12-11. 7. ^ Deutsch, D. (2019). "Hallucinations of music and speech". Musical Illusions and Phantom Words: How Music and Speech Unlock Mysteries of the Brain. Oxford University Press. ISBN 9780190206833. LCCN 2018051786. 8. ^ a b Hammeke, TA; McQuillen, MP; Cohen, BA (1983). "Musical hallucinations associated with acquired deafness". Journal of Neurology, Neurosurgery, and Psychiatry. 46 (6): 570–2. doi:10.1136/jnnp.46.6.570. PMC 1027453. PMID 6875592. 9. ^ a b Sanchez, TG; Rocha, SC; Knobel, KA; Kii, MA; Santos, RM; Pereira, CB (2011). "Musical hallucination associated with hearing loss". Arquivos de Neuro-Psiquiatria. 69 (2B): 395–400. doi:10.1590/s0004-282x2011000300024. PMID 21625772. 10. ^ Janakiraman, R; Wildgoose, K; Seelam, K (2006). "ECT associated musical hallucinations in an elderly patient: a case report". Annals of General Psychiatry. 5: 10. doi:10.1186/1744-859X-5-10. PMC 1557851. PMID 16889667. 11. ^ Schielke, E; Reuter, U; Hoffmann, O; Weber, JR (2000). "Musical hallucinations with dorsal pontine lesions". Neurology. 55 (3): 454–5. doi:10.1212/wnl.55.3.454. PMID 10932294. S2CID 35439732. 12. ^ Williams, VG; Tremont, G; Blum, AS (2008). "Musical hallucinations after left temporal lobectomy". Cognitive and Behavioral Neurology. 21 (1): 38–40. doi:10.1097/WNN.0b013e318165a9e1. PMID 18327022. S2CID 6121424. 13. ^ Coebergh, Jan A. F.; Lauw, R. F.; Bots, R.; Sommer, I. E. C.; Blom, J. D. (2015-06-16). "Musical hallucinations: review of treatment effects". Frontiers in Psychology. 6. doi:10.3389/fpsyg.2015.00814. ISSN 1664-1078. PMC 4468361. PMID 26136708. 14. ^ Gondim, Francisco de Assis Aquino; Costa, Helida A.; Taunay, Tauily C.D.; de Oliveira, Gisele R.; Ferreira, Jamile Magalhães; Rola, Francisco H. (2010). "Transient amantadine‑induced musical hallucinations in a patient with Parkinson's disease". Movement Disorders. Wiley-Blackwell. 25 (10): 1505–1506. doi:10.1002/mds.22553. ISSN 0885-3185. PMID 20629118. 15. ^ Alvarez Perez, Purificacion; Garcia-Antelo, Maria Jose; Rubio-Nazabal, Eduardo (2017-02-28). ""Doctor, I Hear Music": A Brief Review About Musical Hallucinations". The Open Neurology Journal. 11: 11–14. doi:10.2174/1874205X01711010011. ISSN 1874-205X. PMC 5420178. PMID 28567134. 16. ^ a b Sacks, Oliver (2012). Hallucinations (1st American ed.). New York: Alfred A. Knopf. ISBN 978-0-307-95724-5. 17. ^ Miller, TC; Crosby, TW (Mar 1979). "Musical hallucinations in a deaf elderly patient". Annals of Neurology. 5 (3): 301–2. doi:10.1002/ana.410050314. PMID 443762. S2CID 11598486. 18. ^ Ross, Elliott D. (1975-02-10). "Musical Hallucinations in Deafness". Journal of the American Medical Association. 231 (6): 620–2. doi:10.1001/jama.1975.03240180056018. PMID 1172847. 19. ^ Sacks, Oliver (1998). The man who mistook his wife for a hat and other clinical tales (1st Touchstone ed.). New York, NY: Simon & Schuster. ISBN 978-0-684-85394-9. 20. ^ "Donepezil: MedlinePlus Drug Information". medlineplus.gov. Retrieved 2020-12-11. 21. ^ Ukai, Satoshi; Yamamoto, Masakiyo; Tanaka, Michio; Shinosaki, Kazuhiro; Takeda, Masatoshi (2007). "Donepezil in the treatment of musical hallucinations". Psychiatry and Clinical Neurosciences. 61 (2): 190–192. doi:10.1111/j.1440-1819.2007.01636.x. ISSN 1440-1819. 22. ^ a b Berrios, GE (1990). "Musical hallucinations. A historical and clinical study". British Journal of Psychiatry. 156 (2): 188–94. doi:10.1192/bjp.156.2.188. PMID 2180526. * v * t * e Music psychology Areas * Biomusicology * Cognitive musicology * Cognitive neuroscience of music * Culture in music cognition * Evolutionary musicology * Psychoacoustics Topics * Absolute pitch * Auditory illusion * Auditory imagery * Background music * Consonance and dissonance * Deutsch's scale illusion * Earworm * Embodied music cognition * Entrainment * Exercise and music * Eye movement in music reading * Franssen effect * Generative theory of tonal music * Glissando illusion * Hedonic music consumption model * Illusory continuity of tones * Levitin effect * Lipps–Meyer law * Melodic expectation * Melodic fission * Mozart effect * Music and emotion * Music and movement * Music in psychological operations * Music preference * Music-related memory * Musical gesture * Musical semantics * Musical syntax * Octave illusion * Relative pitch * Sharawadji effect * Shepard tone * Speech-to-song illusion * Temporal dynamics of music and language * Tonal memory * Tritone paradox Disorders * Amusia * Auditory arrhythmia * Beat deafness * Musical hallucinations * Musician's dystonia * Music-specific disorders * Tone deafness Related fields * Aesthetics of music * Bioacoustics * Ethnomusicology * Hearing * Melodic intonation therapy * Music education * Music therapy * Musical acoustics * Musicology * Neurologic music therapy * Neuronal encoding of sound * Performance science * Philosophy of music * Psychoanalysis and music * Sociomusicology * Systematic musicology * Zoomusicology Researchers * Jamshed Bharucha * Lola Cuddy * Robert Cutietta * Jane W. Davidson * Irène Deliège * Diana Deutsch * Tuomas Eerola * Henkjan Honing * David Huron * Nina Kraus * Carol L. Krumhansl * Fred Lerdahl * Daniel Levitin * Leonard B. Meyer * Max Friedrich Meyer * James Mursell * Richard Parncutt * Oliver Sacks * Carl Seashore * Max Schoen * Roger Shepard * John Sloboda * Carl Stumpf * William Forde Thompson * Sandra Trehub Books and journals * Music Perception * Musicae Scientiae (journal) * Musicophilia * Music, Thought, and Feeling * Psychology of Music (journal) * The World in Six Songs * This Is Your Brain on Music [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	Musical hallucinations	None	5,795	wikipedia	https://en.wikipedia.org/wiki/Musical_hallucinations	2021-01-18T19:05:18	{"wikidata": ["Q6942549"]}
Inverse psoriasis SpecialtyDermatology Inverse psoriasis or flexural psoriasis is a form of psoriasis that selectively, and often exclusively, involves the folds, recesses, and flexor surfaces such as the ears, axillae, groin folds, inframammary folds, navel, intergluteal cleft, penis, lips, and webspaces.[1]:193 ## Contents * 1 Diagnosis * 1.1 Differential diagnosis * 2 See also * 3 References ## Diagnosis[edit] ### Differential diagnosis[edit] Skin conditions which can present with similar signs and symptoms include seborrheic dermatitis, intertrigo, and tinea versicolor. ## See also[edit] * Psoriasis * Skin lesion ## 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. * v * t * e Papulosquamous disorders Psoriasis Pustular * Generalized pustular psoriasis (Impetigo herpetiformis) * Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid) * Annular pustular psoriasis * Localized pustular psoriasis Other * Guttate psoriasis * Psoriatic arthritis * Psoriatic erythroderma * Drug-induced psoriasis * Inverse psoriasis * Napkin psoriasis * Seborrheic-like psoriasis Parapsoriasis * Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica) * Lymphomatoid papulosis * Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans) * Large plaque parapsoriasis (Retiform parapsoriasis) Other pityriasis * Pityriasis rosea * Pityriasis rubra pilaris * Pityriasis rotunda * Pityriasis amiantacea Other lichenoid Lichen planus * configuration * Annular * Linear * morphology * Hypertrophic * Atrophic * Bullous * Ulcerative * Actinic * Pigmented * site * Mucosal * Nails * Peno-ginival * Vulvovaginal * overlap synromes * with lichen sclerosus * with lupus erythematosis * other: * Hepatitis-associated lichen planus * Lichen planus pemphigoides Other * Lichen nitidus * Lichen striatus * Lichen ruber moniliformis * Gianotti–Crosti syndrome * Erythema dyschromicum perstans * Idiopathic eruptive macular pigmentation * Keratosis lichenoides chronica * Kraurosis vulvae * Lichen sclerosus * Lichenoid dermatitis * Lichenoid reaction of graft-versus-host disease 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	Inverse psoriasis	c0343053	5,796	wikipedia	https://en.wikipedia.org/wiki/Inverse_psoriasis	2021-01-18T18:31:06	{"umls": ["C0343053"], "icd-10": ["L40.8"], "wikidata": ["Q6060418"]}
DOLK-congenital disorder of glycosylation (DOLK-CDG, formerly known as congenital disorder of glycosylation type Im) is an inherited condition that often affects the heart but can also involve other body systems. The pattern and severity of this disorder's signs and symptoms vary among affected individuals. Individuals with DOLK-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Nearly all individuals with DOLK-CDG develop a weakened and enlarged heart (dilated cardiomyopathy). Other frequent signs and symptoms include recurrent seizures; developmental delay; poor muscle tone (hypotonia); and dry, scaly skin (ichthyosis). Less commonly, affected individuals can have distinctive facial features, kidney disease, hormonal abnormalities, or eye problems. Individuals with DOLK-CDG typically do not survive into adulthood, often because of complications related to dilated cardiomyopathy, and some do not survive past infancy. ## Frequency DOLK-CDG is likely a rare condition; at least 18 cases have been reported in the scientific literature. ## Causes DOLK-CDG is caused by mutations in the DOLK gene. This gene provides instructions for making the enzyme dolichol kinase, which facilitates the final step of the production of a compound called dolichol phosphate. This compound is critical for a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Glycosylation changes proteins in ways that are important for their functions. During glycosylation, sugars are added to dolichol phosphate in order to build the oligosaccharide chain. Once the chain is formed, dolichol phosphate transports the oligosaccharide to the protein that needs to be glycosylated and attaches it to a specific site on the protein. Mutations in the DOLK gene lead to the production of abnormal dolichol kinase with reduced or absent activity. Without properly functioning dolichol kinase, dolichol phosphate is not produced and glycosylation cannot proceed normally. In particular, a protein known to stabilize heart muscle fibers, called alpha-dystroglycan, has been shown to have reduced glycosylation in people with DOLK-CDG. Impaired glycosylation of alpha-dystroglycan disrupts its normal function, which damages heart muscle fibers as they repeatedly contract and relax. Over time, the fibers weaken and break down, leading to dilated cardiomyopathy. The other signs and symptoms of DOLK-CDG are likely due to the abnormal glycosylation of additional proteins in other organs and tissues. ### Learn more about the gene associated with DOLK-congenital disorder of glycosylation * DOLK ## 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	DOLK-congenital disorder of glycosylation	c1835849	5,797	medlineplus	https://medlineplus.gov/genetics/condition/dolk-congenital-disorder-of-glycosylation/	2021-01-27T08:25:00	{"gard": ["10307", "12393"], "mesh": ["C563666"], "omim": ["610768"], "synonyms": []}
Acute cerebellar ataxia of childhood SpecialtyPediatrics, neurology Acute cerebellar ataxia of childhood is a childhood condition characterized by an unsteady gait, most likely secondary to an autoimmune response to infection, drug induced or paraneoplastic.[1] Most common virus causing acute cerebellar ataxia are Chickenpox virus and Epstein Barr Virus, leading to a childhood form of post viral cerebellar ataxia. It is a diagnosis of exclusion.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Differential diagnosis * 4 Management * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Acute cerebellar ataxia usually follows 2–3 weeks after an infection. Onset is abrupt. Vomiting may be present at the onset but fever and nuchal rigidity characteristically are absent. Horizontal nystagmus is present is approximately 50% of cases. * Truncal ataxia with deterioration of gait * Slurred speech and nystagmus * Afebrile ## Cause[edit] Possible causes of acute cerebellar ataxia include varicella infection, as well as infection with influenza, Epstein-Barr virus, Coxsackie virus, Echo virus or mycoplasma.[3] ## Diagnosis[edit] Acute Cerebellar ataxia is a diagnosis of exclusion. Urgent CT scan is necessary to rule out cerebellar tumor or hemorrhage as cause of the ataxia; however in acute cerebellar ataxia, the CT will be normal. CSF studies are normal earlier in the course of disease. Later on CSF shows moderate elevation of proteins. ### Differential diagnosis[edit] * Brain tumors, including cerebellar astrocytoma, medulloblastoma, neuroblastoma * Cerebellar contusion * Subdural hematoma * Toxins, including ethanol or anticonvulsants * Cerebellar infarction or hemorrhage * Meningitis * Encephalitis * Acute disseminated encephalomyelitis * Multiple sclerosis ## Management[edit] Supportive treatment is the only intervention for acute cerebellar ataxia of childhood. Symptoms may last as long as 2 or 3 months. ## Epidemiology[edit] Acute cerebellar ataxia is the most common cause of unsteady gait in children. The condition is rare in children older than ten years of age. Most commonly acute cerebellar ataxia affects children between age 2 and 7 years.[3][4] ## See also[edit] * Gluten ataxia ## References[edit] 1. ^ Brown, Miller. "Pediatrics." Lippincott Williams & Wilkins, 2005, pp 380. 2. ^ Textbook of Paediatric Emergency Medicine 3. ^ a b Textbook of Paediatric Emergency Medicine, Elsevier, page 245 4. ^ Acute cerebellar ataxia ## 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	Acute cerebellar ataxia of childhood	c0238014	5,798	wikipedia	https://en.wikipedia.org/wiki/Acute_cerebellar_ataxia_of_childhood	2021-01-18T18:29:31	{"wikidata": ["Q4677914"]}
Not to be confused with Spondylosis, Spondylitis, Spondylolysis, or Slipped disk. Spondylolisthesis Other namesOlisthesis X-ray of the lateral lumbar spine with a grade III anterolisthesis at the L5-S1 level. Pronunciation * /ˌspɒndɪloʊlɪsˈθiːsɪs/ SPON-dil-oh-lis-THEE-sis SpecialtyOrthopedics Spondylolisthesis is the displacement of one spinal vertebra compared to another. While some medical dictionaries define spondylolisthesis specifically as the forward or anterior displacement of a vertebra over the vertebra inferior to it (or the sacrum),[1][2] it is often defined in medical textbooks as displacement in any direction.[3][4] Spondylolisthesis is graded based upon the degree of slippage of one vertebral body relative to the subsequent adjacent vertebral body.[5] Spondylolisthesis is classified as one of the six major etiologies: degenerative, traumatic, dysplastic, isthmic, pathologic, or post-surgical.[6] Spondylolisthesis most commonly occurs in the lumbar spine, primarily at the L5-S1 level with the L5 vertebral body anteriorly translating over the S1 vertebral body.[6] ## Contents * 1 Types * 2 Anterolisthesis * 2.1 Classification * 2.1.1 By causes * 2.1.2 By location * 2.1.3 Severity * 2.2 Signs and symptoms * 2.3 Physical Exam * 2.3.1 Observation * 2.3.2 Palpation * 2.3.3 Maneuvers * 2.4 Diagnostic Imaging * 2.4.1 Plain Radiography (X-Ray) * 2.4.2 Magnetic Resonance Imaging (MRI) * 2.4.3 Computed Tomography (CT) * 2.5 Treatment * 2.5.1 Conservative * 2.5.2 Surgical * 3 Retrolisthesis * 4 History * 5 See also * 6 References * 7 External links ## Types[edit] Olisthesis (synonym olisthy) is a term that more explicitly denotes displacement in any direction.[7] Forward or anterior displacement can specifically be called anterolisthesis.[3][4] Anterolisthesis commonly involves the fifth lumbar vertebra.[8] Backward displacement is called retrolisthesis. Lateral displacement is called lateral listhesis[3] or laterolisthesis.[4] A hangman's fracture is a specific type of spondylolisthesis where the second cervical vertebra (C2) is displaced anteriorly relative to the C3 vertebra due to fractures of the C2 vertebra's pedicles. ## Anterolisthesis[edit] ### Classification[edit] Anterolisthesis can be categorized by cause, location and severity. #### By causes[edit] * Degenerative anterolisthesis (a.k.a. type 3) is a disease of the older adult that develops as a result of facet arthritis and joint remodeling. Joint arthritis, and ligamentum flavum weakness, may result in slippage of a vertebra. Degenerative forms are more likely to occur in women, persons older than fifty, and African Americans.[9] * Traumatic anterolisthesis is rare and results from acute fractures in the neural arch, other than the pars.[10] * Dysplastic anterolisthesis (a.k.a. type 1) results from congenital abnormalities of the upper sacral facets or inferior facets of the fifth lumbar vertebra, and accounts for 14% to 21% of all anterolisthesis.[11] * Isthmic anterolisthesis (a.k.a. type 2) is caused by a defect in the pars interarticularis but it can also be seen with an elongated pars.[citation needed] * Pathologic anterolisthesis (a.k.a. type 5) is caused by either infection or a malignancy. * Post-surgical/iatrogenic anterolisthesis (a.k.a. type 6) is caused by complications after surgery. #### By location[edit] Anterolisthesis location includes which vertebrae are involved, and may also specify which parts of the vertebrae are affected. Isthmic anterolisthesis is where there is a defect in the pars interarticularis.[12] It is the most common form of spondylolisthesis; also called spondylolytic spondylolisthesis, it occurs with a reported prevalence of 5–7 percent in the US population. A slip or fracture of the intravertebral joint is usually acquired between the ages of 6 and 16 years, but remains unnoticed until adulthood. Roughly 90 percent of these isthmic slips are low-grade (less than 50 percent slip) and 10 percent are high-grade (greater than 50 percent slip).[9] It is divided into three subtypes:[13] * * A: pars fatigue fracture * B: pars elongation due to multiple healed stress effects * C: pars acute fracture #### Severity[edit] Classification by degree of the slippage, as measured as percentage of the width of the vertebral body:[14] Grade I spondylolisthesis accounts for approximately 75% of all cases.[6] * Grade I: 0–25% * Grade II: 25- 50% * Grade III: 50–75% * Grade IV: 75–100% * Grade V: greater than 100% * X-ray of measurement of spondylolisthesis at the lumbosacral joint, being 25% in this example. * X-ray picture of a grade 1 isthmic anterolisthesis at L4-5 * MRI of L5-S1 anterolisthesis * X-ray of a grade 4 anterolisthesis at L5-S1 with spinal misalignment indicated * Anterolisthesis L5/S1 * Anterolisthesis L5/S1 * Anterolisthesis L5/S1. Blue arrow normal pars interarticularis. Red arrow is a break in pars interarticularis * Anterolisthesis L5/S1 ### Signs and symptoms[edit] Symptoms of lumbar anterolisthesis include: * A general stiffening of the back and a tightening of the hamstrings, with a resulting change in both posture and gait. * A leaning-forward or semi-kyphotic posture may be seen, due to compensatory changes. * A "waddle" may be seen in more advanced causes, due to compensatory pelvic rotation due to decreased lumbar spine rotation. * A result of the change in gait is often a noticeable atrophy in the gluteal muscles due to lack of use. * Generalized lower-back pain may also be seen, with intermittent shooting pain from the buttocks to the posterior thigh, and/or lower leg via the sciatic nerve. Other symptoms may include tingling and numbness. Coughing and sneezing can intensify the pain. An individual may also note a "slipping sensation" when moving into an upright position. Sitting and trying to stand up may be painful and difficult.[15][16] ### Physical Exam[edit] The major components of the physical exam for spondylolisthesis consists of observation, palpation, and maneuvers. The most common finding is pain with lumbar extension.[17] The following physical involves specific assessment for spondylolisthesis. However, a general examination, most importantly neurological examination, must be done to rule out alternative causes for signs and symptoms. Neurological examination is often normal in patients with spondylolisthesis, but lumbosacral radiculopathy is commonly seen in patients with degenerate spondylolisthesis.[18] #### Observation[edit] The patient should be observed walking and standing. Most patients present with a normal gait. An abnormal gait is often the sign of a high grade case.[19] A patient with high grade spondylolisthesis may present with a posterior pelvic tilt causing a loss in the normal contour of the buttocks.[19] An antalgic gait, rounded back and decreased hip extension, can result from severe pain.[20] While standing, the patient should be observed from the front, back, and signs. Increased and decreased lumbar lordosis, inward curvature of the lower spine, has been seen.[17][21] #### Palpation[edit] Detection of spondylolisthesis by palpation is most often done by palpating for the spinous process.[22] Each level of the lumbar spine should be palpated. Spinous process palpation by itself is not a definitive method for the detection of spondylolisthesis.[22] #### Maneuvers[edit] * Spinal range of motion testing – Range of motion limitations may be seen. * Lumbar hyperextension – Extension often elicits pain. This can be assessed by having the patient hyperextend the lumbar spine, provide resistance against back extensions, or undergo repeated lumbar extensions. * Sport-specific motion – Patient can be asked to repeat aggravating movements that they experience during their activity. During the movement, ask patient to point to any places with focal pain. * Straight leg raise – Maneuver used to assess for hamstring tightness. The straight leg raise has been found to be positive in only 10% of patients with spondylolisthesis.[21] * Muscle strength exercises – Lower abdominal, gluteal, and lumbar extensors should be assessed for weakness. Weakness in these muscles can increase lordosis and contribute to sacroiliac instability.[23] Abdominal flexor strength can be assessed with the abdominal flexor endurance test. The test involves the patient lying supine while holding a 45 degree flexed trunk and 90 degree flexed knees for 30 seconds. Gluteal strength can be assessed with a single leg squat. Lastly, lumbar extension can be assessed with a single leg bridge. * ### Diagnostic Imaging[edit] In adults with non-specific low back pain, strong evidence suggests medical imaging should not be done within the first six weeks.[24] It is also suggested to avoid advanced imaging, such as CT or MRI, for adults without neurological symptoms or "red flags" in the patient's history.[25][26] General recommendations for initial low back pain treatment is remaining active, avoiding twisting and bending, avoiding activities that worsen pain, avoiding bed rest, and possibly initiating a trial of non-steroidal anti-inflammatory drugs after consulting a physician.[27] Children and adolescents with persistent low back pain may require earlier imaging and should be seen by physician. Once imaging is deemed necessary, a combination of plain radiography, computed tomography, and magnetic resonance imaging may be used. Images are most often taken of the lumbar spine due to spondylolisthesis most commonly involving the lumbar region.[6] Images of the thoracic spine can be taken if a patient's history and physical suggest thoracic involvement. #### Plain Radiography (X-Ray)[edit] Plain radiography is often the first step in medical imaging.[17] Anteroposterior (front-back) and lateral (side) images are used to allow the physician to view the spine at multiple angles.[17] Oblique view are no longer recommended.[28][29] In evaluating for spondylolithesis, plain radiographs provide information on the positioning and structural integrity of the spine. Therefore, if further detail is needed a physician may request advanced imaging. #### Magnetic Resonance Imaging (MRI)[edit] Magnetic resonance imaging is the preferred advanced imaging technique for evaluation of spondylolisthesis.[30] Preference is due to effectiveness, lack of radiation exposure, and ability to evaluate for soft tissue abnormalities and spinal canal involvement.[30][31] MRI is limited in its ability to evaluate fractures in great detail, compared to other advanced imaging modalities.[32] #### Computed Tomography (CT)[edit] Computed tomography can be helpful in evaluating bony vertebral abnormalities, such as fractures.[33] This can be helpful in determining if the fracture is a new, old, and/or progressing fracture.[33] CT use in spondylolisthesis evaluation is controversial due to high radiation exposure.[34] ### Treatment[edit] Spondylolisthesis patients without symptoms do not need to be treated.[35] #### Conservative[edit] Non-operative management, also referred to as conservative treatment, is the recommended treatment for spondylolisthesis in most cases with or without neurological symptoms.[36] Most patients with spondylolisthesis respond to conservative treatment.[35] Conservative treatment consists primarily of physical therapy, intermittent bracing, aerobic exercise, pharmacological intervention, and epidural steroid injections. The majority of patients with degenerative spondylolisthesis do not require surgical intervention.[37] * Physical therapy can evaluate and address postural and compensatory movement abnormalities.[38] Physical therapy primarily includes spinal flexion and extension exercises with a focus on core stabilization and muscle strengthening. In particular, lumbar spondylolisthesis may benefit from core stabilization exercises focusing on lower abdominal, lumbar muscles, hamstrings, and hip flexors, which may temporarily or permanently improve symptoms and improve general function.[39] * Some patients may benefit from bracing in combination with physical therapy. Additionally, bracing was found to be beneficial when performed immediately following the onset of symptoms, in particular patients with lumbar pars interarticular defects.[39] * Exercises such as cycling, elliptical training, swimming, and walking are considered low-impact aerobic exercises and are recommended for pain relief.[40] * Anti-inflammatory medications (NSAIDS) in combination with paracetamol (Tylenol) can be tried initially. If a severe radicular component is present, a short course of oral steroids such as prednisone or methylprednisolone can be considered.[40] Epidural steroid injections, either interlaminal or transforaminal, performed under fluoroscopic guidance can help with severe radicular (leg) pain, but lacks conclusive benefit in relieving back pain in lumbar spondylolisthesis.[41] #### Surgical[edit] There are no clear radiological or medical guidelines or indications for surgical interventions in degenerative spondylolisthesis.[42] A minimum of three months of conservative management should be completed prior to considering surgical intervention.[42] Three indications for potential surgical treatment are as follows: persistent or recurrent back pain or neurologic pain with a persistent reduction of quality of life despite a reasonable trial of conservative (non-operative) management, new or worsening bladder or bowel symptoms, or a new or worsening neurological deficit.[43] Degenerative spondylolisthesis at L5 - S1. (A) CT sagittal view of a low grade slip. (B) Lateral radiograph pre-operative intervention. (C) Surgically treated with L5 – S1 decompression, instrumented fusion and placement of an interbody graft between L5 and S1. Both minimally invasive and open surgical techniques are used to treat anterolisthesis.[44] ## Retrolisthesis[edit] Grade 1 retrolistheses of C3 on C4 and C4 on C5 Main article: Retrolisthesis A retrolisthesis is a posterior displacement of one vertebral body with respect to the subjacent vertebra to a degree less than a luxation (dislocation). Retrolistheses are most easily diagnosed on lateral x-ray views of the spine. Views, where care has been taken to expose for a true lateral view without any rotation, offer the best diagnostic quality. Retrolistheses are found most prominently in the cervical spine and lumbar region but can also be seen in the thoracic area. ## History[edit] Spondylolisthesis was first described in 1782 by Belgian obstetrician Herbinaux.[45] He reported a bony prominence anterior to the sacrum that obstructed the vagina of a small number of patients.[46] The term “spondylolisthesis” was coined in 1854 from the Greek σπονδυλος, "spondylos" = "vertebra" and ὀλισθός "olisthos" = "slipperiness," "a slip."[47] ## See also[edit] * Spondylosis * Spondylolysis * Failed back syndrome * Joint dislocation ## References[edit] 1. ^ "spondylolisthesis". Merriam-Webster medical dictionary. Retrieved 2017-09-07. 2. ^ "spondylolisthesis". Farlex medical dictionary. Retrieved 2017-09-07., in turn citing: * Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. Copyright date 2003 * Dorland's Medical Dictionary for Health Consumers. Copyright date 2007 * The American Heritage Medical Dictionary. Copyright date 2007 * Mosby's Medical Dictionary, 9th edition * McGraw-Hill Concise Dictionary of Modern Medicine. Copyright date 2002 * Collins Dictionary of Medicine. Copyright date 2005 3. ^ a b c Introduction to chapter 17 in: Thomas J. Errico, Baron S. Lonner, Andrew W. Moulton (2009). Surgical Management of Spinal Deformities. Elsevier Health Sciences. ISBN 9781416033721.CS1 maint: multiple names: authors list (link) 4. ^ a b c Page 250 in: Walter R. Frontera, Julie K. Silver, Thomas D. Rizzo (2014). Essentials of Physical Medicine and Rehabilitation (3 ed.). Elsevier Health Sciences. ISBN 9780323222723.CS1 maint: multiple names: authors list (link) 5. ^ Shamrock, Alan G.; Donnally III, Chester J.; Varacallo, Matthew (2019), "Lumbar Spondylolysis And Spondylolisthesis", StatPearls, StatPearls Publishing, PMID 28846329, retrieved 2019-10-28 6. ^ a b c d Tenny, Steven; Gillis, Christopher C. (2019), "Spondylolisthesis", StatPearls, StatPearls Publishing, PMID 28613518, retrieved 2019-10-28 7. ^ Frank Gaillard. "Olisthesis". Radiopaedia. Retrieved 2018-02-21. 8. ^ Foreman P, Griessenauer CJ, Watanabe K, Conklin M, Shoja MM, Rozzelle CJ, Loukas M, Tubbs RS (2013). "L5 spondylolysis/spondylolisthesis: a comprehensive review with an anatomic focus". Child's Nervous System. 29 (2): 209–16. doi:10.1007/s00381-012-1942-2. PMID 23089935. S2CID 25145462. 9. ^ a b "Adult Spondylolisthesis in the Low Back". American Academy of Orthopaedic Surgeons. Retrieved 9 June 2013. 10. ^ Syrmou E, Tsitsopoulos PP, Marinopoulos D, Tsonidis C, Anagnostopoulos I, Tsitsopoulos PD (2010). "Spondylolysis: a review and reappraisal". Hippokratia. 14 (1): 17–21. PMC 2843565. PMID 20411054. 11. ^ Leone LD, Lamont DW (1999). "Diagnosis and treatment of severe dysplastic spondylolisthesis". The Journal of the American Osteopathic Association. 99 (6): 326–8. doi:10.7556/jaoa.1999.99.6.326. PMID 10405520. 12. ^ Aruna Ganju (2002). "Isthmic Spondylolisthesis". Neurosurg Focus. 13 (1). 13. ^ "Adult Isthmic Spondylolisthesis – Spine – Orthobullets". 14. ^ "Spondylolysis and Spondylolisthesis of the Lumbar Spine". Massachusetts General Hospital. Retrieved 2016-12-14. 15. ^ "Adult Spondylolisthesis in the Low Back – OrthoInfo – AAOS". 16. ^ "Pain Management: Spondylolisthesis". 17. ^ a b c d Tofte, Josef N.; CarlLee, Tyler L.; Holte, Andrew J.; Sitton, Sean E.; Weinstein, Stuart L. (2017-05-15). "Imaging Pediatric Spondylolysis: A Systematic Review". Spine. 42 (10): 777–782. doi:10.1097/BRS.0000000000001912. ISSN 1528-1159. PMID 27669047. S2CID 4399796. 18. ^ Bolesta, M. J.; Bohlman, H. H. (1989). "Degenerative spondylolisthesis". Instructional Course Lectures. 38: 157–165. ISSN 0065-6895. PMID 2649568. 19. ^ a b Meyers, Laura L.; Dobson, Scott R.; Wiegand, Dave; Webb, Julie D.; Mencio, Gregory A. (September 1999). "Mechanical Instability as a Cause of Gait Disturbance in High-Grade Spondylolisthesis: A Pre-and Postoperative Three-Dimensional Gait Analysis". Journal of Pediatric Orthopaedics. 19 (5): 672–6. doi:10.1097/01241398-199909000-00024. ISSN 0271-6798. PMID 10488874. 20. ^ Al-Obaidi, Saud M.; Al-Zoabi, Baker; Al-Shuwaie, Nadia; Al-Zaabie, Najeeba; Nelson, Roger M. (June 2003). "The influence of pain and pain-related fear and disability beliefs on walking velocity in chronic low back pain". International Journal of Rehabilitation Research. 26 (2): 101–8. doi:10.1097/00004356-200306000-00004. ISSN 0342-5282. PMID 12799603. S2CID 37347323. 21. ^ a b Kalpakcioglu, Banu; Altınbilek, Turgay; Senel, Kazım (2009-03-27). "Determination of spondylolisthesis in low back pain by clinical evaluation". Journal of Back and Musculoskeletal Rehabilitation. 22 (1): 27–32. doi:10.3233/BMR-2009-0212. PMID 20023361. 22. ^ a b Collaer, Jeff W.; McKeough, D. Michael; Boissonnault, William G. (2006-01-01). "Lumbar Isthmic Spondylolisthesis Detection with Palpation: Interrater Reliability and Concurrent Criterion-Related Validity". Journal of Manual & Manipulative Therapy. 14 (1): 22–29. doi:10.1179/106698106790820917. ISSN 1066-9817. S2CID 71855530. 23. ^ Petty, Nicola J.; Moore, Ann P. (2011). Neuromusculoskeletal Examination and Assessment,A Handbook for Therapists with PAGEBURST Access,4: Neuromusculoskeletal Examination and Assessment. Elsevier Health Sciences. ISBN 9780702029905. 24. ^ "Imaging for Low Back Pain". www.aafp.org. Retrieved 2019-11-07. 25. ^ Chou, Roger; Qaseem, Amir; Owens, Douglas K.; Shekelle, Paul; Clinical Guidelines Committee of the American College of Physicians (2011-02-01). "Diagnostic imaging for low back pain: advice for high-value health care from the American College of Physicians". Annals of Internal Medicine. 154 (3): 181–189. doi:10.7326/0003-4819-154-3-201102010-00008. ISSN 1539-3704. PMID 21282698. S2CID 1326352. 26. ^ Chou, Roger; Fu, Rongwei; Carrino, John A.; Deyo, Richard A. (2009-02-07). "Imaging strategies for low-back pain: systematic review and meta-analysis". Lancet. 373 (9662): 463–472. doi:10.1016/S0140-6736(09)60172-0. ISSN 1474-547X. PMID 19200918. S2CID 31602395. 27. ^ Casazza, Brian A. (2012-02-15). "Diagnosis and Treatment of Acute Low Back Pain". American Family Physician. 85 (4): 343–350. ISSN 0002-838X. PMID 22335313. 28. ^ Libson, E.; Bloom, R. A.; Dinari, G. (1982). "Symptomatic and asymptomatic spondylolysis and spondylolisthesis in young adults". International Orthopaedics. 6 (4): 259–261. doi:10.1007/bf00267148. ISSN 0341-2695. PMID 6222997. S2CID 1323431. 29. ^ Saifuddin, A.; White, J.; Tucker, S.; Taylor, B. A. (March 1998). "Orientation of lumbar pars defects: implications for radiological detection and surgical management". The Journal of Bone and Joint Surgery. British Volume. 80 (2): 208–211. doi:10.1302/0301-620x.80b2.8219. ISSN 0301-620X. PMID 9546445. 30. ^ a b Thornhill, Beverly A.; Green, Debra J.; Schoenfeld, Alan H. (2015), Wollowick, Adam L.; Sarwahi, Vishal (eds.), "Imaging Techniques for the Diagnosis of Spondylolisthesis", Spondylolisthesis: Diagnosis, Non-Surgical Management, and Surgical Techniques, Springer US, pp. 59–94, doi:10.1007/978-1-4899-7575-1_6, ISBN 9781489975751 31. ^ Kobayashi, Atsushi; Kobayashi, Tsutomu; Kato, Kazuo; Higuchi, Hiroshi; Takagishi, Kenji (January 2013). "Diagnosis of radiographically occult lumbar spondylolysis in young athletes by magnetic resonance imaging". The American Journal of Sports Medicine. 41 (1): 169–176. doi:10.1177/0363546512464946. ISSN 1552-3365. PMID 23136176. S2CID 6080935. 32. ^ Maurer, Marvin; Soder, Ricardo Bernardi; Baldisserotto, Matteo (February 2011). "Spine abnormalities depicted by magnetic resonance imaging in adolescent rowers". The American Journal of Sports Medicine. 39 (2): 392–397. doi:10.1177/0363546510381365. ISSN 1552-3365. PMID 20889986. S2CID 27402258. 33. ^ a b Morita, T.; Ikata, T.; Katoh, S.; Miyake, R. (July 1995). "Lumbar spondylolysis in children and adolescents". The Journal of Bone and Joint Surgery. British Volume. 77 (4): 620–625. doi:10.1302/0301-620X.77B4.7615609. ISSN 0301-620X. PMID 7615609. 34. ^ Leone, Antonio; Cianfoni, Alessandro; Cerase, Alfonso; Magarelli, Nicola; Bonomo, Lorenzo (2011-06-01). "Lumbar spondylolysis: a review". Skeletal Radiology. 40 (6): 683–700. doi:10.1007/s00256-010-0942-0. ISSN 1432-2161. PMID 20440613. S2CID 7348195. 35. ^ a b Haun, Daniel W.; Kettner, Norman W. (2005). "Spondylolysis and spondylolisthesis: a narrative review of etiology, diagnosis, and conservative management". Journal of Chiropractic Medicine. 4 (4): 206–217. doi:10.1016/S0899-3467(07)60153-0. ISSN 1556-3707. PMC 2647050. PMID 19674664. 36. ^ Vibert, Brady T.; Sliva, Christopher D.; Herkowitz, Harry N. (February 2006). "Treatment of instability and spondylolisthesis: surgical versus nonsurgical treatment". Clinical Orthopaedics and Related Research. 443: 222–227. doi:10.1097/01.blo.0000200233.99436.ea. ISSN 0009-921X. PMID 16462445. 37. ^ Evans, Nick; McCarthy, Michael (2018-12-19). "Management of symptomatic degenerative low-grade lumbar spondylolisthesis". EFORT Open Reviews. 3 (12): 620–631. doi:10.1302/2058-5241.3.180020. ISSN 2058-5241. PMC 6335606. PMID 30697442. 38. ^ Treatment Options for Spondylolisthesis; OrthoConsult 39. ^ a b Garet, Matthew; Reiman, Michael P.; Mathers, Jessie; Sylvain, Jonathan (May 2013). "Nonoperative treatment in lumbar spondylolysis and spondylolisthesis: a systematic review". Sports Health. 5 (3): 225–232. doi:10.1177/1941738113480936. ISSN 1941-7381. PMC 3658408. PMID 24427393. 40. ^ a b Kalichman, Leonid; Hunter, David J. (March 2008). "Diagnosis and conservative management of degenerative lumbar spondylolisthesis". European Spine Journal. 17 (3): 327–335. doi:10.1007/s00586-007-0543-3. ISSN 0940-6719. PMC 2270383. PMID 18026865. 41. ^ Metzger, Robert; Chaney, Susan (2014). "Spondylolysis and spondylolisthesis: What the primary care provider should know". Journal of the American Association of Nurse Practitioners. 26 (1): 5–12. doi:10.1002/2327-6924.12083. ISSN 2327-6924. PMID 24170707. 42. ^ a b Steiger, F.; Becker, H.-J.; Standaert, C. J.; Balague, F.; Vader, J.-P.; Porchet, F.; Mannion, A. F. (May 2014). "Surgery in lumbar degenerative spondylolisthesis: indications, outcomes and complications. A systematic review". European Spine Journal. 23 (5): 945–973. doi:10.1007/s00586-013-3144-3. ISSN 1432-0932. PMID 24402446. S2CID 20342808. 43. ^ Sengupta, Dilip K.; Herkowitz, Harry N. (2005-03-15). "Degenerative spondylolisthesis: review of current trends and controversies". Spine. 30 (6 Suppl): S71–81. doi:10.1097/01.brs.0000155579.88537.8e. ISSN 1528-1159. PMID 15767890. S2CID 41389199. 44. ^ Lu VM, Kerezoudis P, Gilder HE, McCutcheon BA, Phan K, Bydon M (2017). "Minimally Invasive Surgery Versus Open Surgery Spinal Fusion for Spondylolisthesis: A Systematic Review and Meta-analysis". Spine. 42 (3): E177–E185. doi:10.1097/BRS.0000000000001731. PMID 27285899. S2CID 714545. 45. ^ Newman PH (1955). "Spondylolisthesis, its cause and effect". Annals of the Royal College of Surgeons of England. 16 (5): 305–23. PMC 2377893. PMID 14377314. 46. ^ Garrigues, Henry Jacques (1902). "Spondylolisthesic pelvis". A textbook of the science and art of obstetrics. pp. 490–93. OCLC 654149619. 47. ^ "Isthmic Spondylolisthesis and Spondylolysis". ## External links[edit] Classification D * ICD-10: M43.1, Q76.2 * ICD-9-CM: 738.4, 756.12 * OMIM: 184200 * MeSH: D013168 * DiseasesDB: 12318 External resources * MedlinePlus: 001260 * eMedicine: radio/651 * Patient UK: Spondylolisthesis * v * t * e Spinal disease Deforming Spinal curvature * Kyphosis * Lordosis * Scoliosis Other * Scheuermann's disease * Torticollis Spondylopathy inflammatory * Spondylitis * Ankylosing spondylitis * Sacroiliitis * Discitis * Spondylodiscitis * Pott disease non inflammatory * Spondylosis * Spondylolysis * Spondylolisthesis * Retrolisthesis * Spinal stenosis * Facet syndrome Back pain * Neck pain * Upper back pain * Low back pain * Coccydynia * Sciatica * Radiculopathy Intervertebral disc disorder * Schmorl's nodes * Degenerative disc disease * Spinal disc herniation * Facet joint arthrosis * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [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	Spondylolisthesis	c0038016	5,799	wikipedia	https://en.wikipedia.org/wiki/Spondylolisthesis	2021-01-18T18:46:58	{"mesh": ["D013168"], "umls": ["C0038016"], "icd-9": ["738.4", "756.12"], "wikidata": ["Q973524"]}

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.