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A rare, genetic, neurological disorder characterized by childhood to adolescent onset of progressive myoclonus (which becomes very severe and results in major motor impediment) associated with infrequent tonic-clonic seizures, and, occasionally, ataxia. Learning disability prior to seizure onset and mild cognitive decline may be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Progressive myoclonic epilepsy type 7	c4015420	4,700	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435438	2021-01-23T18:40:55	{"omim": ["616187"], "icd-10": ["G40.3"], "synonyms": ["EPM7", "MEAK", "Myoclonus epilepsy and ataxia due to potassium channel mutation", "PME type 7", "Progressive myoclonic epilepsy due to KV3.1 deficiency", "Progressive myoclonus epilepsy type 7"]}
Hydrops fetalis is a severe and challenging fetal condition usually defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities that manifests as edema, pleural and pericardial effusion and ascites. It is the end-stage of a wide variety of disorders. The cause may be immunologic (immune hydrops fetalis, IHF) or non immunologic (non-immune hydrops fetalis, NIHF), depending on the presence or absence of maternal antibodies against fetal red cell antigens (ABO incompatibility or rhesus (Rh) incompatibility). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hydrops fetalis	c0020305	4,701	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1041	2021-01-23T18:54:25	{"gard": ["2783"], "mesh": ["D015160"], "omim": ["236750"], "umls": ["C0020305"], "icd-10": ["P56.0", "P56.9", "P83.2"], "synonyms": ["Fetal anasarca", "Fetal hydrops", "Generalized fetal edema", "HF"]}
A number sign (#) is used with this entry because Gilbert syndrome is caused by homozygous, compound heterozygous, or heterozygous mutation in the UDP-glucuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37. Description The hereditary hyperbilirubinemias (Wolkoff et al., 1983) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I (218800), and Crigler-Najjar syndrome type II (606785); and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (237500), Rotor syndrome (237450), and several forms of intrahepatic cholestasis (147480, 211600, 214950, 243300). Detailed studies show that patients with Gilbert syndrome have reduced activity of bilirubin glucuronosyltransferase (Bosma et al., 1995, Koiwai et al., 1995). ### Genetic Heterogeneity of Hyperbilirubinemia See also Crigler-Najjar syndrome type I (HBLRCN1; 218800), Crigler-Najjar syndrome type II (HBLRCN2; 606785), and transient familial neonatal hyperbilirubinemia (HBLRTFN; 237900), all caused by mutation in the UGT1A1 gene (191740) on chromosome 2q37; Dubin-Johnson syndrome (DJS, HBLRDJ; 237500), caused by mutation in the ABCC2 gene (601107) on chromosome 10q24; and Rotor syndrome (HBLRR; 237450), caused by digenic mutation in the SLCO1B1 (604843) and SLCOB3 (605495) genes, both on chromosome 12p. Clinical Features The characteristics of Gilbert syndrome are normal liver function tests of the usual type, normal liver histology, delayed clearance of bilirubin from the blood, and mild jaundice that tends to fluctuate in severity, particularly after fasting (Nixon and Monahan, 1967). This disorder is difficult to distinguish from prolonged posthepatic hyperbilirubinemia. Arias (1962) demonstrated glucuronyltransferase deficiency in 8 patients with chronic nonhemolytic jaundice and serum unconjugated bilirubin levels of 6.2 to 18.8 mg percent. Arias et al. (1969) concluded that this disorder is distinct from Crigler-Najjar syndrome type I (218800), which also has deficiency of hepatic glucuronyltransferase activity. In Crigler-Najjar syndrome type I, hyperbilirubinemia is severe, with total serum bilirubin levels ranging from 20 to 45 mg/dL, and is frequently accompanied by kernicterus. The bile is almost colorless and contains traces of unconjugated bilirubin only. Transmission is autosomal recessive and phenobarbital does not influence the hyperbilirubinemia. In the Arias type, hyperbilirubinemia is less severe without kernicterus. The bile is pigmented and contains bilirubin glucuronide. Phenobarbital administration causes prompt disappearance of jaundice. Since patients with the Arias type have a disorder almost only of cosmetic significance, long-term phenobarbital treatment is useful. Black and Sherlock (1970) found that all 13 patients treated with phenobarbitone showed a rapid fall in plasma bilirubin; in 3 of the 10 symptomatic patients, the symptoms improved. The reduction in plasma bilirubin was associated with an increase in hepatic bilirubin UDP-glucuronyltransferase activity. Dawson et al. (1979) presented evidence for 2 types of Gilbert disease. One group with normal distribution of neutral alpha-glucosidase, an endoplasmic reticulum marker, had normal endoplasmic reticulum by electron microscopy. Those with an abnormal distribution showed marked hypertrophy of the smooth endoplasmic reticulum by electron microscopy. Strassburg (2008) provided a review of the role of UGT1A1 variants in drug metabolism and noted that the variation of glucuronidation in patients with Gilbert syndrome impacts drug therapy, particularly with drugs that have a narrow therapeutic spectrum. Pathogenesis Billing et al. (1964) presented indirect evidence of a defect of uptake of bilirubin into the liver cell. Black and Billing (1969) found hepatic bilirubin UDP-transferase to be about 25% of normal in 11 patients with Gilbert syndrome. Diagnosis Schmid (1995) pointed out that Gilbert syndrome is an entirely benign and clinically inconsequential entity, requiring neither treatment nor long-term medical attention. Its clinical importance lies in the fact that the mild hyperbilirubinemia may be mistaken for a sign of occult, chronic, or progressive liver disease. Since the diagnosis is largely one of exclusion, clinicians sometimes find it difficult to dispel lingering fears of serious liver disease, causing patients unwarranted anxiety. ### Differential Diagnosis Patients with Gilbert syndrome tend to have total serum bilirubin levels from 1-6 mg/dL. This is distinguished from Crigler-Najjar syndrome type II, in which patients have total serum bilirubin levels between 6 and 20 mg/dL, and Crigler-Najjar syndrome type I, in which patients have total serum bilirubin levels from 20 to 45 mg/dL. Inheritance Gilbert syndrome is generally considered to be an autosomal recessive disorder (Chowdhury et al., 2001). However, there have been cases of heterozygosity and compound heterozygosity reported in patients with Gilbert syndrome, particularly among the Asian population. (See section on Molecular Genetics). In some early reports of Gilbert syndrome, autosomal dominant inheritance had been suggested. In a series of 58 patients, Foulk et al. (1959) found a family history of jaundice in 8; in 5 of these, jaundice had been present in successive generations. Powell et al. (1967) observed affected persons in successive generations. Sleisenger et al. (1967) described an Irish kindred in which persons with lifelong jaundice occurred in 4 generations, in a dominant pedigree pattern with male-to-male transmission. Hepatic glucuronyltransferase activity was low in affected individuals, by direct or indirect test. Molecular Genetics In 6 unrelated Japanese families with Gilbert syndrome, Koiwai et al. (1995) demonstrated that affected members were heterozygous for several different missense mutations in the UGT1 gene, including a G-to-A change at nucleotide 211 in exon 1, resulting in a gly71-to-arg substitution (G71R; 191740.0016), and a C-to-A change at nucleotide 686, resulting in a pro229-to-gln substitution (P229Q; 191740.0010). Interestingly, in a Japanese girl with anorexia nervosa and unconjugated hyperbilirubinemia, Maruo et al. (1999) identified a homozygous G71R mutation. The parents were heterozygous for the mutation. Hsieh et al. (2001) studied 20 unrelated patients with Gilbert syndrome and found several combinations of mutations, including homozygous, heterozygous, and compound heterozygous, all of which led to differing levels of enzyme activity. Sugatani et al. (2002) presented evidence suggesting that a SNP, -3263T-G (191740.0024), in the UGT1A1 promoter, also known as the phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3), may predispose patients to hyperbilirubinemia, particularly in patients with Gilbert syndrome and another mutation in the UGT1A1 gene. ### TATAA Repeat Mutation Bosma et al. (1995) found that the coding region of the UGT1A1 gene was normal in 10 patients with Gilbert syndrome, but that these patients were homozygous for 2 extra bases (TA) in the TATAA element of the 5-prime promoter region of the gene; they found A(TA)7TAA (191740.0011) rather than the normal A(TA)6TAA. The presence of the longer TATAA element resulted in reduced expression of a reporter gene construct encoding firefly luciferase in a human hepatoma cell line. Schmid (1995) pointed out that this is another example of an expanded nucleotide repeat. The frequency of the abnormal allele reported by Bosma et al. (1995) was 40% among normal subjects. The 3 men in the control group who were homozygous for the longer TATAA element had significantly higher serum bilirubin levels than the other 52 normal subjects. In a kindred with a history of Crigler-Najjar syndrome type II, only the 6 heterozygous carriers who had a longer TATAA element on the structurally normal allele had mild hyperbilirubinemia characteristic of Gilbert syndrome. Bosma et al. (1995) concluded that reduced expression of the UGT1A1 gene due to abnormality in the promoter region is a necessary but not sufficient change for Gilbert syndrome. This made it necessary to search for ancillary factors that might modify the serum bilirubin concentration in persons homozygous for the promoter defect. These factors could include hepatic transport abnormalities, occult hemolysis, and stress-related induction of heme oxygenase. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Hsieh et al. (2007) showed that mutant TA7 TATA-box-like sequence has reduced protein binding affinity compared to wildtype, and that binding affinity progressively decreases as the number of TA repeats in the UGT1A1 TATA-box-like sequence increases. The authors stated that this decrease in binding affinity underlies the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome. INHERITANCE \- Autosomal recessive LABORATORY ABNORMALITIES \- Decreased hepatic UDP-glucuronyl-transferase activity \- Hyperbilirubinemia, non-hemolytic unconjugated (may rise with fasting or dehydration) \- Normal liver function test MISCELLANEOUS \- Common (up to 7% of the population) \- Rarely produces clinical jaundice \- Decreased bilirubin concentration with phenobarbital administration \- Does not lead to hepatic failure MOLECULAR BASIS \- Caused by mutations in the uridine diphosphate glycosyltransferase 1 gene (UGT1A1, 191740.0010 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	GILBERT SYNDROME	c0017551	4,702	omim	https://www.omim.org/entry/143500	2019-09-22T16:40:05	{"doid": ["2739"], "mesh": ["D005878"], "omim": ["143500"], "icd-10": ["E80.4"], "synonyms": ["Alternative titles", "HYPERBILIRUBINEMIA, GILBERT TYPE", "HYPERBILIRUBINEMIA, ARIAS TYPE", "HYPERBILIRUBINEMIA I"]}
Spiradenoma Micrograph of a spiradenoma (bottom-center of image). H&E stain. SpecialtyOncology, dermatology Spiradenoma, also spiroma[1][2] or eccrine spiradenoma,[3] is a cutaneous condition that is typically characterized, clinically, as a solitary, deep-seated dermal nodule of approximately one centimeter, occurring on the ventral surface of the body.[4]:666[5] Spiradenoma lesions are benign sudoriferous tumors,[6] and have also been described as cystic epitheliomas of the sweat glands.[7] The histological origin is controversial.[3][6] ## See also[edit] * Malignant acrospiroma * List of cutaneous conditions * Dermal cylindroma * Trichoepithelioma * List of cutaneous neoplasms associated with systemic syndromes ## References[edit] 1. ^ Paul Gerson Unna (1896). The Histopathology of the diseases of the skin. Macmillan. pp. 805–. Retrieved 11 September 2012. 2. ^ Smith Ely Jelliffe & Caroline Wormeley Latimer (1916). Appleton's medical dictionary. D. Appleton and company. pp. 771. Retrieved 11 September 2012. "spiroma spiradenoma." 3. ^ a b article/1062079 at eMedicine 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. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 6. ^ a b Reinhard Dummer (29 October 2010). Skin Cancer - a World-wide Perspective. Springer. pp. 135–. ISBN 978-3-642-05071-8. Retrieved 3 May 2011. 7. ^ Taber's Cyclopedic Medical Dictionary. F.A. Davis Company. 18 February 2009. p. 2176. ## External links[edit] Classification D * ICD-10: ILDS C44.L40, C44.L64, D23.L49 External resources * eMedicine: article/1062079 * v * t * e Cancers of skin and associated structures Glands Sweat gland Eccrine * Papillary eccrine adenoma * Eccrine carcinoma * Eccrine nevus * Syringofibroadenoma * Spiradenoma Apocrine * Cylindroma * Dermal cylindroma * Syringocystadenoma papilliferum * Papillary hidradenoma * Hidrocystoma * Apocrine gland carcinoma * Apocrine nevus Eccrine/apocrine * Syringoma * Hidradenoma or Acrospiroma/Hidradenocarcinoma * Ceruminous adenoma Sebaceous gland * Nevus sebaceous * Muir–Torre syndrome * Sebaceous carcinoma * Sebaceous adenoma * Sebaceoma * Sebaceous nevus syndrome * Sebaceous hyperplasia * Mantleoma Hair * Pilomatricoma/Malignant pilomatricoma * Trichoepithelioma * Multiple familial trichoepithelioma * Solitary trichoepithelioma * Desmoplastic trichoepithelioma * Generalized trichoepithelioma * Trichodiscoma * Trichoblastoma * Fibrofolliculoma * Trichilemmoma * Trichilemmal carcinoma * Proliferating trichilemmal cyst * Giant solitary trichoepithelioma * Trichoadenoma * Trichofolliculoma * Dilated pore * Isthmicoma * Fibrofolliculoma * Perifollicular fibroma * Birt–Hogg–Dubé syndrome Hamartoma * Basaloid follicular hamartoma * Folliculosebaceous cystic hamartoma * Folliculosebaceous-apocrine hamartoma Nails * Neoplasms of the nailbed This Epidermal nevi, neoplasms, cysts 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Spiradenoma	c0334347	4,703	wikipedia	https://en.wikipedia.org/wiki/Spiradenoma	2021-01-18T18:37:14	{"gard": ["8649"], "umls": ["C0334347"], "wikidata": ["Q7577703"]}
Small intestine neuroendocrine tumor SpecialtyGastroenterology/oncology A small intestine neuroendocrine tumor is a carcinoid in the distal small intestine or the proximal large intestine. It is a relatively rare cancer and is diagnosed in approximately 1/100000 people every year. In recent decades the incidence has increased.[1] The prognosis is comparatively good with a median survival of more than 8 years.[2] The disease was named by Siegfried Oberndorfer, a German pathologist, in 1907.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Genetics * 3 Treatment * 4 References ## Signs and symptoms[edit] A large fraction of cases are diagnosed after routine surgery for bowel obstruction.[4] Others may be diagnosed incidentally, or after investigation for carcinoid syndrome. The tumor typically produces serotonin, Tachykinin peptides and other substances, which cause flushing, tachycardia, diarrhea and in some cases fibrosis of the heart valves. There are often several small and highly fibrotic tumors present in the intestine. The tumors often spread to the mesenteries and the liver. ## Cause[edit] Familial clustering of the disease, with several relatives being diagnosed may occur.[5] Relatives of patients have an increased risk of developing the disease.[6] ### Genetics[edit] The tumors often harbour loss of chromosome 18q.[7] Mutations in CDKN1B are present in approximately 8% of cases.[8][9] ## Treatment[edit] The treatment traditionally consists of a combination of medical and surgical treatment. Somatostatin analogues and Interferon decrease the secretion of hormones and the resulting symptoms. Radionuclide therapy with 177-Lutetium-DOTA-Octreotate increases progression-free survival.[10] Traditionally, the primary tumor has been surgically removed even in the case of metastatic disease, although this was in 2017 shown not to improve survival in asymptomatic patients.[11] ## References[edit] 1. ^ Yao, James C.; Hassan, Manal; Phan, Alexandria; Dagohoy, Cecile; Leary, Colleen; Mares, Jeannette E.; Abdalla, Eddie K.; Fleming, Jason B.; Vauthey, Jean-Nicolas (2008-06-20). "One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States". Journal of Clinical Oncology. 26 (18): 3063–3072. doi:10.1200/JCO.2007.15.4377. ISSN 1527-7755. PMID 18565894. 2. ^ Norlén, Olov; Stålberg, Peter; Öberg, Kjell; Eriksson, John; Hedberg, Jakob; Hessman, Ola; Janson, Eva Tiensuu; Hellman, Per; Åkerström, Göran (June 2012). "Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center". World Journal of Surgery. 36 (6): 1419–1431. doi:10.1007/s00268-011-1296-z. ISSN 1432-2323. PMID 21984144. 3. ^ Modlin, Irvin M.; Shapiro, Michael D.; Kidd, Mark; Eick, Geeta (February 2007). "Siegfried oberndorfer and the evolution of carcinoid disease". Archives of Surgery. 142 (2): 187–197. doi:10.1001/archsurg.142.2.187. ISSN 0004-0010. PMID 17309971. 4. ^ Eriksson, John; Garmo, Hans; Hellman, Per; Ihre-Lundgren, Catharina (May 2017). "The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors". Annals of Surgical Oncology. 24 (5): 1214–1220. doi:10.1245/s10434-016-5703-4. ISSN 1534-4681. PMC 5374169. PMID 27904972. 5. ^ Cunningham, Janet L.; Díaz de Ståhl, Teresita; Sjöblom, Tobias; Westin, Gunnar; Dumanski, Jan P.; Janson, Eva T. (February 2011). "Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors". Genes, Chromosomes & Cancer. 50 (2): 82–94. doi:10.1002/gcc.20834. ISSN 1098-2264. PMID 21104784. 6. ^ Neklason, Deborah W.; VanDerslice, James; Curtin, Karen; Cannon-Albright, Lisa A. (February 2016). "Evidence for a heritable contribution to neuroendocrine tumors of the small intestine". Endocrine-Related Cancer. 23 (2): 93–100. doi:10.1530/ERC-15-0442. ISSN 1479-6821. PMC 4684974. PMID 26604321. 7. ^ Kytölä, S.; Höög, A.; Nord, B.; Cedermark, B.; Frisk, T.; Larsson, C.; Kjellman, M. (May 2001). "Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids". The American Journal of Pathology. 158 (5): 1803–1808. doi:10.1016/S0002-9440(10)64136-3. ISSN 0002-9440. PMC 1891959. PMID 11337378. 8. ^ Francis, Joshua M.; Kiezun, Adam; Ramos, Alex H.; Serra, Stefano; Pedamallu, Chandra Sekhar; Qian, Zhi Rong; Banck, Michaela S.; Kanwar, Rahul; Kulkarni, Amit A. (December 2013). "Somatic mutation of CDKN1B in small intestine neuroendocrine tumors". Nature Genetics. 45 (12): 1483–1486. doi:10.1038/ng.2821. ISSN 1546-1718. PMC 4239432. PMID 24185511. 9. ^ Crona, Joakim; Gustavsson, Tobias; Norlén, Olov; Edfeldt, Katarina; Åkerström, Tobias; Westin, Gunnar; Hellman, Per; Björklund, Peyman; Stålberg, Peter (December 2015). "Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors". Annals of Surgical Oncology. 22 Suppl 3: S1428–1435. doi:10.1245/s10434-014-4351-9. ISSN 1534-4681. PMID 25586243. 10. ^ Strosberg, Jonathan; El-Haddad, Ghassan; Wolin, Edward; Hendifar, Andrew; Yao, James; Chasen, Beth; Mittra, Erik; Kunz, Pamela L.; Kulke, Matthew H. (12 January 2017). "Phase 3 Trial of177Lu-Dotatate for Midgut Neuroendocrine Tumors". The New England Journal of Medicine. 376 (2): 125–135. doi:10.1056/NEJMoa1607427. ISSN 1533-4406. PMC 5895095. PMID 28076709. 11. ^ Daskalakis, Kosmas; Karakatsanis, Andreas; Hessman, Ola; Stuart, Heather C.; Welin, Staffan; Tiensuu Janson, Eva; Öberg, Kjell; Hellman, Per; Norlén, Olov (2018-02-01). "Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival". JAMA Oncology. 4 (2): 183–189. doi:10.1001/jamaoncol.2017.3326. ISSN 2374-2445. PMC 5838704. PMID 29049611. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Small intestine neuroendocrine tumor	c0349536	4,704	wikipedia	https://en.wikipedia.org/wiki/Small_intestine_neuroendocrine_tumor	2021-01-18T18:44:58	{"umls": ["C0349536"], "wikidata": ["Q55633353"]}
A number sign (#) is used with this entry because the disorder is caused by mutation in the PLOD3 gene, which encodes lysyl hydroxylase-3 (603066). Clinical Features Salo et al. (2008) described a female proband with a novel connective tissue disorder secondary to lysyl hydroxylase-3 (LH3) deficiency. The patient was born to a nonconsanguineous couple of European descent. Pregnancy was complicated by intrauterine growth retardation. Craniofacial features included flat facial profile, simple, low-set ears, shallow orbits, short, upturned nose, and downturned corners of the mouth. Skeletal features included talipes equinovarus, progressive scoliosis, osteopenia, and several pathologic fractures. She was noted to have profound bilateral sensorineural deafness, myopia, and cataracts. Blistering occurred in her fingers and toes that healed without scarring. Her skin exhibited easy bruisability. In the second decade, spontaneous vascular ruptures occurred. A spontaneous cerebral arterial hemorrhage presented with hemiplegia, and a rupture of popliteal aneurysm presented with pain and swelling. A male sib was stillborn at 28 weeks' gestation. Intrauterine growth retardation complicated the pregnancy. Autopsy revealed a porencephalic cyst with dilation of the cerebral ventricles. Biochemical Features In their proband with a novel connective tissue disorder, Salo et al. (2008) analyzed urinary pyridinium collagen crosslinks and found absence of the disaccharide component of pyridinoline (Glc-Gal-PYD), which normally comprises approximately 15% of free pyridinoline crosslinks. The lack of glycosylated collagen crosslinks suggested a defect of an enzyme glycosylating hydroxylysine residue, for which the lysyl hydroxylase-3 gene was the prime candidate. The patient also had markedly reduced serum collagen glucosyltransferase (GGT) activity and decreased concentration of LH3 protein in lymphoblastoid cells. Molecular Genetics By analysis of LH3 cDNA in a patient with a connective tissue disorder and lysyl hydroxylase-3 deficiency, Salo et al. (2008) identified compound heterozygosity for 2 mutations: an asn223-to-ser (N223S) missense mutation (603066.0001) and a 1-bp deletion (2071delT; 603066.0002). The mutations occurred in conserved regions of the LH3 amino acid sequence responsible for GGT and lysyl hydroxylase activity. INHERITANCE \- Autosomal recessive GROWTH Height \- Birth length below 0.3 percentile Weight \- Birth weight below 0.3 percentile Other \- Intrauterine growth retardation (IUGR) \- Postnatal growth retardation HEAD & NECK Face \- Flat facial profile \- Long philtrum Ears \- Simple ears \- Low-set ears \- Hearing loss, bilateral sensorineural (profound) Eyes \- Shallow orbits \- Myopia \- Cataracts Nose \- Short nose \- Anteverted nares Mouth \- Downturned corners of mouth Teeth \- Normal teeth CARDIOVASCULAR Vascular \- Popliteal aneurysm \- Cerebral aneurysm \- Arterial rupture CHEST Diaphragm \- Diaphragmatic eventration SKELETAL \- Osteopenia \- Pathologic fractures Skull \- J-shaped sella turcica Spine \- Scoliosis (progressive) \- Platyspondyly \- Small odontoid Pelvis \- Small capital femoral epiphyses Limbs \- Prominent knees \- Elbow contractures Hands \- Flexion contractures (PIP joints) \- Thenar muscle atrophy \- Hypothenar muscle atrophy \- Decreased palmar creases Feet \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Easy bruisability \- Blistering (fingers, toes, pinnae) \- Decreased palmar creases Nails \- Dysplastic nails Hair \- Coarse hair MUSCLE, SOFT TISSUES \- Reduced muscle mass NEUROLOGIC Central Nervous System \- Developmental delay \- Cerebral arterial hemorrhage LABORATORY ABNORMALITIES \- Abnormal urinary collagen-derived pyridinium crosslinks (absent Glc-Gal-PYD) \- Decreased serum glucosyltransferase (GGT) activity MOLECULAR BASIS \- Caused by mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 gene (PLOD3, 603066.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	BONE FRAGILITY WITH CONTRACTURES, ARTERIAL RUPTURE, AND DEAFNESS	c2676285	4,705	omim	https://www.omim.org/entry/612394	2019-09-22T16:01:34	{"mesh": ["C567320"], "omim": ["612394"], "orphanet": ["300284"], "synonyms": ["Alternative titles", "LYSYL HYDROXYLASE 3 DEFICIENCY", "LH3 DEFICIENCY"]}
Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in people who are treated with it. Clopidogrel (also known as Plavix) is an antiplatelet drug, which means that it prevents blood cells called platelets from sticking together (aggregating) and forming blood clots. This drug is typically given to prevent blood clot formation in individuals with a history of stroke; heart attack; a blood clot in the deep veins of the arms or legs (deep vein thrombosis); or plaque buildup (atherosclerosis) in the blood vessels leading from the heart, which are opened by placement of a small thin tube (stent). People with clopidogrel resistance who receive clopidogrel are at risk of serious, sometimes fatal, complications. These individuals may have another heart attack or stroke caused by abnormal blood clot formation; those with stents can develop blood clots (thromboses) within the stents, impeding blood flow. People with clopidogrel resistance can be divided into two categories: intermediate metabolizers and poor metabolizers. Intermediate metabolizers are able to process some clopidogrel, so they receive partial benefit from the treatment but are not protected from developing a harmful blood clot. Poor metabolizers process little or no clopidogrel, so they receive very limited benefit from the treatment and are at risk of forming a harmful blood clot. Clopidogrel resistance does not appear to cause any health problems other than those associated with clopidogrel drug treatment. ## Frequency Clopidogrel resistance is a common condition, and its incidence can vary depending on ancestry. About half of individuals with Asian ancestry have clopidogrel resistance, with 10 percent of these individuals classified as poor metabolizers. Among people from western countries, nearly 30 percent are estimated to have clopidogrel resistance, with about 3 percent classified as poor metabolizers. ## Causes Many genes are involved in converting clopidogrel to its active form and in determining the drug's effects in the body. The CYP2C19 gene is particularly important for the activation of clopidogrel, and certain common variations (polymorphisms) in this gene have been associated with clopidogrel resistance. CYP2C19 gene polymorphisms account for most of the variation in clopidogrel activation due to genetic factors. Polymorphisms in other genes likely have smaller effects on clopidogrel activation. The CYP2C19 gene provides instructions for making an enzyme that is found primarily in liver cells. It is active in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The CYP2C19 enzyme plays a role in the processing of many drugs, including clopidogrel. The CYP2C19 enzyme helps to convert clopidogrel to its active form, which is necessary for the drug to function in the body. In its active form, clopidogrel prevents (inhibits) the function of a receptor protein known as P2RY12 that is found on the surface of platelets. During clot formation, the P2RY12 receptor protein helps platelets cluster together to form a clot to seal off damaged blood vessels and prevent blood loss. By inhibiting the function of the P2RY12 receptor, clopidogrel decreases the formation of blood clots, including clots that can cause heart attack, stroke, and deep vein thrombosis. The two most common CYP2C19 gene polymorphisms associated with clopidogrel resistance (known as CYP2C192 and CYP2C193) result in the production of a nonfunctional CYP2C19 enzyme that cannot convert clopidogrel to its active form. Without active clopidogrel to interfere, the P2RY12 receptor continues to promote platelet aggregation and blood clot formation, which can lead to heart attacks, strokes, and thromboses in individuals with a history of these conditions. In addition to changes in specific genes, many other factors, including sex, age, weight, diet, and other medications, play a role in how the body reacts to clopidogrel. ### Learn more about the gene associated with Clopidogrel resistance * CYP2C19 ## Inheritance Pattern Clopidogrel resistance is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene are active (expressed), and both versions influence the genetic trait. Some people with clopidogrel resistance have a reduced ability to convert the drug to its active form because of a polymorphism in one copy of the CYP2C19 gene that results in decreased enzyme activity. These individuals are described as intermediate metabolizers. Other individuals with clopidogrel resistance convert very little or none of the drug to its active form because of polymorphisms in both copies of the CYP2C19 gene, which results in a lack of enzyme activity. These individuals are described as poor metabolizers. It is important to note that not all individuals with CYP2C19 gene mutations have clopidogrel resistance. These individuals who are at increased risk for developing clopidogrel resistance may or may not have a bad reaction when treated with the drug. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Clopidogrel resistance	c1836024	4,706	medlineplus	https://medlineplus.gov/genetics/condition/clopidogrel-resistance/	2021-01-27T08:24:41	{"gard": ["12906"], "omim": ["609535"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that Snijders Blok-Campeau syndrome (SNIBCPS) is caused by heterozygous mutation in the CHD3 gene (602120) on chromosome 17p13. Description Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and delayed speech acquisition. Affected individuals tend to have expressive language deficits, with speech apraxia and dysarthria. Other features include macrocephaly and characteristic facial features, such as prominent forehead and hypertelorism, hypotonia, and joint laxity. The severity of the neurologic deficits and presence of nonneurologic features is variable (summary by Snijders Blok et al., 2018). Clinical Features Snijders Blok et al. (2018) reported 35 patients with a similar neurodevelopmental disorder. The patients were ascertained through the GeneMatcher database and most were unrelated, although there was 1 set of twins and 1 pair of sibs. Most of the patients were in their first or second decades, but 1 man was 59 years of age. All patients had global developmental delay of varying degrees, most with mildly delayed walking by age 5 years and impaired intellectual development that ranged from borderline (IQ in the 70s) to severe (IQ of 35). Nine patients (29%) had autistic features, including stereotypies or hand flapping, but many were happy, social, and pleasant. Many had hypotonia and a broad-based or unsteady gait. All patients had impaired speech and language development, with delayed first words and particular problems with expressive speech, such as dysarthria, speech apraxia, oromotor problems, and stuttering. Most patients (58%) had macrocephaly, and many had enlarged ventricles on brain imaging, even without frank macrocephaly. Common dysmorphic features included prominent, high forehead with frontal bossing, hypertelorism, deep-set eyes, epicanthal folds, broad nasal base with large nose, low-set ears, midface hypoplasia, and pointed chin. Some had a high-arched palate and/or dental abnormalities. Visual abnormalities were common, including strabismus, hypermetropia, and astigmatism; 2 patients had cerebral visual impairment. Other less common features included joint hyperlaxity, umbilical or inguinal hernia, scoliosis, mild foot deformities, and cryptorchidism. Only 1 patient had seizures, and 2 had infantile convulsions. One severely affected patient (patient 5) was a 15-year-old girl who had microcephaly and spastic tetraplegia, was unable to walk, and had no speech. The 59-year-old man developed parkinsonism. Molecular Genetics In a patient (proband 01) with SNIBCPS, Eising et al. (2019) identified a de novo heterozygous missense mutation in the CHD3 gene (R1228W; 602120.0001). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation occurred at a highly conserved residue in the helicase domain. The patient was from a cohort of 19 probands with childhood apraxia of speech (CAS), which is a disorder of language development characterized by difficulties with sequencing speech sounds into syllables, words, and sentences. Eising et al. (2019) noted that CHD3 is an interacting partner with FOXP2 (605317) (Estruch et al., 2016), a well-established gene causing a different form of CAS (SPCH1; 602081). Expression data showed that CHD3 is expressed in the brain and is part of a module of functionally connected genes that are highly expressed during early human brain development. In 35 patients from 33 unrelated families with SNIBCPS, Snijders Blok et al. (2018) identified 23 different de novo heterozygous mutations in the CHD3 gene (see, e.g., 602120.0002-602120.0005). Among the patients, there was a set of monozygotic twins and 2 sibs whose mother was mosaic for the mutation. Except for 4 individuals who carried predicted loss-of-function mutations, all patients carried missense mutations. There were 2 recurrent mutations affecting the same residue: R985W (602120.0002), found in 6 children from 5 families, and R985Q, found in 2 unrelated patients. Seventeen of the 19 missense mutations occurred in and around the ATPase/helicase motif of the protein, which is a functional domain that provides energy for nucleosome remodeling through its ATPase activity. The patients were ascertained from several research and clinical centers through the GeneMatcher program. The mutations, which were found by exome sequencing, were not found in the gnomAD database. In vitro functional expression studies of 6 of the mutations in HEK293 cells showed that 3 (R1121P; R1172Q, 602120.0003; and N1159K) impaired ATP hydrolysis activity, 1 (L915F, 602120.0004) increased activity, and 2 (R1187P; and W1158R, 602120.0005) had no effect. In contrast, further studies showed that 5 of the mutations disturbed chromatin remodeling capacities as measured by restriction enzyme accessibility to nucleosomal DNA, including 4 that severely compromised this ability (R1172Q, R1121P, W1158R, and N1159K), 1 (L915F) that increased it; and 1 (R1187P) that had no significant effect. The findings indicated that chromatin remodeling factors, and specifically CHD3, have an important role in human brain development. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Macrocephaly (in most patients) Face \- Prominent forehead \- Frontal bossing \- Midface hypoplasia Ears \- Low-set ears Eyes \- Hypertelorism \- Epicanthal folds \- Strabismus \- Hypermetropia \- Astigmatism \- Cerebral visual impairment (rare) Nose \- Large nose \- Broad nasal bridge Mouth \- High arched palate Teeth \- Dental abnormalities SKELETAL Spine \- Scoliosis (in some patients) Feet \- Foot deformities, mild MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Delayed walking (usually by 5 years of age) \- Broad-based gait \- Unsteady gait \- Delayed intellectual development, mild to severe \- Speech delay \- Impaired expressive speech \- Dysarthria \- Speech apraxia \- Stuttering \- Enlarged ventricles Behavioral Psychiatric Manifestations \- Autistic features \- Stereotypic behaviors \- Friendly personality MISCELLANEOUS \- Onset in infancy \- Variable severity and features \- De novo mutation (in most patients) MOLECULAR BASIS \- Caused by mutation in the chromodomain helicase DNA-binding protein 3 gene (CHD3, 602120.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SNIJDERS BLOK-CAMPEAU SYNDROME	None	4,707	omim	https://www.omim.org/entry/618205	2019-09-22T15:43:06	{"omim": ["618205"], "synonyms": ["Alternative titles", "INTELLECTUAL DEVELOPMENTAL DISORDER WITH MACROCEPHALY, SPEECH DELAY, AND DYSMORPHIC FACIES"]}
Perniosis are itchy and/or tender red or purple bumps that occur as a reaction to cold. In severe cases, blistering, pustules, scabs and ulceration may also develop. Occasionally, the lesions may be ring-shaped. They may become thickened and persist for months. Perniosis is a form of vasculitis. Signs and symptoms occur hours after cold exposure. Risk factors for perniosis include having poor blood circulation (such as due to diabetes or smoking), a family history of perniosis, poor nutrition, and low body weight. Perniosis may occur alone or in association with an autoimmune condition (e.g., lupus, scleroderma), bone marrow disorder, or cancer. Treatment aims to relieve symptoms and prevent infection. Lifestyle/adaptive changes may also be recommended to prevent future 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Perniosis	c0008058	4,708	gard	https://rarediseases.info.nih.gov/diseases/7373/perniosis	2021-01-18T17:58:22	{"mesh": ["D002647"], "umls": ["C0008058"], "synonyms": ["Chilblains", "Idiopathic perniosis", "Cold-induced painful or pruritic erythematous or violaceous acral papular or nodular lesions", "Pernio"]}
Multiple system atrophy (MSA) causes the progressive loss of nerve cells in the brain (a neurodegenerative disease). MSA affects several areas of the brain, including the cerebellum, which is involved in controlling movement and some emotions, as well as certain types of learning and memory, and the autonomic nervous system, which controls your body’s automatic, or regulating functions, such as blood pressure, digestion and temperature.The initial symptoms of MSA start around age 50, and are very similar to the initial symptoms of Parkinson’s disease. These symptoms may include slowness of movement, tremor, or rigidity (stiffness), clumsiness or coordination problems, difficulties with speech, orthostatic hypotension (a condition in which blood pressure drops when rising from a seated or lying down position), and bladder control problems. Other symptoms of MSA may include muscle contractures, abnormal posture, bending of the neck, involuntary sighing, trouble sleeping and emotional problems. As MSA progresses, breathing problems while sleeping (sleep apnea) and irregular heart rhythms may develop. MSA may be divided in 2 subtypes, depending on the main symptoms at the time when a person with MSA is evaluated: * the parkinsonian type (MSA-P), which have Parkinson disease-like symptoms, such as moving slowly, stiffness, and tremor, along with problems of balance, coordination, and autonomic nervous system dysfunction * the cerebellar type (MSA-C), with primary symptoms of cerebellar ataxia (cerebellum is the part of the brain that is responsible for movement coordination) such as problems with balance and coordination, difficulty swallowing and speaking, and abnormal eye movements The cause of MSA is unknown, although environmental toxins, trauma, and genetic factors may be involved. Most cases occur at random, without any other cases in the family. Diagnosis of MSA is suggested by a combination of symptoms, physical examination, lab test results, and response to certain medications. However, no laboratory or imaging studies are able to confirm the diagnosis. Treatment may include medication, physical, occupational, and speech therapy, and nutritional support. There is no cure for MSA, and there is no known way to prevent the disease from getting worse. The goal of treatment is to control symptoms. Most people with MSA survive between 6-15 years after symptoms first begin. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Multiple system atrophy	c0393571	4,709	gard	https://rarediseases.info.nih.gov/diseases/7079/multiple-system-atrophy	2021-01-18T17:58:54	{"mesh": ["D019578"], "omim": ["146500"], "orphanet": ["102"], "synonyms": ["MSA", "Shy-Drager syndrome (formerly)"]}
A number sign (#) is used with this entry because of evidence that glomerulopathy with fibronectin deposits-2 (GFND2) is caused by heterozygous mutation in the gene encoding fibronectin-1 (FN1; 135600) on chromosome 2q35. Description Glomerulopathy with fibronectin deposits is a genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life. Pathologic examination shows enlarged glomeruli with mesangial and subendothelial fibrillary deposits that show strong immunoreactivity to fibronectin (Castelletti et al., 2008). For a discussion of genetic heterogeneity of GFND, see 137950. Clinical Features Mazzucco et al. (1992) described an Italian mother and daughter with slowly progressive nephrotic syndrome. Proteinuria was first detected at ages 25 and 11 years, respectively. Renal biopsy from both patients showed similar glomerular changes, including marked widening of the mesangial stalk, irregular thickening of the basement membrane, and presence of mesangial and subendothelial deposits. Electron microscopy disclosed huge glomerular electron-dense deposits containing 12-nm fibrils. Immunohistochemical studies showed strong fibronectin staining in the mesangium and along glomerular basement membranes. Most glomerular fibronectin was plasma-derived, as shown by specific monoclonal antibodies. The mother showed a slow decrease of glomerular function, and a second biopsy performed 8 years after the first investigation showed scarcely modified glomerular changes, consistent with an indolent evolution. In a review of the histologic findings of the mother and daughter reported by Mazzucco et al. (1992), Strom et al. (1995) stated that the deposits were granular in nature with a few 12-nm fibrils in the mesangial and subendothelial spaces. In a follow-up of this family, Castelletti et al. (2008) noted that the 53-year-old mother had moderately reduced renal function and the 25-year-old daughter had normal renal function. A paternal aunt of the mother died at 37 years of nephropathy. Assmann et al. (1995) reported an affected father and son from the Netherlands. Low-grade proteinuria and hypertension were discovered in the father at age 30 years, and proteinuria in the son at age 18. Renal biopsies from both patients disclosed a distinct form of fibrillary glomerulonephritis that was characterized by massive deposits of a homogeneous eosinophilic material in the mesangial and subendothelial areas. Staining for amyloid was negative, and staining for immunoglobulins was faint. However, the material stained strongly for plasma-derived fibronectin. Electron microscopy showed that the mesangial and subendothelial deposits were composed of irregularly arranged fibrils or microtubules 10 to 12 nm in diameter. In both patients, the disorder showed indolent course with hardly any deterioration of renal function. Assmann et al. (1995) concluded that fibrillary glomerulonephritis with massive deposits of fibronectin represents a rare form of familial glomerulonephritis. Niimi et al. (2002) reported a 3-year-old Japanese boy with proteinuria, microscopic hematuria, and hypertension. Renal function was intact, but renal biopsy showed enlarged glomeruli with granular fibronectin deposits in the peripheral loop and mesangium. There were no immune deposits and no evidence of systemic disease. Twelve other family members were subsequently found to have mild hematuria or proteinuria, but none were biopsied. Renal function in the proband was preserved during 7 years of follow-up. Inheritance Autosomal dominant inheritance of GFND2 was supported in 6 affected families reviewed by Strom et al. (1995). There were affected individuals in 2 generations in 4 of the families, including a father and 4 sons in 1. Mapping By linkage analysis of a large Italian family with GFND2 first reported by Strom et al. (1995), Castelletti et al. (2008) found linkage to the FN1 gene on chromosome 2q34 (2-point Z-max = 3.084 for markers D2S128 and D2S2361). Linkage was excluded from the GFND1 locus on 1q32. Molecular Genetics In affected individuals from 6 unrelated families with GFND2, Castelletti et al. (2008) identified heterozygous mutations in the FN1 gene (135600.0001-135600.0003). Four of the families had previously been reported by Mazzucco et al. (1992), Strom et al. (1995), Assmann et al. (1995), and Niimi et al. (2002). Although 3 families shared the same mutation, there was no evidence for a founder effect. Six (40%) of 15 affected families were found to have FN1 mutations, suggesting genetic heterogeneity. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension due to renal disease GENITOURINARY Kidneys \- Proteinuria \- Microscopic hematuria \- Nephrotic syndrome \- Renal failure \- End-stage renal disease \- Enlarged glomeruli \- Mesangial and subendothelial granular or fibrillar deposits which show immunoreactivity to fibronectin MISCELLANEOUS \- Onset of proteinuria in the second to fourth decades \- Onset of end-stage renal disease 15 to 20 years after onset \- Slow progression MOLECULAR BASIS \- Caused by mutation in the fibronectin 1 gene (FN1, 135600.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	GLOMERULOPATHY WITH FIBRONECTIN DEPOSITS 2	c3888104	4,710	omim	https://www.omim.org/entry/601894	2019-09-22T16:14:10	{"mesh": ["C536826"], "omim": ["601894"], "orphanet": ["84090"], "synonyms": ["Alternative titles", "GLOMERULAR NEPHRITIS, FAMILIAL, WITH FIBRONECTIN DEPOSITS", "FIBRONECTIN GLOMERULOPATHY"]}
SCARF syndrome Other namesSkeletal abnormalities, Cutis laxa, craniostenosis, Ambiguous genitalia, Retardation, and Facial abnormalities [1] This condition is inherited in an X-linked recessive manner SCARF syndrome is a rare syndrome characterized by skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, psychomotor retardation, and facial abnormalities. These characteristics are what make up the acronym SCARF.[2] It shares some features with Lenz-Majewski hyperostotic dwarfism. It is a very rare disease with an incidence rate of approximately one in a million newborns.[3] It has been clinically described in two males who were maternal cousins, as well as a 3-month old female.[4][3] Babies affected by this syndrome tend to have very loose skin, giving them an elderly facial appearance. Possible complications include dyspnea, abdominal hernia, heart disorders, joint disorders, and dislocations of multiple joints.[3] It is believed that this disease's inheritance is X-linked recessive.[4] ## Contents * 1 Signs & Symptoms * 1.1 Symptoms * 2 Causes * 2.1 Pathophysiology * 3 Diagnosis * 4 Treatment/Prevention * 5 Prognosis * 6 Epidemiology * 7 Current Research * 8 References * 9 External links ## Signs & Symptoms[edit] The most characteristic signs and symptoms of SCARF syndrome are the ones described by the acronym. This includes skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, psychomotor retardation, and facial abnormalities.[4] The severity of the symptoms will vary from person to person.[5] Symptoms will present similarly in both males and females, other than specific genitourinary symptoms. ### Symptoms[edit] * Facial * Long philtrum * Small chin * Ptosis * Epicanthal folds * Strabismus * High, broad nasal root * Enamel hypoplasia Strabismus is a condition where the eyes are not aligned correctly, also known as "crossed-eyes." It is a common facial symptom of SCARF.[6] * Neck * Excess nuchal skin * Neck webs * Short neck * Chest * Barrel-shaped * Short sternum * Pectus carinatum * Hypoplastic nipples Craniosynostosis is a birth defect where the skull closes too soon, before the brain has finished developing.[7] This is a symptom often associated with the presence of SCARF syndrome.[5] * Abdomen * Diastasis recti * Umbilical hernia * Skeletal * Abnormally-shaped vertebrae * Craniosynostosis * Genitourinary * Micropenis * Perineal hypospadias * Inguinal hernia * Cryptorchidism * Clitoromegaly Ambiguous genitalia is a trademark symptom of SCARF syndrome, presented in both males and females.[8] The figure above shows clitoromegaly and hyperpigmentation. * Skin, Hair, and Nails * Cutis Laxa * Sparse hair * Neurological * Mental retardation * mild to moderate (Symptoms were obtained from OMIM catalog[5]) ## Causes[edit] While the specific cause of SCARF syndrome is unknown, it has been deemed as a genetic disorder. It is believed to be typically inherited, and transmitted as both a recessive and dominant gene.[8] ### Pathophysiology[edit] The exact genetic mutation responsible for SCARF syndrome is unknown at this time. However, the mode of inheritance is perceived to be X-linked recessive because the first two cases reported of this syndrome were in two male cousins, who were related through their mothers.[8] This means that the gene that is associated with this disorder is located on the X chromosome.[9] Since males have only one X chromosome, only a single mutation is needed to cause this disorder. In contrast, females would require a mutation on both of their X chromosomes, which is a very rare occurrence. Therefore, SCARF syndrome and X-linked recessive disorders are more common in males.[9] Cutis laxa, one of the most common symptoms associated with SCARF syndrome, is caused by mutations in several different genes. These genes include ATP6V0A2, ATP7A, EFEMP2, ELN, and FBLN5. These genes are responsible for elastic fibers, specifically how they are formed and their function. Elastic fibers allow the skin to stretch, help the lungs expand and contract, as well assist arteries in managing blood flow at high blood pressures. The mode of inheritance for cutis laxa may be X-linked, autosomal dominant, or autosomal recessive. Cutis laxa is known to be the cause of many of the complications associated with SCARF syndrome such as congestive heart failure, respiratory failure, and dysfunction[disambiguation needed] of gastrointestinal and urinary tract.[10] ## Diagnosis[edit] The diagnosis relies on clinical presentations, physical examination, extensive evaluation of past medical history and family history, and karyotype testing. A 46,XX compatibility is an expected finding of the karyotype test. Laboratory tests and diagnostic imaging are typically insignificant for diagnosis. The relationship of the parents as well as family history of X-linked, autosomal dominant, and autosomal disorders should be considered to confirm SCARF syndrome.[3] ## Treatment/Prevention[edit] Due to the fact that the syndrome is a genetic condition, there is no specific cure for this syndrome. Treatment is not for the disease itself, but more for management of the associated signs and symptoms of SCARF syndrome and its complications. The main risk factor is previous family history. This does not guarantee that one will inherit the disease, but it is much more likely compared to someone with no family history. No other risk factors have been identified. Due to this reason, there are not many preventative measures that can be done. If there is family history of the syndrome, genetic counseling should be considered before planning children to assess the risk of passing the disease onto future generations. Regular blood tests and physical examinations should be done as well to ensure no change in health status.[9] ## Prognosis[edit] The prognosis of SCARF syndrome depends on the severity of the signs and symptoms experienced, as well as if there are any associated complications. If the symptoms are mild, the prognosis will be better than that of someone with symptoms that are severe. There is no general prognosis for SCARF syndrome and it should be assessed independently for each case.[9] ## Epidemiology[edit] This syndrome is very rare with a prevalence rate of less than 1/1000000 worldwide.[11] The age of onset is typically neonatal or during infancy, but there has been a case reported in a 7-year-old male as well.[11][8] There is no evidence that the syndrome is more prevalent in a specific ethnicity, but it is more prevalent in males due to its X-linked recessive inheritance. Since males only have one X chromosome, this means that only one mutation is required for the syndrome to be inherited. Females have two X chromosomes, which means that the mutation must be present on both chromosomes in order to be inherited.[9] ## Current Research[edit] There is no current research exclusive to SCARF syndrome. However, research is being actively conducted on finding a treatment and prevention method for both inherited and acquired genetic disorders.[9] This includes research in the Netherlands on the genetic causes of facial abnormalities and its associated complications and symptoms.[12][13] The study involves the identification of new casual genes related to craniosynostosis including EFNB1 and TCF12 as well as genes involved in rare craniofacial malformations, including ALX3 and RAB23. This research can help identify other genes possibly linked to the development of SCARF syndrome. There is a current clinical trial in the United Kingdom that involves the use of Sarilumab injections for the treatment of musculoskeletal and connective tissue disorders.[14] This clinical trial has the potential of developing a treatment that could be applied to numerous disorders of the musculoskeletal system and connective tissue, such as SCARF syndrome. ## References[edit] 1. ^ "SCARF syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 28 June 2019. 2. ^ "Scarf Syndrome disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials". www.malacards.org. Retrieved 2020-11-05. 3. ^ a b c d Rahimpour, Masoume; Sohrabi, Mohammad bager; Kalhor, Sulmaz; Khosravi, Hossein ali; Zolfaghari, Poone; Yahyaei, Elahe (2014-03-16). "A rare case report: SCARF syndrome". Clinical Case Reports. 2 (3): 74–76. doi:10.1002/ccr3.61. ISSN 2050-0904. PMC 4184596. PMID 25356252. 4. ^ a b c "SCARF syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2020-11-11. 5. ^ a b c "OMIM Clinical Synopsis - 312830 - SCARF SYNDROME". omim.org. Retrieved 2020-11-11. 6. ^ "Strabismus (crossed eyes)". www.aoa.org. Retrieved 2020-12-16. 7. ^ CDC (2019-12-04). "Facts about Craniosynostosis \| CDC". Centers for Disease Control and Prevention. Retrieved 2020-12-16. 8. ^ a b c d Koppe, Roswitha; Kaplan, Paige; Hunter, Alasdair; MacMurray, Brock (1989). "Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome)". American Journal of Medical Genetics. 34 (3): 305–312. doi:10.1002/ajmg.1320340302. ISSN 1096-8628. 9. ^ a b c d e f Purohit, Maulik (2018-04-28). "SCARF Syndrome". www.dovemed.com. Retrieved 2020-11-11. 10. ^ "Cutis laxa: MedlinePlus Genetics". medlineplus.gov. Retrieved 2020-11-12. 11. ^ a b "Orphanet: SCARF syndrome". www.orpha.net. Retrieved 2020-11-12. 12. ^ Mathijssen, Irene. "Genetic causes of craniofacial anomalies" (PDF). 13. ^ Mathijssen, Irene. "Disturbed breathing in craniofacial disorders" (PDF). 14. ^ "Orphanet: An Open label, Sequential, Ascending, Repeated Dose finding Study of Sarilumab, Administered with Subcutaneous SC Injection, in Children and Adolescents, Aged 2 to 17 Years, with Polyarticular course Juvenile Idiopathic Arthritis pcJIA Followed by an Extension Phase GB". www.orpha.net. Retrieved 2020-11-12. ## External links[edit] Classification D * ICD-10: Q82.8 * OMIM: 312830 * MeSH: C536625 External resources * Orphanet: 3134 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SCARF syndrome	c1839321	4,711	wikipedia	https://en.wikipedia.org/wiki/SCARF_syndrome	2021-01-18T19:09:35	{"gard": ["247"], "mesh": ["C536625"], "umls": ["C1839321"], "orphanet": ["3134"], "wikidata": ["Q7389072"]}
X-linked intellectual disability-short stature-overweight syndrome is a multiple congenital anomalies syndrome characterized by borderline to severe intellectual disability, speech delay, short stature, elevated body mass index, a pattern of truncal obesity (reported in older males), and variable neurologic features (e.g. hypotonia, tremors, gait disturbances, behavioral problems, and seizure disorders). Less common manifestations include microcephaly, microorchidism and/or microphallus. Dysmorphic features have been reported in some patients but no consitent pattern has been noted. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	X-linked intellectual disability-short stature-overweight syndrome	c0796242	4,712	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=457240	2021-01-23T19:11:31	{"omim": ["300957"]}
Tourism with the purpose to engage in child prostitution Sex and the law Social issues * Age of consent * Antisexualism * Bodily integrity * Censorship * Circumcision * Deviant sexual intercourse * Ethics * Freedom of speech * Homophobia * Intersex rights * LGBT rights * Miscegenation (interracial relations) * Marriageable age * Norms * Objectification * Pornography * Public morality * Red-light district * Reproductive rights * Right to sexuality * Same-sex marriage * Sex industry * Sex workers' rights * Sexual and reproductive health and rights * Survival sex Specific offences (Varies by jurisdiction) * Adultery * Bestiality * Buggery * Child grooming * Child pornography * Child prostitution * Criminal transmission of HIV * Cybersex trafficking * Female genital mutilation * Fornication * Incest * Pimping * Prostitution * forced * procuring * Public indecency * Rape * statutory * marital * Seduction * Sex trafficking * Sexting * Sexual abuse * child * Sexual assault * Sexual harassment * Slavery * Sodomy * UK Section 63 (2008) * Violence * Trafficking * Voyeurism Sex offender registration * Sex offender registry * Sex offender registries in the United States Portals * Human sexuality portal * Law portal * v * t * e Child sex tourism (CST) is tourism for the purpose of engaging in the prostitution of children, which is commercially facilitated child sexual abuse.[1] The definition of child in the United Nations Convention on the Rights of the Child is "every human being below the age of 18 years".[2] Child sex tourism results in both mental and physical consequences for the exploited children, which may include sexually transmitted infections (including HIV/AIDS), "drug addiction, pregnancy, malnutrition, social ostracism, and possibly death", according to the State Department of the United States.[1] Child sex tourism, part of the multibillion-dollar global sex tourism industry, is a form of child prostitution within the wider issue of commercial sexual exploitation of children. Child sex tourism victimizes approximately 2 million children around the world.[1][3][4][5] The children who perform as prostitutes in the child sex tourism trade often have been lured or abducted into sexual slavery.[6][7][8] Users of children for commercial and sexual purposes can be categorized by motive. Although pedophiles are popularly associated with child sex tourism, they are not the majority of users. There are two types of offenders: preferential abusers who specifically prefer children, because they seek to build a relationship with a child or because they perceive the risk of sexually transmitted infections to be lower; and situational users, which are abusers who do not actively seek out children but for whom the actual act is opportunistic. For situational users, there may be a lack of concern to check the age of a prostitute before engaging in sexual activity.[9] Travelling child sex offenders can use the Internet to plan their trips by seeking out and trading information about opportunities for child sex tourism and where the most vulnerable children can be found, generally in areas of low income.[5] A few governments have enacted laws to allow prosecution of its citizens for child sexual abuse committed outside of their home country. However, while laws against child sex tourism may deter situational offenders who may act impulsively, pedophiles who travel specifically for the purpose of exploiting children are not easily deterred.[5] ## Contents * 1 Background * 2 Webcam child sex tourism * 3 Global response * 4 International law enforcement activities * 5 Policing of child sex tourism * 5.1 Asia * 5.2 North America * 5.3 South America * 6 Extraterritorial jurisdiction * 6.1 Australia * 6.2 Canada * 6.3 Hong Kong * 6.4 Israel * 6.5 Japan * 6.6 New Zealand * 6.7 Russia * 6.8 Singapore * 6.9 Switzerland * 6.10 South Korea * 6.11 United Kingdom * 6.12 United States * 6.13 European Union * 7 References * 8 External links ## Background[edit] Child sex tourism has been closely linked to poverty, armed conflicts, rapid industrialization, and exploding population growth.[10] In Latin America and Southeast Asia, for instance, street children often turn to prostitution as a last resort. Additionally, vulnerable children are easy targets for exploitation by traffickers.[10] Thailand, Cambodia, India, Brazil and Mexico have been identified as leading hotspots of child sexual exploitation.[11] Also, child victim ages have been found in Cambodia, Myanmar, the Philippines, and Thailand to range from 6 to 11 years old, followed by 12 to 15 years old, and 15 to 17.[12] Child sex tourism has also been complicated by varying ages of consent laws where, for example, the age of consent is 13 in Japan while it is 21 in Bahrain (see ages of consent in Asia). In 2012, the Special Rapporteur on the sale of children, child prostitution and child pornography reported : "Countries of origin of international child sex tourists vary depending on the regions, but the demand is usually recognized as coming from the industrialized countries, including the richer countries of Europe, North America, the Russian Federation, Japan, Australia and New Zealand. Australians, for instance, have been identified as the largest group of sex tourists prosecuted in Thailand (31 percent of the total). Of the 146 cases investigated by Action Pour Les Enfants (APLE) in Cambodia between 2003 and April 2012, 32 were American, 24 French and 20 Vietnamese. In the coastal regions of Kenya, for example, 30 percent were residents and 70 percent of the abusers were foreign: Italians (18 percent), Germans (14 percent), Swiss (12 percent), with tourists coming from Uganda and the United Republic of Tanzania fifth and sixth on the list. In Costa Rica, according to available information, between the 1999 and 2005, the Child Exploitation Unit had arrested a total of 74 persons on suspicion of commercial sexual exploitation of children. Of those arrested, 56 were Costa Rican nationals and 18 foreign nationals".[13] In Thailand, the exact number of child-prostitutes is not known, but Thailand's Health System Research Institute reports that children in prostitution make up 40% of prostitutes in Thailand.[14] In Cambodia, it has been estimated that about a third of all prostitutes are under 18.[15][16] In India, the federal police say that around 1.2 million children are believed to be involved in prostitution.[17] Up until recently, Brazil has been considered to have the worst child sex trafficking record after Thailand.[18] As per Chris Rogers report on BBC World[19] "Now Brazil is overtaking Thailand as the world's most popular sex-tourist destination". DLN reports that "Brazil at the moment is on a high trend of child sex tourism and is all geared to take up the first spot beating out Thailand."[20] Sex tourism targeting children creates huge monetary incentives for traffickers. Human trafficking impacts an estimated 1.2 million child victims.[21][22] The United Nations Office of Drugs and Crimes (UNODC) recently stated that 79% of all global trafficking is for sexual exploitation, which is one of the fastest growing criminal activities in the world.[22] UNICEF notes that sexual activity is often seen as a private matter, making communities reluctant to act and intervene in cases of sexual exploitation.[22] These attitudes make children far more vulnerable to sexual exploitation. Most exploitation of children takes place as a result of their absorption into the adult sex trade where they are exploited by local people and sex tourists.[22] The Internet provides an efficient global networking tool for individuals to share information on destinations and procurement.[22] In cases involving children, the U.S. has relatively strict domestic laws that hold accountable any American citizen or permanent resident of the U.S. who travels abroad for the purpose of engaging in illicit conduct with a minor.[23] However, child pornography, sex tourism and human trafficking remain fast-growing industries.[23] Rep. Chris Smith, R-N.J. recently introduced H.R. 1623, the international Megan's Law. Similar to the domestic Megan's Law (named after Megan Kanka of New Jersey), which provides for community notification when a sex offender is living in the area, H.R. 1623 would alert officials abroad when U.S. sex offenders intend to travel, and likewise encourage other countries to keep sex offender lists and to notify the U.S. when a known sex offender may be coming to the United States for sex tourism.[23] While there are serious problems with the sex offender registries in the United States, human rights organizations such as ECPAT and UNICEF believe this would be a step in the right direction.[23] One of the factors pushing Brazil to the top of this list of destination countries is the extensive use of the Sport Fishing industry in the Brazilian Amazon as a front. The 2008 U.S. State Department Report[24] states "At midyear Federal Police in Manaus began investigating allegations that a foreign-owned travel company arranged fishing expeditions to the Amazon region that were in reality sex tours for U.S. and European pedophiles. At year's end the investigation was continuing in coordination with foreign law enforcement officials." Another US State Department report states (page 85) "In a newer trend, some arranged fishing expeditions to the Amazon were organized for the purpose of child sex tourism for European and American exploiters."[25] Recent Reports on Fox Atlanta and ABC World News Tonight have helped shine the light on this.[26][27][28][29][30] ECPAT-USA has recently posted a Brazilian National News story with English subtitles.[31] ## Webcam child sex tourism[edit] According to the Federal Bureau of Investigations estimate, there are 750,000 predators online at any given time in 40,000 public chat rooms. Offers from 20,000 internet users to pay for webcam sex performances were found in a 10-week investigation conducted from a warehouse in Amsterdam, in the Terre des hommes Dutch action against WCST, using "Sweetie", a 3D computer model. Out of 21,000 perpetrators, 1,000 were identified from Australia, Canada, Germany, Ghana, India, Italy, Mauritius, the Netherlands, South Africa, Turkey, the United Kingdom, and United States. 110 of the alleged online abusers were based in the UK and another 254 were traced to computers in the US.[32] Together with Avaaz.org, Terre des Hommes Netherlands has created an online petition to pressure governments to adopt proactive investigation policies in order to protect children against webcam child sex tourism. ## Global response[edit] In recent years[when?] there has been an increase in the prosecution of child sex tourism offenses. At least 38 countries have extraterritorial laws that allow their citizens to be prosecuted specifically for child sexual abuse crimes committed while abroad, and another 31 nations have more general extraterritorial laws that could be used to prosecute their citizens for crimes committed during child sex tourism trips.[1] As of May 2016, 173 countries have signed and ratified the Optional Protocol on the Sale of Children, Child Prostitution and Child Pornography which is "Deeply concerned at the widespread and continuing practice of sex tourism, to which children are especially vulnerable". It also obliges parties to pass laws within their own territories against these practices "punishable by appropriate penalties that take into account their grave nature".[33] In response to CST, non-governmental organizations (NGOs), the tourism industry, and governments have begun to address the issue. The World Tourism Organization (WTO) established a task force to combat CST. The WTO, ECPAT (End Child Prostitution, Child Pornography and Trafficking of Children for Sexual Purposes) and Nordic tour operators created a global Code of Conduct for the Sexual Exploitation of Children in Travel and Tourism in Travel and Tourism in 1996. As of April 2013, over 1200 travel companies from 40 countries had signed the code.[34] ## International law enforcement activities[edit] The United States' Homeland Security Investigations participates in investigating and capturing child sex tourists. In 2003 ICE launched “Operation Predator”, leading to the arrest of over 11,000 child sexual abusers, including more than 1,100 outside the United States. While ICE agents refuse to comment on their means and methods of operation, media reports have suggested the use of undercover agents, internet sting operations, and sophisticated technologies. ICE agents in Bangkok did say however that they often receive information from local NGOs about foreigners in Thailand whom they suspect of engaging in child sexual abuse. Sometimes U.S. based law enforcement, such as local sheriffs' departments and parole officers, inform them of known sex offenders who are traveling to the region. In both cases, local ICE agents work with their Royal Thai Police counterparts to monitor the suspects’ movements while in Thailand.[35] The UK police and the Child Exploitation and Online Protection Centre (CEOP) are actively involved in monitoring child sex tourists and do prosecute.[36] INTERPOL actively pursues offenders as well.[37] ## Policing of child sex tourism[edit] ### Asia[edit] * Cambodia: The Trafficking in Persons Report of 2010 reports that the sale of virgin girls continues to be a serious problem in Cambodia, and that a significant number of Asian and other foreign men travel to Cambodia to engage in child sex tourism.[38] Cambodia's 1996 Law on Suppression of the Kidnapping, Trafficking, and Exploitation of Human Persons contains legislation against the commercial sexual exploitation of children, and while the law focuses largely on trafficking, it also addresses prostitution.[39] The age of consent in Cambodia is 15, and the law does not specifically define or prohibit the prostitution of children.[39] It is estimated that 1/3 of prostitutes in Cambodia are children.[40] * China: The Trafficking in Persons Report of 2010 reports that the government of China did not take sufficient measures to reduce demand for forced labor, commercial sex acts, or child sex tourism.[41] * Indonesia: The Trafficking in Persons Report of 2010 reports that child sex tourism is prevalent in most urban areas and tourist destinations, such as Bali and Riau Island in Indonesia.[41] Recently, islands of Indonesia like Bali and Batam have become known for child sex tourism. These islands have also been destinations for sex trafficking.[39] Under a Criminal Code in Indonesia, any Indonesian citizen can be punished for violating the Child Protection Act or the Criminal Code, whether it is inside Indonesia or outside.[39] The Child Protect Act 28 is a general act to protect the rights of children.[39] A few specific sections provide laws specific to sexual mistreatment of children. One law states that it is illegal to use a child for personal or commercial monetary gain.[39] If one does not follow this law, the punishment can be up to ten years in jail and/ or a monetary fine of 200 million rupiahs which is equivalent to 22,000 US dollars.[39] * South Korea: South Korean men have been major drivers of child sex tourism in Asia for some time. In 2005, The Korea Times reported that an international symposium was held to talk about strategies for curbing the high numbers of Korean child sex tourists to southeast Asia. The symposium, "Conditions and Countermeasures to Overseas Child and Youth Sex Tourism by Korean Men" discussed issues concerning Korean male soliciting of child prostitutes across Asia, but Cambodia and The Philippines were especially worrisome. "[Panelists] said male Korean tourists are believed to abuse the unfortunate situation of poor Cambodian children," who are coerced into selling sexual favors in order to help their families.[42] As for the Philippines, the report noted, "An increasing number of Koreans bought sex in the Philippines, sometimes abusing prostitutes. The Philippine government has urged the Korean government to take firm action against soliciting prostitutes, in particular buying sex from children."[42] The Trafficking in Persons Report of 2019 reports that the men of South Korea engage in child sex tourism in Cambodia, China, Mongolia, the Philippines, and Vietnam.[43] Technology such as the internet has helped increase accessibility of child sex tourism in the Republic of Korea. Some South Korean men arrange for children from the Philippines, Thailand, and China as sources of sex.[41] A Korean Institute of Criminology study published in January 2013 shows that South Korean men are the primary market for child sex tourism in Southeast Asia. "Among foreigners visiting Southeast Asia, South Koreans are the majority group driving demand for child prostitution across the region."[44] The article goes on to say, "A 2008 report from the U.S. Department of State, 'Trafficking in Persons Report,' described South Korea as a significant source of demand for child sex tourism in Southeast Asia and the Pacific Islands." Yun Hee-jun, head of a Seoul-based group campaigning against sex trafficking, claims, “If you visit any brothel in Vietnam or Cambodia, you can see fliers written in Korean.”[44] Although South Korea has legislation in place to prosecute Korean nationals who are child sex offenders abroad, a 2014 report stated "The government has not prosecuted or convicted any Korean sex tourists during the past seven years".[45] * Laos: Lao Penal Law, Article 131 states: "Human trafficking means the recruitment, moving, transfer, harbouring, or receipt of any person within or across national borders by means of deception, threats, use of force, debt bondage or any other means [and using such person in] forced labour, prostitution, pornography, or anything that is against the fine traditions of the nation, or removing various body organs [of such person], or for other unlawful purposes. Any of the above-mentioned acts committed against children under 18 years of age shall be considered as human trafficking even though there is no deception, threat, use of force, or debt bondage. Any person engaging in human trafficking shall be punished by five years to fifteen years of imprisonment and shall be fined from 10,000,000 Kip to 100,000,000 Kip".[46] Lao Law on Development and Protection of Women, Article 24 states: "If these acts are committed against children under 18 years old, then even though there is no deception, threat, force, or debt bondage, trafficking shall be regarded to have occurred. Any individual who co-operates with the offender [who commits] an offence mentioned above[,] whether by incitement, providing assets or vehicles to the offender, the provision of shelter, or the concealment or removal of traces of an infraction, shall be considered as an accomplice in trafficking in women and children".[46] According to a 2008 US state department report: "Police corruption, a weak judicial sector and the population’s general lack of understanding of the court system impeded anti-trafficking law enforcement efforts...Corruption remained a problem with government officials susceptible to involvement or collusion in trafficking in persons."[47] * Mongolia: The Trafficking in Persons Report of 2010 reports that South Korean and Japanese tourists engage in child sex tourism in Mongolia.[41] The Mongolian government has implemented laws regarding child prostitution. The Criminal Code bans organized prostitution of anyone under the age of 16, the age of sexual consent in Mongolia.[39] Not only is prostitution of anyone under the age of 16 illegal, sex with a person under the age of 16 is illegal as well. Not complying with this law could lead to three years in jail or eighteen months of community service. Rape is also considered illegal in Mongolia, with the punishment of two to six years in prison. If there are repeated violations or injury to victims these punishments are intensified.[39] * Philippines: Child sex tourism is known as a serious problem in the Philippines. The Trafficking in Persons Report of 2010 reports of tourists coming from Northeast Asia, Australia, Europe and North America to engage in sex with children. With new technology like the internet, some children form cyber relationships with men from other countries and get money by sending pornographic images over the internet.[48] * Thailand: Both governmental organizations and nongovernmental organizations have worked together to shut down brothels. They have also tried to increase awareness of child sex tourism and made attempts to stop it.[41] In 2008, records of 27,000 woman and children were reported as seeking medical treatment from injuries relating to sexual abuse.[48] Many children are not registered at birth in Thailand, allowing them more easily to be trafficked to other countries and forced into child labor, including sexual exploitation.[48] ### North America[edit] * Barbados: There has been no noticeable action taken by the government of Barbados to reduce the demand for commercial sex acts, though public commentary on the problem of sex tourism, including child sex tourism, has been increasing.[38] * Dominican Republic: Some reports say that child sex tourism is a current problem, particularly in coastal resort areas, with child sex tourists arriving year-round from various countries.[38] It is also reported that the current legislation has inconsistencies and gaps which could obstruct the interpretation and application of the legislation.[39] The Code for the Protection of the Rights of Children and Adolescents, Law 136-03 conceptualizes crime of using children and adolescents in paid sexual activity.[39] Only certain modes of production and dissemination of pornographic material are seen as criminal activities, while possession of child pornography is sanctioned.[39] * Cuba: The Trafficking in Persons Report of 2010 reports that the government of Cuba has made no known efforts to reduce the demand for commercial sex.[38] Additionally, it is reported that the government does not acknowledge any child sex tourism problem but has recently banned children under 16 from nightclubs.[38] According to Cuban government documents, training was provided to those in the tourism industry on how to identify and report potential sex tourists.[38] * El Salvador: One-third of the sexually exploited children between 14 and 17 years of age are boys. The median age for entering into prostitution among all children interviewed was 13 years. They worked an average of five days per week, although nearly 10% reported that they worked seven days a week. Recently, the problem has increased, especially due to migration. Many children are lied to with promises of jobs, and are abducted and sent to countries in North America by foreigners from Mexico or neighboring countries. Most victims are Salvadoran children from rural areas who are forced into commercial sexual exploitation in urban areas. The Government of El Salvador does not fully comply with the minimum standards for the elimination of trafficking, but is making significant efforts to do so. During the reporting period, the government sustained anti-trafficking law enforcement efforts and continued to provide services to children who were trafficked for sexual exploitation. The Salvadoran government sustained anti-trafficking prevention efforts during the reporting period. The government forged or continued partnerships with NGOs, international organizations, and foreign governments on anti-trafficking initiatives. In May 2009, the government collaborated with an NGO to launch a campaign aimed specifically at increasing awareness of the commercial sexual exploitation of children, reaching approximately 4,500 children and adults. The government included anti-trafficking information in the training it gives to military forces prior to their deployment for international peacekeeping missions.[49] * Jamaica: The Trafficking in Persons Report of 2010 reports that NGOs (Nongovernmental Organizations) and local observers state that there is a child sex tourism problem near Jamaica's resort areas.[38] * Trinidad and Tobago: According to the governments of Trinidad and Tobago, there were no reports nor prosecutions on child sex tourism.[38] ### South America[edit] * Argentina: The US Department of State reported that child sex tourism is a problem in Argentina, especially on the border and in Buenos Aires. The Argentinean penal code does not specifically prohibit child sex tourism.[39][41] and there were not any child sex related prosecutions in 2009–2010. Hoping to reduce child sex tourism, governmental authorities passed a law commanding law enforcement to seek the closure of all brothels NGOs reported. This is not effective because brothels are often tipped off by local police before the raids.[41][50] * Brazil: The US Department of State reported that child sex tourism remains a serious problem, particularly in tourist areas in Brazil's northeast. Most child sex tourists come from Europe, and some come from the United States. Brazilian authorities are not directly involved with prosecuting sex tourists and instead allow NGOs to prosecute those participating in child sex tourism.[41] A Brazilian law newly introduced in 2000, states, “to submit a child or adolescent, as defined in the caput of article 2 (children: people younger than 12 years ; adolescents: people between 12 and 18), prostitution or sexual exploitation is punishable by imprisonment for four to ten years and a fine.” [39] * Colombia: Article 219 of the Colombian criminal code prohibits, “organizing or facilitating sexual tourism and provides penalties of 3 to 8 years’ imprisonment”, but there were no reported prosecutions or convictions of child sex tourists.[41] In recent years, Colombia has strengthened legislation related to control trafficking of children, particularly to follow the criminal code. However, a law is still pending approval by the Code for Children and Adolescents, which includes the rights and guarantees of children and adolescents victims of commercial sexual exploitation.[39] * Ecuador: Child sex tourism occurs mostly in urban areas, and in tourist destinations, such as the city of Tena and the Galapagos Islands.[41] * Peru: Child sex tourism is present in Iquitos, Madre de Dios, and Cuzco. Traffickers reportedly operate illegally in certain regions where governmental authority lacks.[41] Although some areas of the country are known child sex tourism destinations and Peruvian laws prohibit this practice, there were no reported convictions of child sex tourists. The government trained 710 government officials and tourism service providers about child sex tourism, conducted a public awareness campaign on the issue, and reached out to the tourism industry to raise awareness about child sex tourism; to date, 60 businesses have signed code of conduct agreements nationwide.[41] * Uruguay: Government officials maintained efforts to reach out to hotel workers and to others in the broader tourism sector to raise awareness about child sex tourism and the commercial sexual exploitation of children. Uruguay's educational system continues to include trafficking education to high schools.[41] ## Extraterritorial jurisdiction[edit] A growing number of countries have specific extraterritorial legislation that prosecutes their citizens in their homeland should they engage in illicit sexual conduct in a foreign country with children. In 2008, ECPAT reported that 44 countries had extraterritorial child sex legislation.[51] The following list includes specific citations: ### Australia[edit] Australia was one of the first countries to introduce laws that provide for jail terms for its citizens and residents who engage in sexual activity with children in foreign countries. The laws are contained in the Crimes (Child Sex Tourism) Amendment Act 1994 that came into force on 5 July 1994.[52] The law also makes it an offence to encourage, benefit or profit from any activity that promotes sexual activity with children. It is a crime for Australian citizens, permanent residents or bodies corporate to engage in, facilitate or benefit from sexual activity with children (under 16 years of age) while overseas. These offences carry penalties of up to 25 years imprisonment for individuals and up to $500,000 in fines for companies [53] ### Canada[edit] Canada has included in its Criminal Code provisions that allow for the arrest and prosecution of Canadians in Canada for offences committed in foreign countries related to child sex tourism, such as child prostitution, as well as for child sexual exploitation offences, such as indecent acts, child pornography and incest (Bills C-27 and C-15A that came into force on May 26, 1997, and July 23, 2002, respectively).[54] Convictions carry a penalty of up to 14 years imprisonment. ### Hong Kong[edit] In Hong Kong, the Prevention of Child Pornography Ordinance (Cap. 579) of December 2003 introduced offences in regard to child sex tourism, giving extraterritorial effect to 24 sexual offences listed in a new Schedule 2 to the Crime Ordinance (Cap. 200). This makes illegal an act committed against a child outside Hong Kong if the defendant or the child has connections with Hong Kong. It is also an offence to make any arrangement relating to the commission of such acts against children and to advertise any such arrangement.[55] ### Israel[edit] Israeli Penal Code, Chapter 1, Section 15 states that Israeli penal law shall apply to foreign offenses, felony or misdemeanor which were committed by an Israeli citizen or resident of Israel, without exception, in cases relating to Chapter VIII, Article X (Prostitution and Obscenity) regarding minors. Section 203B under Article X are penal laws to the exploitation of minors for prostitution by way of pimping and trafficking. Section 203C under the same article is a penal law specific to the client: "A person served by an act of prostitution of a minor, shall be liable to three years imprisonment."[56][57] As of February 2016, section 203C is in the process of amendment to an increase of imprisonment from three to five years[58][59] ### Japan[edit] The 1999 Law for Punishing Acts Related to Child Prostitution and Child Pornography, and for Protection of Children stipulates "that a person who is involved in child prostitution, who sells child pornographic products or who transports foreign children to another country for the purpose of forcing them into prostitution shall be punished with imprisonment with labor or a fine. Japanese nationals who commit such crimes abroad shall be punished with the same penalty".[60] ### New Zealand[edit] Under The Crimes Amendment Act 2005 "...it is an offence: For New Zealand citizens and residents to engage in sexual conduct or activities with a child in another country".[2] ### Russia[edit] Criminal Code of Russia, Article 12 states "The Operation of Criminal Law in Respect of Persons Who Have Committed Offences Outside the Boundaries of the Russian Federation[:] 1. Citizens of the Russian Federation and stateless persons permanently residing in the Russian Federation who have committed outside the Russian Federation a crime against the interests guarded by the present Code shall be subject to criminal liability in accordance with the present Code, unless a decision of a foreign state's court exists concerning this crime in respect of these persons".[61] Federal Act No. 380-FZ of 28 December 2013 amended the Criminal Code by also adding laws regarding the receiving of sexual services from a minor. Under the amended article 240.1 of the Criminal Code, "The receipt of sexual services from a minor aged from 16 to 18 by a person who has reached the age of 18 is punishable by up to 240 hours of compulsory work, or restriction of freedom for up to 2 years, or forced labour for up to 4 years, or deprivation of liberty for the same period. In this article, sexual services are understood to mean sexual intercourse, sodomy, lesbianism or other acts of a sexual nature, a condition of the performance of which is monetary or any other remuneration of a minor or third party or the promise of remuneration of a minor or third party".[62] Article 240.3 (amended by Federal Act No. 14-FZ of February 29, 2012) states "The deeds provided for by Parts One and Two of this Article which are committed with the involvement in prostitution of persons who are to be under 14 years old - Shall be punishable by deprivation of liberty for a term of three to 10 years with or without deprivation of the right to hold definite offices or to engage in definite activities for a term of up to fifteen years and with restriction of liberty for a term of from one year to two years or without such".[61] ### Singapore[edit] Singapore Penal Code, Section 376C (Commercial sex with minor under 18 outside Singapore) states: "(1) Any person, being a citizen or a permanent resident of Singapore, who does, outside Singapore, any act that would, if done in Singapore, constitute an offence under section 376B, shall be guilty of an offence".[63] ### Switzerland[edit] Swiss Federal Office of Police state "Swiss federal authorities have stepped up their efforts in fighting child sex tourism in recent years. A special fedpol unit dealing with child pornography and pedocriminality offences co-operates closely with numerous partner services both at home and abroad. Since June 2008, an online form has been available to the general public to report cases of child sex tourism to the appropriate judicial authorities".[64] Swiss Criminal Code Article 5 3. (Territorial scope of application / Offences against minors abroad) states: "1 This Code also applies to any person who is in Switzerland, is not being extradited and has committed any of the following offences abroad: abis.3 sexual acts with dependent persons (Art. 188) and sexual acts with minors against payment (Art. 196); b. sexual acts with children (Art. 187) if the victim was less than 14 years of age;". Article 296 3. (Exploitation of sexual acts / Sexual acts with minors against payment) Amended 27 September 2013, states: "Any person who carries out sexual acts with a minor or induces a minor to carry out such acts and who makes or promises payment in return is liable to a custodial sentence not exceeding three years or to a monetary penalty". Article 187 1. (Endangering the development of minors / Sexual acts with children) states: "1. Any person who engages in a sexual act with a child under 16 years of age, or, incites a child to commit such an activity, or involves a child in a sexual act, is liable to a custodial sentence not exceeding five years or to a monetary penalty. 2. The act is not an offence if the difference in age between the persons involved is not more than three years."[65] ### South Korea[edit] Under The Act on the Protection of Children and Juveniles from Sexual Abuse, Article 33 (Punishment of Korean Citizens who Commit Offenses Overseas) states: "Where criminally prosecuting a Korean citizen who commits a sex offense against a child or juvenile outside the territory of the Republic of Korea, pursuant to Article 3 of the Criminal Act, the State shall endeavor to obtain criminal information swiftly from the relevant foreign country and punish such offender".[66] According to a 2012 ECPAT report "progress is needed with regard to the enforcement of extraterritorial jurisdiction concerning nationals who have sex with children abroad...depending on which South Korean law is being applied, the definition of “child” varies...These varying definitions create uncertainty as to how the various laws will be applied and invite a lack of cooperation or lack of uniformity in enforcement by multiple agencies" [67] ### United Kingdom[edit] The Sexual Offences Act 2003 enables British citizens and residents who commit sexual offences against children overseas to be prosecuted in England, Wales and Northern Ireland.[68] Similar provisions are in force in Scotland under the Criminal Law (Consolidation) (Scotland) Act 1995.[69] Some of the offences carry penalties of up to life imprisonment and anyone found guilty will be placed on the Sex Offenders Register. As of 2013, two British citizens are in jail following trials based on this legislation: Barry McCloud and David Graham.[70] ### United States[edit] Under the PROTECT Act of April 2003, it is a federal crime, prosecutable in the United States, for a U.S. citizen or permanent resident alien, to engage in illicit sexual conduct in a foreign country with a person under the age of 18, whether or not the U.S. citizen or lawful permanent resident alien intended to engage in such illicit sexual conduct prior to going abroad. For purposes of the PROTECT Act, illicit sexual conduct includes any commercial sex act in a foreign country with a person under the age of 18. The law defines a commercial sex act as any sex act, on account of which anything of value is given to or received by a person under the age of 18.[71] Before congressional passage of the Protect Act of 2003, prosecutors had to prove that sex tourists went abroad with the intent of molesting children—something almost impossible to demonstrate. The Protect Act shifted the burden, making predators liable for the act itself. Penalties were doubled from 15 years in prison to 30.[7] ### European Union[edit] Under the 2011 Directive on combating the sexual abuse and sexual exploitation of children and child pornography, Article 17 (Jurisdiction and coordination of prosecution) "1.Member States shall take the necessary measures to establish their jurisdiction over the offences referred to in Articles 3 to 7 where: (a) the offence is committed in whole or in part within their territory; or (b) the offender is one of their nationals.[72] Meaning EU member states should prosecute their citizens for child sex offences committed abroad.[73] By 2015, most member states have transposed this article.[74] ## References[edit] 1. ^ a b c d "The Facts About Child Sex Tourism". Fact Sheet. US Dept of State, Office to Monitor and Combat Trafficking in Persons. 29 February 2008. 2. ^ a b "Combating sex crimes against children \| SafeTravel". Safetravel.govt.nz. Retrieved 12 January 2017. 3. ^ Klain, Prostitution of Children and Child-Sex Tourism: An Analysis of Domestic and International Responses 1999, ABA Center on Children and the Law, page 33 cited in Susan Song. "Global Child Sex Tourism: Children as Tourist Attractions" (PDF). Youth Advocate Program International Resource Paper. Youth Advocate Program International. Archived from the original (PDF) on 3 September 2012. 4. ^ Michael B. Farrell (22 April 2004). "Global campaign to police child sex tourism". Christian Science Monitor. Archived from the original on 28 February 2006. 5. ^ a b c Brittainy Bacon (27 July 2007). "Stolen Innocence: Inside the Shady World of Child Sex Tourism". ABC News. 6. ^ R. BARRI FLOWERS (2001). "The Sex Trade Industry's Worldwide Exploitation of Children". The Annals of the American Academy of Political and Social Science. 575 (1): 147–157. doi:10.1177/000271620157500109. 7. ^ a b Michael Gerson (24 August 2007). "No More Pedophile Tourists". The Washington Post. p. A15. 8. ^ Clift, Stephen; Simon Carter (2000). Tourism and Sex. Cengage Learning EMEA. pp. 75–78, 85. ISBN 978-1-85567-636-7. 9. ^ Koning, A.; Rijksen-van Dijke, L. (July 2017). "Child sex tourists: A review of the literature on the characteristics, motives, and methods of (Dutch) transnational child sex offenders" (PDF). Politie en Wetenschap. Politie en Wetenschap. Archived from the original (PDF) on 3 March 2018. Retrieved 3 March 2018. 10. ^ a b Eirienne, Arielle K. (2009). "Child Sex Tourism: 'Us' and 'Them' in a Globalized World". Student Pulse. 1 (11). 11. ^ "16,000 Victims of Child Sexual Exploitation". www.ipsnews.net. Archived from the original on 23 March 2012. Retrieved 2 September 2020. 12. ^ Bates, Christopher G; Ciment, James (2013). "Sex Tourism and the Sex Trade". Global Social Issues: An Encyclopedia. Routledge. ISBN 978-0-7656-8292-5. 13. ^ "Report of the Special Rapporteur on the sale of children, child prostitution and child pornography, Najat Maalla M'jid" (PDF). Office of the United Nations High Commissioner for Human Rights. pp. 6–7. Retrieved 15 January 2017. 14. ^ "Trafficking in Minors for Commercial Sexual Exploitation - Thailand" (PDF). Archived from the original (PDF) on 12 July 2007. Retrieved 26 June 2012. 15. ^ "Good News, Bad News". Mswallow.typepad.com. Retrieved 13 June 2016. 16. ^ "Facts about child prostitution in Cambodia…". Archived from the original on 9 February 2005. Retrieved 5 February 2014. 17. ^ "Official: More than 1M child prostitutes in India". CNN. 11 May 2009. Retrieved 28 April 2010. 18. ^ "LA_Brazils_Child_Prostitution_Crisis". Archived from the original on 3 June 2016. Retrieved 13 June 2016. 19. ^ "Brazil's sex tourism boom". BBC News. 30 July 2010. 20. ^ "World Tourism Day and the darker sides of Tourism \| Daily Latest News". 29 September 2010. Archived from the original on 29 September 2010. 21. ^ "Child protection from violence, exploitation and abuse". UNICEF. 23 September 2010. Retrieved 9 October 2011. "Some estimates have as many as 1.2 million children being trafficked every year." 22. ^ a b c d e Deena Guzder. "UNICEF: Protecting Children from Commercial Sexual Exploitation". Pulitzer Center on Crisis Reporting. Archived from the original on 10 November 2009. 23. ^ a b c d Deena Guzder. "Local Thai NGOs Discuss Efforts to End Commercial Sexual Exploitation". Pulitzer Center on Crisis Reporting. Archived from the original on 7 September 2009. 24. ^ "Brazil". State.gov. Archived from the original on 26 February 2009. Retrieved 13 June 2016. 25. ^ "Country Narratives" (PDF). State.gov. Retrieved 13 December 2017. 26. ^ "Pleasure Trips or Underage Sex Tourism? - ABC News". 9 April 2010. Archived from the original on 9 April 2010. 27. ^ "Sex Tourism: ABC News Goes Undercover". ABC News. 5 April 2010. Retrieved 13 June 2016. 28. ^ "ABC News Airs Undercover Fishing/Hunting Investigation". Chattanoogan.com. Retrieved 13 June 2016. 29. ^ "FOX 5 Atlanta - Breaking Atlanta News, Weather, SKYFOX Traffic". Myfoxatlanta.com. Retrieved 13 June 2016. 30. ^ "FOX 5 Atlanta - Breaking Atlanta News, Weather, SKYFOX Traffic - WAGA". Myfoxatlanta.com. Archived from the original on 14 September 2011. Retrieved 13 June 2016. 31. ^ Video on YouTube 32. ^ Britons among 1,000 snared in webcam child sex sting, The Guardian, 4 November 2013 33. ^ "Optional Protocol to the Convention on the Rights of the Child on the Sale of Children, Child Prostitution and Child Pornography - The Faculty of Law". Jus.uio.no. Retrieved 14 January 2017. 34. ^ "The Code - We protect children from sex tourism". Thecode.org. Retrieved 13 June 2016. 35. ^ Jon Fox Sex Laws in Thailand Part 3 Civil Society and Law Enforcement 36. ^ "Tackling the sexual exploitation of children by strengthening the cooperation between NGOs, law enforcement and the private ..." (PDF). defenceforchildren.nl. Archived from the original (PDF) on 13 January 2017. Retrieved 13 January 2017. 37. ^ "Sex offenders / Crimes against children / Crime areas / Internet / Home - INTERPOL". Interpol.int. Archived from the original on 13 January 2017. Retrieved 12 January 2017. 38. ^ a b c d e f g h US Department of State, "Trafficking in Persons Report", 14 June 2010 39. ^ a b c d e f g h i j k l m n o ECPAT, “ECPAT World Database” Archived 2013-03-22 at the Wayback Machine 40. ^ World Vision, “The Child Sex Tourism Prevention Project” Archived 2010-05-20 at the Wayback Machine, 2010 41. ^ a b c d e f g h i j k l m US Department of State, “Trafficking in Persons Report”, 14 June 2010 42. ^ a b "Prostitution Korea: More Koreans go abroad for sex tourism". Stopdemand.org. Archived from the original on 6 March 2019. Retrieved 13 June 2016. 43. ^ "2019 Trafficking in Persons Report: Republic of Korea". United States Department of State. Retrieved 18 April 2020. 44. ^ a b "Koreans drive demand for child prostitution in Southeast Asia". 30 January 2013. Retrieved 29 September 2016. 45. ^ "Long way to go on human trafficking". The Korea Times. 24 June 2014. Retrieved 12 January 2017. 46. ^ a b "Law on Development and Protection of Women" (PDF). protectionproject.org. Retrieved 12 January 2017. 47. ^ "Country Narratives -- Countries H through R". U.S. Department of State. Retrieved 12 January 2017. 48. ^ a b c author, page. "UNICEF - Children's Rights & Emergency Relief Organization". Retrieved 29 September 2016. 49. ^ "Facts on commercial sexual exploitation of children" (PDF). ILO. 2004. Archived from the original (PDF) on 6 January 2009. 50. ^ "Department of Labor - Argentina" (PDF). Argentina. United States government. 2012. Archived from the original (PDF) on 27 August 2016. Retrieved 25 August 2016. 51. ^ "What is Child Sex Tourism? - ECPAT International" (PDF). ECPAT. p. 35. Retrieved 12 January 2017. 52. ^ "Child sex offences". Smartraveller.gov.au. Retrieved 13 December 2017. 53. ^ "Travelling child sex offenders". Australian Federal Police. 5 April 2016. Retrieved 13 December 2017. 54. ^ Canada, Government of Canada, Foreign Affairs, Trade and Development (16 November 2012). "Child Sex Tourism : It's a Crime - Travel.gc.ca". Travel.gc.ca. Retrieved 12 January 2017. 55. ^ LC Paper No. CB(2)1311/08-09(06) 56. ^ "Israel's New Comprehensive Trafficking Legislation" (PDF). Ministry of Justice (Israel). p. 13. Retrieved 14 January 2017. 57. ^ "Israel Penal Code - 1977 (In Hebrew)". Haifa University. Archived from the original on 24 August 2012. Retrieved 14 January 2017. 58. ^ Pulwer, Sharon (25 February 2016). "Israel Not Prosecuting Clients of Child Prostitutes". Haaretz. Retrieved 14 January 2017. 59. ^ Harkov, Lahav (29 February 2016). "Bill fighting underage prostitution moves forward". Jerusalem Post. 60. ^ "MOFA: Japan's Action Plan against Commercial Sexual Exploitation of Children". www.mofa.go.jp. Retrieved 12 January 2017. 61. ^ a b "Criminal codes of Russian Federation". Legislationline.org. Retrieved 17 January 2017. 62. ^ "Convention on the Rights of the Child". Office of the United Nations High Commissioner for Human Rights. Retrieved 17 January 2017. 63. ^ "Singapore Statutes Online - Results". statutes.agc.gov.sg. Retrieved 12 January 2017. 64. ^ "Child sex tourism". Federal Office of Police. Retrieved 23 January 2017. 65. ^ "CC 311.0 Swiss Criminal Code of 21 December 1937". Admin.ch. Retrieved 23 January 2017. 66. ^ "The Act on the Protection of Children and Juveniles from Sexual Abuse". elaw.klri.re.kr. Retrieved 12 January 2017. 67. ^ "Executive Summary : South Korea" (PDF). ECPAT. Archived from the original (PDF) on 21 February 2016. Retrieved 12 January 2017. 68. ^ "Jurisdiction: Legal Guidance: The Crown Prosecution Service". Cps.gov.uk. Retrieved 12 January 2017. 69. ^ "New sex offence laws now in force in Scotland". BBC News. 1 December 2010. Retrieved 12 January 2017. 70. ^ David Graham Jailed Under 'Sex Tourism' Law, Sky News, 20 May 2013 71. ^ "Crimes Against Minors Abroad". Travel.state.gov. Retrieved 12 January 2017. 72. ^ "Directive 2011/92/EU of the European Parliament and of the Council of 13 December 2011". eur-lex.europa.eu. Retrieved 12 January 2017. 73. ^ "Child sexual abuse - Migration and Home Affairs". European Commission. 6 December 2016. Retrieved 12 January 2017. 74. ^ "REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL" (PDF). ec.europa.eu. p. 13. Retrieved 12 January 2017. ## External links[edit] * Globalstudysectt.org The Global Study on Sexual Exploitation of Children in Travel and Tourism by ECPAT * The Problem of Enforcement in Extraterritorial Laws Relating to Sex Tourism by John Pascoe * v * t * e Sexual ethics Human sexuality * Adolescent sexuality * Rainbow party * Adultery * Education * Fetishism * Incest * law * Miscegenation * Objectification * Orientation * Pregnancy * Abortion * Prostitution * law * Survival sex Child sexuality * Child marriage * Child pornography * law * Child prostitution * Child sex tourism Sexual abuse * Child-on-child sexual abuse * Child sexual abuse * law * Cybersex trafficking * Harassment * Rape * law * Sex trafficking * Sexual slavery Age of consent (reform) * Africa * Asia * Europe * North America * United States * Oceania * South America * Topical outline * v * t * e Sexual abuse Forms * Bride kidnapping * Child * Child-on-child * Child exploitation * Child pornography * Child 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[SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Child sex tourism	None	4,713	wikipedia	https://en.wikipedia.org/wiki/Child_sex_tourism	2021-01-18T19:00:21	{"wikidata": ["Q4208342"]}
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL; see this term) characterized histologically by malignant lymphocyte predominant (LP) cells and the absence of typical Hodgkin and Reed-Sternberg (HRS) cells. ## Epidemiology NLPHL accounts for only 5-10% of HL cases and has an annual incidence of approximately 1/ 830,000. ## Clinical description Disease onset usually occurs before the age of 40 and there is a 3:1 male predominance for the disease. Unlike classical Hodgkin lymphoma (CHL; see this term) NLPHL has a greater tendency to be restricted to peripheral lymph nodes (neck, axilla or inguino-femoral). Mediastinal involvement is rare and nodal spread is discontiguous. More than 80% of cases present with stage 1 or 2 disease. B-symptoms (fever, drenching night sweats and unexplained weight loss) are also less commonly observed and there is usually no impaired immunity in NLPHL patients. Extranodal disease is extremely uncommon in NLPHL but it can occur in the spleen (10-15% of cases), the liver (<5% of cases) and bone marrow or lungs (<5% of cases). Long-term complications include secondary malignancies (diffuse large B-cell lymphoma (25% risk by 20 years; see this term) or epithelial cancers (lung, breast, GI), which often arise from within a prior irradiated area). ## Etiology The exact cause is unknown. Unlike the Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells seen in CHL, LP cells are usually negative for all EBV markers. Genetics may play a role as LP cells frequently contain rearranged immunoglobulin genes and chromosomal abnormalities are observed in two thirds of cases. ## Diagnostic methods A biopsy (usually of a lymph node) is first performed in order to diagnose NLPHL. Diagnosis is based on the presence of CD20 positive, CD15 negative and CD30 negative LP cells. LP cells are monoclonal B cells of germinal center origin. Staging (based on the Cotswold staging system) is then performed in order to determine the severity and spread of NLPHL and decide on the best course of therapy. ## Differential diagnosis Differential diagnosis includes lymphocyte-rich classical HL (see this term), progressive transformation of germinal centers and T-cell rich large B-cell lymphoma. ## Management and treatment Previously the usual treatment for limited stage 1 or 2 disease was involved-field radiation therapy (IFRT) at 30-36Gy; however; many authorities now recommend that NLPHL be treated the same as CHL. Chemotherapy or combined modality therapy is necessary in advanced disease stages. Relapses are common (seen in 10-15%) and can occur multiple times. In cases where salvage therapies used in CHL are unsuccessful, rituximab shows promise for the treatment of recurrent NLPHL as it attacks LP cells via surface CD20. Patients need to be monitored for secondary malignancies and cardiopulmonary disease as these long-term complications can arise due to therapy-related toxicity. ## Prognosis Prognosis is good with usually a 90-100% remission rate with primary therapy. Relapse is common (seen in 10-15% of patients) and occurs on average 3-6 years after diagnosis. Overall 10 year survival rates are >90% in limited stage disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Nodular lymphocyte predominant Hodgkin lymphoma	c1334968	4,714	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86893	2021-01-23T17:52:48	{"mesh": ["D006689"], "umls": ["C1334968", "C2239290"], "icd-10": ["C81.0"], "synonyms": ["NLPHL"]}
Bronchiolitis obliterans organizing pneumonia (BOOP) is a lung disease that causes inflammation in the small air tubes (bronchioles) and air sacs (alveoli). BOOP typically develops in individuals between 40-60 years old; however the disorder may affect individuals of any age. The signs and symptoms of BOOP vary but often include shortness of breath, a dry cough, and fever. BOOP can be caused by viral infections, various drugs, and other medical conditions. If the cause is known, the condition is called secondary BOOP. In many cases, the underlying cause of BOOP is unknown. These cases are called idiopathic BOOP or cryptogenic organizing pneumonia. Treatment often includes corticosteroid 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Bronchiolitis obliterans organizing pneumonia	c0242770	4,715	gard	https://rarediseases.info.nih.gov/diseases/5961/bronchiolitis-obliterans-organizing-pneumonia	2021-01-18T18:01:41	{"mesh": ["D018549"], "umls": ["C0242770"], "orphanet": ["1303"], "synonyms": ["BOOP", "Constrictive bronchiolitis", "Organizing pneumonia"]}
Mite infestation that involves rash caused by Leptotrombidium deliense Trombiculosis Other namesTrombiculiasis, or Trombiculidiasis Chigger bites on the foot and ankle SpecialtyInfectious disease Trombiculosis, is a rash caused by trombiculid which is often referred to as a chigger bite. ## Contents * 1 Prevention * 2 Additional images * 3 References * 4 External links ## Prevention[edit] Chiggers are commonly found on the tip of blades of grasses to catch a host, so keeping grass short, and removing brush and wood debris where potential mite hosts may live, can limit their impact on an area. Sunlight that penetrates the grass will make the lawn drier and make it less favorable for chigger survival.[citation needed] Chiggers seem to affect warm covered areas of the body more than drier areas.[1][2] Thus, the bites are often clustered behind the knees, or beneath tight undergarments such as socks, underwear, or brassieres. Areas higher in the body (chest, back, waist-band, and under-arms) are affected more easily in small children than in adults, since children are shorter and are more likely than adults to come in contact with low-lying vegetation and dry grass where chiggers thrive. An exceptional case has been described in the eye,[3] producing conjunctivitis. Application of repellent to the shoes, lower trousers and skin is also useful. Because they are found in grass, staying on trails, roads, or paths can prevent contact. Dusting sulfur is used commercially for mite control and can be used to control chiggers in yards. The dusting of shoes, socks and trouser legs with sulfur can be highly effective in repelling chiggers.[4] Another good strategy is to recognize the chigger habitat to avoid exposure in the first place. Chiggers in North America thrive late in summer, in dry tall grasses and other thick, unshaded vegetation. Insect repellents containing one of the following active ingredients are recommended: Permethrin, DEET, catnip oil extract (nepetalactone), citronella oil or eucalyptus oil extract. However, in 1993 issue a study reported on tests of two commercial repellents: DEET and citrus oil: "All chiggers exposed on the filter papers treated with DEET died and did not move off the treated papers. None of the chiggers that were placed on papers treated with citrus oil were killed."[5] It was concluded that DEET was more effective than citrus oil[citation needed]. Chiggers can also be treated using common household vinegar (5% acetic acid).[citation needed] ## Additional images[edit] Chigger rash 36 hours after exposure Chigger bites showing characteristic raised and fluid-filled center ## References[edit] 1. ^ "ArmaXX Pest Control". Retrieved 2008-06-24. 2. ^ Ogg, Barb. "Itchy Chiggers". Retrieved 2009-05-19. 3. ^ Parcell, B. J., Sharpe, G., Jones, B. & Alexander, C. L. 2013: Conjunctivitis induced by a red bodied mite, Neotrombicula autumnalis. Parasite, 20, 25. doi:10.1051/parasite/2013025 4. ^ M Bennett, Stuart (2003). "Mites". Self published by author. Retrieved 2009-05-19. 5. ^ Ho TM, Fauziah MK (March 1993). "Laboratory evaluation of two commercial repellents against Leptotrombidium fletcheri (Acari: Trombiculidae)". Southeast Asian Journal of Tropical Medicine and Public Health. 24 (1): 165–9. PMID 8362291. ## External links[edit] Classification D * ICD-10: B88.0 (ILDS B88.010) * ICD-9-CM: 133.8 * MeSH: D014323 * v * t * e Mite-borne diseases and infestations Infestations * Acariasis * Baker's itch * Cheyletiellosis * Demodicosis * Feather pillow dermatitis * Gamasoidosis * Grain itch * Grocer's itch * Rodent mite dermatitis * Scabies * Trombiculosis Other diseases * House dust mite allergy * Oral mite anaphylaxis * List of mites associated with cutaneous reactions Species and bites Trombidiformes * Demodex brevis / Demodex folliculorum * demodicosis * Demodex mite bite * Trombicula * trombiculosis * Pyemotes herfsi * Cheyletiella (cheyletiellosis) * Leptotrombidium deliense Sarcoptiformes * Sarcoptes scabiei * scabies Mesostigmata * Dermanyssus gallinae * gamasoidosis * Liponyssoides sanguineus * rickettsialpox Other * House dust mite [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Trombiculosis	c0041170	4,716	wikipedia	https://en.wikipedia.org/wiki/Trombiculosis	2021-01-18T18:54:38	{"mesh": ["D014323"], "umls": ["C0041170"], "icd-9": ["133.8"], "icd-10": ["B88.0"], "wikidata": ["Q3540280"]}
Pseudoxanthomatous diffuse cutaneous mastocytosis (PDCM) is a rare form of diffuse cutaneous mastocytosis (DCM; see this term) characterized by yellow-orange infiltrated and xanthogranuloma-like lesions with only limited blistering. ## Epidemiology Only a small number of cases (around 10) of PDCM have been reported in the literature to date. ## Clinical description Onset most commonly occurs in early infancy with small vesicles and pseudoxanthomatous lesions developing after puberty. ## Etiology Mutations in the KIT gene (4q11-q12) have been detected in patients with DCM. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Pseudoxanthomatous diffuse cutaneous mastocytosis	None	4,717	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280794	2021-01-23T17:45:59	{"icd-10": ["Q82.2"], "synonyms": ["Infiltrative small vesicular DCM", "Infiltrative small vesicular diffuse cutaneous mastocytosis", "Pseudoxanthomatous DCM"]}
GM3 synthase deficiency is a rare congenital disorder of glycosylation due to impaired synthesis of complex ganglioside species initially characterized by irritability, poor feeding, failure to thrive and early-onset refractory epilepsy, followed by postnatal growth impairment, severe developmental delay or developmental regression, profound intellectual disability, deafness and abnormalities of skin pigmentation (mostly freckle-like hyperpigmented and depigmented macules). Visual impairment due to cortical atrophy (visible on magnetic resonance imaging), choreoathetosis and hypotonic tetraparesis usually appear gradually. Dysmorphic facial features may be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	GM3 synthase deficiency	c1836824	4,718	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370933	2021-01-23T18:10:44	{"mesh": ["C563799"], "omim": ["609056"], "icd-10": ["E77.8"], "synonyms": ["ST3GAL5-CDG"]}
A number sign (#) is used with this entry because of evidence that Marsili syndrome (MARSIS) is caused by heterozygous mutation in the ZFHX2 gene (617828) on chromosome 14q11. One such family has been reported. Clinical Features Habib et al. (2018) reported an Italian family in which 6 individuals spanning 3 generations had a congenital pain insensitivity disorder. The family had previously been reported by Spinsanti et al. (2008), who found an almost 2-fold increased expression of the TRPV1 receptor (602076), which mediates pain and capsaicin perception, in patient lymphocytes compared to controls. The patients had a history of painless injuries from childhood, most notably bone fractures with use of the broken limbs without painful sensation as well as insensitivity to thermal cutaneous burns. They had severe corneal hyporeflexia but without corneal scarring and with normal tear production. Additional features included decreased or absent sweating, and altered sensation of warm and cold temperatures, although some individuals reported episodes of hyperthermia. However, patients did report headaches, visceral pain, and pain during childbirth. Neurologic examination showed that light touch stimuli could be detected normally, but heat and cold pain thresholds were variably affected. There was no pain in the mechanical pain threshold detection test and a sensation of pleasure at deep pressure, such as massage. All individuals also had low sensitivity to capsaicin, manifest by ability to eat large amounts of hot pepper without discomfort. Odor perception was normal. Skin biopsy of 1 patient showed normal intraepidermal nerve fiber density. Cognitive and motor ability were normal. The authors named the disorder 'Marsili syndrome' after the name of the family. Inheritance The transmission pattern of MARSIS in the family reported by Habib et al. (2018) was consistent with autosomal dominant inheritance. Molecular Genetics In 6 members of a 3-generation Italian family with Marsili syndrome, Habib et al. (2018) identified a heterozygous missense mutation in the ZFHX2 gene (R1913K; 617828.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transgenic mice bearing the orthologous R1907K mutation had significant behavioral deficits in pain sensitivity to noxious heat, and cultured DRG neurons from these mice showed reduced calcium response to capsaicin compared to controls. There was no difference in the number of small diameter nociceptive neurons. Transgenic mice with 4 to 5 copies of the mutant gene had even higher heat pain thresholds. Gene expression profiles in mice bearing 4 genomic copies of the mutant Zfhx2 gene showed altered expression of genes known to be involved in pain signaling, including SST (182450), GFRA3 (605710), and PTGIR (600022). Animal Model Habib et al. (2018) found that Zfhx2-null mice were hyposensitive to noxious mechanical stimuli, but had normal sensitivity to innocuous touch. Dorsal root ganglion neurons isolated from these mice showed a deficit in noxious mechanical coding compared to control, but no differences in response to dynamic low threshold stimuli. Zfhx2-null mice were hypersensitive to noxious heat compared to wildtype, suggesting that Zfhx2 plays a role in both mechanical and thermal acute pain thresholds. History Ervin and Sternbach (1960) reported a family in which 6 persons in 2 generations had congenital insensitivity to pain, consistent with autosomal dominant inheritance. Comings and Amromin (1974) described the disorder in a mother and a son and daughter, with a possibility of the disorder having been present in an earlier generation (see 147530). Landrieu et al. (1990) reported a mother and daughter with possible dominant inheritance of indifference to pain; perception of the other sensory modalities was normal, as was the remainder of the neurologic examination. Electrophysiologic studies and morphometric evaluation of myelinated and unmyelinated fibers from nerve biopsy specimens were normal, and the authors concluded that the disorder was not a variety of HSAN. Because the father of the daughter was unknown, this may have been an instance of pseudodominance, i.e., recessive inheritance. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Absent corneal reflex \- Normal tear production Nose \- Normal odor perception SKELETAL Limbs \- Painless fractures SKIN, NAILS, & HAIR Skin \- Painless cutaneous thermal burns \- Decreased or absent sweating \- Hyperthermia, episodic NEUROLOGIC Peripheral Nervous System \- Pain insensitivity \- Altered temperature sensation \- Low sensitivity to capsaicin MISCELLANEOUS \- One Italian family with a confirmed ZFHX2 mutation has been reported (last curated January 2018) MOLECULAR BASIS \- Caused by mutation in the zinc finger homeobox 2 gene (ZFHX2, 617828.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MARSILI SYNDROME	c1840219	4,719	omim	https://www.omim.org/entry/147430	2019-09-22T16:39:35	{"mesh": ["C564128"], "omim": ["147430"], "synonyms": ["Alternative titles", "INSENSITIVITY TO PAIN, CONGENITAL, AUTOSOMAL DOMINANT", "CONGENITAL ANALGESIA, AUTOSOMAL DOMINANT"]}
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 1C (CMT1C) is caused by heterozygous mutation in the LITAF gene (603795) on chromosome 16p13. Description For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200). Clinical Features Chance et al. (1992) reported 2 unrelated kindreds (K1550 and K1551) with autosomal dominant demyelinating CMT affecting multiple generations. All affected individuals had distal muscle weakness and atrophy and depressed deep tendon reflexes. Variable pes cavus and sensory loss were also present. Mean median motor nerve conduction velocities were 15 and 22.9 m/s, respectively, in the 2 families. The families had previously been part of a linkage study by Chance et al. (1990), who excluded linkage to chromosome 1 or 17 where CMT1B and CMT1A (118220) had been mapped, respectively. Chance et al. (1992) confirmed the lack of linkage of these 2 families to chromosomes 1q and 17p11.2, indicating the presence of a third locus for CMT1. Street et al. (2002) restudied the 2 families reported by Chance et al. (1992), which were of Irish and English descent, respectively. Sural nerve biopsy of 1 patient showed onion bulb hypertrophy, consistent with demyelinating Charcot-Marie-Tooth disease. Inheritance The transmission pattern of CMT1C in the families reported by Chance et al. (1990, 1992) and Street et al. (2002) was consistent with autosomal dominant inheritance. Mapping By genomewide linkage analysis of 2 families (K1550 and K1551) with CMT1 reported by Chance et al. (1990, 1992), Street et al. (2002) found linkage to chromosome 16p13.1-p12.3. A maximum combined lod score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in the 2 families localized the locus, designated CMT1C, within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in the 2 pedigrees were not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. Genetic analysis excluded mutations in the epithelial membrane protein-2 gene (EMP2; 602334), which maps to 16p13.2, with inconclusive results. Molecular Genetics Using a combination of standard positional cloning and candidate gene approaches, Street et al. (2003) identified LITAF as the causal gene for CMT1C. They identified 3 missense mutations in this gene (603795.0001-603795.0003), each in a different CMT1C pedigree. Two of the families had previously been reported by Chance et al. (1990, 1992) and Street et al. (2002). Gerding et al. (2009) identified a heterozygous mutation in the LITAF gene (V144M; 603795.0005) in a German mother and son with CMT1C. Both had typical demyelinating sensorimotor neuropathy, but the son showed initial symptom onset at age 10, whereas the mother had onset of clinical symptoms in her late fifties. Pathogenesis Lee et al. (2011) found that CMT1C-associated LITAF mutations clustered within or around the transmembrane domain and caused mislocalization of the protein from the early endosomal membrane to the cytosol. Mutant proteins were less stable and more prone to aggregation compared to the wildtype protein. Aggregated proteins were degraded by both the proteasome and aggresome-autophagy pathways. Animal Model Lee et al. (2013) found that transgenic mice carrying a homozygous Litaf mutation (W116G; 603795.0003) developed progressive motor and sensory impairment associated with decreased motor and sensory nerve conduction velocities similar to that observed in CMT1C. Peripheral nerves of mutant mice showed dysmyelination with reduced axon caliber and focal myelin infoldings near the paranodal and internodal regions. Myelin infolding was often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. The W116G mutant protein was partially mislocalized to the cytosol from the membrane. The findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. Myelin infolding and paranodal damage appeared to represent pathogenic precursors preceding demyelination and axonal degeneration in this disorder. INHERITANCE \- Autosomal dominant SKELETAL Feet \- Pes cavus NEUROLOGIC Peripheral Nervous System \- Distal limb muscle weakness due to peripheral neuropathy \- Distal limb muscle atrophy due to peripheral neuropathy \- Distal sensory impairment \- Hyporeflexia \- Decreased motor nerve conduction velocity (NCV) (less than 38 m/s) \- Hypertrophic nerve changes \- 'Onion bulb' formations on nerve biopsy \- Segmental demyelination/remyelination on nerve biopsy MISCELLANEOUS \- Onset usually in childhood \- Genetic heterogeneity (see CMT1B, 118200 ) MOLECULAR BASIS \- Caused by mutation in the lipopolysaccharide-induced tumor necrosis factor-alpha factor gene (LITAF, 603795.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1C	c0270913	4,720	omim	https://www.omim.org/entry/601098	2019-09-22T16:15:25	{"doid": ["0110151"], "mesh": ["C537984"], "omim": ["601098"], "orphanet": ["101083"], "synonyms": ["Alternative titles", "CMT, SLOW NERVE CONDUCTION TYPE C", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 1C", "NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE IC", "HMSN IC"]}
Isolated congenital megalocornea is a genetic, non-syndromic developmental defect of the anterior eye segment characterized by bilateral enlargement of the corneal diameter (>12.5 mm) and a deep anterior eye chamber, without an elevation in intraocular pressure. It can manifest with mild to moderate myopia as well as photophobia and iridodonesis (due to iris hypoplasia). Associated complications include lens dislocation, retinal detachment, presenile cataract development, and secondary glaucoma. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Isolated congenital megalocornea	c0344530	4,721	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=91489	2021-01-23T17:24:24	{"gard": ["12648"], "mesh": ["C562829"], "omim": ["309300"], "icd-10": ["Q15.8"], "synonyms": ["Congenital anterior megalophthalmia"]}
## Clinical Features Devriendt et al. (1996) described a 2.5-year-old severely mentally retarded boy with peculiar appearance and generalized ichthyosis. He was born to consanguineous Turkish parents. The histologic finding in the skin biopsy of unusually large oval keratohyalin granules in the granular cells was unique, and had hitherto not been reported in other ichthyosis-mental retardation syndromes. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Generalized ichthyosis Skin Histology \- Unusually large oval keratohyalin granules in granular cells NEUROLOGIC Central Nervous System \- Mental retardation ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ICHTHYOSIS-MENTAL RETARDATION SYNDROME WITH LARGE KERATOHYALIN GRANULES IN THE SKIN	c1832858	4,722	omim	https://www.omim.org/entry/601039	2019-09-22T16:15:29	{"mesh": ["C563402"], "omim": ["601039"]}
Progressive inflammatory neuropathy SpecialtyNeurology Progressive inflammatory neuropathy (PIN) is a disease that was identified in a report, released on January 31, 2008, by the Centers for Disease Control and Prevention.[1] The first known outbreak of this neuropathy occurred in southeastern Minnesota in the United States. The disease was reported among pig slaughterhouse workers who appeared at various care facilities in the area reporting similar neurological symptoms.[2][3] The disease was later identified at pork processing plants in Indiana and Nebraska as well.[4] The condition is characterized by acute paralysis, pain, fatigue, numbness, and weakness, especially in extremities.[5][6] It was initially believed that workers might have contracted the disease through inhaling aerosols from pig brains blown through a compressed-air hose and that this exposure to pig neural tissue induced an autoimmune response that might have produced their mysterious peripheral neuropathy.[1] These suspicions were confirmed in reports and investigations conducted at the Mayo Clinic in Rochester, Minnesota.[6][7][8][9] ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 Prognosis * 5 See also * 6 References ## Cause[edit] An initial comprehensive study of 24 known cases was conducted by multiple doctors from various disciplines at the Mayo Clinic. They identified the cause of this neurological disease to be occupational exposure to aerosolized pig neural tissue.[8] Investigators from the Minnesota Department of Health (MDH) simultaneously determined that the 70 ppsi pressure used to liquefy and extract the pig brains caused the aerosolization of the pig neural tissue, sending it into the air in a fine mist.[1][2][4] The workers closest in proximity to the "head" table, the area in the plant where high pressured air was used to evacuate the brain tissue from the pig's skull, were the most likely to be affected.[4] The aerosolized mist was inhaled and readily absorbed into the workers' mucus membranes. The pig neural tissue was recognized by their systems as foreign and an immune response was initiated.[5][6][7][8][9] The pig antigen was found most prominently in the nerve roots of the spine which were also swollen.[9] Researchers determined that the irritation was due to the voltage-gated potassium channels being blocked.[9] They identified 125 1-α-dendrotoxin as the antagonist that binds to and blocks the channels, causing an intracellular build-up of potassium ions which causes inflammation and irritation, and consequently, hyper-excitability in the peripheral nervous system. It is this hyper-excitability that leads to the tingling, numbness, pain, and weakness.[9] Researchers from the Mayo Clinic developed a mouse model that received twice daily liquefied pig neural tissue intranasally to replicate the symptoms that the workers were experiencing. Physiological testing indicated signature antibodies in the mouse model at 100% in potassium channel antibodies and myelin basic antibodies, and 91% in calcium channel antibodies.[6] This model allowed the researchers to decipher what was causing these neurological symptoms. It was found that the potassium channels were being blocked so that inflammation was occurring at the nerve root and causing hyper-excitability down the peripheral nerves.[9] ## Diagnosis[edit] Over 40 laboratory tests were initially conducted to rule out various pathogens and environmental toxins. These tests were used to try to identify potential viruses carried by humans, pigs, or both, including rotoviruses, adenoviruses, hepatitis A, and hepatitis E. They also tried to identify bacteria such as salmonella and escherichia coli (e. coli), and parasites such as Giardia and cryptosporidium that could be causing the symptoms. All were ruled out.[4][10] Neurodegenerative diseases were considered specifically because of the similarity of symptoms and animal involvement thus included investigation of prion associated diseases such as bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD), and variant Creutzfeldt–Jakob disease (vCJD).[1][4] These all have highly transmissible pathogenic agents that induce brain damage. Since no pathogenic agent had been found, these diseases were ruled out as being related.[3][10] Next two very similar neuropathies were ruled out. Guillain–Barré syndrome (GBS) induces an acute autoimmune response which affects the Schwann cells in the peripheral nervous system. GBS is usually triggered by an infection that causes weakness and tingling that may lead to muscle loss. This condition may be life-threatening if muscle atrophy ascends to affect the pulmonary or cardiac systems. So far, no infectious agents have been found that relate to the current disease, progressive infammatory neuropathy.[2] They looked at chronic inflammatory demyelinating polyneuropathy (CIDP) which is characterized by progressive weakness and sensory impairment in the arms and legs. Damage occurs to the myelin sheath in the peripheral nervous system.[3] As doctors at the Mayo Clinic were beginning to note, the problem they were seeing in progressive inflammatory neuropathy was occurring in the spinal nerve roots.[9] ## Treatment[edit] In October 2007 an astute medical interpreter noticed similar neurological symptoms being reported by Spanish-speaking patients seeking treatment from different physicians at the Austin Medical Center, in Austin, Minnesota.[11] Not only did these patients share similar neurological symptoms, they also worked at the same pork processing plant.[4][6][8][11] Dr. Daniel LaChance, a physician at both the Austin Medical Center and the Mayo Clinic in nearby Rochester, Minnesota, was notified. He launched a request to area physicians to refer other patients with similar symptoms to him.[11] The Minnesota Department of Health (MDH) was notified and began an investigation into the "outbreak."[1] The MDH identified workers from two other pork processing plants in Indiana and Nebraska who also had parallel neurological complaints. Several agencies including the Occupational Safety and Health Administration (OSHA) and the Center for Disease Control and Prevention (CDC) were brought in to assist. Simultaneously investigations were conducted to rule out contagious disease, to locate the source or carrier, and to identify what exactly was causing these workers to develop these symptoms.[4] Removal from exposure was the first line of treatment. Due to progressive sensory loss and weakness, immunotherapy was often required. These treatments included intravenous methylprednisolone, oral prednisone, azathioprine, and/or immunoglobulin.[7] All 24 patients improved, including 7 who received no treatment and 17 who required immunotherapy.[7][8] ## Prognosis[edit] It is expected that there will be no new cases of progressive inflammatory neuropathy since the process of aerosolizing the pig brains has been discontinued at all pork processing facilities.[2][12] ## See also[edit] * Autoimmune disease * Neuropathy * Peripheral neuropathy * Polyneuropathy ## References[edit] 1. ^ a b c d e "Investigation of Progressive Inflammatory Neuropathy Among Swine Slaughterhouse Workers---Minnesota, 2007---2008". Centers for Disease Control and Prevention. 2007-01-31. Retrieved 2008-02-04. 2. ^ a b c d Brown, David. "Inhaling pig brains may be cause of new illness" (PDF). Retrieved 20 March 2012. 3. ^ a b c Genoways, Ted. "The Spam Factory's Dirty Secret". Retrieved 12 May 2012. 4. ^ a b c d e f g Holzbauer, Stacy. "Investigation into risk factors for progressive inflammatory neuropathy among swine abattoir workers in the united states" (PDF). Archived from the original (PDF) on 2 June 2013. Retrieved 1 May 2012. 5. ^ a b DeAngelis, Tracy M.; Shen, Liang (1 October 2009). "Outbreak of Progressive Inflammatory Neuropathy Following Exposure to Aerosolized Porcine Neural Tissue". Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine. 76 (5): 442–447. doi:10.1002/msj.20132. PMID 19787653. 6. ^ a b c d e Rukovets, Olga. "Ani". mal model mirrors human form of occupational neuropathy in pork plant workers. Neurology Today. Archived from the original on 16 January 2013. Retrieved 19 March 2012. 7. ^ a b c d Tracy, Jennifer A.; Dyck, P. James B. (1 June 2011). "Auto-immune polyradiculoneuropathy and a novel IgG biomarker in workers exposed to aerosolized porcine brain". Journal of the Peripheral Nervous System. 16: 34–37. doi:10.1111/j.1529-8027.2011.00303.x. PMID 21696495. S2CID 36231208. 8. ^ a b c d e Lachance, DH; Lennon, VA; Pittock, SJ; Tracy, JA; Krecke, KN; Amrami, KK; Poeschla, EM; Orenstein, R; Scheithauer, BW; Sejvar, JJ; Holzbauer, S; Devries, AS; Dyck, PJ (Jan 2010). "An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study". Lancet Neurology. 9 (1): 55–66. doi:10.1016/S1474-4422(09)70296-0. PMID 19945916. S2CID 19696027. 9. ^ a b c d e f g Meeusen, Jeffrey W.; Klein, Christopher J.; Pirko, Istvan; Haselkorn, Keegan E.; Kryzer, Thomas J.; Pittock, Sean J.; Lachance, Daniel H.; Dyck, P. James; Lennon, Vanda A. (1 March 2012). "Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol". Annals of Neurology. 71 (3): 417–426. doi:10.1002/ana.22674. PMC 3315155. PMID 22451206. 10. ^ a b Center for Disease Control and Prevention. "New brain disease is blowing minds". Retrieved 1 March 2012. 11. ^ a b c Gajilan, A. "Medical mystery solved in slaughterhouse". Retrieved 19 March 2012. 12. ^ National Center for Zoonotic, Vector-Borne, and Enteric Diseases. "Investigation of progressive inflammatory neuropathy among swine slaughterhouse workers". Retrieved 1 March 2012.CS1 maint: multiple names: authors list (link) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Progressive inflammatory neuropathy	None	4,723	wikipedia	https://en.wikipedia.org/wiki/Progressive_inflammatory_neuropathy	2021-01-18T18:46:13	{"wikidata": ["Q2855592"]}
A rare cranial malformation characterized by hyperostosis frontalis interna, variably associated with metabolic and endocrine disorders (such as obesity, diabetes mellitus, and hirsutism, among others). Compression by calvarial thickening may lead to cerebral atrophy and present with cognitive impairment, neuropsychiatric symptoms, headaches, and epilepsy. The condition predominantly affects women. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Morgagni-Stewart-Morel syndrome	c0020494	4,724	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=77296	2021-01-23T17:18:51	{"gard": ["8593"], "mesh": ["D006957"], "omim": ["144800"], "umls": ["C0020494"], "icd-10": ["M85.2"], "synonyms": ["Hyperostosis frontalis interna"]}
Internal carotid agenesis occurs when one or both of the blood vessels that supply blood to the brain (internal carotid arteries) do not develop (agenesis). The missing carotid artery can be on either side of the body. People missing one or both of the internal carotid arteries may not have any symptoms, because the body develops other blood vessel pathways to carry blood to the head. Some people do have symptoms including headaches, blurred vision, paralysis of some of the nerves in the head (palsy), recurrent seizures (epilepsy), or muscle weakness on one side of the body (hemiparesis). People who have internal carotid agenesis have an increased risk for enlargement of the other blood vessels (aneurysm) in the brain. The exact cause of internal carotid agenesis is not known. Diagnosis of internal carotid agenesis often occurs accidentally when a person is having a brain MRI or CT scan. The diagnosis can be confirmed with magnetic resonance angiography (MRA). Due to a higher risk of brain aneurysms seen in people who have internal carotid agenesis, screening for aneurysms may be recommended. In some cases, surgery may be necessary to treat symptoms caused by internal carotid agenesis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Internal carotid agenesis	c4302907	4,725	gard	https://rarediseases.info.nih.gov/diseases/3012/internal-carotid-agenesis	2021-01-18T17:59:45	{"orphanet": ["981"], "synonyms": ["Internal carotid artery agenesis", "Agenesis of the internal carotid artery"]}
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Find sources: "Cri du chat syndrome" – news · newspapers · books · scholar · JSTOR (July 2011) (Learn how and when to remove this template message) Cri du chat, or Cri-du-chat Other names * Chromosome 5p deletion syndrome * 5p− syndrome * Lejeune's syndrome Facial features of a person with Cri du chat syndrome at the age of 8 months (A), 2 years (B), 4 years (C) and 9 years (D) SpecialtyMedical genetics Cri du chat syndrome is a rare genetic disorder due to a partial chromosome deletion on chromosome 5.[1] Its name is a French term ("cat-cry" or "call of the cat") referring to the characteristic cat-like cry of affected children.[2] It was first described by Jérôme Lejeune in 1963.[3] The condition affects an estimated 1 in 50,000 live births across all ethnicities and is more common in females by a 4:3 ratio.[4] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 References * 7 External links ## Signs and symptoms[edit] The syndrome gets its name from the characteristic cry of affected infants, which is similar to that of a meowing kitten, due to problems with the larynx and nervous system. About one third of children lose the cry by age of 2 years. Other symptoms of cri du chat syndrome may include: * feeding problems because of difficulty in swallowing and sucking; * mutism; * low birth weight and poor growth; * severe cognitive, speech and motor disabilities; * behavioural problems such as hyperactivity, aggression, outbursts and repetitive movements; * unusual facial features, which may change over time; * excessive drooling; * small head (microcephaly) and jaw (micrognathism); * widely-spaced eyes (hypertelorism); * skin tags in front of eyes. Other common findings include hypotonia, a round face with full cheeks, epicanthal folds, down-slanting palpebral fissures (eyelids), strabismus, flat nasal bridge, down-turned mouth, low-set ears, short fingers, single palmar creases and cardiac defects (e.g., ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot). Infertility is not associated with Cri du chat. It has also been observed that people with the condition have difficulties communicating. While levels of proficiency can range from a few words to short sentences, it is often recommended by medical professionals for the child to undergo some sort of speech therapy/aid with the help of a professional. Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, intestinal malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, rare renal malformations (e.g., horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly and hyper extensible joints. The syndrome may also include various dermatoglyphics, including transverse flexion creases, distal axial triradius, increased whorls and arches on digits and a single palmar crease. Late childhood and adolescence findings include significant intellectual disability, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion and scoliosis. Affected females reach puberty, develop secondary sex characteristics and menstruate at the usual time. The genital tract is usually normal in females, except for a report of a bicornuate uterus. In males, testes are often small, but spermatogenesis is thought to be normal. Exceptionally, some with Cri du chat are very high-functioning and do not seem very different from developmentally typical individuals, with mostly the exception of mild learning difficulties, and do not have speech difficulties, although they may have milder facial features and a high-pitched voice due to their condition. ## Genetics[edit] Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5, also called "5p monosomy" or "partial monosomy." Approximately 90% of cases result from a sporadic, or randomly occurring, de novo deletion. The remaining 10–15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. These individuals may have more severe disease than those with isolated monosomy of 5p. A recent study suggests this may not be the case where a trisomy of chromosome 4q is involved.[5] Most cases involve total loss of the most distant 10–20% of the material on the short arm. Fewer than 10% of cases have other rare cytogenetic aberrations (e.g., interstitial deletions, mosaicisms, rings and de novo translocations). The deleted chromosome 5 is paternal in origin in about 80% of de novo cases. Loss of a small region in band 5p15.2 (cri du chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's cause. Two genes in these regions, Semaphorine F (SEMA5A) and delta catenin (CTNND2), are potentially involved in cerebral development. The deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 may contribute to the phenotypic changes in cri du chat syndrome as well. ## Diagnosis[edit] Diagnosis is based on the distinctive cry and accompanying physical problems. These common symptoms are quite easily observed in infants. Affected children are typically diagnosed by a doctor at birth. Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome. Prenatally the deletion of the cri du chat related region in the p arm of chromosome 5 can be detected from amniotic fluid or chorionic villi samples with BACs-on-Beads technology. G-banded karyotype of a carrier is also useful.[6] ## Treatment[edit] There is not a specific way to treat the condition as the brain damage caused by this condition occurs in the early stages of embryo development. Intensive treatment is rarely needed in infants and they can be treated in neonatal pathology departments. Children may be treated by speech, physical and occupational therapists. If infants have difficulty in suction or swallowing, then physical therapy should begin in the first weeks of life. Heart abnormalities often require surgical correction and specialist attention.[7] ## Prognosis[edit] Once the child has survived the first few years of life, the prognosis is good and the mortality level is low. In a series of case reports, the mortality rate was about 10%, 75% of deaths occurring within 3 months of birth, and 90% within the 1st year.[7] ## References[edit] 1. ^ "Learning About Cri du Chat". www.genome.gov. Retrieved 2015-12-10. 2. ^ "Cri du Chat Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2015-12-10. 3. ^ Lejeune J, Lafourcade J, Berger R, et al. (1963). "[3 Cases of partial deletion of the short arm of chromosome 5]". C. R. Acad. Sci. (in French). 257: 3098–102. PMID 14095841. 4. ^ Chen, Harold (Apr 21, 2015). "Cri-du-chat Syndrome". Medscape. Retrieved 2015-12-09. 5. ^ Sheth, Frenny; Gohel, Naresh; Liehr, Thomas; Akinde, Olakanmi; Desai, Manisha; Adeteye, Olawaleye; Sheth, Jayesh (2012-01-01). "Gain of Chromosome 4qter and Loss of 5pter: An Unusual Case with Features of Cri du Chat Syndrome". Case Reports in Genetics. 2012: 153405. doi:10.1155/2012/153405. ISSN 2090-6544. PMC 3539376. PMID 23320207. 6. ^ "Cri-du-chat Syndrome". Medscape. 9 June 2017. Retrieved 25 August 2017. 7. ^ a b Cerruti Mainardi, Paola (2006-09-05). "Cri du Chat syndrome". Orphanet Journal of Rare Diseases. 1: 33. doi:10.1186/1750-1172-1-33. ISSN 1750-1172. PMC 1574300. PMID 16953888. ## External links[edit] Classification D * ICD-10: Q93.4 * ICD-9-CM: 758.31 * OMIM: 123450 * MeSH: D003410 * DiseasesDB: 29133 External resources * MedlinePlus: 001593 * eMedicine: ped/504 * Patient UK: Cri du chat syndrome * Orphanet: 281 Cri du chat at Curlie * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Cri du chat syndrome	c0010314	4,726	wikipedia	https://en.wikipedia.org/wiki/Cri_du_chat_syndrome	2021-01-18T18:54:59	{"gard": ["6213"], "mesh": ["D003410"], "umls": ["C0010314"], "orphanet": ["281"], "wikidata": ["Q752298"]}
## Summary ### Clinical characteristics. WAC-related intellectual disability (ID) is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention with respiratory or vision problems. Facial features may be mildly dysmorphic, but are nonspecific. To date, 18 individuals have been identified with WAC-related ID. ### Diagnosis/testing. The diagnosis of WAC-related ID is established in a proband by identification of a heterozygous pathogenic variant in WAC on molecular genetic testing. ### Management. Treatment of manifestations: Standard treatment of developmental delay / intellectual disability, behavioral abnormalities, neonatal hypotonia, and feeding problems. Surveillance: Regular dietary evaluation in infancy to ensure optimal nutritional status; routine monitoring of developmental progress and educational needs; assessment for anxiety, attention, and aggressive or self-injurious behavior. ### Genetic counseling. WAC-related ID is inherited in an autosomal dominant manner. With the exception of one family with presumed parental germline mosaicism, all individuals diagnosed to date have the disorder as the result of a de novo pathogenic variant. Once the WAC pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. ## Diagnosis No formal clinical diagnostic criteria exist for WAC-related intellectual disability. ### Suggestive Findings WAC-related intellectual disability (ID) should be considered in individuals with SOME OR ALL of the following suggestive findings: * Developmental delay or variable degrees of intellectual disability * One or more of the following: * Generalized hypotonia in infancy with or without associated oral hypotonia * Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation * Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD) * Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern * Abnormal vision including cortical visual impairment, strabismus, and refractive errors Other less specific features that may prompt further consideration of this diagnosis include: * Seizures * Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet * Inverted nipples ### Establishing the Diagnosis The diagnosis of WAC-related ID is established in a proband by identification of a heterozygous pathogenic variant in WAC on molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic sequencing) and gene-targeted testing (multigene panel or single-gene testing). Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of inherited intellectual disability overlap, most individuals with WAC-related ID are diagnosed by the following recommended testing or testing to be considered. Recommended testing options to consider * A multigene panel that includes WAC and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Of note, given the rarity of WAC-related intellectual disability, panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * Comprehensive genomic testing (when clinically available), including exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Note: Single-gene testing (sequence analysis of WAC, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. ### Table 1. Molecular Genetic Testing Used in WAC-Related Intellectual Disability View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method WACSequence analysis 317/18 4 Gene-targeted deletion/duplication analysis 5, 61/18 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Hamdan et al [2014], DeSanto et al [2015], Tammimies et al [2015], Lugtenberg et al [2016]. See Molecular Genetics, Pathogenic variants. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Individuals reported to have larger deletions that include more genes in the 10p12.1 region have phenotypic features that overlap those of WAC-related intellectual disability described in this GeneReview [Shahdadpuri et al 2008, Wentzel et al 2011, Okamoto et al 2012, Mroczkowski et al 2014, Sosoi et al 2015, Abdelhedi et al 2016]. Larger deletions may, however, be associated with more severe degrees of intellectual disability or additional features (such as cardiac anomalies) due to haploinsufficiency of other genes. 7\. To date, one individual has been reported with an intragenic deletion encompassing exons 5 to 14 (originally detected by CMA) [Lugtenberg et al 2016]. ## Clinical Characteristics ### Clinical Description WAC-related intellectual disability is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention because of respiratory or vision problems; constipation is common. Although facial features may be mildly dysmorphic, they may not be observed universally and/or are often not specific enough to allow diagnosis. To date, 18 individuals have been identified with a pathogenic variant in WAC [Hamdan et al 2014, DeSanto et al 2015, Tammimies et al 2015, Lugtenberg et al 2016]. #### Most Commonly Seen Features Hypotonia. More than 75% of the infants (14 of 17 for whom this information was available) have significant hypotonia at birth and during infancy which may be the clinical finding for which they are initially evaluated. Oral hypotonia may contribute to the feeding difficulties as well as to speech delay. Neonatal feeding difficulties have been reported in approximately 45% (7/16) of individuals with WAC-related ID. In addition to the hypotonia, gastroesophageal reflux was reported in two children and swallowing difficulties in one. The feeding difficulties are typically managed with oral feedings; only one child was dependent on a G-tube. Developmental delay and intellectual disability. Delay in attainment of speech and/or motor milestones is a universal feature. While the preliminary information available does not allow firm conclusions, approximately two thirds of the individuals reported to date are nonverbal at age 18 months. Although severe speech delay does not seem to be the rule, a few children remained nonverbal at age four years (and in some cases beyond). Dysarthria secondary to oral hypotonia was reported in some [Lugtenberg et al 2016]. Variable degrees of both fine motor and gross motor delay have been observed in almost all individuals for whom this information is available. Walking was achieved after age 21 months in the majority. Fine motor development may be equally affected as some individuals have been reported to have poor hand dexterity or clumsiness and difficulty in global coordination. Intellectual disability, which appears to be present in the majority of affected individuals, is typically in the mild end of the spectrum and was only observed in the moderate-to-severe range in fewer than 20% (3/18). Of note, on formal IQ testing two individuals had results within the normal range (full-scale IQ scores 98 [DeSanto et al 2015] and 89 [Lugtenberg et al 2016]); both had had abnormal prior development, and the latter had a formal diagnosis of autism spectrum disorder. Two additional individuals had borderline intellectual functioning. Behavioral problems of any type are present in more than 80% (15/16) of affected individuals. Sleep disturbances, reported in approximately two thirds of individuals, are among the most common. Although poorly characterized, frequent night awakenings appeared to be a problem in at least two individuals. Attention-deficit/hyperactivity disorder and anxiety have been observed in 30%-40% of individuals. Approximately 20% of reported individuals had a formal diagnosis of autism spectrum disorder (ASD). Autistic traits were reported in one individual. Aggressive and self-injurious behavior was reported in a few individuals. Abnormal vision. More than half of affected individuals had vision problems. Refractive errors as well as strabismus have been reported on several occasions, the latter in approximately one third of affected individuals. In a few individuals with poor vision of unknown cause, the cause was attributed to cortical visual impairment. Gastrointestinal problems. Bowel dysmotility mainly manifest as constipation was observed in approximately one third (5/16) of individuals. Gastroesophageal reflux disease has been observed on occasion. Because the presence of gastrointestinal problems has not been systematically evaluated in all patients, the actual prevalence may be higher. Respiratory abnormalities, a feature in approximately 40% of reported individuals, included recurrent infections (5 individuals), asthma (2 occasions), and an abnormal breathing pattern (2 individuals) [Lugtenberg et al 2016]. Because the presence of respiratory abnormalities has not been evaluated consistently in the available reports, the actual prevalence may be higher. Facial gestalt. The most frequent features are a square-shaped face with a broad or prominent forehead, deeply set eyes with long palpebral fissures, broad or depressed nasal bridge, and wide mouth with a broad chin. Other features that may be observed include synophrys, hypertelorism, epicanthus, and bulbous nose or broad nasal tip. See Figure 1. Although DeSanto et al [2015] argue that loss-of-function pathogenic variants in WAC are associated with a recognizable phenotype, the facial features may not be observed universally and/or are often not specific enough to allow diagnosis. #### Figure 1. Three individuals with WAC-related ID Female at age 19 years (1) Minor ear anomalies have been described in 50% of affected individuals (8/16), including posteriorly rotated ears and prominence of the antihelix (most commonly of the stem, although the superior and inferior crus can also be prominent). Neuroimaging.While abnormal MRI findings have been observed in seven individuals with WAC-related ID, no consistent abnormality has been observed. Ventriculomegaly and prominence/enlargement of subarachnoid spaces have each been reported on two occasions. Other findings (each reported in 1 individual) include asymmetry of the hemispheres and a retrocerebellar arachnoid cyst. #### Features Reported in 10%-30% of Affected Individuals Seizures were observed in four of 17 reported individuals. The following were each reported in one individual: * Tonic-clonic seizures * Absence episodes * Seizure-like activity * Febrile convulsions Obesity, reported in three of 18 individuals, was reported to be truncal in one individual; no details were provided on the other two. Hearing loss, reported in two of 18, was inconsistent (1 had sensorineural hearing loss and 1 had conductive hearing loss) [DeSanto et al 2015]. Nonspecific kidney problems included: * Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [DeSanto et al 2015]; * A girl age nine years with unspecified kidney problems [Lugtenberg et al 2016]. Other * Foot abnormalities. Usually plano-valgus deformity * Hand abnormalities. Brachydactyly, presence of fetal finger pads, short hands, unilateral single tranverse palmar crease * Inverted nipples ### Genotype-Phenotype Correlations To date only loss-of-function WAC variants have been reported in individuals with WAC-related intellectual disability. The small number of reported individuals is not sufficient to draw conclusions about genotype-phenotype correlations. Variability in intellectual function has been observed in individuals with the same WAC variant: * In two unrelated individuals with the variant c.1648C>T intellectual disability was mild in one and moderate in the other [Lugtenberg et al 2016]. * In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [DeSanto et al 2015]. ### Nomenclature WAC-related intellectual disability is also referred to as DeSanto-Shinawi syndrome (DESSH). ### Penetrance To date all individuals with WAC-related intellectual disability have the disorder as the result of a de novo pathogenic variant or germline mosaicism. Based on the published cases, the penetrance is complete (100%). Reliable estimates on the penetrance of the disorder are however difficult to establish given that most affected individuals have been identified through the discovery of a de novo and/or loss-of-function variant in WAC. ### Prevalence To date, 18 individuals with WAC-related intellectual disability (ID) have been reported in the literature. In each of the following cohorts of children with ID and/or autism spectrum disorder (ASD), one child was found to have a de novo WAC pathogenic variant: * One of 1,133 children with severe, undiagnosed, developmental disorders [Deciphering Developmental Disorders Study 2015]. Of note, children with easily recognized syndromes or large pathogenic copy number variants identified in prior genetic testing were excluded from this study. * One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [Tammimies et al 2015] The prevalence of WAC-related ID may, however, be difficult to establish given the under-ascertainment of less severely affected individuals, the ascertainment bias for individuals with de novo or loss-of-function variants, and the genetic testing modalities implemented for prior exclusion of affected individuals in the evaluation of cohorts with ID/ASD. ## Differential Diagnosis Developmental delay, neonatal feeding difficulties, and hypotonia, the most frequent features in WAC-related intellectual disability, are relatively common and have an extensive differential diagnosis. The syndromes in Table 2 show significant phenotypic overlap with WAC-related ID and have been considered in affected individuals before the diagnosis of WAC-related ID was established. ### Table 2. Disorders to Consider in the Differential Diagnosis of WAC-Related Intellectual Disability View in own window DisorderGene/Genetic MechanismMOIClinical Features of the Differential Diagnosis Disorder Overlapping w/WAC-Related IDDistinguishing from WAC-Related ID Prader-Willi syndrome 1Abnormal parent-specific imprinting within the Prader-Willi critical regionSee footnote 2 * Hypotonia, feeding difficulties in early infancy * Delayed motor milestones & language development Obesity & food-seeking behaviors typically not a feature of WAC-related ID Smith-Magenis syndrome 3Deletion or mutation of RAI1 on chromosome 17p11.2 4Virtually all de novoNeonatal hypotonia w/feeding difficulties, DD & ID, & some behavioral disturbances (incl abnormal sleep patterns) 5Some characteristic behaviors (e.g., self-hugging, polyembolokoilamania) Pitt-Hopkins syndromeHaploinsufficiency of TCF4Most de novo * DD & ID; sleep disturbances, seizures, constipation * Facial features incl deep-set eyes & wide mouth w/prominence of the lower face * Abnormal breathing pattern (seen in 2 individuals w/WAC-related ID) 6 ID usually more severe Angelman syndrome 5Disruption of maternally imprinted UBE3ASee footnote 7 * DD, ID, sleep disorders * Seizures variably present in both (rare in WAC-related ID) Usually nonverbal, w/more severe ID KANSL1-related intellectual disability syndrome (Koolen-deVries syndrome)500- to 650-kb heterozygous deletion at chromosome 17q21.31 incl KANSL1 or a heterozygous KANSL1 intragenic pathogenic variant 8Almost all de novo * Neonatal/childhood hypotonia & DD w/associated ID * Abnormal vision, epilepsy, & renal anomalies variably seen in both disorders (rare in WAC-related ID; in ~50% w/KANSL1-related ID Characteristic facial gestalt (incl. upslanting palpebral fissures, tubular/pear shaped nose w/bulbous nasal tip & prominent ears) DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance 1\. One individual reported by DeSanto et al [2015] reportedly had PWS testing. 2\. The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region. 3\. Among the ten individuals with WAC-related ID reported by Lugtenberg et al [2016], three had had normal RAI1 testing prior to establishing the correct diagnosis. 4\. Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing. 5\. Two individuals reported by Lugtenberg et al [2016] had been previously tested for Angelman syndrome. 6\. One individual reported by Lugtenberg et al [2016] had previously undergone TCF4 testing. 7\. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function. 8\. KANSL1-related ID syndrome is, on most occasions, readily diagnosed by detection of the typical 17q21.31 microdeletion on chromosomal microarray. Note: The 17q21.31 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. ## Management ### Evaluations and Referrals Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with WAC-related intellectual disability, the evaluations and referrals outlined in Table 3 are recommended. Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for traits suggestive of autism spectrum disorder [ASD] in an infant). ### Table 3. Recommended Evaluations and Referrals Following Initial Diagnosis of WAC-Related Intellectual Disability View in own window System/ConcernEvaluationComment GrowthAssessment of growth parameters to identify those w/failure to thrive OphthalmologyOphthalmology evaluation ENTAudiology evaluation when clinical history is suggestive of a hearing problemIf abnormal, refer to otolaryngologist Gastroenterology/ FeedingBaseline evaluation for presence of reflux and/or constipation; assessment for feeding problemsIf needed, refer to gastroenterologist &/or feeding therapist for treatment RespiratoryRespiratory assessment when clinical history indicates presence of recurrent infections &/or asthmaIf abnormal, refer to pulmonologist GenitourinaryRenal ultrasound examination when clinical history is suggestive of a renal problemIf abnormal, refer to nephrologist Psychiatric/ BehavioralFor individuals age >12 mos: clinical screening for presence of behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASDConsider referral for formal testing, incl Autism Diagnostic Interview™ & Autism Diagnostic Observation Schedule™ NeurologicAssess for possible seizure activity.If present, consider an EEG &/or referral to neurologist Miscellaneous/ OtherMultidisciplinary developmental evaluation incl motor, speech/language evaluation, general cognitive, & vocational skillsReferral to developmental pediatrician &/or developmental psychologist Consultation w/clinical geneticist &/or genetic counselor ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder ### Treatment of Manifestations Treatment can include the following. ### Table 4. Treatment of Manifestations in Individuals with WAC-Related Intellectual Disability View in own window Manifestation/ConcernTreatment Recurrent infections and/or asthmaStandard treatment(s) as recommended by pulmonologist Poor weight gain / failure to thriveFeeding therapy; gastrostomy tube placement may be required for persistent feeding issues 1 Gastroesophageal reflux disease and/or constipationStandard treatment(s) SeizuresStandard treatment(s) as recommended by neurologist Abnormal vision and/or strabismusStandard treatment(s) as recommended by ophthalmologist Renal abnormalitiesStandard treatment(s) as recommended by nephrologist 1\. Diet diary and calorie counts may be requested. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary by country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a nationwide federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district may be considered. An evaluation will occur before placement to determine needed services and therapies and will be subsequently written into an individualized education plan (IEP). Ages 5-21 years * In the US, an individualized education program (IEP) can be developed by the local public school district based on each individual's level of function. Severely affected children are permitted to remain in the public school district until age 21. * Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. All ages. Consultation with a developmental pediatrician is recommended to ensure appropriate community, state, and educational agencies are involved and to support parents. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility. * Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction. Feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control, assuming the individual is safe to eat by mouth. Communication issues. Consider alternative means of communication for individuals who have expressive language difficulties, such as an Augmentative and Alternative Communication (AAC) evaluation. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ### Surveillance The following are appropriate. ### Table 5. Recommended Surveillance for Individuals with WAC-Related Intellectual Disability View in own window System/ConcernEvaluation 1 EyesOphthalmologic evaluation ENT/MouthAudiologic evaluation GastrointestinalRegular dietary evaluation in infancy to ensure optimal nutritional status GenitourinaryMonitor those w/renal abnormalities as clinically indicated NeurologicMonitor those w/seizures as clinically indicated PsychiatricBehavioral assessment for anxiety, attention, & aggressive or self-injurious behavior Miscellaneous/OtherMonitor developmental progress & educational needs 1\. The frequency with which each evaluation or reassessment occurs should be tailored to the needs of the affected individual. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	WAC-Related Intellectual Disability	None	4,727	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK465012/	2021-01-18T20:50:39	{"synonyms": []}
Lipoic acid synthetase deficiency is a rare condition that affects the mitochondria. Mitochondria are tiny structures found in almost every cell of the body. They are responsible for creating most of the energy necessary to sustain life and support growth. People affected by this condition generally experience early-onset lactic acidosis, severe encephalopathy, seizures, poor growth, hypotonia, and developmental delay. It is caused by changes (mutations) in the LIAS gene and it is inherited in an autosomal recessive pattern. Treatment is based on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Lipoic acid synthetase deficiency	c3280887	4,728	gard	https://rarediseases.info.nih.gov/diseases/12678/lipoic-acid-synthetase-deficiency	2021-01-18T17:59:21	{"omim": ["614462"], "orphanet": ["401859"], "synonyms": ["Pyruvate dehydrogenase lipoic acid synthetase deficiency "]}
For other uses, see Calculus (disambiguation). An 8-mm kidney stone A calculus (plural calculi), often called a stone, is a concretion of material, usually mineral salts, that forms in an organ or duct of the body. Formation of calculi is known as lithiasis (/ˌlɪˈθaɪəsɪs/). Stones can cause a number of medical conditions. Some common principles (below) apply to stones at any location, but for specifics see the particular stone type in question. Calculi are not to be confused with gastroliths. ## Contents * 1 Types * 2 Cause * 3 Pathophysiology and symptoms * 4 Diagnosis * 5 Treatment * 6 History * 7 See also * 8 References * 9 External links ## Types[edit] Human gallstones, all removed from one patient. Grid scale 1 mm. * Calculi in the urinary system are called urinary calculi and include kidney stones (also called renal calculi or nephroliths) and bladder stones (also called vesical calculi or cystoliths). They can have any of several compositions, including mixed. Principal compositions include oxalate and urate. * Calculi of the gallbladder and bile ducts are called gallstones and are primarily developed from bile salts and cholesterol derivatives. * Calculi in the nasal passages (rhinoliths) are rare. * Calculi in the gastrointestinal tract (enteroliths) can be enormous. Individual enteroliths weighing many pounds have been reported in horses. * Calculi in the stomach are called gastric calculi (Not to be confused with gastroliths which are exogenous in nature). * Calculi in the salivary glands are called salivary calculi (sialoliths). * Calculi in the tonsils are called tonsillar calculi (tonsilloliths). * Calculi in the veins are called venous calculi (phleboliths). * Calculi in the skin, such as in sweat glands, are not common but occasionally occur. Calculi are usually asymptomatic, and large calculi may have required many years to grow to their large size. ## Cause[edit] * From an underlying abnormal excess of the mineral, e.g., with elevated levels of calcium (hypercalcaemia) that may cause kidney stones, dietary factors for gallstones. * Local conditions at the site in question that promote their formation, e.g., local bacteria action (in kidney stones) or slower fluid flow rates, a possible explanation of the majority of salivary duct calculus occurring in the submandibular salivary gland. * Enteroliths are a type of calculus found in the intestines of animals (mostly ruminants) and humans, and may be composed of inorganic or organic constituents. * Bezoars are lumps of indigestible material in the stomach and/or intestines; most commonly, they consist of hair (in which case they are also known as hairballs). A bezoar may form the nidus of an enterolith. In kidney stones, calcium oxalate is the most common mineral type (see Nephrolithiasis). Uric acid is the second most common mineral type, but an in vitro study showed uric acid stones and crystals can promote the formation of calcium oxalate stones.[1] ## Pathophysiology and symptoms[edit] Stones can cause disease by several mechanisms: * Irritation of nearby tissues, causing pain, swelling, and inflammation * Obstruction of an opening or duct, interfering with normal flow and disrupting the function of the organ in question * Predisposition to infection (often due to disruption of normal flow) A number of important medical conditions are caused by stones: * Nephrolithiasis (kidney stones) * Can cause hydronephrosis (swollen kidneys) and kidney failure * Can predispose to pyelonephritis (kidney infections) * Can progress to urolithiasis * Urolithiasis (urinary bladder stones) * Can progress to bladder outlet obstruction * Cholelithiasis (gallstones) * Can predispose to cholecystitis (gall bladder infections) and ascending cholangitis (biliary tree infection) * Can progress to choledocholithiasis (gallstones in the bile duct) and gallstone pancreatitis (inflammation of the pancreas) * Gastric calculi can cause colic, obstruction, torsion, and necrosis. ## Diagnosis[edit] Diagnostic workup varies by the stone type, but in general: * Clinical history and physical examination * Imaging studies * Some stone types (mainly those with substantial calcium content) can be detected on X-ray and CT scan * Many stone types can be detected by ultrasound * Factors contributing to stone formation (as in #Etiology) are often tested: * Laboratory testing can give levels of relevant substances in blood or urine * Some stones can be directly recovered (at surgery, or when they leave the body spontaneously) and sent to a laboratory for analysis of content ## Treatment[edit] Modification of predisposing factors can sometimes slow or reverse stone formation. Treatment varies by stone type, but, in general: * Healthy diet & exercise (promotes flow of energy & nutrition) * Drinking fluids (water & electrolytes like lemon juice, diluted vinegar eg. in pickles, salad dressings, sauces, soups, shrubs cocktail) * Surgery (lithotomy) * Medication / Antibiotics * Extracorporeal shock wave lithotripsy (ESWL) for removal of calculi ## History[edit] The earliest operation for curing stones is given in the Sushruta Samhita (6th century BCE).[2] The operation involved exposure and going up through the floor of the bladder.[2] The care of this disease was forbidden to the physicians that had taken the Hippocratic Oath[citation needed] because * There was a high probability of intraoperative and postoperative surgical complication like infection or bleeding * The physicians would not perform surgery as in ancient cultures they were two different professions ## See also[edit] * Bezoar * Calculus (dental) * Lithotomy ## References[edit] 1. ^ Grases F.; Sanchis P.; Isern B.; Perelló J.; Costa-Bauzá A. (2007). "Uric Acid as Inducer of Calcium Oxalate Crystal Development". Scandinavian Journal of Urology and Nephrology. 41 (1): 26–31. doi:10.1080/00365590600831571. PMID 17366099. 2. ^ a b Lock, Stephen etc. (2001). The Oxford Illustrated Companion to Medicine. USA: Oxford University Press. 836. ISBN 0-19-262950-6. ## External links[edit] Wikimedia Commons has media related to Lithiasis. * "The Little Treatise on the Medical Treatment of the Back and of Hemorrhoids" is a manuscript, from the 18th-century, in Arabic, which discusses the treatment of calculi [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Calculus (medicine)	c0023869	4,729	wikipedia	https://en.wikipedia.org/wiki/Calculus_(medicine)	2021-01-18T18:50:47	{"mesh": ["D002137", "D020347"], "umls": ["C0023869", "C1269628"], "wikidata": ["Q617079"]}
Not to be confused with Fanconi anemia. Fanconi syndrome SpecialtyNephrology, endocrinology Fanconi syndrome or Fanconi's syndrome (English: /fɑːnˈkoʊni/, /fæn-/) is a syndrome of inadequate reabsorption in the proximal renal tubules[1] of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from toxic heavy metals), or by adverse drug reactions.[2] It results in various small molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid (for example, glucose, amino acids, uric acid, phosphate, and bicarbonate). Fanconi syndrome affects the proximal tubules, namely, the proximal convoluted tubule (PCT), which is the first part of the tubule to process fluid after it is filtered through the glomerulus, and the proximal straight tubule (pars recta), which leads to the descending limb of loop of Henle. Different forms of Fanconi syndrome can affect different functions of the proximal tubule, and result in different complications. The loss of bicarbonate results in type 2 or proximal renal tubular acidosis. The loss of phosphate results in the bone diseases rickets and osteomalacia (even with adequate vitamin D and calcium levels), because phosphate is necessary for bone development in children and even for ongoing bone metabolism in adults.[3] ## Contents * 1 Presentation * 2 Causes * 2.1 Inherited * 2.2 Acquired * 3 Diagnosis * 4 Treatment * 5 Eponym * 6 See also * 7 References * 8 External links ## Presentation[edit] Main article: renal tubular acidosis The clinical features of proximal renal tubular acidosis are: * Polyuria, polydipsia and dehydration * Hypophosphatemic rickets (in children) and osteomalacia (in adults) * Growth failure * Acidosis * Hypokalemia * Hyperchloremia Other features of the generalized proximal tubular dysfunction of the Fanconi syndrome are: * Hypophosphatemia/hyperphosphaturia * Glycosuria * Proteinuria/aminoaciduria * Hyperuricosuria ## Causes[edit] In contrast to Hartnup disease and related tubular conditions, Fanconi syndrome affects the transport of many different substances, so is not considered to be a defect in a specific channel, but a more general defect in the function of the proximal tubules.[4] Different diseases underlie Fanconi syndrome; they can be inherited, congenital, or acquired. ### Inherited[edit] Cystinosis is the most common cause of Fanconi syndrome in children. Other recognised causes are Wilson's disease (a genetically inherited condition of copper metabolism), Lowe syndrome, tyrosinemia (type I),[5] galactosemia, glycogen storage diseases, and hereditary fructose intolerance. Two forms, Dent's disease and Lowe syndrome, are X linked.[6] A recently described form of this disease is due to a mutation in the peroxisomal protein EHHADH.[7] This mutation misdirects the EHHADH to the mitochondria. This interferes with respiratory complex I and with beta oxidation of fatty acids. The end result is a decrease in the ability of the mitochondria to produce ATP. It was shown that a specific mutation (R76W) of HNF4A, a gene encoding a transcription factor, causes Fanconi syndrome in human.[8] In the kidney, HNF4A is expressed in the proximal tubules specifically.[9] Deletion of Hnf4a in the developing mouse kidney caused Fanconi syndrome phenotypes including polyruia, polydipsia, glycosuria, and phosphaturia.[10] The Hnf4a mutant kidney showed a defect in the formation of proximal tubules.[10] ### Acquired[edit] It is possible to acquire this disease later in life. Causes include ingesting expired tetracyclines (where tetracycline changes to form epitetracycline and anhydrotetracycline which damage the proximal tubule), and as a side effect of tenofovir in cases of pre-existing renal impairment.[11][12] In the HIV population, Fanconi syndrome can develop secondary to the use of an antiretroviral regimen containing tenofovir and didanosine.[13] Lead poisoning also leads to Fanconi syndrome.[14] Multiple myeloma or monoclonal gammopathy of undetermined significance can also cause the condition.[15] Additionally, Fanconi Syndrome can develop as a secondary or tertiary effect of certain autoimmune disorders.[16][17] ## Diagnosis[edit] Urine routine, might not be completely reliable but is an important indicator. ## Treatment[edit] Treatment of children with Fanconi syndrome mainly consists of replacement of substances lost in the urine (mainly fluid and bicarbonate). ## Eponym[edit] It is named after Guido Fanconi, a Swiss pediatrician, although various other scientists, including George Lignac, contributed to its study. It should not be confused with Fanconi anemia, a separate disease. ## See also[edit] * Familial renal disease in animals for Fanconi syndrome in Basenjis ## References[edit] 1. ^ "Fanconi syndrome" at Dorland's Medical Dictionary 2. ^ Fanconi Syndrome at Merck Manual Home Health Handbook 3. ^ Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K (March 2010). "A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome". The New England Journal of Medicine. 362 (12): 1102–9. doi:10.1056/NEJMoa0905647. PMID 20335586. 4. ^ Fanconi Syndrome at eMedicine 5. ^ Cochat P, Pichault V, Bacchetta J, Dubourg L, Sabot JF, Saban C, Daudon M, Liutkus A (March 2010). "Nephrolithiasis related to inborn metabolic diseases". Pediatric Nephrology. 25 (3): 415–24. doi:10.1007/s00467-008-1085-6. PMC 2810370. PMID 19156444. 6. ^ Vilasi A, Cutillas PR, Maher AD, Zirah SF, Capasso G, Norden AW, Holmes E, Nicholson JK, Unwin RJ (August 2007). "Combined proteomic and metabonomic studies in three genetic forms of the renal Fanconi syndrome". American Journal of Physiology. Renal Physiology. 293 (2): F456-67. doi:10.1152/ajprenal.00095.2007. PMID 17494094. 7. ^ Assmann N, Dettmer K, Simbuerger JM, Broeker C, Nuernberger N, Renner K, Courtneidge H, Klootwijk ED, Duerkop A, Hall A, Kleta R, Oefner PJ, Reichold M, Reinders J (May 2016). "Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy" (PDF). Cell Reports. 15 (7): 1423–1429. doi:10.1016/j.celrep.2016.04.037. PMID 27160910. 8. ^ Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, Oram RA, Shields BM, Shepherd M, Inward CD, Hamilton-Shield JP, Kohlhase J, Ellard S, Hattersley AT (March 2014). "The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype". Journal of Medical Genetics. 51 (3): 165–9. doi:10.1136/jmedgenet-2013-102066. PMC 3932761. PMID 24285859. 9. ^ Lee JW, Chou CL, Knepper MA (November 2015). "Deep Sequencing in Microdissected Renal Tubules Identifies Nephron Segment-Specific Transcriptomes". Journal of the American Society of Nephrology. 26 (11): 2669–77. doi:10.1681/ASN.2014111067. PMC 4625681. PMID 25817355. 10. ^ a b Marable SS, Chung E, Adam M, Potter SS, Park JS (July 2018). "Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome". JCI Insight. 3 (14). doi:10.1172/jci.insight.97497. PMC 6124415. PMID 30046000. 11. ^ Viread Label Information, U.S. Food and Drug Administration (FDA)), 2008-04-11 12. ^ Tenofovir (Viread) Associated with Mild Kidney Function Impairment, but not Clinically Relevant Renal Disease, hivandhepatitis.com, 2008-10-14 13. ^ Irizarry-Alvarado JM, Dwyer JP, Brumble LM, Alvarez S, Mendez JC (March 2009). "Proximal tubular dysfunction associated with tenofovir and didanosine causing Fanconi syndrome and diabetes insipidus: a report of 3 cases". The AIDS Reader. 19 (3): 114–21. PMID 19334328. 14. ^ Barbier O, Jacquillet G, Tauc M, Cougnon M, Poujeol P (2005). "Effect of heavy metals on, and handling by, the kidney". Nephron Physiology. 99 (4): 105–10. doi:10.1159/000083981. PMID 15722646. 15. ^ Hashimoto T, Arakawa K, Ohta Y, Suehiro T, Uesugi N, Nakayama M, Tsuchihashi T (2007). "Acquired fanconi syndrome with osteomalacia secondary to monoclonal gammopathy of undetermined significance". Internal Medicine. 46 (5): 241–5. doi:10.2169/internalmedicine.46.1882. PMID 17329920. 16. ^ "Fanconi Syndrome". The Medical Dictionary. 17. ^ Kobayashi T, Muto S, Nemoto J, Miyata Y, Ishiharajima S, Hironaka M, Asano Y, Kusano E (June 2006). "Fanconi's syndrome and distal (type 1) renal tubular acidosis in a patient with primary Sjögren's syndrome with monoclonal gammopathy of undetermined significance". Clinical Nephrology. 65 (6): 427–32. doi:10.5414/CNP65427. PMID 16792139. ## External links[edit] Classification D * ICD-10: E72.0 * ICD-9-CM: 270.0 * MeSH: D005198 * DiseasesDB: 11687 * SNOMED CT: 40488004 External resources * MedlinePlus: 000333 * eMedicine: ped/756 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Fanconi syndrome	c0015624	4,730	wikipedia	https://en.wikipedia.org/wiki/Fanconi_syndrome	2021-01-18T18:51:47	{"gard": ["9120"], "mesh": ["D005198"], "umls": ["C0015624", "C0341703"], "orphanet": ["3337"], "wikidata": ["Q1179460"]}
Neri et al. (1995) raised the possibility of an autosomal dominant form of Wiskott-Aldrich syndrome on the basis of a 3-generation family in which several members presented clinical and laboratory findings of WAS (301000), including decreased CD43 expression on T lymphocytes. The gene for CD43, or sialophorin (SPN; 182160), is located on 16p11.2. However, no alteration of CD43 was found: Southern blot analysis failed to detect gross abnormalities of the CD43 gene and genotype analysis showed that the affected family members did not share a common CD43 allele. INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Head \- Sinusitis Ears \- Otitis media Nose \- Epistaxis Mouth \- Oral bleeding CARDIOVASCULAR Vascular \- Small and large vessel vasculitis RESPIRATORY Airways \- Upper respiratory tract infections \- Lower respiratory tract infections Lung \- Pneumonia ABDOMEN Gastrointestinal \- Diarrhea \- Inflammatory bowel disease GENITOURINARY Kidneys \- Nephropathy SKIN, NAILS, & HAIR Skin \- Eczema NEUROLOGIC Central Nervous System \- Meningitis HEMATOLOGY \- Thrombocytopenia \- Small platelet size \- Hemolytic anemia \- Iron deficiency anemia \- CD43 (sialophorin) defectively expressed on surface of blood cells IMMUNOLOGY \- Moderately depressed antibody response to polysaccharide antigens \- Lymphopenia \- Abnormal delayed hypersensitivity skin test \- Absent microvilli on the surface of peripheral blood lymphocytes \- Decreased CD3+ cells subset \- Decreased CD4+ cells subset \- Decreased CD8+ cells subset LABORATORY ABNORMALITIES \- Prolonged bleeding time \- Normal IgG levels \- Increased IgA levels \- Increased IgE levels \- Reduced IgM levels \- Raised erythrocyte sedimentation rate \- Raised C-reactive protein MISCELLANEOUS \- Normal sialophorin gene ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	WISKOTT-ALDRICH SYNDROME, AUTOSOMAL DOMINANT FORM	c0043194	4,731	omim	https://www.omim.org/entry/600903	2019-09-22T16:15:44	{"mesh": ["D014923"], "omim": ["600903"], "orphanet": ["906"]}
Muscular disease in which the muscle fibers do not function correctly Myopathy SpecialtyRheumatology In medicine, myopathy is a disease of the muscle[1] in which the muscle fibers do not function properly. This results in muscular weakness. Myopathy means muscle disease (Greek : myo- muscle \+ patheia -pathy : suffering). This meaning implies that the primary defect is within the muscle, as opposed to the nerves ("neuropathies" or "neurogenic" disorders) or elsewhere (e.g., the brain). Muscle cramps, stiffness, and spasm can also be associated with myopathy. Muscular disease can be classified as neuromuscular or musculoskeletal in nature. Some conditions, such as myositis, can be considered both neuromuscular and musculoskeletal. ## Contents * 1 Signs and symptoms * 2 Systemic diseases * 2.1 Inherited forms * 2.2 Acquired * 2.3 Myocardium / cardio-myopathy * 2.4 Differential diagnosis * 3 Treatments * 4 References * 5 External links ## Signs and symptoms[edit] Common symptoms include muscle weakness, cramps, stiffness, and tetany.[citation needed] ## Systemic diseases[edit] Myopathies in systemic disease results from several different disease processes including endocrine, inflammatory, paraneoplastic, infectious, drug- and toxin-induced, critical illness myopathy, metabolic, collagen related,[2] and myopathies with other systemic disorders. Patients with systemic myopathies often present acutely or sub acutely. On the other hand, familial myopathies or dystrophies generally present in a chronic fashion with exceptions of metabolic myopathies where symptoms on occasion can be precipitated acutely. Most of the inflammatory myopathies can have a chance association with malignant lesion; the incidence appears to be specifically increased only in patients with dermatomyositis.[3] There are many types of myopathy. ICD-10 codes are provided here where available. ### Inherited forms[edit] * (G71.0) Dystrophies (or muscular dystrophies) are a subgroup of myopathies characterized by muscle degeneration and regeneration. Clinically, muscular dystrophies are typically progressive, because the muscles' ability to regenerate is eventually lost, leading to progressive weakness, often leading to use of a wheelchair, and eventually death, usually related to respiratory weakness. * (G71.1) Myotonia * Neuromyotonia * (G71.2) The congenital myopathies do not show evidence for either a progressive dystrophic process (i.e., muscle death) or inflammation, but instead characteristic microscopic changes are seen in association with reduced contractile ability of the muscles. Congenital myopathies include, but are not limited to: * (G71.2) nemaline myopathy (characterized by presence of "nemaline rods" in the muscle), * (G71.2) multi/minicore myopathy (characterized by multiple small "cores" or areas of disruption in the muscle fibers), * (G71.2) centronuclear myopathy (or myotubular myopathy) (in which the nuclei are abnormally found in the center of the muscle fibers), a rare muscle wasting disorder * (G71.3) Mitochondrial myopathies, which are due to defects in mitochondria, which provide a critical source of energy for muscle * (G72.3) Familial periodic paralysis * (G72.4) Inflammatory myopathies, which are caused by problems with the immune system attacking components of the muscle, leading to signs of inflammation in the muscle * (G73.6) Metabolic myopathies, which result from defects in biochemical metabolism that primarily affect muscle * (G73.6/E74.0) Glycogen storage diseases, which may affect muscle * (G73.6/E75) Lipid storage disorder * (G72.89) Other myopathies * Brody myopathy * Congenital myopathy with abnormal subcellular organelles * Fingerprint myopathy * Inclusion body myopathy 2 * Megaconial myopathy * Myofibrillar myopathy * Rimmed vacuolar myopathy ### Acquired[edit] * (G72.0 - G72.2) External substance induced myopathy * (G72.0) Drug-induced myopathy * Glucocorticoid myopathy is caused by this class of steroids increasing the breakdown of the muscle proteins leading to muscle atrophy.[4] * (G72.1) Alcoholic myopathy * (G72.2) Myopathy due to other toxic agents - including atypical myopathy in horses caused by toxins in Sycamore seeds and seedlings.[5][6] * (M33.0-M33.1) * Dermatomyositis produces muscle weakness and skin changes. The skin rash is reddish and most commonly occurs on the face, especially around the eyes, and over the knuckles and elbows. Ragged nail folds with visible capillaries can be present. It can often be treated by drugs like corticosteroids or immunosuppressants. (M33.2) * Polymyositis produces muscle weakness. It can often be treated by drugs like corticosteroids or immunosuppressants. * Inclusion body myositis is a slowly progressive disease that produces weakness of hand grip and straightening of the knees. No effective treatment is known. * (M61) Myositis ossificans * (M62.89) Rhabdomyolysis and (R82.1) myoglobinurias The Food and Drug Administration is recommending that physicians restrict prescribing high-dose Simvastatin (Zocor, Merck) to patients, given an increased risk of muscle damage. The FDA drug safety communication stated that physicians should limit using the 80-mg dose unless the patient has already been taking the drug for 12 months and there is no evidence of myopathy. "Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug," the agency states. * Statin-associated autoimmune myopathy ### Myocardium / cardio-myopathy[edit] * (I40) Acute myocarditis * (I41) Myocarditis in diseases classified elsewhere * (I42) Cardiomyopathy * (I42.0) Dilated cardiomyopathy * (I42.1) Obstructive hypertrophy cardiomyopathy * (I42.2) Other hypertrophic cardiomyopathy * (I42.3) Endomyocardial (eosinophilic) disease * Eosinophilic myocarditis * Endomyocardial (tropical) fibrosis * Löffler's endocarditis * (I42.4) Endocardial fibroelastosis * (I42.5) Other restrictive cardiomyopathy * (I42.6) Alcoholic cardiomyopathy * (I42.8) Other cardiomyopathies * Arrhythmogenic right ventricular dysplasia * (I43) Cardiomyopathy in diseases classified elsewhere [7] ### Differential diagnosis[edit] At birth * None as systemic causes; mainly hereditary Onset in childhood * Inflammatory myopathies – dermatomyositis, polymyositis (rarely) * Infectious myopathies * Endocrine and metabolic disorders – hypokalemia, hypocalcemia, hypercalcemia Onset in adulthood[3] * Inflammatory myopathies – polymyositis, dermatomyositis, inclusion body myositis, viral (HIV) * Infectious myopathies * Endocrine myopathies – thyroid, parathyroid, adrenal, pituitary disorders * Toxic myopathies – alcohol, corticosteroids, narcotics, colchicines, chloroquine * Critical illness myopathy * Metabolic myopathies * Paraneoplastic myopathy ## Treatments[edit] Because different types of myopathies are caused by many different pathways, there is no single treatment for myopathy. Treatments range from treatment of the symptoms to very specific cause-targeting treatments. Drug therapy, physical therapy, bracing for support, surgery, and massage are all current treatments for a variety of myopathies.[citation needed] ## References[edit] 1. ^ "Myopathy - Definition from the Merriam-Webster Online Dictionary". 2. ^ Voermans NC, van Alfen N, Pillen S, Lammens M, Schalkwijk J, Zwarts MJ, van Rooij IA, Hamel BC, van Engelen BG (June 2009). "Neuromuscular involvement in various types of Ehlers-Danlos syndrome". Ann. Neurol. 65 (6): 687–97. doi:10.1002/ana.21643. PMID 19557868. 3. ^ a b Chawla J (2011). "Stepwise approach to myopathy in systemic disease". Front Neurol. 2: 49. doi:10.3389/fneur.2011.00049. PMC 3153853. PMID 21886637. 4. ^ Seene T (July 1994). "Turnover of skeletal muscle contractile proteins in glucocorticoid myopathy". J. Steroid Biochem. Mol. Biol. 50 (1–2): 1–4. doi:10.1016/0960-0760(94)90165-1. PMID 8049126. 5. ^ "Information On Sycamore Poisoning". Rainbow Equine Hospital. Retrieved 16 May 2017. 6. ^ "Equine Atypical Myopathy toxin and biochemical tests and tree sample testing available at the RVC". Royal Veterinary college - University of London. 13 February 2017. Retrieved 16 May 2017. 7. ^ "2019 ICD-10-CM Diagnosis Code I42.9: Cardiomyopathy, unspecified". The Web's Free 2019 ICD-10-CM/PCS Medical Coding Reference. 2018-10-01. Retrieved 2019-02-05. ## External links[edit] * GeneReviews/NCBI/NIH/UW entry on Myopathy with Deficiency of ISCU * See http://neuromuscular.wustl.edu/ for medical descriptions. * 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 Systemic connective tissue disorders General Systemic lupus erythematosus * Drug-induced SLE * Libman–Sacks endocarditis Inflammatory myopathy * Myositis * Dermatopolymyositis * Dermatomyositis/Juvenile dermatomyositis * Polymyositis* Inclusion body myositis Scleroderma * Systemic scleroderma * Progressive systemic sclerosis * CREST syndrome * Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune * Sjögren syndrome Other * Behçet's disease * Polymyalgia rheumatica * Eosinophilic fasciitis * Eosinophilia–myalgia syndrome * fibrillin * Marfan syndrome * Congenital contractural arachnodactyly * v * t * e Symptoms and conditions relating to muscle Pain * Myalgia * Fibromyalgia * Acute * Delayed onset Inflammation * Myositis * Pyomyositis Destruction * Muscle weakness * Rhabdomyolysis * Muscle atrophy/Amyotrophy Other * Myositis ossificans * Fibrodysplasia ossificans progressiva * Compartment syndrome * Anterior * Diastasis of muscle * Diastasis recti * Muscle spasm [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Myopathy	c0026848	4,732	wikipedia	https://en.wikipedia.org/wiki/Myopathy	2021-01-18T19:09:13	{"mesh": ["D009135"], "umls": ["C0026848"], "wikidata": ["Q692536"]}
Neovascularization is the natural formation of new blood vessels (neo- \+ vascular \+ -ization), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia. Growth factors that inhibit neovascularization include those that affect endothelial cell division and differentiation. These growth factors often act in a paracrine or autocrine fashion; they include fibroblast growth factor, placental growth factor, insulin-like growth factor, hepatocyte growth factor, and platelet-derived endothelial growth factor.[1] There are three different pathways that comprise neovascularization:(1) vasculogenesis,(2) angiogenesis, and (3) arteriogenesis.[2] ## Contents * 1 Three pathways of neovascularization * 1.1 Vasculogenesis * 1.2 Angiogenesis * 1.3 Arteriogenesis * 2 Ocular pathologies * 2.1 Corneal neovascularization * 2.2 Retinopathy of prematurity * 2.3 Diabetic retinopathy * 2.4 Age-related macular degeneration * 2.5 Choroidal neovascularization * 3 Neovascularization and therapy * 3.1 Ischemic heart disease * 4 See also * 5 References ## Three pathways of neovascularization[edit] ### Vasculogenesis[edit] For details on vasculogenesis, see Vasculogenesis. For details on vasculogenesis in adults, see Endothelial progenitor cell. Vasculogenesis is the de novo formation of blood vessels. This primarily occurs in the developing embryo with the development of the first primitive vascular plexus, but also occurs to a limited extent with post-natal vascularization. Embryonic vasculogenesis occurs when endothelial cells precursors (hemangioblasts) begin to proliferate and migrate into avascular areas. There, they aggregate to form the primitive network of vessels characteristic of embryos. This primitive vascular system is necessary to provide adequate blood flow to cells, supplying oxygen and nutrients, and removing metabolic wastes.[2] ### Angiogenesis[edit] For details on angiogenesis, see Angiogenesis. Angiogenesis is the most common type of neovascularization seen in development and growth, and is import to both physiological and pathological processes. Angiogenesis occurs through the formation of new vessels from pre-existing vessels. This occurs through the sprouting of new capillaries from post-capillary venules, requiring precise coordination of multiple steps and the participation and communication of multiple cell types. The complex process is initiated in response to local tissue ischemia or hypoxia, leading to the release of angiogenic factors such as VEGF and HIF-1. This leads to vasodilatation and an increase in vascular permeability, leading to sprouting angiogenesis or intussusceptive angiogenesis.[2] ### Arteriogenesis[edit] For details on arteriogenesis, see Arteriogenesis. Arteriogenesis is the process of flow-related remodelling of existing vasculature to create collateral arteries. This can occur in response to ischemic vascular diseases or increase demand (e.g. exercise training). Arteriogenesis is triggered through nonspecific factors, such as shear stress and blood flow.[2] ## Ocular pathologies[edit] ### Corneal neovascularization[edit] For details on on this condition, see Corneal neovascularization. Corneal neovascularization is a condition where new blood vessels invade into the cornea from the limbus. It is triggered when the balance between angiogenic and antiangiogenic factors are disrupted that otherwise maintain corneal transparency. The immature new blood vessels can lead to persistent inflammation and scaring, lipid exudation into the corneal tissues, and a reduction in corneal transparency, which can affect visual acuity.[3] ### Retinopathy of prematurity[edit] For details on on this condition, see Retinopathy of prematurity. Retinopathy of prematurity is a condition that occurs in premature babies. In premature babies, the retina has not completely vascularized. Rather than continuing in the normal in utero fashion, the vascularization of the retina is disrupted, leading to an abnormal proliferation of blood vessels between the areas of vascularized and avascular retina. These blood vessels grow in abnormal ways and can invade into the vitreous humor, where they can hemorrhage or cause retinal detachment in neonates.[4] ### Diabetic retinopathy[edit] For details on on this condition, see Diabetic retinopathy. Diabetic retinopathy, which can develop into proliferative diabetic retinopathy, is a condition where capillaries in the retina become occluded, which creates areas of ischemic retina and triggering the release of angiogenic growth factors. This retinal ischemia stimulates the proliferation of new blood vessels from pre-existing retinal venules. It is the leading cause of blindness of working age adults.[4] ### Age-related macular degeneration[edit] For details on on this condition, see Age-related macular degeneration. In persons who are over 65 years old, age-related macular degeneration is the leading cause of severe vision loss. A subtype of age-related macular degeneration, wet macular degeneration, is characterized by the formation of new blood vessels that originate in the choroidal vasculature and extend into the subretinal space.[4] ### Choroidal neovascularization[edit] For details on on this condition, see Choroidal neovascularization. In ophthalmology, choroidal neovascularization is the formation of a microvasculature within the innermost layer of the choroid of the eye.[5] Neovascularization in the eye can cause a type of glaucoma (neovascularization glaucoma) if the new blood vessels' bulk blocks the constant outflow of aqueous humour from inside the eye. ## Neovascularization and therapy[edit] ### Ischemic heart disease[edit] For details on on this condition, see Coronary artery disease. Cardiovascular disease is the leading cause of death in the world.[6] Ischemic heart disease develops when stenosis and occlusion of coronary arteries develops, leading to reduced perfusion of the cardiac tissues. There is ongoing research exploring techniques that might be able to induce healthy neovascularization of ischemic cardiac tissues.[7][8] ## See also[edit] * Choroidal neovascularization * Corneal neovascularization * Revascularization * Rubeosis iridis * Inosculation ## References[edit] 1. ^ Neely, Kimberly A.; Gardner, Thomas W. (1998-09-01). "Ocular Neovascularization". The American Journal of Pathology. 153 (3): 665–670. doi:10.1016/S0002-9440(10)65607-6. ISSN 0002-9440. PMC 1852998. PMID 9736014. 2. ^ a b c d Marín-García, José (2007). "11: Cardiac Neovascularization: Angiogenesis, Arteriogenesis, and Vasculogensis". Post-Genomic Cardiology (1 ed.). Academic Press. doi:10.1016/B978-0-12-373698-7.X5000-1. ISBN 978-0-12-373698-7. 3. ^ Chiang, Homer H.; Hemmati, Houman D. (October 2013). Scott, Ingrid U.; Fekrat, Sharon (eds.). "Treatment of Corneal Neovascularization". EyeNet Magazine. American Academy of Ophthalmology: 35–6. Retrieved 14 July 2020. 4. ^ a b c Neely, Kimberly A.; Gardner, Thomas W. (September 1998). "Ocular Neovascularization: Clarifying Complex Interactions". The American Journal of Pathology. Elsevier Inc. 153 (3): 665–670. doi:10.1016/S0002-9440(10)65607-6. PMC 1852998. PMID 9736014. Retrieved 14 July 2020. 5. ^ Reddy U, Krzystolik M (2006). "Antiangiogenic therapy with interferon alfa for neovascular age-related macular degeneration". Cochrane Database Syst Rev (1): CD005138. doi:10.1002/14651858.CD005138.pub2. PMID 16437522. 6. ^ "Cardiovascular diseases (CVDs)". World Health Organization. 17 May 2017. Retrieved 14 July 2020. 7. ^ Lassaletta, Antonio D.; Chu, Louis M.; Sellke, Frank W. (November 2011). "Therapeutic neovascularization for coronary disease: current state and future prospects". Basic Research in Cardiology. 106 (6): 897–909. doi:10.1007/s00395-011-0200-1. PMID 21713563. S2CID 28038901. 8. ^ Johnson, Takerra; Zhao, Lina; Manuel, Gygeria; Taylor, Herman; Liu, Dong (7 February 2019). "Approaches to therapeutic angiogenesis for ischemic heart disease". Journal of Molecular Medicine. 97 (2): 141–151. doi:10.1007/s00109-018-1729-3. PMC 6417498. PMID 30554258. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Neovascularization	c0027686	4,733	wikipedia	https://en.wikipedia.org/wiki/Neovascularization	2021-01-18T18:33:23	{"mesh": ["D009389"], "wikidata": ["Q1281049"]}
The congenital muscle dystrophies are currently classified according to the genetic defects. Historically, congenital muscular dystrophies were classified in two broad groups: Classic CMD (which included the Merosin-deficient CMD and the Merosin-positive CMD) and the CMD with central nervous system (CNS) abnormalities (Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome). Therefore, merosin-positive congenital muscle dystrophy (CMD) is now considered an old term which refers to a group of diseases without structural brain abnormalities that are caused by a variety of gene mutations, resulting in protein defects that do not affect the merosin protein. It usually has a milder phenotype than the merosin-negative CMD dystrophy group and includes, among others: Classic CMD without distinguishing features Rigid spine syndrome associated with mutations in the selenoprotein N1 gene (SEPN1) CMD with hyperextensible distal joints (Ullrich type) CMD with intellectual disability or sensory abnormalities. The pattern of muscle weakness and wasting in the patients within this group of congenital muscular dystrophy conditions is worse in the proximal upper limb-girdle and trunk muscles. Lower limb muscles may be mildly involved. Muscle biopsy shows a dystrophic pattern with normal staining for dystrophin, laminin alpha-2 of merosin and the sarcoglycans. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Muscular dystrophy, congenital, merosin-positive	c1836133	4,734	gard	https://rarediseases.info.nih.gov/diseases/3855/muscular-dystrophy-congenital-merosin-positive	2021-01-18T17:58:52	{"mesh": ["C563716"], "omim": ["609456"], "umls": ["C1836133"], "synonyms": []}
Yesudian and Srinivas (1977) described a disorder which, like Netherton disease (256500), has ichthyosis and abnormality of the hair. Unlike Netherton disease, the ichthyosis is lamellar and the hair abnormality is 'split hairs.' A brother and sister with unrelated parents were born as collodion babies. The girl was mentally retarded. The urine of both showed an excess of arginine, serine, lysine and alanine and absence of proline and hydroxyproline. Hair \- Split hair Inheritance \- Autosomal recessive Neuro \- Mental retardation Lab \- Aminoaciduria \- Excess urinary arginine, serine, lysine and alanine \- Absent urinary proline and hydroxyproline Skin \- Lamellar ichthyosis \- Collodion skin ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ICHTHYOSIS, SPLIT HAIRS, AND AMINO ACIDURIA	c1855786	4,735	omim	https://www.omim.org/entry/242550	2019-09-22T16:26:23	{"mesh": ["C565471"], "omim": ["242550"]}
A congenital respiratory tract anomaly characterized by a supraglottic, interarytenoid cleft above the vocal folds with moderate respiratory symptoms. ## Epidemiology Prevalence of this form of LC is difficult to ascertain because of the moderate nature of the condition, but it is thought to be rare. ## Clinical description Clinical signs include stridor, a toneless or hoarse cry, swallowing disorders such as aspirations, cough, dyspnea, cyanosis during feeding and gastro-esophageal reflux. ## Etiology The causes underlying development of this anomaly are unknown. ## Management and treatment In children with mildly symptomatic type 1 LC, management includes maintaining adequate ventilation, feeding with thickened food, treatment of gastro-esophageal reflux, and maintaining a postprandial upright position. Children with moderate symptoms may also benefit from nasogastric tube feeding. Treatment initially involves conservative measures such as anti-reflux therapy, thickened feeds, and maneuvers during feeding to prevent aspiration. In cases of failure of a conservative approach, surgical correction of the cleft, using an endoscopic treatment approach, is recommended. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Laryngotracheoesophageal cleft type 1	None	4,736	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93938	2021-01-23T18:19:27	{"icd-10": ["Q32.1"], "synonyms": ["LTEC I", "LTEC1", "Laryngo-tracheo-esophageal cleft type 1"]}
A number sign (#) is used with this entry because long QT syndrome-1 (LQT1) is caused by heterozygous mutation in the KQT-like voltage-gated potassium channel-1 gene (KCNQ1; 607542) on chromosome 11p15. Digenic inheritance has also been reported; see MOLECULAR GENETICS. Description Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999). A form of torsade de pointes in which the first beat has a short coupling interval has been described (613600). ### Genetic Heterogeneity of Long QT Syndrome Other forms of LQT syndrome (LQTS) are LQT2 (613688), caused by mutation in the KCNH2 gene (152427); LQT3 (603830), caused by mutation in the SCN5A gene (600163); LQT4 (see 600919), caused by mutation in the ANK2 gene (106410); LQT5 (613695), caused by mutation in the KCNE1 gene (176261); LQT6 (613693), caused by mutation in the KCNE2 gene (603796); LQT7 (Andersen cardiodysrhythmic periodic paralysis, 170390), caused by mutation in the KCNJ2 gene (600681); LQT8 (618447), caused by mutation in the CACNA1C gene (114205); LQT9 (611818), caused by mutation in the CAV3 gene (601253); LQT10 (611819), caused by mutation in the SCN4B gene (608256); LQT11 (611820), caused by mutation in the AKAP9 gene (604001); LQT12 (612955), caused by mutation in the SNTA1 gene (601017); LQT13 (613485), caused by mutation in the KCNJ5 gene (600734); LQT14 (616247), caused by mutation in the CALM1 gene (114180), and LQT15 (616249), caused by mutation in the CALM2 gene (114182). Approximately 10% of LQTS patients in whom a mutation is identified in one ion channel gene carry a second mutation in the same gene or in another ion channel gene (Tester et al., 2005). Clinical Features Ward (1964) observed syncope due to ventricular fibrillation in a brother and sister whose resting electrocardiogram showed abnormal prolongation of the QT interval. The mother, although asymptomatic, had a prolonged QT interval also. Her sister had attacks of syncope and died in one of these at the age of 30 years. Deafness was not a feature, making this disorder distinct from the recessively inherited syndrome described by Jervell and Lange-Nielsen (JLNS; see 220400). Similar families with involvement of multiple generations were reported by Romano et al. (1963), Romano (1965), Barlow et al. (1964), and Garza et al. (1970). Hashiba (1978) concluded that in Japan women are more severely affected than men. (As indicated later, Moss et al. (1991) found that the proband was female in 69% of multiplex families and on the average was younger than other affected members.) Gamstorp et al. (1964) reported a family with prolonged QT interval and cardiac arrhythmias without deafness; affected members were hypokalemic and benefited from administration of potassium. Vincent (1986) found that the resting heart rate was significantly slower in newborns and children under age 3 with WRS but not in older children and adults. He interpreted the data as consistent with right-sided sympathetic deficiency manifested by a slower heart rate in early life, when sympathetic tone is high and contributes to resting heart rate, but not in older persons in whom resting heart rate is predominantly under parasympathetic control. Bonduelle (1993) suggested that death in utero is an expression of the Ward-Romano syndrome in some families. Moss et al. (1991) prospectively investigated the clinical characteristics and long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQT. The 328 probands were younger at first contact (age 21 +/- 15 years) and more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), and a history of ventricular tachyarrhythmia (47%) than other affected and unaffected family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. Gohl et al. (1991) tested the hypothesis of sympathetic imbalance by a scintigraphic display of efferent cardiac sympathetic innervation using I-123-MIBG, an analog of norepinephrine and guanethidine. Single photon emission computed tomography (SPECT) was the method of scanning. All scans of the healthy volunteers showed a uniform tracer uptake with sometimes slightly decreased activity in the apex. All 5 patients with prolonged QT and all who had suffered from at least one episode of torsade de pointes, ventricular fibrillation, or syncope had reduced or abolished MIBG uptakes in the inferior and inferior septal parts of the left ventricle. They referred to this as congenital myocardial sympathetic dysinnervation (CMSD). One woman without symptoms or QT prolongation showed an abnormal MIBG SPECT similar to that of her daughter, who did have LQT with symptoms. One male without LQT who had suffered from ventricular fibrillation showed CMSD similar to that of his father, who had LQT but no symptoms. All members of the families with normal MIBG SPECTs had neither LQT nor symptoms. Pacia et al. (1994) reported 2 cases of LQT presenting as epilepsy and found 8 other cases in the literature. Vincent et al. (1992) obtained medical histories and electrocardiograms from 199 members of families with LQT. Carriers of the LQT gene (83 subjects) and noncarriers (116 subjects) were distinguished by genetic linkage analysis. A history of syncope was obtained in 52 of the carriers of the long QT gene (63%), and 4 (5%) had a history of aborted sudden death. The QT intervals corrected for heart rate in gene carriers ranged from 0.41 to 0.59 seconds (mean, 0.49). The values for noncarriers ranged from 0.38 to 0.47 seconds (mean, 0.42). Although the QT intervals were, on the average, longer in carriers, there was substantial overlap in the 2 groups. The use of a directed QT interval above 0.44 seconds as a diagnostic criterion resulted in 22 misclassifications among the 199 family members (11%). A corrected QT interval of 0.47 seconds or longer in males and 0.48 seconds or longer in females was completely predictive but resulted in false-negative diagnoses in 40% of the males and 20% of the females. Vincent et al. (1992) concluded that the QT interval cannot be used as the basis of accurate diagnosis and that, whenever possible, DNA markers should be used to obtain a reliable diagnosis. Ohkuchi et al. (1999) described a fetus who exhibited transient (at most 30 seconds long), repeated episodes of tachyarrhythmia (240 beats per minute). The infant was born at 36 weeks' gestation and showed a markedly prolonged QT interval and transient, repeated episodes of polymorphic ventricular tachycardia. Retrospective analysis of the videotape showing fetal cardiac movement showed that atrioventricular dissociation was present prenatally and thus, that fetal tachyarrhythmia was due to ventricular tachycardia. An excess of females with long QT syndrome is well recognized. The QT interval is longer in females, even in LQTS, which may bias the diagnostic rate in this group. To investigate the possible age- and sex-related differences in phenotype in carriers of mutations in LQTS genes (KVLQT1 (KCNQ1, 607542); HERG (KCNH2, 152427), and SCN5A, 600163), Locati et al. (1998) analyzed data from 479 probands (335 females and 144 males) referred to the International LQTS Registry. The first cardiac event (defined as syncope, nonfatal cardiac arrest, or sudden unexplained death before the age of 40) occurred significantly earlier in males. In 69 KVLQT1 mutation carriers this effect was more marked, with all first cardiac events occurring before puberty in males. A persisting cumulative risk was demonstrated beyond puberty in females. Locati et al. (1998) suggested that this apparent age- and sex-related phenomenon placed young male gene carriers in a high-risk category and that all female gene carriers should be considered for long-term prophylactic therapy. Imboden et al. (2006) investigated the distribution of mutant alleles for the long-QT syndrome in 484 nuclear families with type I disease (LQT1 due to mutation in the KCNQ1 gene) and 269 nuclear families with type II disease (LQT2 (613688) due to mutation in the KCNH2 gene; 152427). In offspring of the female carriers of LQT1 or male and female carriers of LQT2, classic mendelian inheritance ratios were not observed. Among the 1,534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%) (P less than 0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476; 55%) than to male offspring (394; 45%) (P = 0.005). Increased maternal transmission of the long QT syndrome to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long QT syndrome. Priori et al. (1999) identified 9 families, each with a 'sporadic' case of LQTS, i.e., only the proband was diagnosed clinically as being affected by LQTS. Six probands were symptomatic for syncope, 2 were asymptomatic with QT prolongation found on routine examination, and 1 was asymptomatic but showed QT prolongation when examined following her brother's sudden death while swimming. Five had mutations in HERG (4 missense, 1 nonsense) and 4 had missense mutations in KCNQ1. Four of the mutations were de novo; in the remaining families at least 1 silent gene carrier was found, allowing estimation of penetrance at 25%. This contrasted greatly with the prevailing view that LQTS gene mutations may have penetrances of 90% or more. This study highlighted the importance of detecting such silent gene carriers since they are at risk of developing torsade de pointes if exposed to drugs that block potassium channels. Further, the authors stated, carrier status cannot be reliably excluded on clinical grounds alone. In 108 first-degree relatives of 26 patients with the sudden infant death syndrome (SIDS), Kukolich et al. (1977) found normal QT intervals in all. Thus, they were unable to confirm the notion that the Ward-Romano syndrome is the basis for a large proportion of cases of SIDS. On the other hand, Schwartz et al. (1998) maintained that a relationship exists between prolongation of the QT interval and the sudden infant death syndrome. The conclusions of this study and the recommendations based thereon were the target of multiple criticisms, as reviewed elsewhere (272120). Clinical Management Beta-adrenergic blockade using propranolol may prevent ventricular dysrhythmia (Gale et al., 1970). Mitsutake et al. (1981) found that the Valsalva maneuver lengthened the QT interval more in patients with this disorder than in controls, and could lead to T-wave alternans and short runs of ventricular tachycardia in patients having attacks. Propranolol suppressed this effect of the Valsalva maneuver, which, therefore, can be used to evaluate the risk of ventricular tachyarrhythmia and the efficacy of drug treatment. In a nonfamilial case, Moss and McDonald (1971) observed benefit from sympathetic denervation of the heart. Stellectomy may also have value (Moss and Schwartz, 1979). The usual cause of syncope and sudden death in the Ward-Romano syndrome, as well as in acquired forms of prolonged QT, is a specific arrhythmia known as polymorphous ventricular tachycardia, or as torsade de pointes (meaning 'turning of the points,' an allusion to the alternately positive and negative major QRS complex). Secondary torsade de pointes is produced by various drugs and by intracranial disease such as subarachnoid hemorrhage. Stimulation of the left stellate ganglion causes QT prolongation, and ablation causes QT abbreviation. These procedures applied to the right stellate ganglion have opposite effects. Left stellate ganglion block or ablation has been used in the treatment of the long QT syndrome. The automatic implantable defibrillator has usefulness in patients with frequent ventricular arrhythmia from the long QT syndrome. Di Segni et al. (1980) reported a case of congenital LQT in a patient in whom recurrent torsades were noted on the third day after birth. The only effective drug treatment was continuous isoproterenol infusion. A permanent pacemaker with epicardial leads was implanted at 19 days of age. Pacing decreased the QT interval, and all arrhythmias were gradually suppressed. Klein et al. (1996) reported that the child thrived and was symptom free during the next 12 years; however, attempts to decrease the rate to levels under 110 beats/minute always resulted in immediate prolongation of the QT interval and subsequent emergence of torsades. Furthermore, the prolonged rapid-rate pacing led to progressive left ventricular dilatation and diffuse hypokinesia. For this reason, orthotopic cardiac transplantation was required at 12 years of age. Shimizu et al. (1998) studied 6 patients with known KVLQT1 mutations. Five had a history of stress-induced syncope and one had experienced occasional palpitations. Four had documented episodes of torsade de pointes. Eight control patients with Wolff-Parkinson-White syndrome were selected. Intravenous infusion of epinephrine resulted in QT prolongation, early after-depolarization phenomena, and ventricular premature complexes in LQT1 patients but in not controls. Co-infusion of the drug nicorandil improved these repolarization abnormalities. The authors commented that nicorandil increases outward cellular potassium current through an ion channel distinct from the KVLQT1 channel and may have a role in the future treatment of patients with LQT1. It was unclear whether nicorandil offered any benefit over conventional beta-blocker therapy. In the case of the forms of LQT defined at the molecular level, Wang et al. (1996) noted that the information may be useful in devising therapy. For example, the LQT3 form due to the sodium channel abnormality caused by mutations in the SCN5A gene (600163) can be treated with sodium channel blockers, whereas the LQT1 and LQT2 forms caused by mutations in the KCNH2 (152427) and KVLQT1 genes, respectively, should respond to drugs that open potassium channels. In a retrospective study, Itoh et al. (2001) found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than did those with mutations in the KCNH2 gene (12 of 13 vs 1 of 5; p = 0.0077, Fisher exact test). The authors stated that this is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology. Miller et al. (2001) assessed the value of screening ECG for long QT syndrome in the family with LQT1 originally studied by Ackerman et al. (1998), in which there were 10 carriers of the F339del mutation (607542.0018) and 13 noncarriers. Using a QTc of greater than or equal to 460 ms as a diagnostic cutoff, the positive and negative predictive values for identifying at-risk individuals were 100%. Despite this, the computer-generated ECG diagnostic interpretation erroneously classified 6 of 23 family members, and half of the mutation-positive family members received the diagnostic interpretation 'normal ECG.' Miller et al. (2001) concluded that reliance on computer-generated ECG diagnostic interpretation alone will fail to identify many at-risk family members. Brink et al. (2005) studied a South African LQTS founder population (SA-A341V) of Afrikaner origin (de Jager et al., 1996) in which there were 166 carriers of the A341V mutation in the KCNQ1 gene (607542.0010; see MOLECULAR GENETICS). Functional analysis revealed that the A341V mutant reduced the magnitude of wildtype channel repolarizing current I(Ks) by approximately 50%. In the South African cohort, patients with a resting HR greater than 73 bpm were at higher risk for cardiac events, whereas among patients with a QTc less than 500 ms, there was a linear correlation between risk of cardiac events and HR. Brink et al. (2005) concluded that HR plays a significant modulating role on the risk for cardiac events and that this arrhythmogenic role is accentuated in the presence of moderate, but not excessive, QT prolongation. Brink et al. (2005) proposed that the activation of I(Ks) during increased heart rate (HR), essential for QT interval adaptation during tachycardia, partly explains the high efficacy of beta-blocker therapy in LQT1 patients, since beta-blocking agents act not only on triggers but on the substrate by modifying HR. The long-term combined incidence of cardiac arrest and sudden death among LQT1 patients taking beta-blockers had been reported to be approximately 1% (Vincent et al., 2009; Priori et al., 2004). Mapping In a family estimated to contain more than 400 affected persons, Keating et al. (1991) observed no recombination between the LQT phenotype and the HRAS gene (190020), which is located on the short arm of chromosome 11. As rationale for HRAS as a candidate gene for the site of the mutation, Keating et al. (1991) pointed to the similarity of ras proteins to G proteins, which regulate myocardial and cardiac pacemaker ion channels. Physiologic data showed that p21 ras protein and GAP (guanosine triphosphatase-activating protein; 139150) regulate cardiac potassium channels. In a further study of 6 additional unrelated families with LQT, Keating et al. (1991) again found 'complete linkage' to HRAS; the lod score in these families was 5.25 at a recombination fraction of 0.0. By complete sequencing of the HRAS gene, Keating (1993) probably excluded this gene as the site of the mutation. Roy et al. (1994) presented evidence indicating that HRAS is not in the region containing the LQT gene and that LQT is more centromeric in 11p15.5 than previously thought. The existence of more than one genetic form of LQT was indicated by the studies of Kerem et al. (1992), which excluded linkage with HRAS1 in a very large affected Jewish family originating from the island of Jerba near Tunis and later residing in Israel; see Benhorin et al. (1993). Curran et al. (1993) likewise found indications of genetic heterogeneity; linkage to HRAS1 and MUC2 (158370) was excluded in 2 kindreds. Genetic heterogeneity was established unequivocally by Jiang et al. (1994), who found linkage to a chromosome 7 marker, D7S483, in 9 families with a combined lod score of 19.41, and to a chromosome 3 marker, D3S1100, in 3 families with a combined lod score of 6.72. These findings localized major LQT genes to 7q35-q36 (LQT2; 613688) and 3p24-p21 (LQT3; 603830). However, in 3 families linkage to loci on chromosomes 3, 7, and 11 were excluded, indicating additional heterogeneity. In Taiwan, Ko et al. (1994) excluded linkage to 11p15.5 markers in a Chinese family. In the course of studies of 13 Japanese families, Tanaka et al. (1994) encountered evidence of genetic heterogeneity, making the 11p15.5 markers unsuitable for genetic diagnosis in most cases. In 15 of 23 families, Towbin et al. (1994) found linkage to HRAS1 on 11p15.5; of the remaining 8 families with negative lod scores, 4 were definitively excluded from linkage with HRAS1. Dausse et al. (1995) readjusted the localization of the LQT1 gene on 11p15 by use of more extensive markers. Molecular Genetics In affected members of 16 families with long QT syndrome, Wang et al. (1996) identified heterozygous mutations in the KVLQT1 gene, including a 3-bp deletion (607542.0001) and 10 different missense mutations (607542.0002-607542.0011). De Jager et al. (1996) restudied 4 South African families of northern European Afrikaner origin (designated as pedigrees 161, 162, 163, and 164) previously reported by Wang et al. (1996), in which affected individuals were heterozygous for an A341V substitution in the KCNA1 gene (607542.0010). Heterozygosity for the same mutation was identified in affected members of a fifth Afrikaner family with LQT (pedigree 166), and haplotype reconstruction revealed that all 5 families shared a common haplotype, indicating a founder effect. Clinical analysis of the 2 largest pedigrees showed that family 162 had an earlier age of onset of symptoms, fewer asymptomatic carriers, and more syncopal episodes per person, as well as significantly longer QTc interval range and mean in both carriers and noncarriers of the mutation, compared to family 161. De Jager et al. (1996) suggested that these differences in the spectrum of clinical symptoms might reflect the influence of different modulating environmental or genetic backgrounds on expression of the same mutant allele. ### Modifier Effects of Variation in the AKAP9 Gene In 349 members of a South African founder population of Afrikaner origin with long QT syndrome (LQT1; 192500), 168 of whom carried an identical-by-descent A341V mutation in the KCNQ1 gene (607542.0010), de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (604001) and found statistically significant associations between certain alleles, genotypes, and haplotypes and phenotypic traits such as QTc interval length, risk of cardiac events, and/or disease severity. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects. Russell et al. (1996) used SSCP analysis to screen 2 large and 9 small LQT families for mutations of the KVLQT1 potassium channel gene. They identified a mutation (607542.0012) in the KVLQT1 gene in 2 unrelated families and, in a third family, another mutation (607542.0010) that resulted in the spontaneous occurrence of LQT in monozygotic twin offspring of unaffected parents. A comprehensive review of the genetic and molecular basis of long QT syndromes was given by Priori et al. (1999, 1999). Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2; SCN5A; KCNE1, 176261; KCNE2, 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). From a cohort of 2,008 healthy individuals, Gouas et al. (2005) analyzed a group of 200 individuals with the shortest QTc intervals and a group of 198 with the longest QTc intervals, comparing the allele, genotype, and haplotype frequencies of polymorphisms in cardiac ion channel genes (10 SNPs in KCNQ1, 2 in KCNE1, 4 in SCN5A, and 1 in KCNH2) between the 2 groups. Based on observed differences, Gouas et al. (2005) suggested that genetic determinants located in these genes influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular disease. Napolitano et al. (2005) screened the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 430 consecutive patients with LQT syndrome and identified 235 different mutations in 310 (72%) of the patients, 49% of whom had mutations in KCNQ1, 39% in KCNH2, 10% in SCN5A, 1.7% in KCNE1, and 0.7% in KCNE2. Fourteen (4.5%) of the patients carried more than 1 mutation in a gene. Fifty-eight percent of probands carried nonprivate mutations in 64 codons of the KCNQ1, KCNH2, and SCN5A genes; screening in a prospective cohort of 75 probands confirmed the occurrence of mutations at these codons (52%). Arbour et al. (2008) identified a missense mutation (607542.0040) in the KCNQ1 gene causing long QT syndrome-1 among a First Nations community of northern British Columbia. Johnson et al. (2008) sought the history of documented atrial fibrillation (AF) in 2 independent cohorts of LQT patients known to carry mutations in LQTS genes. Overall, early-onset AF was documented in 8 (1.7%) of 457 patients: 5 (2.4%) of 211 patients with LQT1 had documented AF (ATFB3; 607554), compared to 0 of 174 patients with LQT2, 1 (1.7%) of 59 patients with LQT3, 1 of 1 patient with Andersen-Tawil syndrome (170390), and 1 (2.9%) of 34 patients with multiple mutations. Johnson et al. (2008) noted that compared to the background prevalence of 0.1%, early-onset AF was observed in almost 2% of patients with mutation-positive LQTS, and concluded that AF should be viewed as an uncommon but possible LQT-related dysrhythmia. ### Acquired Long QT Syndrome In a patient who developed QT prolongation and torsade de pointes while taking the drug dofetilide, Yang et al. (2002) identified heterozygosity for a missense mutation in the KCNQ1 gene (R583C; 607542.0031). In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents, suggesting that the R583C mutation was responsible for the patient's response to dofetilide. ### Digenic Inheritance Berthet et al. (1999) studied a large Belgian family with LQTS in which both parents of 3 affected sisters had long QT intervals and family histories of sudden death. Haplotype analysis using microsatellite markers revealed linkage to LQT1 in the father and 2 severely affected daughters and linkage to LQT2 in the mother, the same 2 daughters, another more mildly affected daughter, and a grandson. In the 2 most severely affected sisters, who required multiple medications, cardiac sympathectomy, and pacemaker implantation for control of symptoms, Berthet et al. (1999) identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; 607542.0009) and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). The father, 2 of his brothers, and a niece were all heterozygous for the A341E mutation in KCNQ1; the mother, the more mildly affected sister, and the grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected members of the family. Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see 607542.0038, 607542.0039, 152427.0023, and 600163.0007). Millat et al. (2006) suggested that because double heterozygosity appears to be more common than expected, molecular diagnosis should be performed on all LQTS-related genes, even after a single mutation has been identified. ### Associations Pending Confirmation For a discussion of a possible association between LQT and mutation in the KCNE3 gene, see 604433. Genotype/Phenotype Correlations In a large collaborative study, Zareba et al. (1998) demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although the cumulative mortality was similar regardless of the genotype, the percentage of cardiac events that were lethal was significantly higher in families with mutations at the LQT3 locus. In this large study, 112 patients had mutations at the LQT1 locus, 72 at the LQT2 locus, and 62 at the LQT3 locus. Thus, paradoxically, cardiac events were less frequent in LQT3 but more likely to be lethal; the likelihood of dying during a cardiac event was 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. Kimbrough et al. (2001) reported the findings of a study of 211 LQT syndrome probands and 791 first-degree relatives. They found that the clinical severity profile of the disease in the proband was not a useful indicator of disease status in parents or sibs. Priori et al. (2003) stratified risk according to genotype, in conjunction with other clinical variables such as sex and QT interval length, in 647 patients from 193 consecutively genotyped families with LQTS, of whom 386 carried a mutation at the LQT1 locus, 206 a mutation at the LQT2 locus, and 55 a mutation at the LQT3 locus. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype, Priori et al. (2003) also assessed risk in the 4 categories derived from the combination of sex and QTc (less than 500 ms and 500 ms or more). They found that the incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30%) than among those with a mutation at the LQT2 or LQT3 loci (46% and 42%, respectively). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at either the LQT1 or the LQT2 locus but not among those with a mutation at the LQT3 locus. Among patients with a mutation at the LQT3 locus, sex was an independent predictor of events, i.e., male patients became symptomatic much earlier than female patients even when their QTc was below 500 ms; the authors noted, however, that caution was required in drawing conclusions from this group because of its relatively small size. Vincent (2003) noted that even with the important work of Priori et al. (2003), risk prediction remained difficult, which he illustrated with several cases. A 13-year-old boy with the LQT1 genotype died suddenly while running, with no prior symptoms. His electrocardiogram, obtained 2 weeks earlier as part of family screening, was normal, with a QTc of 450 ms. A 20-year-old woman with the LQT2 genotype died in her sleep; her electrocardiogram has been found to be normal, with a QTc of 460 ms. Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound heterozygous (monogenic) or double heterozygous (digenic) and 1 was homozygous. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin, including the LQTS pedigrees designated 161, 162, 163, 164, and 166 that were previously reported by Wang et al. (1996) and de Jager et al. (1996), all traceable to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Among the 166 carriers of the A341V mutation in the KCNQ1 gene (607542.0010), 131 (79%) were symptomatic, with a median age of 6 years at first cardiac event, and 23 (14%) had sudden cardiac death before 20 years of age. The mutation carriers exhibited a wide range of QTc values, from 406 to 676 ms, with 12% having a normal QTc (440 ms or less); QTc was longer in symptomatic than asymptomatic individuals. Both QTc of 500 ms or greater and heart rate of 73 bpm or greater were significant risk factors for experiencing cardiac events after controlling for other covariates. Brink et al. (2005) compared the Afrikaner patients to the general LQT1 population (Priori et al., 2003) and found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of the wildtype channel repolarizing current I(Ks) by approximately 50%, indicating that the mutation exerts a dominant-negative effect. Brink et al. (2005) noted that this effect on I(Ks), which activates during increased heart rate and is essential for QT interval adaptation during tachycardia, might explain why 79% of lethal arrhythmic episodes in LQT1 patients with mutations impairing I(Ks) occur during exercise. In contrast, most lethal episodes in LQT2 and LQT3 patients occur during startle reaction and at rest or during sleep, respectively. Nomenclature It has been pointed out by many, e.g., Martini (1998), that this syndrome should be called Romano-Ward syndrome since Romano et al. (1963) described it 1 year before Ward (1964). History Itoh et al. (1982) reported a family in which 10 persons with the Ward-Romano syndrome had the same HLA haplotype and suggested that a chromosome 6 gene may cause the disorder. Weitkamp and Moss (1985) did a lod score analysis of the Itoh family and of a second family studied by them and arrived at a maximum lod score of 3.68 at theta 0.04 and 0.05. The single recombinant showed no evidence of recombination within the region demarcated by the loci HLA-A, -B, -C, and -DR and the GLO locus. Therefore, the LQT locus was thought to be outside the HLA-A:GLO segment on 6p. Melki et al. (1987) provided further data corroborating the linkage to HLA. However, analysis of HLA haplotypes in kindreds with the long QT syndrome forced Weitkamp et al. (1989) to conclude that the LQT locus is in fact not linked to HLA. Giuffre et al. (1990) and Keating et al. (1991) also excluded linkage to HLA. Weitkamp et al. (1994) presented an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected persons derived from both affected and unaffected parents. They also found a nonrandom distribution of the HLA-DR gene in patients with LQT compared with controls, suggesting an association between LQT phenotype and specific HLA-DR genes. Their data indicated that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Normal hearing CARDIOVASCULAR Heart \- Prolonged QT interval on EKG \- Syncope \- Ventricular fibrillation \- Torsade de pointes \- Sudden cardiac death MISCELLANEOUS \- Association of cardiac events with exercise \- Genetic heterogeneity \- Patients with a more severe phenotype have been reported with mutations in more than 1 LQTS-related gene \- GEI (gene-environment interaction) - association of cardiac events with drug administration MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, KQT-like subfamily, member 1 gene (KCNQ1, 192500.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	LONG QT SYNDROME 1	c1141890	4,737	omim	https://www.omim.org/entry/192500	2019-09-22T16:32:02	{"doid": ["0110644"], "omim": ["192500"], "orphanet": ["768", "101016"], "synonyms": ["Alternative titles", "WARD-ROMANO SYNDROME", "ROMANO-WARD SYNDROME", "VENTRICULAR FIBRILLATION WITH PROLONGED QT INTERVAL"], "genereviews": ["NBK1129"]}
Narcolepsy is a chronic brain disorder that involves poor control of sleep-wake cycles. People with narcolepsy have episodes of extreme daytime sleepiness and sudden, irresistible bouts of sleep (called "sleep attacks") that can occur at any time, and may last from seconds or minutes. Other signs and symptoms may include cataplexy (a sudden loss of muscle tone that makes a person go limp or unable to move); vivid dream-like images or hallucinations; and/or total paralysis just before falling asleep or after waking-up. Narcolepsy may have several causes, the most common being low levels of the neurotransmitter hypocretin (for various possible reasons). The disorder is usually sporadic but some cases are familial. There is no cure, but some symptoms can be managed with medicines and lifestyle changes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Narcolepsy	c0027404	4,738	gard	https://rarediseases.info.nih.gov/diseases/7162/narcolepsy	2021-01-18T17:58:47	{"mesh": ["D009290"], "omim": ["161400"], "orphanet": ["2073"], "synonyms": ["Narcoleptic syndrome", "Gelineau syndrome", "Gelineau's syndrome", "Narcolepsy-cataplexy syndrome", "Paroxysmal sleep"]}
A rare immunodysregulatory disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections. ## Epidemiology Immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome prevalence is unknown. The disease has probably been underestimated, and milder clinical phenotypes surviving to adult life are being described. ## Clinical description IPEX syndrome most commonly develops during the first few days or weeks of life and affects exclusively boys. It classically manifests with the sequential appearance of the triad of enteropathy, autoimmune disease (particularly Type I diabetes mellitus), and cutaneous involvement, but the clinical features and severity of the disease can vary considerably between individuals. Severe autoimmune enteropathy manifests with intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive. Vomiting, ileus, gastritis or colitis can also be observed. Patients also present with autoimmune endocrinopathies, generally insulin-dependent diabetes mellitus (type 1 DM) often in infancy or early childhood, but also thryroiditis leading to hypothyroidism or hyperthyroidism. Skin involvement consists of a generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis. Less frequently, alopecia or onychodystrophy can be observed. Patients may develop autoimmune cytopenias, thrombocytopenia, hemolytic anemia and neutropenia. Autoimmune involvement may also lead to pneumonitis, hepatitis, nephritis, myositis, splenomegaly and/or lymphadenopathy. Local or systemic infections (e.g. pneumonia, Staphylococcus aureus infections, candidiasis) may occur but seem to be due to loss of skin and gut barriers, immunosuppressive therapies, and poor nutrition rather than a primary immunodeficiency. Neurological findings including peripheral neuropathy, myopathy and hypotonic are described, ## Etiology IPEX syndrome is caused by mutations in the FOXP3 gene (Xp11.23). This gene codes for a forkhead transcription factor which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in self-tolerance and downregulation of immune responses. ## Diagnostic methods Diagnosis is based on clinical examination, family history, and laboratory findings revealing autoimmune enteropathy (anti-enterocyte, harmonin and villin autoantibodies), type 1 DM (antibodies against insulin, pancreatic islet cells, or anti-glutamate decarboxylase), thyroiditis (anti-thyroglobulin and anti-microsome peroxidase antibodies) and cytopenia (anti-platelets and anti-neutrophils antibodies, positive Coombs test). Molecular genetic testing confirms the diagnosis. ## Differential diagnosis Differential diagnosis includes Wiskott-Aldrich and Omenn syndromes, susceptibility to viral and mycobacterial infections, CD25 deficiency, IL10R deficiency, STAT5b deficiency, transient neonatal diabetes, severe combined immunodeficiency or intermediate forms of combined immunodeficiency, X-linked thrombocytopenia and pancreatic hypoplasia or agenesis. ## Antenatal diagnosis Prenatal diagnosis from chorionic villus samples is possible after determination of the fetal sex by karyotype analysis for families in which the disease-causing mutation has been identified. ## Genetic counseling Transmission is X-linked recessive. There is a 50% risk of transmission when the fetus is a male. 50% of females will be carriers. ## Management and treatment The only curative treatment for IPEX is hematopoietic stem cell transplantation (HSCT), which is much more successful when performed in the early stages of the disease. Supportive measures include monotherapy or combined immunosuppressive therapy with glucocorticoids (prednisone and methylprednisolone), cyclosporin A (CSA), tacrolimus, azathriopine, rapamycin, lifelong insulin and thyroid hormones supplementation in case of organ failure, topical CSA for skin manifestations, and parenteral nutrition for severe cases of enteropathy. ## Prognosis Without timely diagnosis and treatment, the disease is usually fatal within the first 2 years of life in severe cases. Increasingly, patients survive into childhood when treated with appropriate immunosuppression. With HSCT, life expectancy is likely to be normal, and disease progression halted, although feeding difficulties may persist for many months post HSCT. Neurodevelopment is usually 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome	c0342288	4,739	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=37042	2021-01-23T18:03:45	{"gard": ["1850"], "mesh": ["C580192"], "omim": ["304790"], "umls": ["C0342288"], "icd-10": ["E31.0"], "synonyms": ["Autoimmune enteropathy type 1", "IPEX"]}
Periodic paralysis with transient compartment-like syndrome is a rare, genetic, neuromuscular disease characterized by normokalemic episodes of painful muscle cramping followed by progressive, permanent, flaccid weakness, triggered by stress, cold and exercise, associated with myopathic myopathy and painful acute edema with neuronal compression, foot drop and muscle degeneration when located in the tibialis anterior muscle group. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Periodic paralysis with transient compartment-like syndrome	None	4,740	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=397755	2021-01-23T17:15:36	{"icd-10": ["G72.3"]}
Beckwith-Wiedemann syndrome (BWS) is a growth disorder that can affect several parts of the body. Babies and children are larger than normal usually until age 8, when growth slows down, resulting in an average height in adults. Symptoms may include one side or area of the body growing more than the other side (asymmetric growth or hemihyperplasia), omphalocele or other abdominal wall defect at birth, low blood sugar (hypoglycemia) in infancy, an abnormally large tongue (macroglossia), abnormally large abdominal organs, creases or pits in the skin near the ears, and kidney abnormalities. Affected children have an increased risk to develop tumors, particularly a rare form of kidney cancer called Wilms tumor, a cancer of muscle tissue called rhabdomyosarcoma, and a form of liver cancer called hepatoblastoma. Some people only have one symptom while others may have many of the symptoms. The cause of BWS is complex and is different for different people, but involves genes that control body growth. The genes, including the CDKN1C, H19, IGF2, and KCNQ1OT1 genes, are located on chromosome 11. In most cases BWS is caused by problems with the genomic imprinting of these genes. Genomic imprinting refers to having some genes that are active (expressed) only when inherited from the father and others that are active only when inherited from the mother. Less commonly, changes or mutations in the CDKN1C gene or larger changes to chromosome 11, such as a translocation, deletion, or duplication, may cause BWS. Diagnosis of BWS is based on symptoms with the support of genetic testing. At present however, there is no clearly accepted diagnostic criteria as doctors are trying to understand the full spectrum of possible symptoms. While there is no cure for BWS, there are treatments available for many of the symptoms. Treatment may include medication for hypoglycemia, surgery to repair an omphalocele or other birth defect, or surgery to reduce size of the tongue (macroglossia repair). Early intervention, speech therapy, occupational therapy, and physical therapy may also be recommended. Evaluation by an orthopedic surgeon may be helpful depending on the areas of the body affected by overgrowth. Recommended management of BWS includes screening for the development of Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Beckwith-Wiedemann syndrome	c0004903	4,741	gard	https://rarediseases.info.nih.gov/diseases/3343/beckwith-wiedemann-syndrome	2021-01-18T18:01:51	{"mesh": ["D001506"], "omim": ["130650"], "umls": ["C0004903"], "orphanet": ["116"], "synonyms": ["Wiedemann-Beckwith Syndrome (WBS)", "Exomphalos macroglossia gigantism syndrome", "EMG Syndrome"]}
A number sign (#) is used with this entry because X-linked congenital nystagmus-6 (NYS6) is caused by mutation in the GPR143 gene (300808) on chromosome Xp22. Ocular albinism-1 (OA1; 300500) is an allelic disorder. Description Classic congenital or infantile nystagmus presents as conjugate, horizontal oscillations of the eyes, in primary or eccentric gaze, often with a preferred head turn or tilt. Other associated features may include mildly decreased visual acuity, strabismus, astigmatism, and occasionally head nodding. Eye movement recordings reveal that infantile nystagmus is predominantly a horizontal jerk waveform, with a diagnostic accelerating velocity slow phase. However, pendular and triangular waveforms may also be present. The nystagmus may rarely be vertical. As these patients often have normal visual acuity, it is presumed that the nystagmus represents a primary defect in the parts of the brain responsible for ocular motor control; thus the disorder has sometimes been termed 'congenital motor nystagmus' (Tarpey et al., 2006; Shiels et al., 2007). For a discussion of genetic heterogeneity of congenital nystagmus, see NYS1 (310700). Clinical Features Liu et al. (2007) reported a large 6-generation Chinese family in which 8 affected males had nystagmus. Foveal hypoplasia and decreased visual acuity were also present in 4 affected males. Three of the affected males and 1 carrier female had mottling of the retinal pigmentation. None of the carrier females had nystagmus, consistent with X-linked recessive inheritance. Pigmentation of the hair and skin was normal in all family members examined. Liu et al. (2007) noted that some of the features were consistent with ocular albinism, and called the disorder a 'variant phenotype of ocular albinism.' Zhou et al. (2008) reported a 4-generation Han Chinese family with X-linked congenital nystagmus. Affected individuals, all of whom were male, had nystagmus and amblyopia, but none had evidence of retinal hypopigmentation. Peng et al. (2009) reported a Chinese family with X-linked congenital nystagmus. All patients were male and had binocular spontaneous horizontal oscillations without head nodding. They all had reduced vision, amblyopia, and mild compound hypermetropic astigmatism. None of the patients had classic features of ocular albinism. Female carriers were unaffected, consistent with X-linked recessive inheritance. Molecular Genetics In a large 6-generation Chinese family with a 'variant phenotype of ocular albinism' mapping to Xp22, Liu et al. (2007) analyzed 21 candidate genes and identified a missense mutation in the GPR143 gene (S89F; 300808.0009) in affected males and carrier females. Zhou et al. (2008) identified a 37-bp deletion in the GPR143 gene (300808.0011) in affected male members of a 4-generation Chinese family with X-linked congenital nystagmus without evidence of ocular albinism. Obligate mutation carriers did not have nystagmus, consistent with X-linked recessive inheritance. Peng et al. (2009) identified a 14-bp duplication in the GPR143 gene (300808.0012) in a Chinese family with X-linked recessive congenital nystagmus without features of ocular albinism. Female carriers were unaffected. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	NYSTAGMUS 6, CONGENITAL, X-LINKED	c3151752	4,742	omim	https://www.omim.org/entry/300814	2019-09-22T16:19:33	{"omim": ["300814"]}
A rare systemic disease characterized by characterized by acute or subacute onset of thrombocytopenia, anasarca (edema, pleural effusion, ascites), and systemic inflammation (fever and/or elevated C-reactive protein). Minor diagnostic categories are Castleman's disease-like features on lymph node biopsy, reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow, progressive renal insufficiency, and mild organomegaly including hepatosplenomegaly and lymphadenopathy. Most patients show elevated levels of serum alkaline phosphatase, while marked polyclonal hypergammopathy is rare. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	TAFRO syndrome	c4552543	4,743	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=457077	2021-01-23T17:54:48	{"icd-10": ["M35.8"], "synonyms": ["Thrombocytopenia-anasarca-fever-renal insufficiency-organomegaly syndrome"]}
Dilated cardiomyopathy Other namesCongestive cardiomyopathy, idiopathic cardiomyopathy, primary cardiomyopathy[1] Mouse heart slice showing dilated cardiomyopathy SpecialtyCardiology SymptomsFeeling tired, leg swelling, shortness of breath, chest pain, fainting[2] ComplicationsHeart failure, heart valve disease, irregular heartbeat[3][4] Usual onsetMiddle age[5] TypesTachycardia-induced,[6][7] others CausesGenetics, alcohol, cocaine, certain toxins, complications of pregnancy, in many cases the cause remains unclear , certain infections[8][9][7] Diagnostic methodSupported by electrocardiogram, chest X-ray, echocardiogram[9] Differential diagnosisCoronary artery disease, heart valve disease, pulmonary embolism, other cardiomyopathy[5] TreatmentLifestyle changes, medications, implantable cardioverter defibrillator, cardiac resynchronization therapy (CRT) , heart transplant[9] MedicationACE inhibitor, beta blocker, diuretic, blood thinners[9] PrognosisFive-year survival rate ~50%[9] Frequency1 in 2,500[9] Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively.[3] Symptoms vary from none to feeling tired, leg swelling, and shortness of breath.[2] It may also result in chest pain or fainting.[2] Complications can include heart failure, heart valve disease, or an irregular heartbeat.[3][4] Causes include genetics, alcohol, cocaine, certain toxins, complications of pregnancy, and certain infections.[8][9] Coronary artery disease and high blood pressure may play a role, but are not the primary cause.[5][8] In many cases the cause remains unclear.[8] It is a type of cardiomyopathy, a group of diseases that primarily affects the heart muscle.[3] The diagnosis may be supported by an electrocardiogram, chest X-ray, or echocardiogram.[9] In those with heart failure, treatment may include medications in the ACE inhibitor, beta blocker, and diuretic families.[9] A low salt diet may also be helpful.[5] In those with certain types of irregular heartbeat, blood thinners or an implantable cardioverter defibrillator may be recommended. Cardiac resynchronization therapy (CRT) may be necessary , [9] If other measures are not effective a heart transplant may be an option in some.[9] About 1 per 2,500 people is affected.[9] It occurs more frequently in men than women.[10] Onset is most often in middle age.[5] Five-year survival rate is about 50%.[9] It can also occur in children and is the most common type of cardiomyopathy in this age group.[9] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Genetics * 3 Pathophysiology * 3.1 Compensation effects * 3.2 Computational models * 3.3 Valvular effects * 4 Diagnosis * 5 Treatment * 5.1 Medical therapy * 5.2 Electrical treatment * 5.3 Surgical treatment * 6 Epidemiology * 7 Research directions * 8 Other animals * 9 References * 10 External links ## Signs and symptoms[edit] Main article: Heart failure § Signs and symptoms Dilated cardiomyopathy develops insidiously, and may not initially cause symptoms significant enough to impact on quality of life.[11][12] Nevertheless, many people experience significant symptoms. These might include: * Shortness of breath * Syncope (fainting) * Angina, but only in the presence of ischemic heart disease A person suffering from dilated cardiomyopathy may have an enlarged heart, with pulmonary edema and an elevated jugular venous pressure and a low pulse pressure. Signs of mitral and tricuspid regurgitation may be present.[12] ## Causes[edit] Although in many cases no cause is apparent, dilated cardiomyopathy is probably the result of damage to the myocardium produced by a variety of toxic, metabolic, or infectious agents. In many cases the cause remains unclear. It may be due to fibrous change of the myocardium from a previous myocardial infarction. Or, it may be the late sequelae of acute viral myocarditis, such as with Coxsackie B virus and other enteroviruses[13] possibly mediated through an immunologic mechanism.[14] Other causes include: * Chagas disease, due to Trypanosoma cruzi. This is the most common infectious cause of dilated cardiomyopathy in Latin America[15] * Pregnancy. Dilated cardiomyopathy occurs late in gestation or several weeks to months postpartum as a peripartum cardiomyopathy.[13] It is reversible in half of cases.[13] * Alcohol abuse (alcoholic cardiomyopathy)[13] * Nonalcoholic toxic insults include administration of certain chemotherapeutic agents, in particular doxorubicin (Adriamycin), and cobalt.[13] * Thyroid disease[12] * Inflammatory diseases such as sarcoidosis and connective tissue diseases[12] * Tachycardia-induced cardiomyopathy[7] * Muscular dystrophy * Tuberculosis \- 1 to 2% of TB cases.[16] * Autoimmune mechanisms[17] * Thiamine deficiency Recent studies have shown that those subjects with an extremely high occurrence (several thousands a day) of premature ventricular contractions (extrasystole) can develop dilated cardiomyopathy. In these cases, if the extrasystole are reduced or removed (for example, via ablation therapy) the cardiomyopathy usually regresses.[18][19] ### Genetics[edit] Genetic associations with dilated cardiomyopathy Type OMIM Gene Locus CMD1A 115200 LMNA 1q21 CMD1B 600884 unknown (TMOD1 candidate) 9q13 CMD1C 601493 LDB3 10q22-q23 CMD1D 601494 TNNT2 1q32 CMD1E 601154 SCN5A 3p CMD1F 602067 6q23 CMD1G 604145 TTN 2q31 CMD1H 604288 2q14-q22 CMD1I 604765 DES CMD1K 605582 6q12-q16 CMD1L 606685 SGCD 5q33 CMD1M 607482 CSRP3 11p15.1 CMD1N 607487 TCAP 17q12 CMD1O 608569 ABCC9 12p12.1 CMD1P 609909 PLN 6q22.1 CMD1Q 609915 7q22.3-q31.1 CMD1R ACTC 15q14 CMD1S MYH7 14q12 CMD1T TMPO 12q22 CMD1U PSEN1 14q24.3 CMD1V PSEN2 1q31-q42 CMD1W 611407 VCL 10q22-q23 CMD1X FCMD 9q31 CMD1Y 611878 TPM1 15q22.1 CMD1Z 611879 TNNC1 3p21.3-p14.3 CMD1AA 612158 ACTN2 1q42-q43 CMD2A 611880 TNNI3 19q13.4 CMD3A 300069 TAZ Xq28 CMD3B 302045 DMD Xp21.2 ALPK3 15q25.3 About 25–35% of affected individuals have familial forms of the disease,[13] with most mutations affecting genes encoding cytoskeletal proteins,[13] while some affect other proteins involved in contraction.[20] The disease is genetically heterogeneous, but the most common form of its transmission is an autosomal dominant pattern.[13] Autosomal recessive (as found, for example, in Alström syndrome[13]), X-linked (as in Duchenne muscular dystrophy), and mitochondrial inheritance of the disease is also found.[21] Some relatives of those affected by dilated cardiomyopathy have preclinical, asymptomatic heart-muscle changes.[22] Other cytoskeletal proteins involved in DCM include α-cardiac actin, desmin, and the nuclear lamins A and C.[13] Mitochondrial deletions and mutations presumably cause DCM by altering myocardial ATP generation.[13] Kayvanpour et al. performed 2016 a meta-analysis with the largest dataset available on genotype-phenotype associations in DCM and mutations in lamin (LMNA), phospholamban (PLN), RNA Binding Motif Protein 20 (RBM20), Cardiac Myosin Binding Protein C (MYBPC3), Myosin Heavy Chain 7 (MYH7), Cardiac Troponin T 2 (TNNT2), and Cardiac Troponin I (TNNI3). They also reviewed recent studies investigating genotype-phenotype associations in DCM patients with titin (TTN) mutations. LMNA and PLN mutation carriers showed a high prevalence of cardiac transplantation and ventricular arrhythmia. Dysrhythmias and sudden cardiac death (SCD) was shown to occur even before the manifestation of DCM and heart failure symptoms in LMNA mutation carriers.[23] ## Pathophysiology[edit] Illustration of a Normal Heart vs. Heart with Dilated Cardiomyopathy The progression of heart failure is associated with left ventricular remodeling, which manifests as gradual increases in left ventricular end-diastolic and end-systolic volumes, wall thinning, and a change in chamber geometry to a more spherical, less elongated shape. This process is usually associated with a continuous decline in ejection fraction. The concept of cardiac remodeling was initially developed to describe changes that occur in the days and months following myocardial infarction.[24] ### Compensation effects[edit] As DCM progresses, two compensatory mechanisms are activated in response to impaired myocyte contractility and reduced stroke volume:[12] * Frank-Starling law * Neurohormonal feedback, via activation of the sympathetic nervous system and the renin-angiotensin system. These responses initially compensate for decreased cardiac output and maintain those with DCM as asymptomatic. Eventually, however, these mechanisms become detrimental, intravascular volume becomes too great, and progressive dilatation leads to heart failure symptoms. ### Computational models[edit] Cardiac dilatation is a transversely isotropic, irreversible process resulting from excess strains on the myocardium.[25] A computation model of volumetric, isotropic, and cardiac wall growth predicts the relationship between cardiac strains (e.g. volume overload after myocardial infarction) and dilation using the following governing equations: F = F e ⋅ F g {\displaystyle F=F^{e}\cdot F^{g}\,} where F e {\displaystyle F^{e}} is elastic volume stretch that is reversible and F g {\displaystyle F^{g}} is irreversible, isotropic volume growth described by: F g = I + [ λ g − 1 ] f 0 ⊗ f 0 {\displaystyle F^{g}=\mathbb {I} +[\lambda ^{g}-1]f_{0}\otimes f_{0}\,} where f 0 {\displaystyle f_{0}} is a vector, which points along a cardiomyocyte's long axis and λ g {\displaystyle \lambda ^{g}} is the cardiomyocyte stretch due to growth. The total cardiomyocyte growth is given by: λ = λ e ⋅ F λ g {\displaystyle \lambda =\lambda ^{e}\cdot F\lambda ^{g}\,} The above model reveals a gradual dilation of the myocardium, especially the ventricular myocardium, to support the blood volume overload in the chambers. Dilation manifests itself in an increase in total cardiac mass and cardiac diameter. Cardiomyocytes reach their maximum length of 150 μ {\displaystyle \mu } m in the endocardium and 130 μ {\displaystyle \mu } m in the epicardium by the addition of sarcomeres.[26] Due to the increase in diameter, the dilated heart appears spherical in shape, as opposed the elliptical shape of a healthy human heart. In addition, the ventricular walls maintain the same thickness, characteristic of pathophysiological cardiac dilation. ### Valvular effects[edit] As the ventricles enlarge, both the mitral and tricuspid valves may lose their ability to come together properly. This loss of coaptation may lead to mitral and tricuspid regurgitation. As a result, those with DCM are at increased risk of atrial fibrillation. Furthermore, stroke volume is decreased and a greater volume load is placed on the ventricle, thus increasing heart failure symptoms.[12] ## Diagnosis[edit] Serial 12-lead ECGs from a 49-year-old black man with cardiomyopathy. (TOP): Sinus tachycardia (rate about 101/min) with LBBB accompanied by RAD (here about 108°). Frequent multifocal PVCs (both singly and in pairs) and left atrial enlargement. (BOTTOM): Same patient about 5 months later status-post orthotopic heart transplant. Dilated cardiomyopathy on CXR Dilated cardiomyopathy on CT Generalized enlargement of the heart is seen upon normal chest X-ray. Pleural effusion may also be noticed, which is due to pulmonary venous hypertension. The electrocardiogram often shows sinus tachycardia or atrial fibrillation, ventricular arrhythmias, left atrial enlargement, and sometimes intraventricular conduction defects and low voltage. When left bundle-branch block (LBBB) is accompanied by right axis deviation (RAD), the rare combination is considered to be highly suggestive of dilated or congestive cardiomyopathy.[27][28] Echocardiogram shows left ventricular dilatation with normal or thinned walls and reduced ejection fraction. Cardiac catheterization and coronary angiography are often performed to exclude ischemic heart disease. Genetic testing can be important, since one study has shown that gene mutations in the TTN gene (which codes for a protein called titin) are responsible for "approximately 25% of familial cases of idiopathic dilated cardiomyopathy and 18% of sporadic cases."[29] The results of the genetic testing can help the doctors and patients understand the underlying cause of the dilated cardiomyopathy. Genetic test results can also help guide decisions on whether a patient's relatives should undergo genetic testing (to see if they have the same genetic mutation) and cardiac testing to screen for early findings of dilated cardiomyopathy. Cardiac magnetic resonance imaging (cardiac MRI) may also provide helpful diagnostic information in patients with dilated cardiomyopathy.[30] ## Treatment[edit] ### Medical therapy[edit] Drug therapy can slow down progression and in some cases even improve the heart condition. Standard therapy may include salt restriction, ACE inhibitors, diuretics, and beta blockers.[12] Anticoagulants may also be used for antithrombotic therapy. There is some evidence for the benefits of coenzyme Q10 in treating heart failure.[31][32][33] ### Electrical treatment[edit] Artificial pacemakers may be used in patients with intraventricular conduction delay, and implantable cardioverter-defibrillators in those at risk of arrhythmia. These forms of treatment have been shown to prevent sudden cardiac death, improve symptoms, and reduce hospitalization in patients with systolic heart failure.[34] ### Surgical treatment[edit] In patients with advanced disease who are refractory to medical therapy, heart transplantation may be considered. For these people 1-year survival approaches 90% and over 50% survive greater than 20 years.[34] ## Epidemiology[edit] Although the disease is more common in African-Americans than in Caucasians,[35] it may occur in any patient population. ## Research directions[edit] Therapies that support reverse remodeling have been investigated, and this may suggests a new approach to the prognosis of cardiomyopathies (see ventricular remodeling).[24][36] ## Other animals[edit] Dilated cardiomyopathy is a heritable disease in some dog breeds, including the Boxer, Dobermann, Great Dane, Irish Wolfhound, and St Bernard.[37] Treatment is based on medication, including ACE inhibitors, loop diuretics, and phosphodiesterase inhibitors. In 2019, researchers at University of California, Davis School of Veterinary Medicine published a report describing a link between certain diets and the development of dilated cardiomyopathy in dog breeds lacking the genetic predisposition, particularly in Golden Retrievers. The diets associated with DCM were described as "BEG" (boutique, exotic-ingredient, and/or grain-free) dog foods, as well as legume-rich diets. For treating diet-related DCM, food changes and taurine supplementation are typically indicated, along with traditional treatments as necessary. Dilated cardiomyopathy is also a disease affecting some cat breeds, including the Oriental Shorthair, Burmese, Persian, and Abyssinian. In cats, taurine deficiency is the most common cause of dilated cardiomyopathy.[38] As opposed to these hereditary forms, non-hereditary DCM used to be common in the overall cat population before the addition of taurine to commercial cat food. There is also a high incidence of heritable dilated cardiomyopathy in captive Golden Hamsters (Mesocricetus auratus), due in no small part to their being highly inbred. The incidence is high enough that several strains of Golden Hamster have been developed to serve as animal models in clinical testing for human forms of the disease.[39] ## References[edit] 1. ^ "Other Names for Cardiomyopathy". NHLBI. June 22, 2016. Retrieved 31 August 2016. 2. ^ a b c "What Are the Signs and Symptoms of Cardiomyopathy?". NHLBI. 22 June 2016. Retrieved 10 November 2017. 3. ^ a b c d "What Is Cardiomyopathy?". NHLBI. 22 June 2016. Retrieved 10 November 2017. 4. ^ a b "Types of Cardiomyopathy". NHLBI. 22 June 2016. Retrieved 10 November 2017. 5. ^ a b c d e Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 244. ISBN 9780323529570. 6. ^ "Tachycardia-induced cardiomyopathy". European Society of Cardiology. 2019-03-29. Retrieved 2019-03-29. "Tachycardia-induced cardiomyopathy is a reversible cause of heart failure and dilated cardiomyopathy. Tachycardia-induced cardiomyopathy should be considered in all patients with a dilated cardiomyopathy of uncertain origin and who have tachycardia or atrial fibrillation with a fast ventricular rate." 7. ^ a b c Umana, Ernesto; Solares, C. Arturo; Alpert, Martin A (2003-01-01). "Tachycardia-induced cardiomyopathy". The American Journal of Medicine. 114 (1): 51–55. doi:10.1016/S0002-9343(02)01472-9. PMID 12543289. 8. ^ a b c d "What Causes Cardiomyopathy?". NHLBI. 22 June 2016. Retrieved 10 November 2017. 9. ^ a b c d e f g h i j k l m n Weintraub, RG; Semsarian, C; Macdonald, P (22 July 2017). "Dilated cardiomyopathy". Lancet. 390 (10092): 400–414. doi:10.1016/S0140-6736(16)31713-5. PMID 28190577. S2CID 46801202. 10. ^ "Who Is at Risk for Cardiomyopathy? - NHLBI, NIH". NHLBI. 22 June 2016. Retrieved 10 November 2017. 11. ^ Watkins, Hugh; Ashrafian, Houman; Redwood, Charles (2011-04-27). "Inherited Cardiomyopathies". New England Journal of Medicine. 364 (17): 1643–1656. doi:10.1056/nejmra0902923. PMID 21524215. 12. ^ a b c d e f g Pathophysiology of heart disease : a collaborative project of medical students and faculty. Lilly, Leonard S., Harvard Medical School. (5th ed.). Baltimore, MD: Wolters Kluwer/Lippincott Williams & Wilkins. 2011. ISBN 9781605477237. OCLC 649701807.CS1 maint: others (link) 13. ^ a b c d e f g h i j k Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 14. ^ Martino TA, Liu P, Sole MJ (February 1994). "Viral infection and the pathogenesis of dilated cardiomyopathy". Circ. Res. 74 (2): 182–8. doi:10.1161/01.res.74.2.182. PMID 8293557. 15. ^ "Dilated Cardiomyopathy - Cardiovascular Disorders". 16. ^ Agarwal Ritesh, Malhotra Puneet, Awasthi Anshu, Kakkar Nandita, Gupta Dheeraj (2005). "Tuberculous dilated cardiomyopathy: an under-recognized entity?". BMC Infect Dis. 5: 29. doi:10.1186/1471-2334-5-29. PMC 1090580. PMID 15857515.CS1 maint: multiple names: authors list (link) 17. ^ San Martín MA, García A, Rodríguez FJ, Terol I (May 2002). "[Dilated cardiomyopathy and autoimmunity: an overview of current knowledge and perspectives]". Rev Esp Cardiol. (in Spanish). 55 (5): 514–24. doi:10.1016/s0300-8932(02)76644-x. PMID 12015932. Archived from the original on 2009-01-09. 18. ^ Belhassen B (April 2005). "Radiofrequency ablation of "benign" right ventricular outflow tract extrasystoles: a therapy that has found its disease?". J. Am. Coll. Cardiol. 45 (8): 1266–8. doi:10.1016/j.jacc.2005.01.028. PMID 15837260. 19. ^ Shiraishi H, Ishibashi K, Urao N, et al. (November 2002). "A case of cardiomyopathy induced by premature ventricular complexes". Circ. J. 66 (11): 1065–7. doi:10.1253/circj.66.1065. PMID 12419942. 20. ^ Ross J (March 2002). "Dilated cardiomyopathy: concepts derived from gene deficient and transgenic animal models". Circ. J. 66 (3): 219–24. doi:10.1253/circj.66.219. PMID 11922267. 21. ^ Schönberger J, Seidman CE (August 2001). "Many roads lead to a broken heart: the genetics of dilated cardiomyopathy". American Journal of Human Genetics. 69 (2): 249–60. doi:10.1086/321978. PMC 1235300. PMID 11443548. 22. ^ Mahon NG, Murphy RT, MacRae CA, Caforio AL, Elliott PM, McKenna WJ (July 2005). "Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease". Annals of Internal Medicine. 143 (2): 108–15. doi:10.7326/0003-4819-143-2-200507190-00009. PMID 16027452. S2CID 22278646. 23. ^ Kayvanpour, Elham; Sedaghat-Hamedani, Farbod; Amr, Ali; Lai, Alan; Haas, Jaan; Holzer, Daniel B.; Frese, Karen S.; Keller, Andreas; Jensen, Katrin; Katus, Hugo A.; Meder, Benjamin (2016-08-30). "Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals". Clinical Research in Cardiology. 106 (2): 127–139. doi:10.1007/s00392-016-1033-6. PMID 27576561. S2CID 27511518. 24. ^ a b Pieske B (2004). "Reverse remodeling in heart failure – fact or fiction?". Eur Heart J Suppl. 6: D66–78. doi:10.1016/j.ehjsup.2004.05.019. 25. ^ Goektepe, Serdar; Abilez, Oscar John; Kuhl, Ellen (2010). "Generic approach towards finite growth with examples of athlete's heart, cardiac dilation, and cardiac wall thickening". Mechanics and Physics of Solids. 58 (10): 1661–1680. Bibcode:2010JMPSo..58.1661G. doi:10.1016/j.jmps.2010.07.003. 26. ^ Goektepe, Serdar; Abilez, Oscar John; Parker, K; Kuhl, Ellen (2010). "A multiscale model for eccentric and concentric cardiac growth through sarcomerogenesis". Theoretical Biology. 58: 1661–1680. Bibcode:2010JMPSo..58.1661G. doi:10.1016/j.jmps.2010.07.003. 27. ^ Nikolic G, Marriott HJ (Oct 1985). "Left bundle branch block with right axis deviation: a marker of congestive cardiomyopathy". J Electrocardiol. 18 (4): 395–404. doi:10.1016/s0022-0736(85)80022-4. PMID 3906012. 28. ^ Childers R, Lupovich S, Sochanski M, Konarzewska H (2000). "Left bundle branch block and right axis deviation: a report of 36 cases". J Electrocardiol. 33 (Suppl): 93–102. doi:10.1054/jclc.2000.20326. PMID 11265743. 29. ^ Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (Feb 16, 2012). "Truncations of Titin causing dilated cardiomyopathy". N Engl J Med. 366 (7): 619–628. doi:10.1056/NEJMoa1110186. PMC 3660031. PMID 22335739. 30. ^ Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, van Rossum AC, Shaw LJ, Yucel EK (Nov 2004). "Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report". Eur Heart J. 25 (21): 1940–1965. doi:10.1016/j.ehj.2004.06.040. PMID 15522474. 31. ^ Langsjoen PH, Langsjoen PH, Folkers K (1990). "A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10". Int J Tissue React. 12 (3): 169–71. PMID 2276895. 32. ^ Folkers K, Langsjoen P, Langsjoen PH (January 1992). "Therapy with coenzyme Q10 of patients in heart failure who are eligible or ineligible for a transplant". Biochem Biophys Res Commun. 182 (1): 247–53. doi:10.1016/S0006-291X(05)80137-8. PMID 1731784. 33. ^ Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G (1994). "Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators". Mol. Aspects Med. 15 (Suppl): s287–94. doi:10.1016/0098-2997(94)90040-X. PMID 7752841. 34. ^ a b McPhee, Stephen J.; Rabow, Michael W.; Papadakis, Maxine A. (2016-09-01). Current medical diagnosis & treatment 2017. Papadakis, Maxine A.,, McPhee, Stephen J.,, Rabow, Michael W. (Fifty-sixth ed.). New York. ISBN 978-1259585111. OCLC 957316517. 35. ^ Coughlin SS, Labenberg JR, Tefft MC (March 1993). "Black-white differences in idiopathic dilated cardiomyopathy: the Washington DC dilated Cardiomyopathy Study". Epidemiology. 4 (2): 165–72. doi:10.1097/00001648-199303000-00013. PMID 8452906. 36. ^ Reis Filho JR, Cardoso JN, Cardoso CM, Pereira-Barretto AC (2015). "Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure". Arq. Bras. Cardiol. 104 (6): 502–6. doi:10.5935/abc.20150025. PMC 4484683. PMID 26131706. 37. ^ Oyama MA, Chittur S (July 2005). "Genomic expression patterns of cardiac tissues from dogs with dilated cardiomyopathy". Am J Vet Res. 66 (7): 1140–55. doi:10.2460/ajvr.2005.66.1140. PMID 16111151. 38. ^ Pion, P. D.; Kittleson, M. D.; Thomas, W. P.; Skiles, M. L.; Rogers, Q. R. (1992-07-15). "Clinical findings in cats with dilated cardiomyopathy and relationship of findings to taurine deficiency". Journal of the American Veterinary Medical Association. 201 (2): 267–274. ISSN 0003-1488. PMID 1500323. 39. ^ Nigro V, Okazaki Y, Belsito A, et al. (April 1997). "Identification of the Syrian hamster cardiomyopathy gene". Hum. Mol. Genet. 6 (4): 601–7. doi:10.1093/hmg/6.4.601. PMID 9097966. ## External links[edit] * Dilated cardiomyopathy information for parents. Classification D * ICD-10: I42.0 * ICD-9-CM: 425.4 * OMIM: 212110 * MeSH: D002311 * DiseasesDB: 3066 * SNOMED CT: 74368002 External resources * MedlinePlus: 000168 * eMedicine: med/289 emerg/80 ped/2502 * GeneReviews: Dilated Cardiomyopathy Overview * Orphanet: 217604 * 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 Cytoskeletal defects Microfilaments Myofilament Actin * Hypertrophic cardiomyopathy 11 * Dilated cardiomyopathy 1AA * DFNA20 * Nemaline myopathy 3 Myosin * Elejalde syndrome * Hypertrophic cardiomyopathy 1, 8, 10 * Usher syndrome 1B * Freeman–Sheldon syndrome * DFN A3, 4, 11, 17, 22; B2, 30, 37, 48 * May–Hegglin anomaly Troponin * Hypertrophic cardiomyopathy 7, 2 * Nemaline myopathy 4, 5 Tropomyosin * Hypertrophic cardiomyopathy 3 * Nemaline myopathy 1 Titin * Hypertrophic cardiomyopathy 9 Other * Fibrillin * Marfan syndrome * Weill–Marchesani syndrome * Filamin * FG syndrome 2 * Boomerang dysplasia * Larsen syndrome * Terminal osseous dysplasia with pigmentary defects IF 1/2 * Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1 * Striate palmoplantar keratoderma 3 * Epidermolytic hyperkeratosis * IHCM * KRT2E (Ichthyosis bullosa of Siemens) * KRT3 (Meesmann juvenile epithelial corneal dystrophy) * KRT4 (White sponge nevus) * KRT5 (Epidermolysis bullosa simplex) * KRT8 (Familial cirrhosis) * KRT10 (Epidermolytic hyperkeratosis) * KRT12 (Meesmann juvenile epithelial corneal dystrophy) * KRT13 (White sponge nevus) * KRT14 (Epidermolysis bullosa simplex) * KRT17 (Steatocystoma multiplex) * KRT18 (Familial cirrhosis) * KRT81/KRT83/KRT86 (Monilethrix) * Naegeli–Franceschetti–Jadassohn syndrome * Reticular pigmented anomaly of the flexures 3 * Desmin: Desmin-related myofibrillar myopathy * Dilated cardiomyopathy 1I * GFAP: Alexander disease * Peripherin: Amyotrophic lateral sclerosis 4 * Neurofilament: Parkinson's disease * Charcot–Marie–Tooth disease 1F, 2E * Amyotrophic lateral sclerosis 5 * Laminopathy: LMNA * Mandibuloacral dysplasia * Dunnigan Familial partial lipodystrophy * Emery–Dreifuss muscular dystrophy 2 * Limb-girdle muscular dystrophy 1B * Charcot–Marie–Tooth disease 2B1 * LMNB * Barraquer–Simons syndrome * LEMD3 * Buschke–Ollendorff syndrome * Osteopoikilosis * LBR * Pelger–Huet anomaly * Hydrops-ectopic calcification-moth-eaten skeletal dysplasia Microtubules Kinesin * Charcot–Marie–Tooth disease 2A * Hereditary spastic paraplegia 10 Dynein * Primary ciliary dyskinesia * Short rib-polydactyly syndrome 3 * Asphyxiating thoracic dysplasia 3 Other * Tauopathy * Cavernous venous malformation Membrane * Spectrin: Spinocerebellar ataxia 5 * Hereditary spherocytosis 2, 3 * Hereditary elliptocytosis 2, 3 Ankyrin: Long QT syndrome 4 * Hereditary spherocytosis 1 Catenin * APC * Gardner's syndrome * Familial adenomatous polyposis * plakoglobin (Naxos syndrome) * GAN (Giant axonal neuropathy) Other * desmoplakin: Striate palmoplantar keratoderma 2 * Carvajal syndrome * Arrhythmogenic right ventricular dysplasia 8 * plectin: Epidermolysis bullosa simplex with muscular dystrophy * Epidermolysis bullosa simplex of Ogna * plakophilin: Skin fragility syndrome * Arrhythmogenic right ventricular dysplasia 9 * centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II) Related topics: Cytoskeletal proteins * v * t * e Genetic disorder, membrane: ABC-transporter disorders ABCA * ABCA1 (Tangier disease) * ABCA3 (Surfactant metabolism dysfunction 3) * ABCA4 (Stargardt disease 1, Retinitis pigmentosa 19) * ABCA12 (Harlequin-type ichthyosis, Lamellar ichthyosis 2) ABCB * ABCB4 (Progressive familial intrahepatic cholestasis 3) * ABCB7 (ASAT) * ABCB11 (Progressive familial intrahepatic cholestasis 2) ABCC * ABCC2 (Dubin–Johnson syndrome) * ABCC6 (Pseudoxanthoma elasticum) * ABCC7 (Cystic fibrosis) * ABCC8 (HHF1, TNDM2) * ABCC9 (Dilated cardiomyopathy 1O) ABCD * ABCD1 (Adrenoleukodystrophy, Adrenomyeloneuropathy) ABCG * ABCG5 (Sitosterolemia) * ABCG8 (Gallbladder disease 4, Sitosterolemia) see also ABC transporters [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Dilated cardiomyopathy	c0007193	4,744	wikipedia	https://en.wikipedia.org/wiki/Dilated_cardiomyopathy	2021-01-18T18:40:18	{"gard": ["221"], "mesh": ["D002311"], "umls": ["C0007193"], "icd-9": ["425.4"], "orphanet": ["217604"], "wikidata": ["Q283656"]}
A rare metabolic disorder belonging to the neutral aminoacidurias, mainly characterized by skin photosensitivity, ocular and neuropsychiatric features, due to abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine). ## Epidemiology The estimated prevalence is approximately 1 in 30,000. ## Clinical description Most subjects who fulfil the biochemical diagnostic criteria (mostly detected by newborn screening programs) remain asymptomatic. In the few symptomatic subjects, clinical symptoms usually appear in childhood (3-9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (intermittent cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), and psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations). Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs. ## Etiology Hartnup disease is caused by mutations in SLC6A19 gene (5p15.33), encoding the sodium-dependent and chloride-independent neutral amino acid transporter B(0)AT1, expressed predominately in proximal renal tubules and intestinal epithelium. ## Diagnostic methods Neutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Diagnostic confirmation relies upon the mutation analysis of the SLCA19 gene (broad allelic heterogeneity). ## Differential diagnosis Pellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum should be excluded. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment Symptomatic subjects benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Treatment includes nicotinamide supplements (40 to 200 mg per day). Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment. ## Prognosis The presentation of the disorder is commonly benign. Hartnup disease probably does not adversely affect pregnancy and would be harmless to the fetus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hartnup disease	c0018609	4,745	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2116	2021-01-23T18:30:43	{"gard": ["6569"], "mesh": ["D006250"], "omim": ["234500"], "umls": ["C0018609"], "icd-10": ["E72.0"], "synonyms": ["Aminoaciduria, Hartnup type", "Hartnup disorder"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Blanch" medical – news · newspapers · books · scholar · JSTOR (July 2018) (Learn how and when to remove this template message) This article is missing information about difficulty of observation in people with dark skin. Please expand the article to include this information. Further details may exist on the talk page. (December 2020) When skin is blanched, it takes on a whitish appearance as blood flow to the region is prevented. This occurs during and is the basis of the physiologic test known as diascopy.[citation needed] Blanching of the fingers is also one of the most clinically evident signs of Raynaud's phenomenon.[citation needed] Blanching is prevented in gangrene as the red blood corpuscles are extravasated and impart red color to the gangrenous part. ## See also[edit] * Diascopy * v * t * e Symptoms and signs relating to skin and subcutaneous tissue Disturbances of skin sensation * Hypoesthesia * Paresthesia * Formication * Hyperesthesia * Hypoalgesia * Hyperalgesia Circulation * Cyanosis * Pallor * Livedo * Livedo reticularis * Flushing * Petechia * Blanching Edema * Peripheral edema * Anasarca Other * Rash * Desquamation * Induration * Diaphoresis * Mass * Neck mass Skin * Asboe-Hansen sign * Auspitz's sign * Borsari's sign * Braverman's sign * Crowe sign * Dennie–Morgan fold * Darier's sign * Fitzpatrick's sign * Florid cutaneous papillomatosis * Gottron's sign * Hutchinson's sign * Janeway lesion * Kerr's sign * Koebner's phenomenon * Koplik's spots * Leser-Trelat sign * Nikolsky's sign * Pastia's sign * Russell's sign * Wickham striae * Wolf's isotopic response * Munro's microabscess Nails * Aldrich-Mees' lines * Beau's lines * Muehrcke's lines * Terry's nails This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Blanch (medical)	c0277941	4,746	wikipedia	https://en.wikipedia.org/wiki/Blanch_(medical)	2021-01-18T19:05:16	{"umls": ["C0277941"], "wikidata": ["Q4924780"]}
Osteomyelitis of the jaws is osteomyelitis (which is infection and inflammation of the bone marrow, sometimes abbreviated to OM) which occurs in the bones of the jaws (i.e. maxilla or the mandible). Historically, osteomyelitis of the jaws was a common complication of odontogenic infection (infections of the teeth). Before the antibiotic era, it was frequently a fatal condition.[1] Former and colloquial names include Osteonecrosis of the jaws (ONJ), cavitations, dry or wet socket, and NICO (Neuralgia-Inducing Cavitational osteonecrosis). The current, more correct, term, osteomyelitis of the jaws, differentiates the condition from the relatively recent and better known iatrogenic phenomenon of bisphosphonate-caused osteonecrosis of the jaws. The latter is found primarily in post-menopausal women given bisphosphonate medications, usually against osteoporosis. ## Contents * 1 Classification * 2 Signs and symptoms * 3 Cause * 4 Pathogenesis * 5 Prevention * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 References ## Classification[edit] The classification is similar to the classification of OM generally, according to the length of time the inflammation has been present and whether there is suppuration (the formation of pus). Acute osteomyelitis is loosely defined as OM which has been present for less than one month and chronic osteomyelitis is the term used for when the condition lasts for more than one month. Suppurative osteomyelitis of the jaws is uncommon in developed regions, and more common in developing countries. In Europe and the United States, most cases follow dental infections, oral surgery or mandibular fractures. There have been many reported cases occurring in Africa which are coexistent with acute necrotizing ulcerative gingivitis or cancrum oris.[2] In the pre-antibiotic era, acute OM of the jaws was more extensive. Massive, diffuse infections commonly involved the whole side of the mandible, or the whole of one side and the opposite side as far as the mental foramen. Localized osteomyelitis tended to be described as either vertical, where a short segment of the body of the mandible from the alveolar crest to the lower border was involved, and alveolar, where a segment of alveolar bone down to the level of the inferior alveolar canal would sequestrate, including the sockets of several teeth. Treatment with antibiotics has significantly altered the natural history of OM of the jaws. Today, however, the condition is often a hidden infection, due in part to not being visible on most dental X-rays unless there is a substantial loss of bone density. In addition, some schools of dentistry do not recognize "silent" OM of the jaws—occurrence of the condition without visually obvious manifestations—in their curriculum. In addition, as circulation is intrinsically diminished in jawbones, antibiotics are frequently ineffective. ## Signs and symptoms[edit] The signs and symptoms depend upon the type of OM, and may include: * Pain, which is severe, throbbing and deep seated and often radiates along the nerve pathways. * Initially fistula are not present. * Headache or facial pain, as in the descriptive former term "neuralgia-inducing" (cavitational osteonecrosis). * Fibromyalgia. * Chronic fatigue syndrome. * Swelling. External swelling is initially due to inflammatory edema with accompanying erythema (redness), heat and tenderness, and then later may be due to sub-periosteal pus accumulation. Eventually, subperiosteal bone formation may give a firm swelling. * Trismus (difficulty opening the mouth), which may be present in some cases and is caused by edema in the muscles. * Dysphagia (difficulty swallowing), which may be present in some cases and is caused by edema in the muscles. * Cervical lymphadenitis (swelling of the lymph nodes in the neck). * Aesthesia or paresthesia (altered sensation such as numbness or pins and needles) in the distribution of the mental nerve. * Fever which may be present in the acute phase and is high and intermittent * Malaise (general feeling of being unwell) which may be present in the acute phase * Anorexia (loss of appetite). * Leukocytosis (elevated numbers of white blood cells) which may be present in the acute phase * Elevated erythrocyte sedimentation rate and C reactive protein are sometimes present. * An obvious cause in the mouth (usually) such as a decayed tooth. * Teeth that are tender to percussion, which may develop as the condition progresses. * Loosening of teeth, which may develop as the condition progresses. * Pus may later be visible, which exudes from around the necks of teeth, from an open socket, or from other sites within the mouth or on the skin over the involved bone. * Fetid odor. Unlike acute OM in the long bones, acute OM in the jaws gives only a moderate systemic reaction and systemic inflammatory markers, such as blood tests, usually remain normal. Acute OM of the jaws may give a similar appearance to a typical odontogenic infection or dry socket, but cellulitis does not tend to spread from the periosteal envelope of the involved bone. If the infection is not controlled, the process becomes chronic and visible signs may be present, including draining fistulas, loosening of teeth and sequestra formation. Untreated chronic osteomyelitis tends to feature occasional acute exacerbations. ## Cause[edit] OM is usually a polymicrobial, opportunistic infection, caused primarily by a mixture of alpha hemolytic streptococci and anaerobic bacteria from the oral cavity such as Peptostreptococcus, Fusobacterium and Prevotella, (in contrast to OM of the long bones, usually caused by isolated Staphylococcus aureus infection). These are the same as the common causative organisms in odotonogenic infections. However, when OM in the jaws follows trauma, is the likely cause is still staphylococcal (usually Staphylococcus epidermis.[3] Other risk factors can be any familial hypercoagulation tendency, including for example, Factor V (Five) Leiden heterozygosity. ## Pathogenesis[edit] OM may occur by direct inoculation of pathogens into the bone (through surgery or injury), by spread of an adjacent area of infection or by seeding of the infection from a non adjacent site via the blood supply (hematogenous spread). Unlike OM of the long bones, hematogenous OM in the bones of the jaws is rare. OM of the jaws is mainly caused by spread of adjacent odontogenic infection. The second most common cause is trauma, including traumatic fracture and usually following a compound fracture (i.e. one that communicates with the mouth or the external environment). In OM of the long bones, a single invading pathogenic micro-organism is usually found (commonly staphylococci spp.).[3] The mandible is affected more commonly than the maxilla. This is thought to be related to the differences in blood supply between the mandible and the maxilla. The maxilla has a better blood supply, and has thin cortical plates and less medullary spaces. These factors mean that infections of the maxilla are not readily confined to the bone, and readily dissipate edema and pus into the surrounding soft tissues and the paranasal air sinuses. OM of the maxilla may rarely occur during an uncontrolled infection of the middle ear or in infants who have sustained birth injury due to forceps. The mandible in contrast has a relatively poor blood supply, which deteriorates with increasing age. The cortical plates are thick and there is a medullary cavity. The sites of the mandible most commonly affected by OM are (decreasing order of frequency) the body, the symphysis, the angle, the ramus and finally the condyle. The mandible's blood supply is primarily via the inferior alveolar artery, and secondarily via the periosteum. Compromise of this supply is a critical factor in the development of OM in the mandible.[3] Most periapical and periodontal infections are isolated by the body which produces a protective pyogenic membrane or abscess wall to keep the area of infection localized. Micro-organisms which are sufficiently virulent may destroy this barrier. Factors which may contribute to this are decreased host resistance, surgery or repeated movement of fracture segments, as may occur with an untreated fracture. Mechanical trauma burnishes the bone, causing ischemia by crushing blood vessels and seeds micro-organisms into the tissues.[3] The events preceding OM are acute inflammatory changes such as hyperemia, increased capillary permeability and infiltration of granulocytes. Proteolytic enzymes are released, and thrombus formation in the blood vessels and tissue necrosis occur. Pus accumulates in the medullary spaces of the bone, which increases the pressure and leads to collapse of the blood vessels, venous stasis and ischemia. Pus may also spread to the sub-periosteal layer, dissecting it away from the surface of the bone and further reducing the blood supply. The inferior alveolar neurovascular bundle is compressed within the mandible, causing anesthesia or paresthesia in the distribution of the mental nerve. Pus may drain via sinuses on the skin and in the mouth, and these may in time become lined with epithelium, when they are termed fistulas.[3] Chronic OM is characterized by a degree of healing which takes place as a lesser degree of inflammation is present. Granulation tissue and new blood vessels form, and fragments of necrotic bone (sequestra) are separated from vital bone. Small sections of necrotic bone may be resorbed completely, and larger segments may become surrounded by granulation tissue and new bone (an involucrum). Sequestra may also be revascularized by new blood vessels, cause no symptoms or become chronically infected. Sometimes the involucrum is penetrated by channels (cloacae) through which pus drains to the skin or mouth.[3] OM of the jaws often occurs in the presence of one or more predisposing factors. These factors are related to compromised vascular perfusion locally, regionally or systemically, causes of immunocompromise and poor wound healing. Specific examples include familial hypercoagulation, diabetes, autoimmune diseases, Agranulocytosis, leukemia, severe anemia, syphilis, chemotherapy, corticosteroid therapy, sickle cell disease, acquired immunodeficiency syndrome, old age, malnutrition, smoking and alcohol consumption, radiotherapy, osteoporosis, Paget's disease of bone, fibrous dysplasia, bone malignancy and causes of bone necrosis such as Bismuth, Mercury or arsenic. Poor compliance or access to health care is also a risk factor.[3] Rarely, OM of the jaws may be a complication of trigeminal herpes zoster. ## Prevention[edit] Regular dental and periodontal assessment and care. ## Treatment[edit] Culture and sensitivity of the wound site determines the choice of antibiotic; however positive cultures rates are generally low for OM, leading to the need for empirical treatment and an increased risk of antibiotic failure. PCR testing may also be done to identify microbe DNA. Repeated culture and sensitivity testing is often carried out in OM since the treatment is prolonged and antibiotic resistance may occur, when a change in the drug may be required.[3] ## Prognosis[edit] Pathologic fracture of the mandible is a possible complication of OM where the bone has been weakened significantly. ## Epidemiology[edit] OM of the jaws can occur in all genders, races and age groups. The mandible is affected more commonly than the maxilla. Globally, the most common cause of OM of the jaws is the spread of adjacent odontogenic infection, followed by trauma, including fracture and surgery. ## References[edit] 1. ^ Peravali RK, Jayade B, Joshi A, Shirganvi M, Bhasker Rao C, Gopalkrishnan K (1 October 2011). "Osteomyelitis of Maxilla in Poorly Controlled Diabetics in a Rural Indian Population". Journal of Maxillofacial and Oral Surgery. 11 (1): 57–66. doi:10.1007/s12663-011-0283-0. PMC 3319832. PMID 23449555. 2. ^ Neville BW, Damm DD, Allen CA, Bouquot JE (2002). Oral & maxillofacial pathology (2nd ed.). Philadelphia: W.B. Saunders. pp. 126–132. ISBN 0721690033. 3. ^ a b c d e f g h Topazian RG, Goldberg MH, Hupp JR (2002). Oral and maxillofacial infections (4th ed.). Philadelphia: W.B. Saunders. pp. 214–235. ISBN 978-0721692715. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Osteomyelitis of the jaws	c0266968	4,747	wikipedia	https://en.wikipedia.org/wiki/Osteomyelitis_of_the_jaws	2021-01-18T18:59:27	{"umls": ["C0266968"], "wikidata": ["Q17155549"]}
Facioscapulohumeral muscular dystrophy is a disorder characterized by muscle weakness and wasting (atrophy). This condition gets its name from the areas of the body that are affected most often: muscles in the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of facioscapulohumeral muscular dystrophy usually appear in adolescence. However, the onset and severity of the condition varies widely. Facioscapulohumeral muscular dystrophy results from a deletion of genetic material from a region of DNA known as D4Z4. This region is located near one end of chromosome 4. It is inherited in an autosomal dominant pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Facioscapulohumeral muscular dystrophy	c0238288	4,748	gard	https://rarediseases.info.nih.gov/diseases/9941/facioscapulohumeral-muscular-dystrophy	2021-01-18T18:00:37	{"mesh": ["D020391"], "omim": ["158900"], "orphanet": ["269"], "synonyms": ["FSHD", "Muscular dystrophy, facioscapulohumeral", "Facioscapulohumeral muscular dystrophy 1A", "FSHMD1A", "Muscular dystrophy, facioscapulohumeral, type 1a", "FSHD1A", "Landouzy-Dejerine muscular dystrophy"]}
## Mapping Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes (IDDM; see 222100), combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with type 1 diabetes in the metaanalysis (P less than 10(-6)). Using an analysis that combined comparisons over the 3 studies, Barrett et al. (2009) confirmed several previously reported associations. Barrett et al. (2009) further tested 27 novel regions in an independent set of 4,267 cases and 4,463 controls, and 2,319 affected sib pair families. Of these, 18 regions were replicated (P less than 0.01; overall P less than 5 x 10(-8)) and 4 additional regions provided nominal evidence of replication. The strongest evidence of association among these novel regions was achieved at rs10509540 (combined P = 1.3 x 10(-28)), on chromosome 10q23.31 near the RNLS gene (609360). ### Possible Role in Insulin-Dependent Diabetes Mellitus For discussion of a possible role of the SIRT1 gene in type 1 diabetes mapping to 10q23, see 604479.0001. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	DIABETES MELLITUS, INSULIN-DEPENDENT, 24	c2751697	4,749	omim	https://www.omim.org/entry/613006	2019-09-22T16:00:04	{"mesh": ["C567818"], "omim": ["613006"]}
A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is caused by homozygous mutation in the OTUD6B gene (612021) on chromosome 8q21. Description IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by Santiago-Sim et al., 2017). Clinical Features Santiago-Sim et al. (2017) reported 9 patients from 5 unrelated families with a neurodevelopmental disorder characterized by significant global developmental delay apparent since infancy and absent speech even in the teenaged patients. All patients had early-onset seizures; most seizures were generalized tonic-clonic, but some were absence, myoclonic, and atonic. The severity and the frequency of seizures was highly variable, with 1 patient having only a single seizure at age 4. The patients had hypotonia and poor motor development; all but 1 were nonambulatory. Most patients had intrauterine growth retardation, and all had severe feeding difficulties, often associated with failure to thrive and poor overall growth; 3 patients required a feeding tube. Two sibs had spastic quadriplegia, and 3 sibs from another family had autism spectrum disorder. Brain imaging was normal in 3 patients, but showed nonspecific changes in 6 patients, including cortical changes, white matter atrophy, enlarged ventricles, and hypoplastic corpus callosum. All patients had variable dysmorphic features, including microcephaly (up to -6.5 SD), brachycephaly, flat occiput, arched eyebrows, long downslanting palpebral fissures, long nose, broad nasal root, smooth long philtrum, thin upper lip, retrognathia, high-arched palate, large protruding low-set ears, and short neck. Other congenital malformations included cardiac septal defects (4 patients), sacral dimple (2 patients), cryptorchidism (3 patients), scoliosis, and abnormalities of the distal extremities, such as broad thumbs, hyperextensibility of the interphalangeal joints, clubfeet, and overlapping toes. Two of the patients had deceased sibs with a similar disorder. ### Clinical Variability Santiago-Sim et al. (2017) reported 3 sibs, born of consanguineous Turkish parents, with a slightly less severe form of IDDFSDA. They presented with seizures at 18 months, 7 years, and 8 years of age. The patients, who ranged in age from 14 to 20 years, had mild to moderate intellectual disability and no speech or motor delay. They had dysmorphic features, including wide forehead, narrow long face, and high-arched palate; 1 patient had downslanting palpebral fissures, tubular nose, and prominent dysplastic ears. Other features included arachnodactyly and hyperextensibility of the elbows. Brain imaging was normal. Inheritance The transmission pattern of IDDFSDA in the families reported by Santiago-Sim et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 12 patients from 6 unrelated families with IDDFSDA, Santiago-Sim et al. (2017) identified 4 homozygous mutations in the OTUD6B gene (612021.0001-612021.0004). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients from 5 families had a truncating mutation associated with a more severe phenotype; patients in the sixth family had a missense mutation and a slightly less severe phenotype. The findings were consistent with a loss-of-function effect. Peripheral blood cells from 1 patient with a truncating mutation (612021.0002) showed decreased chymotrypsin-like activity of the 26S proteasome complex and substantially reduced incorporation of 19S subunits into 26S proteasomes. This was associated with accumulation of ubiquitin-protein conjugates. Transmission electron microscopy showed abnormal cytoplasmic inclusions in lymphocytes, suggesting that these inclusions represent accumulation of protein substrates due to an imbalance in ubiquitination/deubiquitination activities. The findings indicated that dysregulation of the ubiquitin system is the cause of this multisystem disease. Animal Model Santiago-Sim et al. (2017) reported that homozygous Otud6b-null mice die between embryonic day 18.5 and shortly after birth. Mutant embryonic mice showed intrauterine growth retardation and a high percentage of ventricular septal cardiac defects. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Low weight Other \- Intrauterine growth retardation (IUGR) \- Failure to thrive HEAD & NECK Head \- Microcephaly (up to -6.5 SD) \- Brachycephaly \- Flat occiput Face \- Long face \- Long philtrum \- Retrognathia Ears \- Large ears \- Protruding ears \- Low-set ears \- Dysplastic ears \- Hearing loss Eyes \- Arched eyebrows \- Downslanting palpebral fissures \- Long palpebral fissures \- Long eyelashes Nose \- Broad nasal root \- Prominent nasal bridge Mouth \- Thin upper lip \- High-arched palate Neck \- Short neck CARDIOVASCULAR Heart \- Cardiac septal defects (in some patients) ABDOMEN Gastrointestinal \- Feeding difficulties GENITOURINARY External Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint contractures Spine \- Scoliosis Hands \- Broad thumbs \- Hyperextensibility of phalanges \- Tapered fingers Feet \- Club feet \- Overriding toes SKIN, NAILS, & HAIR Skin \- Sacral dimple MUSCLE, SOFT TISSUES \- Hypotonia \- Hypertonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Intellectual disability, severe \- Absence of speech \- Inability to walk \- Spastic quadriplegia \- Seizures, early-onset, multiple types \- Cortical abnormalities \- Enlarged ventricles \- Hypoplastic corpus callosum Behavioral Psychiatric Manifestations \- Autism spectrum disorder MISCELLANEOUS \- Variable phenotype \- One family with a slightly less severe phenotype has been reported MOLECULAR BASIS \- Caused by mutation in the OTU domain-containing protein 6B gene (OTUD6B, 612021.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES, SEIZURES, AND DISTAL LIMB ANOMALIES	c4479520	4,750	omim	https://www.omim.org/entry/617452	2019-09-22T15:45:48	{"omim": ["617452"], "orphanet": ["505237"], "synonyms": []}
Condition of the spinal cord with symptoms of rapid onset of arm or leg weakness Acute flaccid myelitis Other namesAcute flaccid paralysis with anterior myelitis, polio-like syndrome[1] Magnetic resonance imaging of the spinal cord in a case of AFM showing cord swelling in (d) which has resolved three weeks later in (e).[2] SpecialtyNeurology[3] SymptomsWeakness, decreased reflexes, trouble swallowing or speaking[3] ComplicationsTrouble breathing, urinary retention[3] Usual onsetRapid[3] CausesGenerally unknown,Thought to be caused by Viral infection[4] Diagnostic methodMedical imaging, nerve conduction studies, cerebral spinal fluid testing[3][5] Differential diagnosisTransverse myelitis, Guillain–Barré syndrome, acute disseminated encephalomyelitis[3][5] PreventionPolio vaccination, avoiding mosquitoes bites[5] TreatmentSupportive care, physical therapy, mechanical ventilation[3][5] PrognosisVariable[5] FrequencyRare[4] Acute flaccid myelitis (AFM) is a serious condition of the spinal cord.[3][5] Symptoms include rapid onset of arm or leg weakness and decreased reflexes.[3] Difficulty moving the eyes, speaking, or swallowing may also occur.[3] Occasionally, numbness or pain may be present.[3] Complications can include trouble breathing.[3] The cause of most cases is unclear as of 2018.[4] More than 90% of recent cases have followed a mild viral infection such as from enteroviruses.[4] While polio can cause AFM, since 2014, it has not been involved in cases in the United States.[3][6] The underlying mechanism involves damage to the spinal cord's grey matter.[3] Diagnosis may be supported by medical imaging of the spine, nerve conduction studies, and cerebrospinal fluid testing.[3][5] Prevention includes polio vaccination and avoiding mosquito bites.[5] Treatment involves supportive care.[5][3] Physical therapy may be recommended.[3] Occasionally, mechanical ventilation is required to support breathing.[3] Outcomes are variable.[5] The condition is rare and occurs most commonly in children.[4] Fewer than one in 500,000 children is affected per year in the United States.[3] Although the illness is not new, an increase in cases has been seen since 2014 in the United States.[3] In 2018, 233 cases were confirmed in the United States.[7] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Outcomes * 7 Epidemiology * 8 History * 9 References ## Signs and symptoms[edit] Symptoms include: * Difficulty moving the eyes or drooping eyelids * Facial droop or weakness * Difficulty with swallowing or slurred speech * Sudden arm or leg weakness[8] A summary of the condition by the Centers for Disease Control and Prevention (CDC) in 2014:[9] > Common features included acute focal limb weakness and specific findings on magnetic resonance imaging (MRI) of the spinal cord consisting of nonenhancing lesions largely restricted to the grey matter. In most cases, these lesions spanned more than one level of the spinal cord. Some also had acute cranial nerve dysfunction with correlating nonenhancing brainstem lesions on MRI. None of the children experienced altered mental status or seizures. None had any cortical, subcortical, basal ganglial, or thalamic lesions on MRI. Most children reported a febrile respiratory illness in the two weeks preceding development of neurologic symptoms. In most cases, cerebrospinal fluid (CSF) analyses demonstrated mild-moderate pleocytosis (increased cell count in the CSF) consistent with an inflammatory or infectious process. ## Causes[edit] Maximum likelihood phylogenetic trees of enterovirus species A, B, C, D and rhinovirus A, B, or C isolates from Latin America: The 5'UTR region is much more affected by recombination events than the VP4/VP2 coding sequence.[10] Polio is in the enterovirus C species; enterovirus 71, a strain of enterovirus A, has been reported to cause rare neurological complications; the suspected cause of the 2014 cases is a strain of enterovirus D. Most enteroviruses and rhinoviruses cause only common cold symptoms. As of October 2018[update], the U.S. CDC regarded the cause of AFM as having "a variety of possible causes such as viruses, environmental toxins, and genetic disorders", listing poliovirus, nonpolio enteroviruses, West Nile virus, and adenoviruses among the potential causes.[3][7] More than 90% of people with AFM reported having symptoms consistent with a mild viral infection before the onset of AFM.[11] Much research has focused on the nonpolio enteroviruses 68 (EV-D68) and 71 (EV-A71), a common cause of hand, foot, and mouth disease in infants and young children, members of the enterovirus D and enterovirus A species, respectively, as suspected causes.[7] Some evidence supports a causal role of EV-D68.[12] Coxsackievirus A16 may also play a role in some cases.[13] A 2014 Morbidity and Mortality Weekly Report report noted the difficulty of establishing causation by the virus.[14] Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke and president of the International Society for NeuroVirology, compared the situation to the prolonged investigations that led to confirmation of HIV as the cause of AIDS. In response to the suggestion that the enterovirus might be taking over the role of polio, Nath said that EV-D68 was far less virulent and spread much more slowly than polio, and that unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should also be evaluated for neurological deficits, and that infectious disease should be considered as a cause when patients presented with neurological symptoms.[15] A subsequent report described 29 cases of EV-D68-associated AFM in Europe in 2016, noting, "these probably represent only the tip of the iceberg."[16] ## Diagnosis[edit] AFM is diagnosed by examining a person's nervous system in combination with reviewing images of the spinal cord. A doctor can examine a person's nervous system and the places on the body where he or she has weakness, poor muscle tone, and decreased reflexes. In addition, a doctor can do magnetic resonance imaging to look at a person's brain and spinal cord, do laboratory tests on the cerebrospinal fluid (CSF, the fluid around the brain and spinal cord), and may check nerve conduction (impulse sent along a nerve fiber) and response.[17] Diagnosis of AFM requires acute onset limb paralysis and at least one gray-matter spinal-cord lesion. CSF should show pleocytosis.[18] ## Prevention[edit] The CDC recommends, "To prevent infections in general, persons should stay home if they are ill, wash their hands often with soap and water, avoid close contact (such as touching and shaking hands) with those who are ill, and clean and disinfect frequently touched surfaces."[14] ## Treatment[edit] Treatment involves supportive care.[5][3] Physical therapy may be recommended.[3] Occasionally mechanical ventilation is required to support breathing.[3][7] If immunoglobulin, corticosteroids, plasma exchange, or antiviral medication are useful is unclear.[5][7] ## Outcomes[edit] Studies from 2014 to 2017 indicated a poor outcome for many cases. Seven of 61 cases with EVD68 detected and eight long‐term follow‐ups had full recovery; two deaths were described in severely immunocompromised people (one with EVD68 and one with both EVD68 and coxsackie A16 detected).[19] Six of 10 children in Denver were sent home for outpatient treatment; some with mild symptoms have recovered from temporary limb weakness, while the fate of those more severely affected remains unclear. Intensive physical therapy and occupational therapy may be beneficial for recovery.[20][21][22] ## Epidemiology[edit] Graph showing the seasonal nature of the occurrence of AFM: Notable increases occurred in the late summers of 2014, 2016, and 2018. A seasonal pattern is seen in outbreaks, with a marked increase in cases reported in the late summer and early fall.[23] The CDC has determined and submitted to GenBank complete or nearly complete genomic sequences for three known strains of the virus, which are "genetically related to strains of EV-D68 virus that were detected in previous years in the United States, Europe, and Asia."[24] While rates of paralytic symptoms appear to be correlated with the number of respiratory infections, in initial anecdotal reports, the cases are not clustered within a family or school, suggesting that the paralysis per se is not directly contagious, but arises as a very rare complication of the common respiratory infection.[20] Cases of similar illnesses have been reported in Canada, Northern Europe, and Japan.[18] Over 90% of reported cases are in children.[25] ## History[edit] AFM has only been formally tracked since 2014, since the incidence has spiked in recent years.[citation needed] A group in Texas reported having observed a pattern in 2013 of one to four cases per year with similar polio-like characteristics.[20] In 2014, the CDC Morbidity and Mortality Weekly Report[14] and a CDC Clinician Outreach and Communication Activity (COCA) conference call,[26] noted that many cases had neck, back, or extremity pain, but otherwise those affected generally had normal sensation in their limbs.[27] A few participants in the conference call discussed whether pain, later abating, might precede the onset of paralysis.[26][28] An October 2014 report described outbreaks in California and Colorado, suggesting that the number of cases might be 100 or more nationwide.[29] Diagnosis included a detailed medical history, MRI imaging, and the elimination of transverse myelitis or Guillain–Barré syndrome as potential causes. Physicians were using an online mailing list to communicate about similar cases in Alabama and Kansas. The largest known cluster of cases was in Colorado, with 29 total, 12 of whom had been reported from August and onwards of that year.[29] Three of four cases treated in Alabama involved a complete inability to move one arm, reminiscent of peripheral nerve injury: > The three cases since August really look like each other. They have severe arm flaccidity and no mental status changes. All of them have similar spine MRIs showing gray-matter involvement. You could lay all three MRIs on top of each other and they look almost the same. It's pretty striking. ... It you lift the arm up, it literally drops. Sensation is usually intact. There might be slightly decreased sensation in the other arm, but these are younger kids, so they're not always so cooperative in giving you a good sensory exam.[29] Children's Mercy Hospital, which had three or four cases in 2014, reported that the MRI images and symptoms closely mimicked polio. They reported: "The sudden onset of flaccid paralysis in single or multiple limbs with absolutely no sensory findings, the MRIs all showing uniformly a signal increase in the ventral horns of the spinal cord — this is exactly the same region of the spinal cord affected in polio ... Almost all of the patients have an increase in their white blood cells in the cerebrospinal fluid. Some of the patients have brainstem findings and cranial-nerve findings."[29] Of 64 patients meeting the CDC criteria before October 29, 2014, 80% had had a preceding respiratory illness and 75% reported fever in the days leading up to limb weakness, the onset of which was generally abrupt.[30] By November 20, the number of confirmed cases stood at 88 from 29 states.[31] The CDC requested that physicians provide information about cases meeting these criteria: patients diagnosed after August 1, 2014, who are no older than 21 years of age, showing acute onset of focal limb weakness, with a spinal-cord lesion largely restricted to grey matter visualized by MRI.[9][29] In November 2018, the CDC reported that they were investigating 286 cases, with at least 116 confirmed cases in 31 states.[32] The CDC is setting up a task force to investigate the causes and to find treatments.[33] ## References[edit] 1. ^ "Acute Flaccid Myelitis" (PDF). www.dhs.wisconsin.gov. January 2017. Archived (PDF) from the original on 1 May 2018. Retrieved 22 December 2018. 2. ^ Esposito, S; Chidini, G; Cinnante, C; Napolitano, L; Giannini, A; Terranova, L; Niesters, H; Principi, N; Calderini, E (11 January 2017). "Acute flaccid myelitis associated with enterovirus-D68 infection in an otherwise healthy child". Virology Journal. 14 (1): 4. doi:10.1186/s12985-016-0678-0. PMC 5234096. PMID 28081720. 3. ^ a b c d e f g h i j k l m n o p q r s t u v w x "About Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). Archived from the original on 2018-10-11. Retrieved 2018-10-11. This article incorporates text from this source, which is in the public domain. 4. ^ a b c d e "Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). 17 December 2018. Archived from the original on 21 December 2018. Retrieved 21 December 2018.CS1 maint: unfit URL (link) This article incorporates text from this source, which is in the public domain. 5. ^ a b c d e f g h i j k l "Acute flaccid myelitis". rarediseases.info.nih.gov. 2018. Archived from the original on 22 December 2018. Retrieved 22 December 2018. 6. ^ Bitnun, A; Yeh, EA (29 June 2018). "Acute Flaccid Paralysis and Enteroviral Infections". Current Infectious Disease Reports. 20 (9): 34. doi:10.1007/s11908-018-0641-x. PMID 29959591. S2CID 49619082. 7. ^ a b c d e Lopez A, Lee A, Guo A, Konopka-Anstadt JL, Nisler A, Rogers SL, et al. (July 9, 2019). "Vital Signs: Surveillance for Acute Flaccid Myelitis — United States, 2018" (PDF). MMWR Morb Mortal Wkly Rep. 68 (27): 608–14. doi:10.15585/mmwr.mm6827e1. PMID 31295232. Archived (PDF) from the original on July 13, 2019. Retrieved July 13, 2019. "During 2018, 233 confirmed AFM cases were reported, the largest number since surveillance began in 2014. Upper limb involvement only was more prevalent in confirmed cases (42%), as was report of respiratory symptoms or fever (92%) within four weeks preceding limb weakness onset. Median intervals from onset of limb weakness to hospitalization, magnetic resonance imaging, and reporting to CDC were 1, 2, and 18 days, respectively" This article incorporates text from this source, which is in the public domain. 8. ^ "How to Spot Symptoms of Acute Flaccid Myelitis in Your Child Infographic". Centers for Disease Control and Prevention (CDC). Archived from the original on 11 October 2018. Retrieved 10 October 2018. This article incorporates text from this source, which is in the public domain. 9. ^ a b "Acute neurologic illness with focal limb weakness of unknown etiology in children". Centers for Disease Control and Prevention (CDC). 2014-09-26. Archived from the original on 2018-11-15. Retrieved 2018-11-15. This article incorporates text from this source, which is in the public domain. 10. ^ Josefina Garcia; et al. (2013). "Human rhinoviruses and enteroviruses in influenza-like illness in Latin America". Virol. J. 10: 305. doi:10.1186/1743-422x-10-305. PMC 3854537. PMID 24119298. 11. ^ "Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). 1 March 2019. Archived from the original on 29 March 2019. Retrieved 29 March 2019. This article incorporates text from this source, which is in the public domain. 12. ^ Dyda, Amalie (1 January 2018). "The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) - what is the evidence for causation?". Eurosurveillance. 23 (3). doi:10.2807/1560-7917.ES.2018.23.3.17-00310. PMC 5792700. PMID 29386095. 13. ^ "Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). 22 October 2018. Archived from the original on 22 October 2018. Retrieved 22 October 2018. This article incorporates text from this source, which is in the public domain. 14. ^ a b c Pastula DM, Aliabadi N, Haynes AK, Messacar K, Schreiner T, Maloney J, et al. (2014-10-10). "Acute neurologic illness of unknown etiology in children - Colorado, August-September 2014" (PDF). MMWR Morb. Mortal. Wkly. Rep. 63 (40): 901–2. PMC 4584613. PMID 25299607. Archived (PDF) from the original on 2017-06-24. Retrieved 2019-07-13. This article incorporates text from this source, which is in the public domain. 15. ^ Pauline Anderson (2014-10-17). "Neurovirologists Confer Over Mysterious Neurologic Disease". Medscape. Archived from the original on 2014-10-23. Retrieved 2014-10-25. 16. ^ Knoester, Marjolein et al. on behalf of the 2016 EV-D68 AFM Working Group (2018-09-18). "Twenty-Nine Cases of Enterovirus-D68 Associated Acute Flaccid Myelitis in Europe 2016; A Case Series and Epidemiologic Overview". The Pediatric Infectious Disease Journal. 38 (1): 16–21. doi:10.1097/INF.0000000000002188. hdl:11250/2588203. PMC 6296836. PMID 30234793. 17. ^ "About Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). Archived from the original on 10 October 2018. Retrieved 10 October 2018. This article incorporates text from this source, which is in the public domain. 18. ^ a b "UpToDate". www.uptodate.com. Archived from the original on 1 November 2018. Retrieved 31 October 2018. 19. ^ Suresh, Sneha; Forgie, Sarah; Robinson, Joan (2018). "Non‐polio Enterovirus detection with acute flaccid paralysis: A systematic review". Journal of Medical Virology. 90 (1): 3–7. doi:10.1002/jmv.24933. PMID 28857219. S2CID 33163720. 20. ^ a b c "An Update on Outbreak of Paralysis in US: Acute Flaccid Myelitis". The transverse myelitis association. 2014-10-16. Archived from the original on 2018-08-02. Retrieved 2018-08-02. (audio) 21. ^ Enterovirus D68 and Paralysis (2014-10-03). "Enterovirus D68 and Paralysis". The Disease Daily/Outbreak News/Healthmap. Archived from the original on 2014-10-25. Retrieved 2014-10-25. 22. ^ "Children's Hospital: 10th Colorado child has paralysis-like symptoms; may be tied to Enterovirus 68". Thedenverchannel.com. 2014-09-29. Archived from the original on 2014-10-25. Retrieved 2014-10-25. 23. ^ "AFM Cases in the US". Centers for Disease Control and Prevention (CDC) Centers for Disease Control and Prevention (CDC). 1 March 2019. Archived from the original on 29 March 2019. Retrieved 29 March 2019. This article incorporates text from this source, which is in the public domain. 24. ^ Pediatrics, American Academy of (2014-10-03). "CDC continues investigation of neurologic illness; will issue guidelines". AAP News. AAP News/American Academy of Pediatrics: E141003-1. doi:10.1542/aapnews.20141003-1 (inactive 2021-01-17). Archived from the original on 2014-10-26. Retrieved 2014-10-26.CS1 maint: DOI inactive as of January 2021 (link) 25. ^ "Acute Flaccid Myelitis". Centers for Disease Control and Prevention (CDC). 1 March 2019. Archived from the original on 29 March 2019. Retrieved 29 March 2019. This article incorporates text from this source, which is in the public domain. 26. ^ a b "Neurologic Illness with Limb Weakness in Children". Centers for Disease Control and Prevention (CDC). 2014-10-03. Archived from the original on 2014-10-25. Retrieved 2014-10-25. This article incorporates text from this source, which is in the public domain. 27. ^ "Neurologic Deficits in Children Preceded by Febrile Illness". American Academy of Family Physicians. 2014-10-13. Archived from the original on 2014-10-25. Retrieved 2014-10-25. 28. ^ Robert Roos (2014-10-03). "Role of EV-D68 in polio-like illnesses still unclear". Center for Infectious Disease Research and Policy. Archived from the original on 2014-10-25. Retrieved 2014-10-25. 29. ^ a b c d e Dan Hurley (2014-10-21). "Cases of acute flaccid myelitis in children suspected in multiple states, prompting comparisons to polio". Neurology News. Archived from the original on 2014-10-24. Retrieved 2014-10-24. 30. ^ Pediatrics, American Academy of (2014-11-12). "CDC releases guidance on acute flaccid myelitis". AAP News. AAP News (American Academy of Pediatrics): E141112-1. doi:10.1542/aapnews.20141112-1 (inactive 2021-01-17).CS1 maint: DOI inactive as of January 2021 (link) 31. ^ "Investigation of Acute Neurologic Illness with Focal Limb Weakness of Unknown Etiology in Children, Fall 2014". Centers for Disease Control and Prevention (CDC). Archived from the original on 2014-11-18. Retrieved 2014-11-21. This article incorporates text from this source, which is in the public domain. Note: despite the URL, this Web document is regularly updated, including the text: "As of November 20, CDC has verified reports of 88 cases in 32 states. We are working with healthcare professionals and state and local officials to investigate all of these cases. We are also in the process of verifying less than half a dozen additional reports." 32. ^ Fox, Maggie (November 26, 2018). "More cases of this paralyzing condition have been reported to CDC". NBC News. Archived from the original on November 27, 2018. Retrieved 2018-11-27. 33. ^ "CDC confirms 116 cases of rare polio-like illness, acute flaccid myelitis". www.msn.com. Archived from the original on 2018-11-27. Retrieved 2018-11-27. * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Acute flaccid myelitis	c4290000	4,751	wikipedia	https://en.wikipedia.org/wiki/Acute_flaccid_myelitis	2021-01-18T18:30:51	{"gard": ["13142"], "mesh": ["C000629404"], "umls": ["CL508662"], "wikidata": ["Q18350119"]}
A number sign (#) is used with this entry because of evidence that this form of congenital diarrhea, designated DIAR6, is caused by heterozygous mutation in the GUCY2C gene (601330) on chromosome 12p12. Description Diarrhea-6 is a relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis (Fiskerstrand et al., 2012). For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700). Clinical Features Fiskerstrand et al. (2012) studied 32 affected and 14 unaffected individuals from 3 branches of a large pedigree segregating autosomal dominant early-onset chronic diarrhea. The diarrhea started in infancy and was fairly constant over the years, but improved by middle age in some. Patients had an average of 3.6 stools per day, which typically were watery or of loose consistency and were accompanied by gaseous distention of the abdomen (meteorism) and in some cases abdominal pain. Eight patients were hospitalized as newborns for dehydration, metabolic acidosis, and electrolyte disturbances. Four family members had been diagnosed with irritable bowel syndrome although they did not meet strict criteria for diagnosis; however, 5 other cases did meet the criteria. Most family members reported food sensitivities, and several limited their intake of fruits, vegetables, and sweets. Ten patients underwent laparotomy for suspected bowel obstruction, and in 8 cases, obstruction due to volvulus, adhesions, or ileal inflammation was confirmed. Of 5 patients who underwent bowel resection, 4 had verified or suspected Crohn disease (see 266600), as did 3 other affected family members, and another patient was diagnosed with possible eosinophilic enteritis. Fiskerstrand et al. (2012) noted that there were several other conditions present in affected family members that might be associated with the inherited disorder, including vitamin B12 deficiency in 6 patients, esophagitis with or without esophageal hernia in 5, and urolithiasis in 4. Mapping Fiskerstrand et al. (2012) performed linkage analysis using DNA samples from 11 affected and 14 unaffected members of a large pedigree segregating autosomal dominant early-onset chronic diarrhea and identified only 1 significant shared region among affected members, a 2.9-Mb interval on chromosome 12p (chr12:14,466,726-17,410,570, NCBI36), with a maximum lod score of 5.1. There was complete segregation with disease in the family. Molecular Genetics In a large pedigree with early-onset chronic diarrhea mapping to chromosome 12p, Fiskerstrand et al. (2012) sequenced the candidate gene GUCY2C (601330) and identified a heterozygous missense mutation (S840I; 601330.0001) that segregated with the disease and was not found in 190 healthy local blood donors or in the NCBI human dbSNP database (build 132). Whole-exome sequencing in 1 patient from each of 3 branches of the pedigree did not identify any other rare coding variant, and the S840I mutation was confirmed to be present in all affected family members by Sanger sequencing. Functional analysis suggested that the mutation represented a gain-of-function change. INHERITANCE \- Autosomal dominant ABDOMEN External Features \- Meteorism (gaseous distention of the stomach or intestine) Gastrointestinal \- Diarrhea, chronic, early-onset mild \- Abdominal pain (in some patients) \- Dehydration in infancy (in some patients) \- Metabolic acidosis in infancy (in some patients) \- Electrolyte disturbances in infancy (in some patients) \- Small-bowel obstruction due to volvulus (in some patients) \- Small-bowel obstruction due to adhesions (in some patients) \- Small-bowel obstruction due to ileal inflammation (in some patients) \- Crohn disease (in some patients) \- Irritable bowel syndrome (in some patients) \- Esophagitis, with or without esophageal hernia (in some patients) GENITOURINARY Ureters \- Urolithiasis (in some patients) METABOLIC FEATURES \- Metabolic acidosis in infancy (in some patients) \- Electrolyte disturbances in infancy (in some patients) LABORATORY ABNORMALITIES \- Vitamin B12 deficiency (in some patients) MOLECULAR BASIS \- Caused by mutation in the guanylate cyclase 2C gene (GUCY2C, 601330.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	DIARRHEA 6	c3553270	4,752	omim	https://www.omim.org/entry/614616	2019-09-22T15:54:48	{"doid": ["0060780"], "omim": ["614616"], "orphanet": ["314373"], "synonyms": []}
Tension myositis syndrome Pseudomedical diagnosis RisksNocebo Tension myositis syndrome (TMS), also known as tension myoneural syndrome or mindbody syndrome is a name given by John E. Sarno to a condition of psychogenic musculoskeletal and nerve symptoms, most notably back pain.[1][2][3] Sarno described TMS in four books,[4][5][6][7] and stated that the condition may be involved in other pain disorders as well.[2] The treatment protocol for TMS includes education, writing about emotional issues, resumption of a normal lifestyle and, for some patients, support meetings and/or psychotherapy.[1][8] In 2007, David Schechter (a medical doctor and former student and research assistant of Sarno's) published a peer-reviewed study of TMS treatment in the journal "Alternative Therapies in Health and Medicine," showing a 54% success rate for chronic back pain. In terms of statistical significance and success rate, the study outperformed similar studies of other psychological interventions for chronic back pain.[1] The TMS diagnosis and treatment protocol are not accepted by the mainstream medical community.[9][10] However, TMS and Sarno's treatment methods have received national attention, including a segment on ABC's 20/20;[10] an episode of Larry King Live;[11] an interview with Medscape;[2] and articles in Newsweek,[12] The Seattle Times,[13] and The New York Times.[9] Celebrity doctors who support TMS treatment include Andrew Weil[14][15] and Mehmet Oz.[16] Notable patients treated for tension myositis syndrome include Senator Tom Harkin, John Stossel,[3] Howard Stern,[17] and Anne Bancroft.[9] In 2017, TMS was covered favorably in journalist C. J. Ramin's book "Crooked". Ramin, who herself suffered from back pain for decades, criticized many of the popular back pain treatments and remarked Sarno as "the rock star of the back world".[18] ## Contents * 1 Theory * 2 Symptoms * 3 Diagnosis * 4 Treatment * 4.1 Treatment protocol * 4.2 Medical evidence * 5 Notable patients * 6 Controversy * 7 Notes and references * 8 External links ## Theory[edit] According to Sarno, TMS is a condition in which unconscious emotional issues (primarily rage) initiate a process that causes physical pain and other symptoms. His theory suggests that the unconscious mind uses the autonomic nervous system to decrease blood flow to muscles, nerves or tendons, resulting in oxygen deprivation (temporary micro-ischemia) and metabolite accumulation, experienced as pain in the affected tissues.[2][8][19] Sarno theorizes that because patients often report that back pain seems to move around, up and down the spine, or from side to side, that this implies the pain may not be caused by a physical deformity or injury.[7] Sarno states that the underlying cause of the pain is the mind's defense mechanism against unconscious mental stress and emotions such as anger, anxiety and narcissistic rage. The conscious mind is distracted by the physical pain, as the psychological repression process keeps the anger/rage contained in the unconscious and thereby prevented from entering conscious awareness.[20][21] Sarno believes that when patients recognize that the symptoms are only a distraction, the symptoms then serve no purpose, and they go away. TMS can be considered a psychosomatic condition and has been referred to as a "distraction pain syndrome".[22] Sarno is a vocal critic of conventional medicine with regard to diagnosis and treatment of back pain, which is often treated by rest, physical therapy, exercise and/or surgery.[5] ## Symptoms[edit] Back pain is frequently mentioned as a TMS symptom,[1][8][23][20] but Sarno defines TMS symptoms much more broadly than that: * Symptom type: TMS symptoms include pain, stiffness, weakness, tingling, numbness, muscle contractures, cramps and other negative sensations, according to Sarno. * Symptom location: In addition to the back, Sarno states that TMS symptoms can occur in the neck, knee, arms, wrists, and other parts of the body.[2] Schechter states that the symptoms have a tendency to move to other parts of the body. He considers symptom movement an important indicator that the pain is from TMS.[1] ## Diagnosis[edit] Below is a list of criteria for diagnosing TMS, according to Schechter and Sarno: * Lack of known physical cause: Schechter and Sarno state that a physical examination, tests and imaging studies is needed to rule out serious conditions, such as tumors.[1][5] Sarno considers spinal disc herniations to generally be harmless, because he says the symptom location does not even correlate to the herniation location.[5] * Tender points:[1] While medical doctors use eleven of eighteen tender points as a diagnostic criteria for fibromyalgia, Sarno states that he uses six main tender points to diagnose TMS: two tender points in the upper trapezius muscles, two in the lumbar paraspinal muscles and two in the lateral upper buttocks. He states that these are found in 99% of TMS patients.[7] * History of other psychosomatic disorders: Schechter and Sarno consider a prior history of other psychosomatic disorders an indication that the patient may have TMS. They list irritable bowel syndrome and tension headache as examples of psychosomatic disorders.[1][7] Schechter and Sarno state that if a patient is unable to visit a medical doctor who is trained in TMS, then the patient should see a traditional medical doctor to rule out serious disorders, such as fractures, tumors and infections.[13][22] ## Treatment[edit] ### Treatment protocol[edit] The treatment protocol for TMS includes education, writing about emotional issues and resumption of a normal lifestyle. For patients who do not recover quickly, the protocol also includes support groups and/or psychotherapy.[1][8] Sarno's protocol for treatment of TMS is used by the Harvard RSI Action Group, a student volunteer organization, as part of their preventative education and support program for people with repetitive strain injury, also referred to as "RSI".[24] Education Education may take the form of office visits, lectures and written and audio materials. The content of the education includes the psychological and physiological aspects of TMS.[1][8] According to Schechter, the education allows the patients to "learn that their physical condition is actually benign and that any disability they have is a function of pain-related fear and deconditioning, not the actual risk of further 're-injury.'"[1] Writing about emotional issues Sarno states that each patient should set aside time daily to think and write about issues that could have led to the patient's repressed emotions. He recommends the following two writing tasks: * Writing a list of issues. Dr. Sarno states that each patient should try to list out all issues that might contribute to the patient's repressed emotions. He suggests looking in the following areas: * (a) certain childhood experiences, such as abuse or lack of love, * (b) personality traits such as perfectionism, conscientiousness and a strong need to be liked, approved or validated by everyone, * (c) current life stresses and pressures, * (d) aging and mortality and * (e) situations in which the patient experiences conscious but unexpressed anger. * Writing essays. Dr. Sarno recommends that the patient write an essay for each item on the above list. He prefers longer essays because they force the patient to examine the emotional issues in depth.[6] Schechter developed a 30-day daily journal called "The MindBody Workbook" to assist the patient in recording emotionally significant events and making correlations between those events and their physical symptoms. According to Sarno and Schechter, daily repetition of the psychological process over time defeats the repression through conscious awareness.[25] Resumption of a normal lifestyle To return to a normal lifestyle, patients are told to take the following actions: * Discontinuation of physical treatments - Sarno advises patients to stop using spinal manipulation, physical therapy and other physical treatments because "they tend to reinforce erroneously a structural causation for the chronic pain."[8] * Resumption of normal physical activity - Schechter states that patients are encouraged to "gradually be more active, and begin to resume a normal life."[1] In addition, patients are encouraged "to discontinue the safety behaviours aimed at protecting their 'damaged' backs".[22] Support meetings Sarno uses support meetings for patients who do not make a prompt recovery. Sarno states that the support meetings (a) allow the patients to explore emotional issues that may be causing their symptoms and (b) review concepts covered during the earlier education.[8] Psychotherapy Sarno says that about 20% of his patients need psychotherapy. He states that he uses "short-term, dynamic, analytically oriented psychotherapy."[8] Schechter says that he uses psychotherapy for about 30% of his patients, and that six to ten sessions are needed per patient.[1] Recovery Program Alan Gordon, LCSW has created a TMS recovery program which includes various articles, exercises, and segments from sessions exemplifying therapeutic concepts. ### Medical evidence[edit] While psychogenic pain and pain disorder are accepted diagnoses in the medical community, the TMS modality is more controversial. A non-peer-reviewed 2005 study by Schechter at the Seligman Medical Institute (SMI), co-authored with institute director Arthur Smith, found that treatment of TMS achieved a 57% success rate among patients with chronic back pain.[26] A peer-reviewed[27] 2007 study with Schechter, Smith and Stanley Azen, Professor and Co-Director of Biostatistics in the Department of Preventative Medicine at the USC Keck School of Medicine, found a 54% success rate for treatment of TMS (P<.00001). The treatment consisted of office visits, at-home educational materials, writing about emotional issues and psychotherapy. The average pain duration for the study's patients was 9 years. Patients with less than 6 months of back pain were excluded to "control for the confounder that most back pain episodes typically resolve on their own in a few weeks."[1] Schechter, Smith and Azen also compared their results to the results of three studies of other psychological treatments for chronic back pain. The three non-TMS studies were selected because of (a) their quality, as judged by the Cochrane Collaboration, and (b) the similarity of their pain measurements to those used in the TMS study. Of the three non-TMS studies, only one (the Turner study) showed a statistically significant improvement. Compared to the 2007 TMS study, the Turner study had a lower success rate (26–35%, depending on the type of psychological treatment) and a lower level of statistical significance (P<.05).[1] Schechter, et al. state that one advantage of TMS treatment is that it avoids the risks associated with surgery and medication, but they caution that the risks of TMS treatment are somewhat unknown due to the relatively low number of patients studied so far.[1] To see current and past research, go to https://clinicaltrials.gov/ct2/home and search for Condition or disease "Mind Body Syndrome" with status all studies. ## Notable patients[edit] Notable patients who have been treated for TMS include the following: * Radio personality Howard Stern credited TMS treatment with the relief of his "excruciating back and shoulder pain",[17] as well as his obsessive-compulsive disorder.[17][28] * 20/20 co-anchor John Stossel was treated by Sarno for his chronic debilitating back pain.[3] In a 20/20 segment on his former doctor, Stossel stated his opinion that the TMS treatment "cured" his back pain, although he admitted that he continues to have relapses of pain.[10] * Television writer and producer Janette Barber said that for three years, she had been increasingly unable to walk, and eventually began to use a wheelchair, due to severe ankle pain originally diagnosed as tendinitis.[11] She was later diagnosed and treated for TMS. According to Barber, she was "pain-free one week after [Sarno's] lecture" and able to walk and run within a few months,[10][11][29] notwithstanding her "occasional" relapses of pain.[11] * The late actress Anne Bancroft said that she saw several doctors for back pain, but only Sarno's TMS treatment helped her.[9][10] * The acclaimed filmmaker Terry Zwigoff said he was on the verge of suicide due to his debilitating back pain, until he turned in desperation to Sarno's method and it "saved [his] life", as well as the life of a woman he told about it more recently.[30] * Mindbody health consultant, life-coach, and author Steven Ray Ozanich suffered from TMS back pain for 27 years and at one point had a paralyzed left leg before understanding the truth of his condition through Dr. John E. Sarno. Steven wrote a book entitled The Great Pain Deception[31] where he tells his story and brings together a wealth of TMS related information spanning the last half century. His book is endorsed on the cover by Dr. Sarno and TMS physician Marc D. Sopher. Ozanich has subsequently written two more books on Tension Myositis Syndrome; Dr. John Sarno's Top 10 Healing Discoveries and Back Pain Permanent Healing: Understanding the Myths, Lies and Confusion. ## Controversy[edit] The TMS diagnosis and treatment protocol are not accepted by the mainstream medical community.[9][10] Sarno himself stated in a 2004 interview with Medscape Orthopaedics & Sports Medicine that "99.999% of the medical profession does not accept this diagnosis."[2] Although the vast majority of medical doctors do not accept TMS, there are prominent doctors who do. Andrew Weil, a notable medical doctor and alternative medicine proponent, endorses TMS treatment for back pain.[14][15] Mehmet Oz, a television personality and Professor of Surgery at Columbia University, includes TMS treatment in his four recommendations for treating back pain.[16] Richard E. Sall, a medical doctor who authored a book on worker's compensation, includes TMS in a list of conditions he considers possible causes of back pain resulting in missed work days that increase the costs of worker's compensation programs.[32] Patients typically see their doctor when the pain is at its worst and pain chart scores statistically improve over time even if left untreated; most people recover from an episode of back pain within weeks without any medical intervention at all.[33] The TMS theory has also been criticized as too simplistic to account for the complexity of pain syndromes.[10] James Rainville, a medical doctor at New England Baptist Hospital, said that while TMS treatment works for some patients, Sarno mistakenly uses the TMS diagnosis for other patients who have real physical problems.[34] Sarno's response was that he had success with many patients who have exhausted every other means of treatment, which he said is proof that regression to the mean is not the cause.[10] TMS was covered favorably in a recent book on back pain "Crooked: Outwitting the Back Pain Industry and Getting on the Road to Recovery" by Cathryn Jakobson Ramin with her remarking that : "Every time I told anyone I was writing about back pain, I learned to expect questions about whether I knew Sarno’s work. Almost everyone had run into someone who had been cured by Sarno, often after years of discomfort. I was happy to be able to inform his many admirers that, yes, I had actually spoken with the rock star of the back world."[18] ## Notes and references[edit] 1. ^ a b c d e f g h i j k l m n o p Schechter D, Smith AP, Beck J, Roach J, Karim R, Azen S (2007). "Outcomes of a Mind-Body Treatment Program for Chronic Back Pain with No Distinct Structural Pathology-A Case Series of Patients Diagnosed and Treated as Tension Myositis Syndrome". Alternative Therapies in Health and Medicine. 13 (5): 26–35. PMID 17900039. 2. ^ a b c d e f Wysong, Pippa (6 July 2004). "An Expert Interview With Dr. John Sarno, Part I: Back Pain Is a State of Mind". Medscape Orthopaedics & Sports Medicine. Retrieved 14 September 2007. 3. ^ a b c McGrath, Mike (3 November 2004). "When Back Pain Starts in Your Head: Is repressed anger causing your back pain?". Prevention.com. Rodale Inc. Retrieved 28 April 2012. 4. ^ Sarno, John E. (1982). Mind Over Back Pain. Berkley Books. ISBN 0-425-08741-7. 5. ^ a b c d Sarno, John E. (1991). Healing Back Pain: The Mind-Body Connection. Warner Books. ISBN 0-446-39230-8. 6. ^ a b Sarno, John E. (2006). The Divided Mind: The Epidemic of Mindbody Disorders. HarperCollins. ISBN 0-06-085178-3. 7. ^ a b c d Sarno, John E. (1998). The Mindbody Prescription: Healing the Body, Healing the Pain. Warner Books. ISBN 0-446-52076-4. 8. ^ a b c d e f g h Rashbaum IG, Sarno JE (2003). "Psychosomatic concepts in chronic pain". Archives of Physical Medicine and Rehabilitation. 84 (3 Suppl 1): S76–80, quiz S81–2. doi:10.1053/apmr.2003.50144. PMID 12708562. 9. ^ a b c d e Neporent, Liz (17 February 1999). "Straightening Out Back Pain". The New York Times. 10. ^ a b c d e f g h "Dr. Sarno's Cure". 20/20. 25 July 1999. ABC. 11. ^ a b c d "How Can Chronic Back Pain Be Cured?". Larry King Live. 12 August 1999. CNN. Transcript. 12. ^ Kalb, Claudia (26 April 2004). "The Great Back Debate – Page 3: Alternative and Complementary Therapies Offer New Hope". Newsweek. 13. ^ a b Martin, Molly (23 July 2000). "Minding the Back". The Seattle Times. 14. ^ a b Weil, Andrew. "Help for an Aching Back?". Retrieved 2 March 2010. 15. ^ a b Weil, Andrew (1996). Spontaneous Healing: How to Discover and Enhance Your Body's Natural Ability to Maintain and Heal Itself. Ballantine Books. ISBN 0-449-91064-4. Archived from the original on 11 January 2013. 16. ^ a b Oz, Mehmet (15 September 2009). "4 Treatments for Low Back Pain". Oprah.com. Retrieved 16 March 2010. 17. ^ a b c Sarno, John E. (1998). The Mindbody Prescription: Healing the Body, Healing the Pain. Warner Books. back cover. ISBN 0-446-52076-4. 18. ^ a b Ramin, Cathryn Jakobson (9 May 2017). Crooked : outwitting the back pain industry and getting on the road to recovery. New York. ISBN 9780062641809. OCLC 985013332. 19. ^ Ruden RA (2008). "Encoding States: A Model for the Origin and Treatment of Complex Psychogenic Pain" (PDF). Traumatology. 14 (1): 119–126. doi:10.1177/1534765608315625. Archived from the original (PDF) on 23 March 2012. 20. ^ a b Coen SJ, Sarno JE (1989). "Psychosomatic avoidance of conflict in back pain". The Journal of the American Academy of Psychoanalysis. 17 (3): 359–76. doi:10.1521/jaap.1.1989.17.3.359. PMID 2530198. 21. ^ Cailliet, René (2003). Low Back Disorders: A Medical Enigma. Wolters Kluwer Health. p. 14. ISBN 0-7817-4448-2. 22. ^ a b c Schechter D, Smith AP (2005). "Back pain as a distraction pain syndrome (DPS): A window to a whole new dynamic in integrative medicine". Evidence Based Integrative Medicine. 2 (1): 3–8. doi:10.2165/01197065-200502010-00002. Archived from the original on 8 April 2016. 23. ^ Greenberg, Jerome (1 February 2000). "Back Pain: An Unconventional Approach". Proceedings of UCLA Healthcare. UCLA Department of Medicine. Archived from the original on 11 January 2008. 24. ^ Harvard RSI Action Group: handout document, and website 25. ^ Schechter D. The MindBody Workbook. Los Angeles: MindBody Medicine Publications, 1999, ISBN 1-929997-05-1. 26. ^ Schechter D, Smith AP (2005). "Long-Term Outcome of Back Pain Patients Treated by a Psychologically Based Program (Abstract #1112)" (PDF). Psychosomatic Medicine. 67 (1): A–101. Archived from the original (PDF) on 27 September 2006. 27. ^ "Info for Authors". Alternative Therapies in Health and Medicine. InnoVision Communications, LLC. Retrieved 30 January 2010. 28. ^ Stern, Howard (1995) [1995-11]. Judith Regan (ed.). Miss America (Mass Market Paperback ed.). HarperCollins. Chapter 3. ISBN 0-06-109550-8. 29. ^ "Janette Barber (Food Network host biography)". Archived from the original on 8 March 2005. Retrieved 25 January 2008. 30. ^ "TERRY ZWIGOFF". Vice. Retrieved 30 April 2017. 31. ^ Ozanich, Steven (2011). The Great Pain Deception. Warren, OH: Silver Cord Records, Inc. ISBN 978-1-544-90449-8. 32. ^ Sall, MD, Richard E. (2004). Strategies in Workers' Compensation. Hamilton Books. p. 91. ISBN 0-7618-2771-4. 33. ^ Pengel LH, Herbert RD, Maher CG, Refshauge KM (2003). "Acute low back pain: systematic review of its prognosis". BMJ. 327 (7410): 323. doi:10.1136/bmj.327.7410.323. PMC 169642. PMID 12907487. 34. ^ Lasalandra, Michael (11 May 1999). "Gettin back to basics; Doctor believes tension, trauma to blame for pain". The Boston Herald. Archived from the original on 31 October 2013. Retrieved 28 August 2013. – via HighBeam Research (subscription required) ## External links[edit] * What Is the Mind-Body Connection? [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Tension myositis syndrome	None	4,753	wikipedia	https://en.wikipedia.org/wiki/Tension_myositis_syndrome	2021-01-18T18:38:37	{"wikidata": ["Q7700684"]}
SAPHO syndrome involves any combination of: Synovitis (inflammation of the joints), Acne, Pustulosis (thick yellow blisters containing pus) often on the palms and soles, Hyperostosis (increase in bone substance) and Osteitis (inflammation of the bones). The cause of SAPHO syndrome is unknown and treatment is focused on managing 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SAPHO syndrome	c0263859	4,754	gard	https://rarediseases.info.nih.gov/diseases/7606/sapho-syndrome	2021-01-18T17:57:50	{"mesh": ["D020083"], "umls": ["C0263859"], "orphanet": ["793"], "synonyms": ["Acquired hyperostosis syndrome", "Synovitis, Acne, Pustlosis, Hyperostosis, and Osteomyelitis", "Synovitis acne pustulosis hyperostosis osteitis"]}
Kaposiform lymphangiomatosis (KLA) is a rare type of tumor and vascular malformation that results from the abnormal development of the lymphatic system. The lymphatic system is part of the immune system made up of vessels that help to protect the body from infection and foreign substances. KLA involves multiple parts of the body, especially the lungs and chest. Symptoms of KLA usually start during childhood, and include shortness of breath (dyspnea) and cough due to the accumulation of fluid around the lungs (pleural effusion) and heart (pericardial effusion). Other common symptoms include chest and body pain, abnormal bleeding and bruising, and soft masses under the skin. Blood collections may form under the skull (epidural hematoma). The cause for KLA is unknown and it is not thought to be inherited in families. KLA is diagnosed based on the symptoms, laboratory testing, and a biopsy of tumor tissue. There is no specific treatment for KLA. Treatment is based on the symptoms and treatment options may include surgical procedures to drain excess fluid and reduce the size of masses, chemotherapy medications and steroids. KLA tends to be a progressive condition that gets worse with time. The most serious complications include the build-up of fluid around the lungs and heart, and the risk for abnormal bleeding. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Kaposiform lymphangiomatosis	None	4,755	gard	https://rarediseases.info.nih.gov/diseases/13451/kaposiform-lymphangiomatosis	2021-01-18T17:59:38	{"icd-10": ["D18.1"], "orphanet": ["464329"], "synonyms": []}
A number sign (#) is used with this entry because bilateral frontoparietal polymicrogyria (BFPP) is caused by homozygous mutation in the ADGRG1 gene (604110) on chromosome 16q21. Mutation in a cis-regulatory region of ADGRG1 causes bilateral perisylvian polymicrogyria (BPPR; 615752). See also unilateral polymicrogyria (610031). Clinical Features In 2 sisters, aged 7 and 10 years, Harbord et al. (1990) described developmental delay and a nonprogressive cerebellar ataxia with similar neurophysiologic and neuroradiologic findings of an extensive neuronal migration defect. There were no dysmorphic features, metabolic abnormalities, chromosomal defects or evidence of prenatal environmental toxins. Harbord et al. (1990) considered that these sibs had an autosomal recessive neuronal migration defect that had not previously been recorded. It appeared that other recognized causes of neuronal migration defects such as the Miller-Dieker syndrome (247200), the Norman-Roberts syndrome (257320), the Neu-Laxova (256520) and Joubert syndrome (213300) could be excluded on the basis of clinical and radiologic features. The absence of muscle disease differentiated these patients from children with migration defects associated with congenital muscular dystrophy, e.g., Fukuyama type (253800). Piao et al. (2002) studied 2 consanguineous Palestinian pedigrees with an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP) using linkage analysis. The first pedigree was originally reported by Straussberg et al. (1996) and was described as having pachygyria, but improved magnetic resonance imaging (MRI) clearly showed that the core disorder was polymicrogyria. The parents were first cousins and 3 of 4 children were affected. They all had normal prenatal and perinatal history and normal head growth but showed gross developmental delay and moderate mental retardation. At ages 14, 9, and 7.5 years they could speak a few words and walk independently. All 3 developed medically refractory seizures. All 3 had esotropia, increased muscle tone, mild truncal ataxia, and finger dysmetria, without dysmorphic features or other congenital anomalies. They also had strabismus. The second pedigree came from the same village as the first, although there was no known relationship between the 2 families. The proposita, a 13-year-old girl, was the first child of healthy Palestinian parents who were first cousins. The course and physical findings were similar to those in the affected members of the first pedigree. A younger son was also affected in the second pedigree. Chang et al. (2003) reported 19 patients from 10 kindreds with apparent autosomal recessive bilateral frontoparietal polymicrogyria. Included were the 2 families reported previously by Piao et al. (2002), and the family reported by Harbord et al. (1990). Eight of the 10 families were consanguineous. Clinical features included motor and cognitive developmental delay, esotropia, strabismus, pyramidal signs, and seizures. Brain MRI of all patients showed bilateral symmetric polymicrogyria, most often in a frontoparietal distribution, although in some patients it was diffuse. All patients also had enlarged ventricles, reduced white matter volume, patchy white matter signal changes, and hypoplasia of the cerebellum and brainstem. Chang et al. (2003) noted that several of the patients had previously been reported as having 'cobblestone lissencephaly,' a 'neuronal migration abnormality,' pachygyria, or 'lissencephaly with cerebellar hypoplasia,' but reinterpretation or repeats of the imaging showed that these patients had findings consistent with BFPP. Jansen and Andermann (2005) reviewed the clinical and radiologic features as well as the genetics of the various forms of polymicrogyria. Piao et al. (2005) reported 6 unrelated families with BFPP confirmed by genetic analysis; 4 were consanguineous. Affected individuals demonstrated considerable clinical homogeneity, with moderate to severe mental retardation, motor developmental delay, seizures, cerebellar ataxia, and dysconjugate gaze. Brain imaging showed bilateral polymicrogyria with anterior to posterior gradient, patchy white matter changes, and brainstem and cerebellar hypoplasia. By contrast, no GPR56 mutations were identified in 5 additional patients with BFPP but who showed fewer diagnostic criteria than for typical GPR56-related BFPP, lacking white matter changes and cerebellar hypoplasia. In addition, no GPR56 mutations were identified in 7 additional patients with bilateral frontal, perisylvian, or generalized polymicrogyria. The findings indicated that the phenotype of BFPP is specific. Mapping In 2 Palestinian families with bilateral frontoparietal polymicrogyria, Piao et al. (2002) mapped the phenotype to 16q12.2-q21, with a minimal interval of 17 cM. A genomewide linkage screen revealed a single locus that was identical by descent in affected children in both families and showed a single disease-associated haplotype, suggesting a common founder mutation. For D16S514, the maximum pooled 2-point lod score was 3.98, and the maximum multipoint lod score was 4.57. By linkage analysis in 10 families with BFPP, Chang et al. (2003) found linkage of the disorder to 16q12-q21 (lod scores ranging from 0.6 to 2.92). Affected patients from consanguineous families were homozygous across multiple consecutive markers and shared a common overlapping interval. Molecular Genetics Piao et al. (2004) identified splice site, frameshift, and missense mutations in the GPR56 gene (see, e.g., 604110.0001-604110.0008) in 12 families with bilateral frontoparietal polymicrogyria of various ethnic origins. All missense mutations affected regions of the protein predicted to represent the extracellular portion of GPR56; 4 mutations affected the extracellular N terminus of the protein, and 1 the extracellular loop between transmembrane domains 4 and 5. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Dysconjugate gaze \- Esotropia \- Nystagmus \- Strabismus \- Exotropia MUSCLE, SOFT TISSUES \- Increased muscle tone NEUROLOGIC Central Nervous System \- Developmental delay \- Psychomotor delay \- Mental retardation, moderate to severe \- Increased muscle tone \- Hyperreflexia \- Extensor plantar responses \- Ankle clonus \- Seizures \- Cerebellar signs \- Pyramidal signs \- Wide-based gait \- Truncal ataxia \- Finger dysmetria \- Polymicrogyria, most severe in the frontoparietal regions \- Polymicrogyria, anterior to posterior gradient \- Areas of dysmyelination on MRI \- Brainstem hypoplasia \- Cerebellar hypoplasia MOLECULAR BASIS \- Caused by mutation in the G protein-coupled receptor 56 gene (GPR56, 604110.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	POLYMICROGYRIA, BILATERAL FRONTOPARIETAL	c1847352	4,756	omim	https://www.omim.org/entry/606854	2019-09-22T16:09:57	{"mesh": ["C564652"], "omim": ["606854"], "orphanet": ["268940", "101070"], "synonyms": ["Alternative titles", "CEREBELLAR ATAXIA WITH NEURONAL MIGRATION DEFECT"], "genereviews": ["NBK1329"]}
Diffuse myelinoclastic sclerosis Other namesDms SpecialtyNeurology Diffuse myelinoclastic sclerosis, sometimes referred to as Schilder's disease, is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, making its diagnosis difficult. It usually begins in childhood, affecting children between 5 and 14 years old,[1][2] but cases in adults are also possible.[3] This disease is considered one of the borderline forms of multiple sclerosis because some authors consider them different diseases and others MS variants. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis and Marburg multiple sclerosis.[4] ## Contents * 1 Symptoms * 2 Diagnostic * 2.1 Neuropathological examination * 2.2 Immunology * 3 Treatments * 4 Prognosis * 5 History * 6 References * 7 External links ## Symptoms[edit] Symptoms are similar to those in multiple sclerosis and may include dementia, aphasia, seizures, personality changes, poor attention, tremors, balance instability, incontinence, muscle weakness, headache, vomiting, and vision and speech impairment.[5] ## Diagnostic[edit] The Poser criteria for diagnosis are:[6] * One or two roughly symmetrical large plaques. Plaques are greater than 2 cm diameter. * No other lesions are present and there are no abnormalities of the peripheral nervous system. * Results of adrenal function studies and serum very long chain fatty acids are normal. * Pathological analysis is consistent with subacute or chronic myelinoclastic diffuse sclerosis. ### Neuropathological examination[edit] The typical demyelinating plaques in Schilder's sclerosis are usually found bilaterally in the semioval center; both hemispheres are almost completely occupied by large, well defined lesions. Although plaques of this kind are largely prevalent in Schilder's sclerosis, smaller lesions can also be observed.[citation needed] ### Immunology[edit] It has been reported that DMS cases show no oligoclonal bands, being therefore distinct from standard MS.[7] ## Treatments[edit] Management Corticosteroids may be effective in some patients. Additional treatment options are beta-interferon or immunosuppressive therapy. Otherwise management is supportive and includes physiotherapy, occupational therapy and nutritional support in the later stages as patients lose their ability to eat.[citation needed] ## Prognosis[edit] The prognosis of this disease is very variable and can take three different courses: a monophasic, not remitting;[2][8] remitting;[9][10][11] and finally, progressive, with increase in deficits.[12] ## History[edit] It was first described by Paul Ferdinand Schilder in 1912,[13][14] and for nearly one hundred years the term "Schilder disease" was used to describe it, but the same name was also used for some other white matter pathologies described by him.[15] In 1986 Poser tried to restrict the use of Schilder's disease name to the disease described here, but this name has still remained ambiguous.[citation needed] The name comes from a traditional classification of demyelinating diseases in two groups: demyelinating myelinoclastic diseases and demyelinating leukodystrophic diseases. In the first group, a normal and healthy myelin is destroyed by a toxic, chemical, or autoimmune substance. In the second group, myelin is abnormal and degenerates.[16] The second group was denominated dysmyelinating diseases by Poser.[17] ## References[edit] 1. ^ Garrido C, Levy-Gomes A, Teixeira J, Temudo T (2004). "[Schilder's disease: two new cases and a review of the literature]". Revista de Neurología (in Spanish). 39 (8): 734–8. doi:10.33588/rn.3908.2003023. PMID 15514902. 2. ^ a b Afifi AK, Bell WE, Menezes AH, Moore SA (1994). "Myelinoclastic diffuse sclerosis (Schilder's disease): report of a case and review of the literature". J. Child Neurol. 9 (4): 398–403. CiteSeerX 10.1.1.1007.559. doi:10.1177/088307389400900412. PMID 7822732. S2CID 38765870. 3. ^ Bacigaluppi, S; Polonara, G; Zavanone, ML; Campanella, R; Branca, V; Gaini, SM; Tredici, G; Costa, A (2009). "Schilder's disease: non-invasive diagnosis? :A case report and review". Neurological Sciences. 30 (5): 421–30. doi:10.1007/s10072-009-0113-z. PMID 19609739. S2CID 21649760. 4. ^ Fontaine B (2001). "[Borderline forms of multiple sclerosis]". Rev. Neurol. (Paris) (in French). 157 (8–9 Pt 2): 929–34. PMID 11787357. 5. ^ "NINDS Schilder's Disease Information Page". Archived from the original on 2009-09-23. Retrieved 2009-05-28. 6. ^ Poser CM, Goutières F, Carpentier MA, Aicardi J (1986). "Schilder's myelinoclastic diffuse sclerosis". Pediatrics. 77 (1): 107–12. PMID 3940347. 7. ^ S. Jarius et al. Myelinoclastic diffuse sclerosis (Schilder’s disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures, Journal of Neuroinflammation, 28 Feb. 2019, https://doi.org/10.1186/s12974-019-1425-4 8. ^ Pretorius ML, Loock DB, Ravenscroft A, Schoeman JF (1998). "Demyelinating disease of Schilder type in three young South African children: dramatic response to corticosteroids". J. Child Neurol. 13 (5): 197–201. doi:10.1177/088307389801300501. PMID 9620009. S2CID 33472806. 9. ^ de Lacour A, Guisado F, Zambrano A, Argente J, Acosta J, Ramos C (1998). "[Pseudotumor forms of demyelinating diseases. Report of three cases and review of the literature]". Revista de Neurología (in Spanish). 27 (160): 966–70. PMID 9951014. 10. ^ Leuzzi V, Lyon G, Cilio MR, Pedespan JM, Fontan D, Chateil JF, Vital A (1999). "Childhood demyelinating diseases with a prolonged remitting course and their relation to Schilder's disease: report of two cases". J. Neurol. Neurosurg. Psychiatry. 66 (3): 407–8. doi:10.1136/jnnp.66.3.407. PMC 1736247. PMID 10084548. 11. ^ Brunot E, Marcus JC (1999). "Multiple sclerosis presenting as a single mass lesion". Pediatr. Neurol. 20 (5): 383–6. doi:10.1016/S0887-8994(98)00164-7. PMID 10371386. 12. ^ Garell PC, Menezes AH, Baumbach G, Moore SA, Nelson G, Mathews K, Afifi AK (1998). "Presentation, management and follow-up of Schilder's disease". Pediatric Neurosurgery. 29 (2): 86–91. doi:10.1159/000028695. PMID 9792962. S2CID 46812200. 13. ^ synd/1554 at Who Named It? 14. ^ P. F. Schilder, Zur Kenntnis der sogenannten diffusen Sklerose (über Encephalitis periaxialis diffusa). Zeitschrift für die gesamte Neurologie und Psychiatrie, 1912, 10 Orig.: 1-60. 15. ^ Martin JJ, Guazzi GC (1991). "Schilder's diffuse sclerosis". Dev. Neurosci. 13 (4–5): 267–73. doi:10.1159/000112172. PMID 1817032. 16. ^ Fernández O.; Fernández V.E.; Guerrero M. (2015). "Demyelinating diseases of the central nervous system". Medicine. 11 (77): 4601–4609. doi:10.1016/j.med.2015.04.001. 17. ^ Poser C. M. (1961). "Leukodystrophy and the Concept of Dysmyelination". Arch Neurol. 4 (3): 323–332. doi:10.1001/archneur.1961.00450090089013. PMID 13737358. ## External links[edit] * Schilders at NINDS Classification D * ICD-10: G37.0 * ICD-9-CM: 341.1 * OMIM: 272100 * MeSH: D002549 * DiseasesDB: 11849 External resources * eMedicine: neuro/92 * v * t * e Multiple sclerosis and other demyelinating diseases of the central nervous system Signs and symptoms * Ataxia * Depression * Diplopia * Dysarthria * Dysphagia * Fatigue * Incontinence * Nystagmus * Optic neuritis * Pain * Uhthoff's phenomenon Investigations and diagnosis * Multiple sclerosis diagnosis * McDonald criteria * Poser criteria * Clinical * Clinically isolated syndrome * Expanded Disability Status Scale * Serological and CSF * Oligoclonal bands * Radiological * Radiologically isolated syndrome * Lesional demyelinations of the central nervous system * Dawson's fingers Approved[by whom?] treatment * Management of multiple sclerosis * Alemtuzumab * Cladribine * Dimethyl fumarate * Fingolimod * Glatiramer acetate * Interferon beta-1a * Interferon beta-1b * Mitoxantrone * Natalizumab * Ocrelizumab * Ozanimod * Siponimod * Teriflunomide Other treatments * Former * Daclizumab * Multiple sclerosis research Demyleinating diseases Autoimmune * Multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis Inflammatory * Acute disseminated encephalomyelitis * MOG antibody disease * Balo concentric sclerosis * Marburg acute multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis * Tumefactive multiple sclerosis * Experimental autoimmune encephalomyelitis Hereditary * Adrenoleukodystrophy * Alexander disease * Canavan disease * Krabbe disease * Metachromatic leukodystrophy * Pelizaeus–Merzbacher disease * Leukoencephalopathy with vanishing white matter * Megalencephalic leukoencephalopathy with subcortical cysts * CAMFAK syndrome Other * Central pontine myelinolysis * Marchiafava–Bignami disease * Mitochondrial DNA depletion syndrome Other * List of multiple sclerosis organizations * List of people with multiple sclerosis * Multiple sclerosis drug pipeline * Pathophysiology [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Diffuse myelinoclastic sclerosis	c0007795	4,757	wikipedia	https://en.wikipedia.org/wiki/Diffuse_myelinoclastic_sclerosis	2021-01-18T18:29:52	{"mesh": ["D002549"], "umls": ["C0007795"], "icd-9": ["341.1"], "icd-10": ["G37.0"], "orphanet": ["59298"], "wikidata": ["Q2909420"]}
The palmomental reflex is an ipsilateral or bilateral contraction of the mentalis muscle elicited by a scratch applied to the thenar eminence. In Japanese, Abe (1965) found it in one-third of 3-year-old children and one-sixth of the mothers, suggesting that about half the positive children become negative by adulthood. The reflex was much more often positive in mothers of children with the reflex than in mothers of 'negative' children. Further analysis of the data suggested dominant inheritance. The design of this study did not permit exclusion of X-linked dominance. A marked, slowly subsiding reflex in an adult may indicate cerebral disease. Neuro \- Ipsilateral or bilateral contraction of the mentalis muscle elicited by scratching the thenar eminence 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	PALMOMENTAL REFLEX	c0751470	4,758	omim	https://www.omim.org/entry/167700	2019-09-22T16:36:47	{"mesh": ["D012021"], "omim": ["167700"]}
## Summary ### Clinical characteristics. FLNA-related periventricular nodular heterotopia (PVNH), a neuronal migration disorder, is characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles. Affected individuals are predominantly heterozygous females; males most often show early lethality. Affected females present with seizures at an average age of 14-15 years; intelligence ranges from normal to borderline. The risk for cardiovascular disease, stroke, and other vascular/coagulation problems appears to be increased. ### Diagnosis/testing. The diagnosis of FLNA-related PVNH is established by the identification of: * Characteristic head MRI findings; and * Heterozygous pathogenic variants in FLNA in females or hemizygous pathogenic variants in FLNA in males. ### Management. Treatment of manifestations: Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. Antiepileptic drugs are typically selected based on specific attributes (e.g., teratogenic risk during pregnancy, tolerability, and efficacy). Because of the risk for aortic or carotid dissection, it may also be wise to ensure good blood pressure control. Standard treatment for aortic or carotid dissection, congenital heart disease, and valvular disease. Surveillance: Echocardiogram and cardiac MRI may be used to screen for FLNA-associated cardiovascular problems. Special attention should be paid to the presence of congenital heart disease, valvular abnormalities, and also dilatation of the ascending aorta. Evaluation of relatives at risk: Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Pregnancy management: The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. There are currently no guidelines regarding the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy. ### Genetic counseling. FLNA-related PVNH is inherited in an X-linked manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a de novo pathogenic variant. For women with FLNA-related PVNH, the risk of passing the pathogenic variant to each child is 50%. Because of the high rate of prenatal lethality in males, most sons born to women with FLNA-related PVNH are unaffected. Prenatal diagnosis by molecular genetic testing is possible if the pathogenic variant has been identified in an affected relative. Periventricular nodules may be visualized by imaging as early as 24 weeks' gestation; however, the sensitivity of imaging for the prenatal detection of PVNH is not known. ## Diagnosis ### Suggestive Findings FLNA-related periventricular nodular heterotopia (PVNH) should be suspected in an individual with the following clinical features, neuroimaging studies, and family history. Clinical findings. No clinical findings are diagnostic. Affected individuals typically have seizures and normal intellect. Neuroimaging studies reviewed by an experienced neuroradiologist reveal the following: * On MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging. * Thinning of the corpus callosum and malformations of the posterior fossa (mild cerebellar hypoplasia, enlarged cisterna magna) in some (see Figure 1) #### Figure 1. Anatomic phenotype of PVNH in an individual with a heterozygous pathogenic variant in FLNA A. MRI of the head demonstrating characteristic periventricular nodular heterotopia Family history consistent with X-linked inheritance with male lethality is strongly suggestive. ### Establishing the Diagnosis Female proband. The diagnosis of FLNA-related PVNH is established in a female proband by the identification of characteristic head MRI findings and a heterozygous pathogenic variant in FLNA by molecular genetic testing (see Table 1). Male proband. Affected males typically show male lethality; however the diagnosis of FLNA-related PVNH is established in a male proband by the identification of characteristic head MRI findings and a hemizygous pathogenic variant in FLNA by molecular genetic testing (see Table 1). Molecular testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of FLNA is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes FLNA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in FLNA-Related Periventricular Nodular Heterotopia View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method FLNASequence analysis 3, 493% 5, 6 Gene-targeted deletion/duplication analysis 73/33 8 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. 93% (8/8 [Parrini et al 2006] and 5/6 [Sheen et al 2001]) for individuals with classic bilateral PVNH and an X-linked inheritance pattern. 93% of individuals with a FLNA pathogenic variant were female and 7% were male. 6\. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female. 7\. 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. 8\. Of 33 individuals with PVNH and a family history of X-linked inheritance who were not found to have an FLNA pathogenic variant by sequence analysis, genomic rearrangements were identified in three [Clapham et al 2012]. ## Clinical Characteristics ### Clinical Description FLNA-related periventricular nodular heterotopia (PVNH) is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. The following clinical features have been associated with FLNA-related PVNH: * Seizure disorder * Cardiovascular findings including patent ductus arteriosus; dilatation and rupture of the thoracic aorta; atrial and ventricular septal defects; valvular dystrophy; and vasculopathy and/or coagulopathy leading to stroke * Congenital strabismus * Shortened digits * Hyperflexible joints [Sheen et al 2005] * Dyslexia Seizure disorder. Approximately 88% of individuals diagnosed with FLNA-related PVNH present with a seizure disorder [Guerrini & Carrozzo 2001]. Age of onset may be within the first years of life, but more typically individuals present during childhood. The severity of the seizure disorder may range from mild (with rare frequency and remission without need of antiepileptic drugs) to intractable seizures. No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations. The ectopic heterotopias act as foci for abnormal neuronal activity. Anatomic studies have shown aberrant projections extending from the periventricular heterotopias. Depth electrode recordings have demonstrated epileptogenic discharges from these nodules [Kothare et al 1998]. Thus, the seizure disorder appears to arise from the heterotopias in most individuals. Cardiovascular findings. Over the last decade there have been reports of several serious cardiovascular anomalies in individuals with FLNA-related PVNH. The most important abnormality is thoracic aortic dilatation or aneurysm formation that may lead to sudden aortic rupture or dissection [Feng & Walsh 2004]. In a study examining cardiovascular lesions in a cohort of individuals with PVNH, five of the six individuals with heterozygous (female) or hemizygous (male) pathogenic variants in FLNA had one or more cardiac anomaly. Lesions included patent ductus arteriosus, thoracic aortic aneurysm, atrial septal defect, ventricular septal defect, and dysplasia of the mitral and aortic valves [de Wit et al 2011] (see Molecular Pathogenesis). A study of a family in which five males had FLNA-related PVNH found that four of the five boys had one or more cardiovascular diagnoses (PDA in 2, ASD in 1, dysplastic mitral valve in 2), demonstrating that not all males with FLNA-related PVNH die during the perinatal period [Oegema et al 2013]. Some individuals with FLNA-related PVNH display connective tissue and vascular anomalies also seen in classic Ehlers-Danlos syndrome [Sheen et al 2005]. In a recent review of the vascular and connective tissue anomalies associated with pathogenic variants in FLNA, ten of the eleven affected individuals showed one or more congenital cardiac or vascular anomalies. In this particular study, thoracic aortic aneurysm emerged as the most frequent lesion – a significant finding given its potential lethality [Reinstein et al 2013]. Such anomalies include joint hypermobility, aortic dilation and other vascular anomalies, and nodular brain heterotopias. Increasingly, the Ehlers-Danlos variant of PVNH is considered to fall within the spectrum of X-linked PVNH caused by pathogenic variants in FLNA [Reinstein et al 2013]. Pulmonary findings. There are several case reports of individuals with FLNA-related PVNH who have pulmonary disease. Several reported individuals(both male and female) had cardiorespiratory failure before age one year. The severity of the poorly defined respiratory disease, resembling bronchopulmonary dysplasia, has led to lung transplantation in several of these young children [Masurel-Paulet et al 2011, Clapham et al 2012, Lord et al 2014]. Other. Other associated clinical findings in individuals with FLNA-related PVNH included gastric immotility (1/11), strabismus (2/11), and shortened digits (1/11). Note: Immune compromise with recurrent infection was reported in two of the individuals in the initial report, but immune compromise has not been seen in any other affected individual; therefore, the association with PVNH is unknown. Intelligence is normal to borderline. Formal cognitive testing of 12 affected individuals with FLNA pathogenic variants demonstrated an average IQ of 95, but also a strikingly high number of affected people with dyslexia [Chang et al 2005, Chang et al 2007]. Women with FLNA-related PVNH may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies. Affected males. Two simplex males (affected males with no family history of PVNH) with documented hemizygous FLNA pathogenic variants presented with seizures. One of the males died from sudden rupture of the aorta at age 36 years [Sheen et al 2001]. Five other males ranging in age from five days to five months died suddenly and unexpectedly; while their deaths were consistent with sudden cardiovascular or hematologic collapse, the actual causes of death were unknown [Parrini et al 2004, Parrini et al 2006]. A single affected male with a hemizygous complete loss-of-function variant in FLNA also showed overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development [Huttenlocher et al 1994]. Two affected dizygotic twin males have been reported, one with early death, the other with intellectual disability but not epilepsy [Gérard-Blanluet et al 2006]. Mosaicism. Somatic mosaicism for an A>G substitution at the intron 11 acceptor splice site was reported by Parrini et al [2004] in a male with bilateral PVNH. Sequence analysis and denaturing high-performance liquid chromatography of genomic DNA on a pool of hair roots, single hair roots, and white blood cells revealed that only 42% and 69% of the samples for hair and blood, respectively, had the pathogenic variant. Moreover, the affected male's daughter did not inherit the pathogenic variant, thought to be causal for the male phenotype. Other somatic pathogenic variants were recently reported [Jamuar et al 2014]. Note: Although three affected brothers with West syndrome/hypsarrhythmia were initially reported to have a hemizygous FLNA pathogenic variant [Masruha et al 2006] this reported sequence variant has subsequently been thought to be a rare polymorphism [Robertson 2006]. ### Genotype-Phenotype Correlations All individuals known to have a heterozygous (female) or hemizygous (male) FLNA pathogenic variant, including those who are asymptomatic, have heterotopia identifiable by brain MRI or CT [Fox et al 1998, Poussaint et al 2000, Sheen et al 2001, Moro et al 2002]. While more studies correlating genotype and phenotype are needed, pathogenic truncation variants tend to cluster near the N-terminal and presumably lead to severe loss of function and a more severe phenotype (male lethality). Pathogenic missense variants are found throughout the extent of FLNA and some appear to have milder phenotypes, as males with these pathogenic variants can survive to term. Presumably, these milder pathogenic variants lead to a partially functional protein [Sheen et al 2001]. A hemizygous pathogenic FLNA splice variant has been associated with PVNH, facial dysmorphism, and severe constipation [Hehr et al 2006]. ### Penetrance Penetrance is unknown. All individuals with known deleterious loss-of-function FLNA variants have shown periventricular nodular heterotopia. ### Nomenclature Frequently used terms are periventricular heterotopia (PVH or PH) or periventricular nodular heterotopia (PNH or PVNH). ### Prevalence The prevalence of PVNH is difficult to assess because individuals with the mild phenotype may never seek medical evaluation. ## Differential Diagnosis The frequent occurrence of familial or nonfamilial periventricular nodular heterotopia (PVNH) in males and females with no documented FLNA pathogenic variant suggests that it is a heterogeneous disorder. Of 120 females with classic bilateral PVNH who were simplex cases (i.e., no family history of PVNH), 31 (26%) had an identifiable heterozygous pathogenic variant in FLNA. Overall, Parrini et al [2006] found that the probability of identifying an FLNA pathogenic variant in an individual with classic bilateral PVNH was 49% and the probability of identifying an FLNA pathogenic variant in an individual with another phenotype (e.g., polymicrogyria, microcephaly) was 4%. Periventricular nodular heterotopia also occurs in the following syndromes (whether each of these represents a truly distinct disorder or FLNA-related PVNH plus a concurrent condition remains to be determined): * Nonfamilial PVNH caused by perinatal insult or chromosomal rearrangement * Autosomal recessive PVNH (OMIM 608097). Several families with PVNH consistent with autosomal recessive inheritance have been reported. Biallelic pathogenic variants in ARFGEF2 on chromosome 20 have been identified in two Turkish families with autosomal recessive PVNH with microcephaly [Sheen et al 2003a, Sheen et al 2004] and in a female with a movement disorder, neuronal migration disorder, and acquired microcephaly [de Wit et al 2009]. * Autosomal dominant forms of PVNH (OMIM 608098) (chromosome 5p15, 1p36, 7q11) [Sheen et al 2003b, Neal et al 2006, Ferland et al 2009] * Bilateral periventricular nodular heterotopia (BPNH)/frontonasal malformations (OMIM 300049) [Guerrini & Dobyns 1998] * PVNH (unilateral/bilateral and isolated) in two boys with fragile X syndrome [Moro et al 2006] * BPNH with micronodules * BPNH with ambiguous genitalia * BPNH with microcephaly * BPNH/intellectual disability/syndactyly [Dobyns et al 1997] * BPNH/nephrosis syndrome * BPNH/short gut syndrome * Unilateral PVNH * Bilateral anterior PVNH with fronto-perisylvian polymicrogyria [Parrini et al 2006] * Bilateral PVNH involving temporo-occipital and trigones with hippocampal malformation, and subclassified into polymicrogyria or cerebellar hypoplasia or hydrocephalus [Parrini et al 2006] * Periventricular nodular heterotopia, intellectual disability, and epilepsy associated with 5q14.3-q15 deletion (OMIM 612881) [Cardoso et al 2009] Laminar heterotopia occurring in deep white matter and band-like heterotopia occurring between the cortex and ventricular surface are seen in X-linked subcortical band heterotopia. PVNH may be misdiagnosed initially as tuberous sclerosis complex; however, MRI findings distinguish the two disorders. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with FLNA-related periventricular nodular heterotopia (PVNH) the following evaluations are recommended: * Evaluation by a neurologist * Evaluation by an epileptologist if seizures are present * Magnetic resonance angiography (MRA) of the intracranial vessels, carotid arteries, and aorta to address the increased risk for stroke * Echocardiogram or cardiac magnetic resonance imaging (MRA) to evaluate for valvular dysplasia, congenital cardiac anomalies, or aortic and vascular disease. Because of the potential risk for congenital cardiovascular anomalies and/or aortic aneurysm, a baseline evaluation by a cardiologist may be prudent. * Evaluation by a hematologist if findings suggest a bleeding diathesis * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Management of individuals with FLNA-related PVNH is directed toward symptomatic treatment. Treatment of epilepsy generally follows basic principles for a seizure disorder caused by a known structural brain abnormality, including: * Detailed initial history and evaluation to confirm the suspicion of a seizure disorder. Testing may include an electroencephalogram (EEG) to define the location and severity of electrical brain dysfunction that may be present in individuals with epilepsy. Repeat imaging may be necessary only in the setting of new neurologic findings on examination. * Treatment with antiepileptic agents. Choice of antiepileptics is generally made empirically based on the clinical features of the seizure disorder. However, because no significant differences exist between medications for newly diagnosed, presumably localized epilepsy, choices may be made on the specific attributes of each antiepileptic drug (i.e., risk of teratogenicity of the antiepileptic drug during pregnancy), tolerability, and efficacy. Because of the risk for aortic or carotid dissection, it may also be wise to ensure good blood pressure control. Treatment of aortic/carotid dissection, congenital heart disease, and valvular disease is the same as in the general population. Many individuals with periventricular nodular heterotopia have dyslexia. Therefore, it may be prudent for those with a family history of PVNH to have children tested for dyslexia at an early age. ### Prevention of Secondary Complications The secondary complications are those associated with prolonged seizure medication usage. ### Surveillance Because of the associated increased incidence of aortic or carotid dissection in PVNH, affected individuals should be screened by echocardiogram and cardiac MRI. There is insufficient data at present to provide definitive guidelines. However, given that such complications have occurred in early adulthood, it is reasonable to perform evaluation initially in late adolescence, with follow up as needed. Cardiology evaluation of those who have connective tissue findings and classic PVNH would be prudent. ### Evaluation of Relatives at Risk Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. * If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. * If the pathogenic variant in the family is not known, head MRI can be used to clarify the disease status of at-risk relatives. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Ideally, women should seek information prior to conception regarding risks to the fetus associated with taking an anti-seizure medication during pregnancy so that changes in the anti-seizure medication regimen (if needed) can be made prior to conception. If not done prior to conception, discussion of the risks and benefits of anti-seizure medication use during pregnancy should occur as soon as the pregnancy is recognized. The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. Currently no guidelines exist on the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy in women with PVNH. See Marfan Syndrome and Ehlers-Danlos Syndrome, Classic Type for possible pregnancy management recommendations. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. ### Other Surgical resection has been attempted but has not proven beneficial [Li et al 1997]. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	FLNA-Related Periventricular Nodular Heterotopia	c1848213	4,759	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1213/	2021-01-18T21:27:27	{"mesh": ["D054091"], "synonyms": ["X-Linked Periventricular Heterotopia"]}
A number sign (#) is used with this entry because of evidence that hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (HLTRS) is caused by heterozygous mutation in the SOX18 gene (601618) on chromosome 20q13. Biallelic mutations in the SOX18 gene result in hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; 607823), which has overlapping features with HLTRS. Description Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome is an autosomal dominant disorder characterized by these 4 features, which begin in early childhood and are progressive (summary by Moalem et al., 2015). Clinical Features Sherwood et al. (1987) described an English family in which the father and his only son, aged 4 years, had an unusual association of uncommon facies, including telangiectasia in a butterfly distribution, similar skin lesions on extensor surfaces, sparse hair, and membranoproliferative glomerulonephritis. Eyebrows and eyelashes were sparse. The son had had pyloric stenosis. The father had been found to have a dermatologic disorder of uncertain nature at the age of 22 years; by the age of 30, he was in end-stage renal failure. Electron microscopy of renal biopsies showed focal subendothelial deposits of electron-dense granular material in the glomeruli. The father underwent renal transplantation at the age of 33. Irrthum et al. (2003) reported a boy who had sparse hair at birth and presented with swelling of the upper eyelids, scrotal edema, and very large bilateral hydroceles. Hair loss began at approximately 6 months of age, accompanied by a lightening of hair color. Alopecia was almost complete, including eyebrows and eyelashes, at about 6 years of age. The patient also had mild eczema on the cheeks and telangiectases on the scalp, scrotum, and legs; nails and teeth were normal. His brother had died in utero at 30 weeks' gestation. The fetus had nonimmune hydrops fetalis, with chylous effusions in the pleural and peritoneal cavities. The lungs showed generalized vascular congestion and a mild dilatation of lymphatic vessels; postmortem examination showed pulmonary lymphangiectasia. The parents were unrelated and unaffected. Moalem et al. (2015) reported follow-up of the proband of the family reported by Irrthum et al. (2003). At age 5 years, he developed renal failure and severe hypertension. Renal biopsy showed a chronic microangiopathy, and electron microscopy showed microvillous hyperplasia and effacement of foot processes. The renal dysfunction was slowly progressive, necessitating renal transplant at age 14 years. Moalem et al. (2015) noted that the patient had dysmorphic features, including puffy eyelids, broad nasal root and tip, full lips, and prognathism. Proesmans et al. (1989) reported a 10-year-old Belgian boy with sparse hair, absent eyebrows and eyelashes, and skin abnormalities including mild epidermal hyperkeratosis, reduced levels of subcutaneous fat, cutaneous telangiectases, and dense freckles in a butterfly distribution. He had a 2-year history of proteinuria and arterial hypertension. Renal biopsy showed membranoproliferative glomerulonephritis with normal serum complement levels. He had an unusual facial appearance, with oval face, prognathism, and long nose with high nasal bridge. He also had mild developmental delay. The paternal grandmother and a great aunt were reported to have absent eyebrows and eyelashes and hypertension. Proesmans et al. (1989) noted the phenotypic similarities to the father and son reported by Sherwood et al. (1987). Moalem et al. (2015) reported follow-up of the patient reported by Proesmans et al. (1989), noting that he was born with a hydrocele. Additional facial features included puffy eyelids and long, narrow nose with broad nasal tip and root. He developed progressive chronic renal failure in his late teens, necessitating renal transplantation at age 27 years. Radiographs showed calcified choroid plexus and renal artery arteriosclerosis, suggestive of premature aging. He did not have peripheral lymphedema. Inheritance The transmission pattern of HLTRS in the family reported by Sherwood et al. (1987) was consistent with autosomal dominant inheritance. Molecular Genetics In 2 brothers originally diagnosed with HLTS, Irrthum et al. (2003) identified a heterozygous nonsense mutation in the SOX18 gene (C240X; 601618.0003). The father was unaffected, suggesting gonadal mosaicism. Moalem et al. (2015) reported that the surviving brother reported by Irrthum et al. (2003) had developed renal failure, and proposed that the diagnosis be revised to HLTS with renal defect (HLTRS). Functional studies were not performed, but Moalem et al. (2015) postulated a dominant-negative effect. In the patient with HLTRS reported by Proesmans et al. (1989), Moalem et al. (2015) identified a de novo heterozygous C240X mutation in the SOX18 gene. History Shultz et al. (1991) reported a mouse mutation called 'hairpatches' (Hpt), characterized by pigmentation abnormalities and progressive glomerulosclerosis resulting in renal failure, and stated that the disorder was similar to that reported in humans by Sherwood et al. (1987) and Proesmans et al. (1989). The Hpt locus was mapped to mouse chromosome 4. Thus, according to the suggestion of Shultz et al. (1991), 9p would be a plausible location for a homologous condition in humans. However, Hosur et al. (2013) determined that the Hpt mouse results from a heterozygous mutation in the Tal1 gene (187040). INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Oval face \- Prognathism Eyes \- Absent eyebrows \- Absent eyelashes \- Puffy eyelids \- Epicanthal folds Nose \- Long nose \- High nasal bridge \- Broad nasal root Mouth \- Full lips RESPIRATORY Lung \- Pulmonary lymphangiectasia (1 affected fetus) GENITOURINARY External Genitalia (Male) \- Hydrocele \- Scrotal edema Kidneys \- Renal failure, progressive \- Membranoproliferative glomerulonephritis \- Thrombotic microangiopathy SKIN, NAILS, & HAIR Skin \- Telangiectasia \- Freckling in a butterfly pattern on the face Hair \- Hypotrichosis \- Sparse hair \- Absent eyebrows \- Absent eyelashes \- Alopecia MUSCLE, SOFT TISSUES \- Decreased subcutaneous fat NEUROLOGIC Central Nervous System \- Delayed development, mild (1 patient) PRENATAL MANIFESTATIONS \- Nonimmune fetal hydrops (1 patient) MISCELLANEOUS \- Onset at birth \- Progressive disorder \- Three patients with SOX 18 mutations from 2 unrelated families have been reported (last curated June 2015) MOLECULAR BASIS \- Caused by mutation in the SRY-box 18 gene (SOX18, 601618.0003 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA-RENAL DEFECT SYNDROME	c1841989	4,760	omim	https://www.omim.org/entry/137940	2019-09-22T16:40:41	{"mesh": ["C536825"], "omim": ["137940"], "orphanet": ["69735"], "synonyms": ["Hypotrichosis-lymphedema-telangiectasia-membranoproliferative glomerulonephritis syndrome", "Alternative titles", "TELANGIECTATIC MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS", "GLOMERULONEPHRITIS WITH SPARSE HAIR AND TELANGIECTASES"]}
Tardive psychosis is a term for a hypothetical form of psychosis, proposed in 1978.[by whom?] It was defined as a condition caused by long term use of neuroleptics, noticeable when the medication had become decreasingly effective, requiring higher doses, or when not responding to higher doses.[citation needed] Evaluation suggests that tardive psychosis as a whole is a combination of "several different and not necessarily correlated phenomena related to neuroleptic treatment of schizophrenia."[1][2] Some articles equate tardive psychosis to supersensitivity psychosis. However, descriptions of symptoms of the latter do not match the former. Specific supersensitivity psychosis articles only address psychotic episodes in the wake of psychotic medication withdrawal associated with Clozapine. They do not mention medication resistance, which is the cornerstone of tardive psychosis theory.[citation needed] A hypothetical condition related to tardive psychosis, tardive dysmentia, has also been questioned.[3] ## Contents * 1 Description * 2 See also * 3 References ## Description[edit] The theoretical tardive psychosis is distinct from schizophrenia and induced by the use of current (dopaminergic) antipsychotics by the depletion of dopamine and related to the known side effect caused by their long-term use, tardive dyskinesia.[citation needed] > In addition to dopaminergic upregulation in the nigrostriatal tracts, many investigators have suggested that dopaminergic upregulation may occur in mesolimbic or mesocortical tracts, leading to a worsening of psychosis beyond the original level. This phenomenon has been called 'tardive psychosis' or 'supersensitivity psychosis'.[4] Tardive psychosis was researched in 1978 and 1989, and sporadic research continues. Some studies have found it to be associated with psychotic depression and potentially, dissociation. For people with any tardive conditions clozapine remains an option but since it can create blood dyscrasias, which require frequent blood work, as well as other severe side effects, it is used increasingly less in clinical practice. Although tardive psychosis continues to be studied, it still has not been established as a fact but it is known that the study classes of antipsychotics such as the NMDA receptor modulators (glutamate antagonists) in not creating tardive dyskinesia will not create this condition.[citation needed] ## See also[edit] * Supersensitivity psychosis * Tardive dyskinesia * Tardive dysmentia ## References[edit] 1. ^ Palmstierna, T; Wistedt, B (1988). "Tardive psychosis: Does it exist?". Psychopharmacology. 94 (1): 144–5. doi:10.1007/BF00735897. PMID 2894699. 2. ^ "Tardive psychosis: does it exist?" (pdf download link) 3. ^ Wilson, I. C; Garbutt, J. C; Lanier, C. F; Moylan, J; Nelson, W; Prange, A. J (1983). "Is There a Tardive Dysmentia?". Schizophrenia Bulletin. 9 (2): 187–92. doi:10.1093/schbul/9.2.187. PMID 6135252. 4. ^ Ross, David E (2004). "Clozapine and Typical Antipsychotics". American Journal of Psychiatry. 161 (10): 1925–6. doi:10.1176/ajp.161.10.1925-a. PMID 15465996. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Tardive psychosis	None	4,761	wikipedia	https://en.wikipedia.org/wiki/Tardive_psychosis	2021-01-18T18:44:32	{"wikidata": ["Q7685723"]}
Fasciolopsiasis Eggs of Fasciolopsis buski SpecialtyInfectious disease Fasciolopsiasis results from an infection by the trematode Fasciolopsis buski,[1] the largest intestinal fluke of humans (up to 7.5 cm in length). ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] Most infections are light, almost asymptomatic. In heavy infections, symptoms can include abdominal pain, chronic diarrhea, anemia, ascites, toxemia, allergic responses, sensitization caused by the absorption of the worms' allergenic metabolites (may eventually cause death of patient), and intestinal obstruction.[2] ## Cause[edit] The parasite infects an amphibic snail (Segmentina nitidella, Segmentina hemisphaerula, Hippeutis schmackerie, Gyraulus, Lymnaea, Pila, Planorbis (Indoplanorbis)) after being released by infected mammalian feces; metacercaria released from this intermediate host encyst on aquatic plants like water spinach, which are eaten raw by pigs and humans. Water itself can also be infective when drunk unheated ("Encysted cercariae exist not only on aquatic plants, but also on the surface of the water.")[3] ## Diagnosis[edit] Microscopic identification of eggs, or more rarely of the adult flukes, in the stool or vomitus is the basis of specific diagnosis. The eggs are indistinguishable from those of the very closely related Fasciola hepatica liver fluke, but that is largely inconsequential since treatment is essentially identical for both. ## Prevention[edit] Infection can be prevented by immersing vegetables in boiling water for a few seconds to kill the infective metacercariae, avoiding the use of untreated feces ("nightsoil") as a fertilizer, and maintenance of proper sanitation and good hygiene. Additionally, snail control should be attempted. ## Treatment[edit] Praziquantel is the drug of choice for treatment. Treatment is effective in early or light infections. Heavy infections are more difficult to treat. Studies of the effectiveness of various drugs for treatment of children with F. buski have shown tetrachloroethylene as capable of reducing faecal egg counts by up to 99%. Other anthelmintics that can be used include thiabendazole, mebendazole, levamisole and pyrantel pamoate.[4] Oxyclozanide, hexachlorophene and nitroxynil are also highly effective.[5] ## Epidemiology[edit] Distribution of Fasciolopsis buski F. buski is endemic in Asia including China, Taiwan, Southeast Asia, Indonesia, Malaysia, and India. It has an up to 60% prevalence in worst-affected communities in southern and eastern India and mainland China and has an estimated 10 million human infections. Infections occur most often in school-aged children or in impoverished areas with a lack of proper sanitation systems.[6] F. buski was endemic in central Thailand, affecting about 2,936 people due to infected aquatic plants called water caltrops and the snail hosts which were associated with them. The infection, or the eggs which hatch in the aquatic environment, were correlated with the water pollution in different districts of Thailand such as Ayuthaya Province. The high incidence of infection was prevalent in females and children ages 10–14 years of age.[7] ## References[edit] 1. ^ Lankester, E.; Küchenmeister, F. (1857). "Appendix B: On the occurrence of species of Distoma in the human body". On animal and vegetable parasites of the human body: a manual of their natural history, diagnosis, and treatment. 1. Sydenham society. pp. 433–7. Odhner TH (1902). "Fasciolopsis Buski (Lank.)[= Distomum crassum Cobb.], ein bisher wenig bekannter Parasit des Menschen in Ostasien". Centr. Bakt. U. Par. XXXI. 2. ^ Bhattacharjee HK, Yadav D, Bagga D (2001). "Fasciolopsiasis presenting as intestinal perforation: a case report". Trop Gastroenterol. 30 (1): 40–1. PMID 19624087. 3. ^ Weng YL, Zhuang ZL, Jiang HP, Lin GR, Lin JJ (1989). "Studies on ecology of Fasciolopsis buski and control strategy of fasciolopsiasis". Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi (in Chinese). 7 (2): 108–11. PMID 2805255. 4. ^ Rabbani GH, Gilman RH, Kabir I, Mondel G (1985). "The treatment of Fasciolopsis buski infection in children: a comparison of thiabendazole, mebendazole, levamisole, pyrantel pamoate, hexylresorcinol and tetrachloroethylene". Trans R Soc Trop Med Hyg. 79 (4): 513–5. doi:10.1016/0035-9203(85)90081-1. PMID 4082261. 5. ^ Probert AJ, Sharma RK, Singh K, Saxena R (1981). "The effect of five fasciolicides on malate dehydrogenase activity and mortality of Fasciola gigantica, Fasciolopsis buski and Paramphistomum explanatum". J Helminthol. 55 (2): 115–22. doi:10.1017/S0022149X0002558X. PMID 7264272. 6. ^ Keiser J, Utzinger J (2009). "Food-borne trematodiases". Clin Microbiol Rev. 22 (3): 466–83. doi:10.1128/CMR.00012-09. PMC 2708390. PMID 19597009. 7. ^ Sadun EH, Maiphoom C (1953). "Studies on the epidemiology of the human intestinal fluke, Fasciolopsis Buski in Central Thailand". American Journal of Tropical Medicine and Hygiene. 2 (6): 1070–84. doi:10.4269/ajtmh.1953.2.1070. PMID 13104816. ## Further reading[edit] * Graczyk TK, Gilman RH, Fried B (2001). "Fasciolopsiasis: is it a controllable food-borne disease?". Parasitol. Res. 87 (1): 80–3. doi:10.1007/s004360000299. PMID 11199855. S2CID 19075125. * Mas-Coma S, Bargues MD, Valero MA (2005). "Fascioliasis and other plant-borne trematode zoonoses". Int. J. Parasitol. 35 (11–12): 1255–78. doi:10.1016/j.ijpara.2005.07.010. PMID 16150452. * http://www.ijmm.org/text.asp?2017/35/4/551/224440 * Fasciolopsiasis in children: Clinical, Sociodemographic Profile and outcome. Indian Journal of Medical Microbiology2017 vol 35, issue 4 page 551-554 DOI:10.4103/ijmm.IJMM_17_7 ## External links[edit] Classification D * ICD-10: B66.5 * ICD-9-CM: 121.4 * MeSH: D014201 * v * t * e Parasitic disease caused by helminthiases Flatworm/ platyhelminth infection Fluke/trematode (Trematode infection) Blood fluke * Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum * Schistosomiasis * Trichobilharzia regenti * Swimmer's itch Liver fluke * Clonorchis sinensis * Clonorchiasis * Dicrocoelium dendriticum / D. hospes * Dicrocoeliasis * Fasciola hepatica / F. gigantica * Fasciolosis * Opisthorchis viverrini / O. felineus * Opisthorchiasis Lung fluke * Paragonimus westermani / P. kellicotti * Paragonimiasis Intestinal fluke * Fasciolopsis buski * Fasciolopsiasis * Metagonimus yokogawai * Metagonimiasis * Heterophyes heterophyes * Heterophyiasis Cestoda (Tapeworm infection) Cyclophyllidea * Echinococcus granulosus / E. multilocularis * Echinococcosis * Taenia saginata / T. asiatica / T. solium (pork) * Taeniasis / Cysticercosis * Hymenolepis nana / H. diminuta * Hymenolepiasis Pseudophyllidea * Diphyllobothrium latum * Diphyllobothriasis * Spirometra erinaceieuropaei * Sparganosis * Diphyllobothrium mansonoides * Sparganosis Roundworm/ Nematode infection Secernentea Spiruria Camallanida * Dracunculus medinensis * Dracunculiasis Spirurida Filarioidea (Filariasis) * Onchocerca volvulus * Onchocerciasis * Loa loa * Loa loa filariasis * Mansonella * Mansonelliasis * Dirofilaria repens * D. immitis * Dirofilariasis * Wuchereria bancrofti / Brugia malayi / \|B. timori * Lymphatic filariasis Thelazioidea * Gnathostoma spinigerum / G. hispidum * Gnathostomiasis * Thelazia * Thelaziasis Spiruroidea * Gongylonema Strongylida (hookworm) * Hookworm infection * Ancylostoma duodenale / A. braziliense * Ancylostomiasis / Cutaneous larva migrans * Necator americanus * Necatoriasis * Angiostrongylus cantonensis * Angiostrongyliasis * Metastrongylus * Metastrongylosis Ascaridida * Ascaris lumbricoides * Ascariasis * Anisakis * Anisakiasis * Toxocara canis / T. cati * Visceral larva migrans / Toxocariasis * Baylisascaris * Dioctophyme renale * Dioctophymosis * Parascaris equorum Rhabditida * Strongyloides stercoralis * Strongyloidiasis * Trichostrongylus spp. * Trichostrongyliasis * Halicephalobus gingivalis Oxyurida * Enterobius vermicularis * Enterobiasis Adenophorea * Trichinella spiralis * Trichinosis * Trichuris trichiura (Trichuriasis / Whipworm) * Capillaria philippinensis * Intestinal capillariasis * C. hepatica [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Fasciolopsiasis	c0015656	4,762	wikipedia	https://en.wikipedia.org/wiki/Fasciolopsiasis	2021-01-18T19:01:37	{"mesh": ["D014201"], "umls": ["C0015656"], "wikidata": ["Q2140729"]}
A rare familial cardiomyopathy characterized by left ventricular enlargement and/or reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias including bradyarrhythmias, supraventricular or ventricular arrhythmias. Disease onset is usually in early to mid-adulthood. Sudden cardiac death may occur and may be the presenting symptom. In some cases, it is associated with skeletal myopathy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation	c1449563	4,763	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300751	2021-01-23T18:55:36	{"mesh": ["D002311"], "omim": ["115200"], "icd-10": ["I42.0"]}
Micrograph of an ovarian clear cell carcinoma. H&E stain. Clear cell ovarian carcinoma is one of several subtypes of ovarian carcinoma. Clear cell is a subtype of epithelial ovarian cancer in contrast to non-epithelial cancers. According to research, most ovarian cancers start at the epithelial layer which is the lining of the ovary. Within this epithelial group clear cell ovarian carcinoma makes up about 5-10%. Clear cell ovarian carcinoma was recognized as a separate category of ovarian cancer by the World Health Organization in 1973. Its incidence rate differs across various ethnic groups. Reports from the United States show that the highest rates are among Asians with 11.1% versus whites with 4.8% and blacks at 3.1%. These numbers are consistent with the finding that although clear cell carcinomas are rare in Western countries they are much more common in parts of Asia.[1] ## Contents * 1 Background * 2 Structure and function * 3 Clinical relevance * 4 References ## Background[edit] There are two subtypes of ovarian carcinoma \- epithelial and nonepithelial; clear cell ovarian carcinoma is an epithelial ovarian cancer. The other major subtypes within this group include high-grade serous, endometrioid, mucinous, and low-grade serous. The serous type is the most common form of epithelial ovarian tumors. Cord-stromal and germ cell belong to the nonepithelial category which are much less common.[2] ## Structure and function[edit] Clear-cell ovarian carcinoma often occurs as a pelvic mass that rarely appears bilaterally. The cells usually contain glycogen with large clear cytoplasm. It is also associated with endometriosis, a disorder of abnormal tissue growth outside of the uterus.[3] The tumor cells emerge in a stepwise manner from adenofibromas which are benign endometriotic cysts. They also hold molecular genetic mutations in both ARID1A and PIK3CA, similar to other epithelial ovarian cancers. Mutations in ARID1A commonly contain phosphatase and tensin homolog (PTEN) that are hypothesized to contribute to clear cell tumorigenesis. However, research also shows that inactivation of ARID1A alone does not lead to tumor initiation. However, clear cell tumors rarely carry p53, BRCA1, or BRCA2 mutations.[4] In addition, they also test negative for estrogen and progesterone receptors and Wilm tumor suppressor 1.[5] Studies have also suggested that clear-cell can occur with thromboembolic complications and hypercalcemia. Recurrence of tumor cells have been reported to involve lymph nodes and parenchymal organs. Research continues to look for ways to understand clear cell tumor progression. A suggested mechanism is the amplification and overexpression of CCNE1 which is thought to promote the tumor's aggressive behavior. In addition, they also test negative for estrogen and progesterone receptors and Wilm tumor suppressor 1.[6] The CCNE1 gene encodes for the cyclin E1 protein which accumulates at the G1-S phase transition point of the cell cycle. Detecting the cancerous tumor progression can be difficult for pathologists. While some tumors will appear in the ovary, others spread over the outer lining of the ovary and to other organs such as the uterus, fallopian tube, and lymph glands. ## Clinical relevance[edit] Clear cell tumors are frequently found at an early stage and therefore can be cured with surgery. Through clinical examination or preoperative imaging techniques, tumors have been reported to range from 3-20 cm. Most ovarian tumors are benign and rarely spread past the ovary. Therefore, surgical removal of the ovary or partial removal of the ovary is sufficient for treatment for malignant tumors. When diagnosed beyond FIGO (International Federation of Gynecology and Obstetrics) stage 1 patients usually have a poor prognosis. If the malignant tumors metastasize and spread throughout the body then they could potentially be fatal. Clear cell tumors have been found to be resistant to conventional chemotherapy using platinum and taxane. Although the cause of this chemoresistance is unknown, there is research that provides partial explanation of this occurrence. For example, studies show that clear cell tumor cells proliferate at lower rates than serous adenocarcinomas which then could aid in a lower response from clear cell tumors to chemotherapies.[7] Given that treatment options are limited for clear cell ovarian cancer patients, researchers are studying biomarkers or specific pathways that could aid in developing future treatment. These patients are good candidates for targeted therapies since the standard does not adequately help their care. Some suggested therapeutic targets include the PI3K/AKT/mTOR, VEGF, Il-6/STAT3, MET, and HNF-1beta pathways.[8] Better insight into genomic heterogeneity would also provide a personalized approach to identifying treatment targets for clear cell tumor patients that share similar phenotypes. Developing stronger options is also beneficial because ovarian cancer is the fifth leading cause of cancer deaths for women and is one of the most lethal gynecological cancers. ## References[edit] 1. ^ Fujiwara, K., Shintani, D., Nishikawa, T. (2016). Clear-cell carcinoma of the ovary. Annals of Oncology, 50i-52i. 2. ^ Kalloger, S.E., Kobel, M., Leung, S., Mehl, E., Gao, D., Marcon, K.M. (2011). Calculator for ovarian carcinoma subtype prediction. Modern Pathology, 24, 512-521 3. ^ Sugiyama, T., Kamura, T., Kigawa, J., Terakawa, N., Kikuchi, Y., Kita, T., Suzuki, M. (2000). Clinical Characteristics of Clear Cell Carcinoma of the Ovary. Cancer, 88(11), 2584-2589. 4. ^ Ayhan, A., Kuhn. E., Wu, R., Ogawa, H., Talbott, A., Mao. T., Sugimura, H. (2017). CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. Modern Pathology, 30, 297-303. 5. ^ Fujiwara, K., Shintani, D., Nishikawa, T. (2016). Clear-cell carcinoma of the ovary. Annals of Oncology, 50i-52i. 6. ^ Fujiwara, K., Shintani, D., Nishikawa, T. (2016). Clear-cell carcinoma of the ovary. Annals of Oncology, 50i-52i. 7. ^ Chan, J.K., Teoh, D., Hu, J.M., Shin, J.Y., Osann, K., Kapp, D.S. (2008). Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecologic Oncology, 109(3), 370-376. 8. ^ Mabuchi, S., Sugiyama, T., Kimura, T. (2016). Clear cell carcinoma of the ovary: molecular insights and future therapeutic perspectives. Journal of Gynecologic Oncology, 27(3), 1-14. * 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Clear-cell ovarian carcinoma	c1518230	4,764	wikipedia	https://en.wikipedia.org/wiki/Clear-cell_ovarian_carcinoma	2021-01-18T18:29:25	{"umls": ["C1518230"], "wikidata": ["Q5130609"]}
Splenosis is the result of spleen tissue breaking off the main organ and implanting at another site inside the body. This is called heterotopic autotransplantation of the spleen. It most commonly occurs as a result of traumatic splenic rupture or abdominal surgery. Depending on the location of the spleen, the new piece usually implants in another part of the abdominal cavity (including the pelvic cavity). Single case reports also describe splenosis in the thoracic cavity, in subcutaneous tissue, in the liver or in the cranial cavity. Splenosis must be distinguished from the presence of additional spleens, which are innate and are the result of differences in embryological development. Additionally, splenosis must be differentiated from malignant tumors.[1] ## Contents * 1 History * 2 Cause * 3 Pathology * 4 Clinical presentation * 5 Diagnosis * 6 Treatment * 7 Epidemiology * 8 References ## History[edit] Ectopic splenic tissue was first described in 1896 by Albrecht in Germany, whereas the term “splenosis” was first used by Buchbinder and Lipkoffin to describe their findings in 1939 [2] ## Cause[edit] A necessary requirement for splenosis is the rupture of the spleen, through a traumatic injury (such as a car wreck) or abdominal surgery, especially splenectomy. Splenosis in the abdominal category may occur in up to 65% of traumatic ruptures of the spleen.[3] Splenosis in the thoracic cavity is rarer, because it requires the simultaneous rupture of the diaphragm. The implantation of spleen tissue under the skin may result from abdominal surgery or gunshot wounds. Splenosis of the brain or liver is hypothesized to be the result of tiny pieces of spleen tissue traveling through the bloodstream. ## Pathology[edit] Several implants of splenic tissue have implanted in the soft tissue of the left upper abdomen. The person had experienced splenic rupture during a car wreck and subsequent surgical removal of the spleen four years before this photo was taken. Macroscopically, splenosis manifests as individual pieces of reddish-blue tissue with variable shape, which can be as few as one and as many as 300,[4] mostly in the abdominal cavity, and varying in size from a few millimeters to as large as 12 cm. Due to the limited blood supply to these nodules, the typical size of splenic implants is usually less than 3 cm. The implants can be separate pieces or connect to other pieces of splenic tissue by a thin stem.[5] Histologically, the regular spleen tissue is made up of red and white pulp, similar to the structure of an accessory spleen. ## Clinical presentation[edit] About a decade commonly passes between the injury and the discovery of splenosis. As little as five months and as much as 32 years have been reported. Most people with splenosis have no symptoms, so the splenosis is discovered by chance through screening or in the process of diagnosing another disease. Some people experience symptoms, such as abdominal pain, intestinal obstruction, hemorrhage, or hydronephrosis. Tissue infarction due to limited blood supply can be a cause of symptomatic splenosis.[6] Symptoms of splenosis affecting the thoracic cavity sometimes include hemoptysis or pleurisy. ## Diagnosis[edit] A definitive diagnosis is often made through biopsy and histological examination of the tissue by a pathologist. Multiple implants of splenic tissue can mimic the appearance of some cancerous conditions. This can be clarified through diagnostic imaging (for example, ultrasound, CT scan, and MRI). In particular, splenosis is differentiated from different forms of lymphoma, metastisized cancers, cancer of the abdomen and pleural tissues, primary kidney or liver tumors, endometriosis or non-cancerous swollen lymph nodes. ## Treatment[edit] Treatment of splenosis is often unnecessary, because it is benign and usually asymptomatic. For people experiencing symptoms, the splenic tissue can be removed by surgery. ## Epidemiology[edit] Splenosis is slightly more common in males than females, probably due to the greater frequency of physical trauma experienced by men.[7] ## References[edit] 1. ^ R. D. Fremont, T. W. Rice: Splenosis: A Review. 2. ^ Younan, George; Wills, Edward; Hafner, Gordon (2015). "Splenosis: A Rare Etiology for Bowel Obstruction—A Case Report and Review of the Literature". Case Reports in Surgery. 2015: 890602. doi:10.1155/2015/890602. ISSN 2090-6900. PMC 4620401. PMID 26543660. 3. ^ A. H. Huang, K. Shaffer: Case 93: thoracic splenosis. 4. ^ Widmann, MAJ Warren D. (1971-02-01). "Splenosis: A Disease or a Beneficial Condition?". Archives of Surgery. 102 (2): 152–8. doi:10.1001/archsurg.1971.01350020062018. ISSN 0004-0010. PMID 5101334. 5. ^ C. R. Fleming, E. R. Dickson, E. G. Harrison, Jr: Splenosis: auto-transplantation of splenic tissue. 6. ^ Widmann, MAJ Warren D. (1971-02-01). "Splenosis: A Disease or a Beneficial Condition?". Archives of Surgery. 102 (2): 152–8. doi:10.1001/archsurg.1971.01350020062018. ISSN 0004-0010. PMID 5101334. 7. ^ J. N. Yammine, A. Yatim, A. Barbari: Radionuclide imaging in thoracic splenosis and a review of the literature. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Splenosis	c0206369	4,765	wikipedia	https://en.wikipedia.org/wiki/Splenosis	2021-01-18T18:54:01	{"mesh": ["D017890"], "wikidata": ["Q2311755"]}
Walker–Warburg syndrome Other namesHARD syndrome,Warburg syndrome Walker–Warburg syndrome has an autosomal recessive pattern of inheritance. SpecialtyOphthalmology, neurology, medical genetics Walker–Warburg syndrome (WWS), also called Warburg syndrome, Chemke syndrome, HARD syndrome (Hydrocephalus, Agyria and Retinal Dysplasia), Pagon syndrome, cerebroocular dysgenesis (COD) or cerebroocular dysplasia-muscular dystrophy syndrome (COD-MD),[1] is a rare form of autosomal recessive congenital muscular dystrophy.[2] It is associated with brain (lissencephaly, hydrocephalus, cerebellar malformations) and eye abnormalities.[3] This condition has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years.[3] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Prognosis * 5 Eponym * 6 References * 7 Further reading * 8 External links ## Presentation[edit] The clinical manifestations present at birth are generalized hypotonia, muscle weakness, developmental delay with mental retardation and occasional seizures.[4] The congenital muscular dystrophy is characterized by hypoglycosylation of α-dystroglycan. Those born with the disease also experience severe ocular and brain defects. Half of all children with WWS are born with encephalocele, which is a gap in the skull that will not seal. The meninges of the brain protrude through this gap due to the neural tube failing to close during development. A malformation of the a baby's cerebellum is often a sign of this disease. Common ocular issues associated with WWS are abnormally small eyes and retinal abnormalities cause by an underdeveloped light-sensitive area in the back of the eye.[5] ## Genetics[edit] Several genes have been implicated in the etiology of Walker–Warburg syndrome,[6] and others are as yet unknown. Several mutations were found in the protein O-Mannosyltransferase POMT1 and POMT2 genes, and one mutation was found in each of the fukutin and fukutin-related protein genes. Another gene that has been linked to this condition is Beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).[7] ## Diagnosis[edit] Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered α-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown.[citation needed] ## Prognosis[edit] No specific treatment is available. Management is only supportive and preventive. Those who are diagnosed with the disease often die within the first few months of life. Almost all children with the disease die by the age of three.[8] ## Eponym[edit] WWS is named for Arthur Earl Walker and Mette Warburg (1926-2015), a Danish ophthalmologist.[9][10][11] Its alternative names include Chemke’s syndrome and Pagon’s syndrome, named after Juan M. Chemke and Roberta A. Pagon.[12] ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 236670 2. ^ Vajsar J, Schachter H (2006). "Walker–Warburg syndrome". Orphanet J Rare Dis. 1: 29. doi:10.1186/1750-1172-1-29. PMC 1553431. PMID 16887026. 3. ^ a b "Walker-Warburg syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-09. 4. ^ Reference, Genetics Home. "Walker-Warburg syndrome". Genetics Home Reference. Retrieved 2018-04-17. 5. ^ Weiss, Thomas C.. "Walker-Warburg Syndrome - Facts and Information." Disabled World. N.p., 6 Mar. 2010. Web. 8 Dec. 2013. <http://www.disabled-world.com/disability/types/mobility/md/walker-warburg.php>. 6. ^ Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, et al. (November 2002). "Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome". Am. J. Hum. Genet. 71 (5): 1033–43. doi:10.1086/342975. PMC 419999. PMID 12369018. 7. ^ Maroofian R, Riemersma M, Jae LT, Zhianabed N, Willemsen MH, Wissink-Lindhout WM, Willemsen MA, de Brouwer APM, Mehrjardi MYV, Ashrafi MR, Kusters B, Kleefstra T, Jamshidi Y, Nasseri M, Pfundt R, Brummelkamp TR, Abbaszadegan MR, Lefeber DJ, van Bokhoven H (2017) B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies. Genome Med 9(1):118. doi: 10.1186/s13073-017-0505-2 8. ^ Vajsar J, Schachter H (2006). "Walker-Warburg syndrome". Orphanet J Rare Dis. 1: 29. doi:10.1186/1750-1172-1-29. PMC 1553431. PMID 16887026. 9. ^ synd/1202 at Who Named It? 10. ^ Walker AE (1942). "Lissencephaly". Archives of Neurology and Psychiatry. 48: 13–29. doi:10.1001/archneurpsyc.1942.02290070023002. 11. ^ Warburg M (March 1971). "The heterogeneity of microphthalmia in the mentally retarded". Birth Defects Orig. Artic. Ser. 7 (3): 136–54. PMID 4950916. 12. ^ "Walker-Warburg syndrome". ## Further reading[edit] * HARD syndrome; Walker–Warburg syndrome; Chemke syndrome; COD (cerebroocular dysgenesis) at NIH's Office of Rare Diseases ## External links[edit] Classification D * OMIM: 236670 * MeSH: D058494 * DiseasesDB: 29495 External resources * Orphanet: 899 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Walker–Warburg syndrome	c0265221	4,766	wikipedia	https://en.wikipedia.org/wiki/Walker%E2%80%93Warburg_syndrome	2021-01-18T18:55:58	{"gard": ["2599"], "mesh": ["D058494"], "umls": ["CN033898"], "orphanet": ["899", "588"], "wikidata": ["Q1629483"]}
## Clinical Features Dundar et al. (2008) reported a Turkish family in which a father and 2 sons had scoliosis, arachnodactyly, and progressive loss of vision resulting in blindness. The proband was a 16-year-old boy with scoliosis, arachnodactyly of both fingers and toes, and progressive visual loss and strabismus since he was 8. The right eye showed esotropia, bilateral lens subluxation, hypertrophy of the retinal pigment epithelium, and eventual total retinal detachment. A 20-year-old brother had severe kyphoscoliosis, arachnodactyly of fingers and toes, and complete blindness associated with opaque small lenses. The 60-year-old father had mild scoliosis, blindness, and arachnodactyly. A 23-year-old sister of the proband had blindness associated with small opaque lenses, but no scoliosis or arachnodactyly. The combination of clinical abnormalities in these patients did not suggest Marfan syndrome (MFS; 154700) or other connective tissue disorders associated with ectopia lentis, and genetic analysis excluded mutations in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes. Dundar et al. (2008) suggested that the disorder in this family represented an autosomal dominant gene defect with possible sex influence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SCOLIOSIS, ARACHNODACTYLY, AND BLINDNESS	c2676234	4,767	omim	https://www.omim.org/entry/612445	2019-09-22T16:01:28	{"mesh": ["C567309"], "omim": ["612445"], "orphanet": ["171844"]}
A very rare syndrome characterized by intellectual deficit, horseshoe kidney, and congenital heart defects. ## Epidemiology Four cases have been reported in the literature in two unrelated families. ## Clinical description Dysmorphic features include plagiocephaly, malar hypoplasia, broad nasal bridge, poorly developed philtrum and nasal alae, cleft palate and hypodontia. Congenital heart defects were endocardial fibroelastosis in one family and prolapse of the tricuspid valve in the other. ## Genetic counseling The condition is probably hereditary, and transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Faciocardiorenal syndrome	c0795936	4,768	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1973	2021-01-23T19:06:52	{"gard": ["2230"], "mesh": ["C536388"], "omim": ["227280"], "umls": ["C0795936"], "icd-10": ["Q87.8"], "synonyms": ["Eastman-Bixler syndrome"]}
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(July 2014) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Diastematomyelia SpecialtyMedical genetics Diastematomyelia (occasionally diastomyelia) is a congenital disorder in which a part of the spinal cord is split, usually at the level of the upper lumbar vertebra. Diastematomyelia is a rare congenital anomaly that results in the "splitting" of the spinal cord in a longitudinal (sagittal) direction. Females are affected much more commonly than males. This condition occurs in the presence of an osseous (bone), cartilaginous or fibrous septum in the central portion of the spinal canal which then produces a complete or incomplete sagittal division of the spinal cord into two hemicords. When the split does not reunite distally to the spur, the condition is referred to as a diplomyelia, or true duplication of the spinal cord. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] The signs and symptoms of diastematomyelia may appear at any time of life, although the diagnosis is usually made in childhood. Cutaneous lesions (or stigmata), such as a hairy patch, dimple, Hemangioma, subcutaneous mass, Lipoma or Teratoma over the affected area of the spine is found in more than half of cases. Neurological symptoms are nonspecific, indistinguishable from other causes of cord tethering. The symptoms are caused by tissue attachments that limit the movement of the spinal cord within the spinal column. These attachments cause an abnormal stretching of the spinal cord. The course of the disorder is progressive. In children, symptoms may include the "stigmata" mentioned above and/or foot and spinal deformities; weakness in the legs; low back pain; scoliosis; and incontinence. In adulthood, the signs and symptoms often include progressive sensory and motor problems and loss of bowel and bladder control. This delayed presentation of symptoms is related to the degree of strain placed on the spinal cord over time. Tethered spinal cord syndrome appears to be the result of improper growth of the neural tube during fetal development, and is closely linked to spina bifida. Tethering may also develop after spinal cord injury and scar tissue can block the flow of fluids around the spinal cord. Fluid pressure may cause cysts to form in the spinal cord, a condition called syringomyelia. This can lead to additional loss of movement, feeling or the onset of pain or autonomic symptoms. Cervical diastematomyelia can become symptomatic as a result of acute trauma, and can cause major neurological deficits, like hemiparesis, to result from otherwise mild trauma.[1] The following definitions may help to understand some of the related entities: * Diastematomyelia (di·a·stem·a·to·my·elia) is a congenital anomaly, often associated with spina bifida, in which the spinal cord is split into halves by a bony spicule or fibrous band, each half being surrounded by a dural sac. * Myeloschisis (my·elos·chi·sis) is a developmental anomaly characterized by a cleft spinal cord, owing to failure of the neural plate to form a complete neural tube or to rupture of the neural tube after closure. * Diplomyelia (diplo.my.elia) is a true duplication of spinal cord in which these are two dural sacs with two pairs of anterior and posterior nerve roots. ## Pathophysiology[edit] Diastematomyelia is a "dysraphic state" of unknown embryonic origin, but is probably initiated by an accessory neurenteric canal (an additional embryonic spinal canal.) This condition may be an isolated phenomenon or may be associated with other segmental anomalies of the vertebral bodies such as spina bifida, kyphoscoliosis, butterfly vertebra, hemivertebra and block vertebrae which are observed in most of the cases. Scoliosis is identified in more than half of these patients. In most of the symptomatic patients, the spinal cord is split into halves by a bony spicule or fibrous band, each half being surrounded by a dural sac. Other conditions, such as intramedullary tumors, tethered cord, dermoids, lipoma, syringomyelia, hydromyelia and Arnold–Chiari malformations have been described in medical literature, but they are exceptionally rare. Diastematomyelia usually occurs between 9th thoracic and 1st sacral levels of the spinal column with most being at the level of the upper lumbar vertebra. Cervical diastematomyelia is a very rare entity. The extent (or length of spinal cord involved) varies from one affected individual to another. In approximately 60% of patients with diastematomyelia, the two hemicords, each covered by an intact layer of pia arachnoid, travel through a single subarachnoid space surrounded by a single dural sac. Each hemicord has its own anterior spinal artery. This form of diastematomyelia is not accompanied by any bony spur or fibrous band and is rarely symptomatic unless hydromyelia or tethering is present. The other 40% of patients have a bony spur or a fibrous band that passes through the two hemicords. In these cases, the dura and arachnoid are split into two separate dural and arachnoidal sacs, each surrounding the corresponding hemicord which are not necessarily symmetric. Each hemicord contains a central canal, one dorsal horn (giving rise to a dorsal nerve root), and one ventral horn (giving rise to a ventral nerve root.) One study showed the bony spur typically situated at the most inferior aspect of the dural cleft. They advised that if the imaging appears to show otherwise, a second spur (present in about 5% of patients with diastematomyelia) is likely to be present. The conus medullaris is situated below the L2 level in more than 75% of these diastematomyelia patients. Thickening of the filum terminale is seen in over half of the cases. While the level of the cleft is variable, it is most commonly found in the lumbar region. The two hemicords usually reunite caudally to the cleft. Occasionally, however, the cleft will extend unusually low and the cord will end with two separate coni medullarae and two fila terminale ("Diplomyelia"). ## Diagnosis[edit] Diastematomelia in MRI of lumbar spine. Adult presentation in diastematomyelia is unusual. With modern imaging techniques, various types of spinal dysraphism are being diagnosed in adults with increasing frequency. The commonest location of the lesion is at first to third lumbar vertebrae. Lumbosacral adult diastematomyelia is even rarer. Bony malformations and dysplasias are generally recognized on plain x-rays. MRI scanning is often the first choice of screening and diagnosis. MRI generally give adequate analysis of the spinal cord deformities although it has some limitations in giving detailed bone anatomy. Combined myelographic and post-myelographic CT scan is the most effective diagnostic tool in demonstrating the detailed bone, intradural and extradural pathological anatomy of the affected and adjacent spinal canal levels and of the bony spur. Prenatal ultrasound diagnosis of this anomaly is usually possible in the early to mid third-trimester. An extra posterior echogenic focus between the fetal spinal laminae is seen with splaying of the posterior elements, thus allowing for early surgical intervention and have a favorable prognosis. Prenate ultrasound could also detect whether the diastematomyelia is isolated, with the skin intact or association with any serious neural tube defects. Progressive neurological lesions may result from the "tethering cord syndrome" (fixation of the spinal cord) by the diastematomyelia phenomenon or any of the associated disorders such as myelodysplasia, dysraphia of the spinal cord. ## Treatment[edit] Surgery Surgical intervention is warranted in patients who present with new onset neurological signs and symptoms or have a history of progressive neurological manifestations which can be related to this abnormality. The surgical procedure required for the effective treatment of diastematomyelia includes decompression (surgery) of neural elements and removal of bony spur. This may be accomplished with or without resection and repair of the duplicated dural sacs. Resection and repair of the duplicated dural sacs is preferred since the dural abnormality may partly contribute to the "tethering" process responsible for the symptoms of this condition. Post-myelographic CT scanning provides individualized detailed maps that enable surgical treatment of cervical diastematomyelia, first performed in 1983.[1][2] Observation Asymptomatic patients do not require surgical treatment. These patients should have regular neurological examinations since it is known that the condition can deteriorate. If any progression is identified, then a resection should be performed. ## References[edit] 1. ^ a b Kuchner, E.F., Anand, A.K. & Kaufman, B.M., "Cervical Diastematomyelia" Neurosurgery, 16(4): 538-542, 1985 2. ^ Anand, A.K., Baim, R.S. & Kuchner, E.F., "Cervical Diastematomyelia" Computerized Radiology. 9(1):45-49, 1985 ## External links[edit] Classification D * ICD-10: Q06.2 * ICD-9-CM: 742.51 * OMIM: 222500 * DiseasesDB: 33901 * v * t * e Congenital malformations and deformations of nervous system Brain Neural tube defect * Anencephaly * Acephaly * Acrania * Acalvaria * Iniencephaly * Encephalocele * Chiari malformation Other * Microcephaly * Congenital hydrocephalus * Dandy–Walker syndrome * other reduction deformities * Holoprosencephaly * Lissencephaly * Microlissencephaly * Pachygyria * Hydranencephaly * Septo-optic dysplasia * Megalencephaly * Hemimegalencephaly * CNS cyst * Porencephaly * Schizencephaly * Polymicrogyria * Bilateral frontoparietal polymicrogyria Spinal cord Neural tube defect * Spina bifida * Rachischisis Other * Currarino syndrome * Diastomatomyelia * Syringomyelia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Diastematomyelia	c0011999	4,769	wikipedia	https://en.wikipedia.org/wiki/Diastematomyelia	2021-01-18T18:40:26	{"gard": ["1851"], "mesh": ["D009436"], "umls": ["C0011999"], "icd-9": ["742.51"], "icd-10": ["Q06.2"], "orphanet": ["1671"], "wikidata": ["Q3026420"]}
An X-linked syndromic muti-systemic ectodermal dysplasia presenting neonatally in females with a bullous rash along Blaschko's lines (BL) followed by verrucous plaques and hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and can affect the retinal and the central nervous system (CNS) microvasculature. It may have other aspects of ectodermal dysplasia such as sweat gland abnormalities. Germline pathogenic variants in males result in embryonic lethality. ## Epidemiology The birth prevalence is approximately 1/ 143,000. The female to male ratio is 20:1. ## Clinical description The disorder cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Classically, Stage I evolves to a verrucous stage II characterized by wart-like plaques then to Stage III hyperpigmentation along BL that can persist to adulthood. This evolution varies and some adults report persistence of Stages I and II, usually with febrile illness, well into adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. The so-called Stage IV findings have hypopigmented, hairless regions following BL mostly evident on the lower extremities; however, it is possible that these areas of skin dysplasia may be present from an earlier age, but not visible until the growth of adult body hair. About 50% of IP symptoms are extracutaneous. Delayed dentition, missing, and/or malformed cone shaped teeth occur in most cases. Other manifestations include onycodystrophy, alopecia and a wide range of ophthalmologic abnormalities from primary microphthalmia, to reactive retinal neovascularization (RNV) conferring risk of retinal detachment. CNS abnormalities may comprise microcephaly and neonatal stroke that can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal. ## Etiology IP is caused by familial (10-25%) or sporadic de novo (>50%) mutations of the NF-kappaB essential modulator gene IKBKG (formerly NEMO). In females, a common exon 4-10 deletion underlies 65% of cases, 8.6% have a sequence variant, and about 4% have a gene deletion. ## Diagnostic methods Typical skin lesions and genetic testing are sufficient for diagnosis. Leukocytosis and eosinophilia may be noted. Skin histology shows eosinophilic spongisostic bulles (stage I); hyperkeratotic and acanthotic epidermis with dyskeratotic keratinocytes (stage II) and loose dermal melanine deposits (stage III). ## Differential diagnosis Stage I may be misdiagnosed as bullous impetigo, inherited epidermolysis bullosa, herpes, or varicella. Differential diagnosis of stage II includes warts, molluscum contagiosum, and epidermal nevus syndrome. Any condition with 'linear and swirled' pigmentation overlaps with stage III. Stage IV resembles scarring, vitiligo, or other hypopigmentations with localized alopecia. Note that chromosomal mosaicism can manifest swirled and linear pigmentation abnormalities in both males and females. Additional reported differential diagnoses are Naegeli-Franceschetti-Jadassohn syndrome and Norrie's disease. ## Antenatal diagnosis Fertility is normal except for the miscarriage of affected males. Genetic prenatal diagnosis is available. ## Genetic counseling IP is inherited X-linked dominantly. An affected woman has a 50% risk of having affected children. Live-born affected males should be checked for a 47,XXY karyotype. ## Management and treatment Treatment is symptomatic, including standard management of blisters (not opening them and avoidance of trauma), topical treatment (medication, oatmeal baths) and addressing infections (as in cellulitis). Dental abnormalities should be managed by a pedodontist in combination with speech therapy and a pediatric nutritional program as needed. Appropriate specialists are required for RNV monitoring and treatment (cryotherapy and laser photocoagulation) and regular procedures should be followed if retinal detachment occurs. Early retinal angiograms may be indicated. Neurological involvement necessitates a pediatric neurologist, whereas developmental screening and additional complementary therapy may be recommended in cases with developmental delay. ## Prognosis Life expectancy is normal. Those without neonatal CNS abnormalities typically have normal physical and cognitive development. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Incontinentia pigmenti	c0021171	4,770	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=464	2021-01-23T18:46:43	{"gard": ["6778"], "mesh": ["D007184"], "omim": ["308300"], "umls": ["C0021171", "C0022283", "C2930820"], "icd-10": ["Q82.3"], "synonyms": ["Bloch-Siemens syndrome", "Bloch-Sulzberger syndrome"]}
Barber Say syndrome Other namesHypertrichosis-atrophic skin-ectropion-macrostomia syndrome Barber-Say syndrome has an autosomal dominant pattern of inheritance Usual onsetNeonatal Barber-Say syndrome (BSS) is a very rare congenital disorder associated with excessive hair growth (hypertrichosis), fragile (atrophic) skin, eyelid deformities (ectropion), and an overly broad mouth (macrostomia).[1] Barber-Say syndrome is phenotypically similar to Ablepharon macrostomia syndrome, which is also associated with dominant mutations in TWIST2.[2] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Epidemiology * 4 References * 5 External links ## Signs and symptoms[edit] * Severe hypertrichosis, especially of the back * Skin abnormalities, including hyperlaxity and redundancy * Facial dysmorphism, including macrostomia * Eyelid deformities, including ectropion * Ocular telecanthus * Abnormal and low-set ears * Bulbous nasal tip with hypoplastic alae nasi * Low frontal hairline ## Genetics[edit] Multiple cases of parent-to-child transmission suggest that Barber-Say syndrome exhibits autosomal dominant inheritance.[3] Exome sequencing and expression studies have shown that BSS is caused by mutations in the TWIST2 gene that affect a highly conserved residue of TWIST2 (twist-related protein 2). TWIST2 is a basic helix-loop-helix transcription factor that binds to E-box DNA motifs (5'-CANNTG-3') as a heterodimer and inhibits transcriptional activation.[4] Because TWIST2 mediates mesenchymal stem cell differentiation[5] and prevents premature or ectopic osteoblast differentiation,[6] mutations in TWIST2 that disrupt these functions by altering DNA-binding activity could explain many of the phenotypes of BSS.[2] ## Epidemiology[edit] The prevalence of Barber Say syndrome is less than 1 in 1,000,000.[7] As of 2017, only 15 cases have been reported in the literature.[8] ## References[edit] 1. ^ "Barber Say syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-01-21. 2. ^ a b Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, et al. (July 2015). "Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes". American Journal of Human Genetics. 97 (1): 99–110. doi:10.1016/j.ajhg.2015.05.017. PMC 4572501. PMID 26119818. 3. ^ Online Mendelian Inheritance in Man (OMIM): BARBER-SAY SYNDROME; BBRSAY - 209885 4. ^ Universal protein resource accession number Q8WVJ9 for "TWIST2 – Twist-related protein 2 – Homo sapiens (Human) – TWIST2 gene & protein " at UniProt. 5. ^ Isenmann S, Arthur A, Zannettino AC, Turner JL, Shi S, Glackin CA, Gronthos S (October 2009). "TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment". Stem Cells. 27 (10): 2457–68. doi:10.1002/stem.181. PMID 19609939. 6. ^ Lee MS, Lowe G, Flanagan S, Kuchler K, Glackin CA (November 2000). "Human Dermo-1 has attributes similar to twist in early bone development". Bone. 27 (5): 591–602. doi:10.1016/S8756-3282(00)00380-X. PMID 11062344. 7. ^ "Orphanet: Barber Say syndrome". www.orpha.net. January 2014. Retrieved 2019-01-21. 8. ^ Yohannan MD, Hilgeman J, Allsbrook K (July 2017). "TWIST2 gene mutation". Clinical Case Reports. 5 (7): 1167–1169. doi:10.1002/ccr3.1014. PMC 5494409. PMID 28680619. ## External links[edit] Classification D * ICD-10: Q87.0 * OMIM: 209885 * MeSH: C537908 * DiseasesDB: 33294 External resources * Orphanet: 1231 * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Barber–Say syndrome	c1319466	4,771	wikipedia	https://en.wikipedia.org/wiki/Barber%E2%80%93Say_syndrome	2021-01-18T18:59:32	{"gard": ["819"], "mesh": ["C537908"], "umls": ["C1319466"], "orphanet": ["1231"], "wikidata": ["Q18616565"]}
A number sign (#) is used with this entry because Fanconi anemia of complementation group A (FANCA) is caused by homozygous or compound heterozygous mutation in the FANCA gene (607139) on chromosome 16q24. Description Fanconi anemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). Soulier et al. (2005) noted that the FANCA, -C, -E, -F, -G, and -L proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. Some cases of Fanconi anemia have presented with a VACTERL (192350) or VACTERL-H (276950, 314390) phenotype. In a group of 27 patients with Fanconi anemia group D1 (605724) due to biallelic mutations in the BRCA2 gene (600185), Alter et al. (2007) found that 5 patients had 3 or more VATER association anomalies and 1 was diagnosed with VACTERL-H. A VATER phenotype has also been reported in Fanconi anemia of complementation groups A, C (227645), E (600901), F (603467), and G (602956); VACTERL-H has also been described in patients with FANCB (300515) mutations (McCauley et al., 2011). Savage et al. (2015) added patients with FANCI (609053) to this list and stated that patients with FANCD2 (227646) and FANCL (614083) had also been reported to have features of VACTERL association. ### Genetic Heterogeneity of Fanconi Anemia Other Fanconi anemia complementation groups include FANCB (300514), caused by mutation in the FANCB (300515) on chromosome Xp22; FANCC (227645), caused by mutation in the FANCC (613899) on chromosome 9q22; FANCD1 (605724), caused by mutation in the BRCA2 (600185) on chromosome 13q12; FANCD2 (227646), caused by mutation in the FANCD2 gene (613984) on chromosome 3p25; FANCE (600901), caused by mutation in the FANCE gene (613976) on chromosome 6p21; FANCF (603467), caused by mutation in the FANCF gene (613897) on chromosome 11p15; FANCG (614082), caused by mutation in the XRCC9 gene (FANCG; 602956) on chromosome 9p13; FANCI (609053), caused by mutation in the FANCI gene (611360) on chromosome 15q26; FANCJ (609054), caused by mutation in the BRIP1 gene (605882) on chromosome 17q22; FANCL (614083), caused by mutation in the PHF9 gene (FANCL; 608111) on chromosome 2p16; FANCN (610832), caused by mutation in the PALB2 gene (610355) on chromosome 16p12; FANCO (613390), caused by mutation in the RAD51C (602774) on chromosome 17q22; FANCP (613951), caused by mutation in the SLX4 gene (613278) on chromosome 16p13; FANCQ (615272), caused by mutation in the ERCC4 gene (133520) on chromosome 16p13; FANCR (617244), caused by mutation in the RAD51 gene (179617) on chromosome 15q15; FANCS (617883), caused by mutation in the BRCA1 gene (113705) on chromosome 17q21; FANCT (616435), caused by mutation in the UBE2T gene (610538) on chromosome 1q31; FANCU (617247), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; FANCV (617243), caused by mutation in the MAD2L2 gene (604094) on chromosome 1p36; and FANCW (617784), caused by mutation in the RFWD3 gene (614151) on chromosome 16q23. The previously designated FANCH complementation group (Joenje et al., 1997) was found by Joenje et al. (2000) to be the same as FANCA. A patient originally reported to have Fanconi anemia of complementation group M (FANCM) due to mutation in the FAAP250 gene (609644) by Meetei et al. (2005) was subsequently found by Singh et al. (2009) to have FANCA. Clinical Features Clinical manifestations of Fanconi anemia include pre- and postnatal growth retardation; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); a typical facial appearance with small head, eyes, and mouth; hearing loss; hypogonadism and reduced fertility; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); bone marrow failure; and susceptibility to cancer, predominantly acute myeloid leukemia. The life expectancy of FA patients is reduced to an average of 20 years (range, 0-50) (summary by Joenje and Patel, 2001). Giampietro et al. (1993) pointed to the 'extreme clinical heterogeneity' among patients with Fanconi anemia based on an analysis of clinical data from 370 patients enrolled in the International Fanconi Anemia Registry. Of these, 220 (60%) represented probands with congenital malformations. In addition to short stature, cafe-au-lait spots, and radial-ray and renal malformations, affected patients presented with cardiac, gastrointestinal, central nervous system, and various skeletal abnormalities. Genital anomalies were common in male patients. Approximately 50% of the patients had radial-ray abnormalities, which ranged from bilateral absent thumbs and radii to a unilateral hypoplastic thumb or bifid thumb. Among the patients with congenital malformations, the diagnosis of Fanconi anemia was made in only 28% before the onset of hematologic manifestations. About one-third of all patients enrolled in the registry did not have congenital malformations; of these patients, 85% had at least one of the following: skin pigmentation abnormalities, microphthalmia, or height, weight, or head circumference in the lowest 5% for their age. Minor congenital anomalies were noted in approximately 20% of these patients. Leukemia is a fatal complication (Garriga and Crosby, 1959) and may occur in family members lacking full-blown features. Zaizov et al. (1969) described 2 sisters and a brother with pancytopenia similar to that of Fanconi anemia but without congenital malformations. Chromosomal changes similar to those of Fanconi anemia were present and patchy areas of hyperpigmentation were noted in 2 of the sibs. Hirschman et al. (1969) reported 2 brothers with aplastic anemia similar to Fanconi anemia but without associated congenital anomalies. Both responded to androgen therapy and showed increased chromosomal breakage as in Fanconi anemia. One had a stable translocation chromosome in bone marrow cells. The other's skin fibroblasts showed increased susceptibility to 'malignant' transformation by SV40 virus, as in Fanconi anemia. Skin fibroblasts of the mother and a sister, both normal, also showed increased susceptibility to 'malignant' transformation. Alter (1981) considered the cases of Hirschman et al. (1969) to be instances of Fanconi anemia. Swift et al. (1974) concluded that male heterozygotes for Fanconi anemia have a risk of malignant neoplasm 3.4 times that of the general population. Li and Potter (1978) reported typical Fanconi anemia in a close relative of the 5 sibs with hypoplastic anemia reported by Estren and Dameshek (1947). The parents of the Fanconi patient were second cousins and both were first cousins of the 5 sibs. Li and Potter (1978) suggested that these 5 sibs may have been genetic compounds for Fanconi anemia and Blackfan-Diamond hypoplastic anemia (105650). Welshimer and Swift (1982) studied families of homozygotes for ataxia-telangiectasia (AT; 208900), Fanconi anemia, and xeroderma pigmentosum (XP) to test the hypothesis that heterozygotes may be predisposed to some of the same congenital malformations and developmental disabilities that are common among homozygotes. Among XP relatives, 11 of 1,100 had unexplained mental retardation, whereas only 3 of 1,439 relatives of FA and AT homozygotes showed mental retardation. Four XP relatives and no FA or AT relatives had microcephaly. Idiopathic scoliosis and vertebral anomalies occurred in excess in AT relatives, while genitourinary and distal limb malformations were found in FA families. Considerable intergenic heterogeneity has been found in xeroderma pigmentosum and some in ataxia-telangiectasia. Berkovitz et al. (1984) concluded that abnormal sexual development in Fanconi anemia represents hypergonadotropic hypogonadism. De Vroede et al. (1982) observed simultaneous onset of pancytopenia in a brother and sister, 5 years apart in age, suggesting possible exposure to a common external agent. One of the patients showed ropalocytosis, i.e., club-shaped cell processes, affecting the erythropoietic series from basophilic erythroblasts to reticulocytes. Macdougall et al. (1990) described FA in 25 black African children seen in Johannesburg over an 11-year period. Seventeen (68%) of the children died during the period of observation. Leukemia was the terminal event in 2. Response to androgens was poor and most patients required regular transfusion. Mean age of death was 9.8 years and the mean time between diagnosis and death 2.3 years. According to Auerbach (1992), a review of all cases of FA reported to the International Fanconi Anemia Registry indicated that at least 15% manifested acute myelogenous leukemia (AML) or preleukemia. These patients usually have karyotypically abnormal bone marrow clones but do not exhibit chromosomal translocations involving breakpoints associated with specific oncogenes. Hagerman and Williams (1993) illustrated the characteristically short thumb and a cafe-au-lait spot in a patient with Fanconi anemia, together with cytogenetic studies showing chromatid fragments and a dicentric chromosome. Young and Alter (1994) concluded that the proportion of FA homozygotes without external anomalies is underestimated by literature review. Literature reports of homozygotes identified because they had affected sibs indicated that at least 25% do not have anomalies. Young and Alter (1994) stated that such patients represent one end of the spectrum of FA. Kwee et al. (1997) reported atypical cases of FA in 2 elderly sibs. The 56-year-old proband had no hematologic findings of FA and was found by complementation study to belong to FA group A. Her elder brother had thrombocytopenia and leukopenia, and died of heart failure, uremia, and anemia at the age of 50. Earlier cytogenetic investigation in the brother did not show hypersensitivity to mitomycin C. In a study of 54 patients with FA, Wajnrajch et al. (2001) found that endocrinopathy was a frequent finding, occurring in 81% of patients. Seventy-two percent of patients had hyperinsulinemia, 25% had impaired glucose tolerance or overt diabetes mellitus, 44% had a subnormal response to growth hormone stimulation, 100% had abnormal spontaneous growth hormone secretion profiles, and 36% had thyroid hormone deficiency. The patients with low growth hormone responses tended to have a greater degree of growth retardation than the group as a whole, and stature was significantly worse for those with hypothyroidism. The patients with no demonstrable endocrinopathy had a mean height of 2 standard deviations below normal, demonstrating that a significant degree of short stature is typical of FA. Patients with complementation group A seemed to have a relatively mild endocrine phenotype, whereas patients with complementation group C had greater impairment of stature and a greater tendency toward primary hypothyroidism. Bakhshi et al. (2006) described the case of a 17-year-old boy with a seemingly unique lymphocyte mitomycin-C (MMC)-sensitive chromosomal breakage syndrome. He had failure to thrive, microcephaly, slight facial dysmorphism, and constitutional short stature but no other phenotypic or hematologic manifestations of FA. He developed B-cell lymphoma of the neck, which was treated with standard doses of alkylating agents without adverse side effects related to chemotherapy. Normal erythrocyte corpuscular volume, MMC-insensitive fibroblasts, and the occurrence of lymphoma rather than AML set this patient apart from typical FA. The combination of constitutional dwarfism, microcephaly, MMC-sensitive lymphocytes, and susceptibility to lymphoma appeared to represent an unusual constellation of symptoms among genetic disorders. Krausz et al. (2019) studied a 43-year-old infertile Spanish man (patient 04-170), born of first-cousin parents, who was found to be homozygous for a missense mutation in the FANCA gene. The proband had nonobstructive azoospermia, and testicular biopsy showed complete absence of germ cells in the tubules (Sertoli cell-only syndrome type I; see 400042). The DEB-induced chromosomal breakage test was consistent with FA somatic mosaicism, and the presence of 2 to 3% wildtype alleles on next-generation sequencing suggested a possible mechanism of genetic reversion by back mutation. In the proband's azoospermic brother, who was also homozygous for the FANCA mutation, DEB-induced chromosomal breakage was present in the majority of cells, indicating typical complete FA. The proband showed some facial dysmorphism, but his brother did not have dysmorphic features. Although previously the brother had exhibited mildly low platelets, red blood cells, and leukocytes, no further analysis had been performed at that time; however, follow-up laboratory evaluation after molecular diagnosis showed a pronounced decrease of all 3 cell types. Biochemical Features In 2 brothers and a third unrelated patient, Lohr et al. (1965) found marked reduction of red cell, leukocyte, and platelet hexokinase activity. This is apparently a different defect from the hexokinase deficiency (235700) that is limited to red cells and results in hemolytic anemia alone. A consistent defect in hexokinase cannot be considered as proved (Brunetti et al., 1966). Joenje et al. (1979) found deficiency of red cell superoxide dismutase in Fanconi anemia by 2 independent methods of assay. The activity per antigenic unit and the electrophoretic mobility of the enzyme were normal, suggesting that the deficiency is due to a regulatory disturbance, not a mutation in the structural gene for the enzyme. Joenje and Patel (2001) noted that patients with Fanconi anemia have elevated levels of serum alpha-fetoprotein (Cassinat et al., 2000). Other Features The G2 phase of the cell cycle is very long in Fanconi anemia (Dutrillaux et al., 1982), a feature that might be used for diagnosis when no other manifestations are present (Schindler et al., 1985). Schindler et al. (1985) performed tests with BrdU-Hoechst flow cytometry, with the ratio of G2 to G1 as the measure. The results showed arrest at the G2 phase in lymphocytes. Similar findings have been found in ataxia-telangiectasia (Schindler et al., 1987). Heterozygotes for both conditions have intermediate values (Schinzel, 1991). Inheritance Using family data on Fanconi anemia, Rogatko and Auerbach (1988) tested a new method of segregation analysis when no information about mode of ascertainment is available. The results confirmed a monogenic autosomal recessive mode of inheritance. Cytogenetics Since particular mutation predisposes to multiple chromosomal breaks (Schroeder et al., 1964; Bloom et al., 1966), spontaneous chromosome breakage is a feature of FA. Bloom syndrome (210900) is another single gene disorder accompanied by chromosomal breakage and predisposition to leukemia. Schroeder and German (1974) showed that aberrations were more numerous in Fanconi cells than in Bloom cells. In Bloom syndrome most interchanges were between homologous chromosomes, whereas in Fanconi anemia they were usually between nonhomologous chromosomes. In a review of cytogenetic studies of FA-associated leukemias, Auerbach and Allen (1991) found a high frequency of monosomy 7 and duplications involving 1q. There were no occurrences of t(8;21), t(15;17), or abnormalities of 11q, which are associated with M2, M3, and M5 leukemias, respectively. The mean age of death in FA patients developing leukemia was 15 years. Callen et al. (2002) studied several markers of telomere integrity and function in lymphocytes of FA group A patients and age-matched controls. A higher frequency of extrachromosomal TTAGGG signals and of chromosome ends with undetectable TTAGGG repeats were observed in FA cells by FISH, suggesting intensive breakage at telomeric sequences. Consistent with previous reports, quantitative FISH analysis showed an accelerated telomere shortening of 0.68 kb in both arms of FA chromosomes. A 10-fold increase in chromosome end fusions was observed in FA cells, despite normal binding of TRF2 (602027), a telomere binding factor that protects human telomeres from end fusions. The authors concluded that telomere erosion in FA is caused by a higher rate of breakage at TTAGGG sequences in vivo in differentiated cells, and that the increased occurrence of end fusions is independent of TRF2 binding. Mapping Fanconi anemia complementation group A is caused by mutation in the FANCA gene, which maps to chromosome 16q24.3 (Fanconi Anaemia/Breast Cancer Consortium, 1996). ### Exclusion Studies By linkage studies in families from the International Fanconi Anemia Registry which contained 2 or more affected offspring, one or more offspring from consanguineous marriages, or multiple affected children in collateral sibships, Auerbach et al. (1989) excluded the long arm of chromosome 19 as the location for the Fanconi anemia mutation. Chromosome 19q had been considered a candidate location for the gene because 3 DNA repair genes (126340, 126380, 194360) are located there. Molecular Genetics Poon et al. (1974) showed that cells from patients with Fanconi anemia are deficient in their ability to excise UV-induced pyrimidine dimers from their DNA. They are capable, however, of single strand break production and unscheduled DNA synthesis. From this the authors inferred deficiency in an exonuclease which specifically recognizes and excises distortions in the tertiary structure of DNA. Hirsch-Kauffmann et al. (1978), like some other workers, could find no defect in exonuclease but found reduction in DNA ligase activity in both a patient and the heterozygous mother. Fujiwara et al. (1977) presented evidence that Fanconi anemia fibroblasts have an impaired capacity of removing DNA interstrand crosslinks induced by mitomycin C. They favored the view that a DNA crosslink repair deficiency is responsible for chromosomal damage in this disorder. Wunder et al. (1981) suggested that the defect in Fanconi anemia is in the passage of DNA-repair-related enzymes from the site of synthesis in the cytoplasm to the site of action in the nucleus. Studying the placenta of an affected infant, an unusual distribution of DNA topoisomerase was noted: high in the cytoplasm, very low in the nuclear sap. Whether the defect resides in the nuclear membrane or in the enzyme molecule is not clear. Wunder (1984) extended the studies suggesting that relatively high cytoplasmic DNA topoisomerase I in Fanconi placenta and fibroblasts may be due to an impediment to entry into the nucleus or perhaps binding to chromatin. In somatic cell hybrid studies, Duckworth-Rysiecki et al. (1985) presented evidence for the existence of at least 2 FA complementation groups. They correspond to phenotypically distinct classes of cells exhibiting different rates of recovery of semiconservative DNA synthesis after treatment with DNA crosslinking agents in culture (Moustacchi et al., 1987) and different rates of removal of DNA crosslinks as shown by electron microscopy (Rousset et al., 1990). However, these studies do not provide a reliable method for determining the complementation group of a given patient, nor is there any apparent correlation between clinical phenotype and genetic class. Cultured FA cells are unusually sensitive to DNA crosslinking agents such as mitomycin C whereas their sensitivity to radiation is close to normal. In the hands of Zakrzewski and Sperling (1982), complementation studies based on mitomycin C sensitivity showed no evidence of heterogeneity when fusion was done between cells from different ethnic groups. Complementation studies with hybrids of cell lines derived from 4 patients in whom different biochemical lesions had been postulated led Zakrzewski et al. (1983) to conclude that the mutations are allelic. Heterogeneous responses of various cell lines to DNA crosslinking treatments suggest genetic heterogeneity (Moustacchi and Diatloff-Zito, 1985), as do complementation studies (see 300514). Diatloff-Zito et al. (1986) found that normal DNA transfected into FA cells rendered the cells resistant to the effects of mitomycin C. Transfection of DNA of their own cells or DNA of yeast or salmon sperm did not give resistance. Shaham et al. (1987) likewise found by transfection experiments that DNA sequences present in both the human and the Chinese hamster will correct the 2 cellular defects that are hallmarks of FA: spontaneous chromosome breakage and hypersensitivity to the cell-killing and clastogenic effects of the difunctional alkylating agent diepoxybutane. These observations opened the way for cloning 'the FA gene,' mapping it, and determining its gene product and precise function. Chaganti and Houldsworth (1991) gave a review. Strathdee et al. (1992) suggested that there are at least 4 different FA genes, mutations at any one of which can lead to the FA phenotype. Auerbach (1992) suggested that the cellular defect in FA results in chromosomal instability, hypersensitivity to DNA damage, and hypermutability for allele-loss mutations, thus predisposing to leukemia as a multistep process. Auerbach (1992) pointed to topoisomerase I (TOP1; 126420) and proliferating cell nuclear antigen (PCNA; 176740) as candidate genes for FA of complementation group A because of their location on chromosome 20 as well as their known function. Saito et al. (1994) performed a mutation analysis on topoisomerase I cDNA from FA cells by using chemical cleavage mismatch scanning and nucleotide sequencing. No mutation was detected from GM1309, an FA cell line of group A. Levran et al. (1997) used SSCP analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene (607139). A total of 85 variant bands were detected. Forty-five of the variants were probably benign polymorphisms and forty variants were considered probable pathogenic mutations. Wijker et al. (1999) investigated the molecular pathology of Fanconi anemia by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations were identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most were predicted to result in the absence of the FAA protein. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. Joenje and Patel (2001) reviewed the molecular basis of Fanconi anemia. They referred to Fanconi anemia, xeroderma pigmentosum (see 278700), and hereditary nonpolyposis colorectal cancer (see 120435), all of which feature genomic instability in combination with a strong predisposition to cancer, as 'caretaker-gene diseases.' The common feature of these disorders is an impaired capacity to maintain genomic integrity, which results in the accelerated accumulation of key genetic changes that promote cellular transformation and neoplasia. Cancer predisposition in these diseases is therefore an indirect result of the primary genetic defect. Grompe and D'Andrea (2001) reviewed the molecular genetics of FA and noted the presumed interaction of BRCA1 with the 8 FA complementation group proteins in a model of interstrand crosslink repair. D'Andrea (2003) reviewed studies indicating that disruption of the FA/BRCA pathway, by germline mutations, somatic mutations, or epigenetic silencing of FA genes, may contribute to epithelial cancer progression. Soulier et al. (2005) found that 8 (15%) of 53 patients with Fanconi anemia had spontaneous genetic reversion correcting the FA mutations. Immunoblot analysis of peripheral blood cells from all 8 revertant patients detected FANCD2 monoubiquitination, illustrating that the FA/BRCA pathway was intact in these cells. In contrast, fibroblasts from 6 of the 8 revertants showed abnormal FANCD2 patterns, indicating functional FA reversion in the peripheral blood cells. The 2 remaining revertants had positive chromosomal breakage tests, suggesting somatic mosaicism. Genetic reversion was associated with higher blood counts and with clinical stability or improvement. In cell lines derived from 2 sibs originally reported by Meetei et al. (2005) as having FANCM due to biallelic mutations in the FAAP250 gene (FANCM; 609644), Singh et al. (2009) identified biallelic mutations in the FANCA gene (607139.0011 and 607139.0012). Singh et al. (2009) noted that only 1 of the sibs had clinical features of the disorder and that the clinically affected sib carried only 1 FANCM mutation. The clinically unaffected sib (EUFA867) carried both biallelic FANCA mutations and biallelic FANCM variants (609644.0001 and 609644.0002). Singh et al. (2009) reclassified the affected sib as having FANCA, and suggested that FANCM deficiency in the unaffected sib may have overruled the FANCA defect and changed the clinical outcome, possibly even attenuating the phenotype. By exome sequencing in a 43-year-old infertile Spanish man (patient 04-170) with nonobstructive azoospermia and Sertoli cell-only syndrome (SCO) on testicular biopsy, in whom known causes of azoospermia had been excluded, Krausz et al. (2019) identified homozygosity for a missense mutation in the FANCA gene (R880Q; 607139.0013). His affected brother was also homozygous for the mutation. Screening for FANCA variants in a cohort of 27 additional infertile Spanish men with azoospermia and SCO, who also had a platelet count less than 200,000/L and mean corpuscular volume greater than 85 fL, revealed 1 patient (patient 14-339) who was compound heterozygous for FANCA mutations (607139.0014-607139.0015). The authors suggested that screening for FANCA variants in infertile men with SCO might identify undiagnosed FA patients before the appearance of severe clinical manifestations of the disease. ### Exclusion Studies Schweiger et al. (1987) suggested that the defect in Fanconi anemia is one of impaired ADP-ribosylation. Several independent observations have suggested that ADPRT (173870) might be the site of the mutation in Fanconi anemia; however, Flick et al. (1992) could find no abnormality in cells from an FA patient of complementation group A (cell line GM6914). Diagnosis Rosendorff and Bernstein (1988) concluded that in vitro enhancement of chromosome breakage by DEB and mitomycin C is usually a reliable technique to identify FA homozygotes but could not be depended on to identify individual FA heterozygotes. ### Prenatal Diagnosis Auerbach et al. (1985) attempted prenatal diagnosis in 30 fetuses at risk, using increased baseline and DEB-induced chromosomal breakage in amniotic fluid cells (and in 4 cases, chorion villus cells) as the measure of affection. Seven of the fetuses were diagnosed as affected; 2 were carried to term and 5 were terminated. The 2 who went to term were clinically affected; 2 of the abortuses showed congenital malformations, including abnormalities of the thumb and radius. No clinical suggestion of FA was found in the other 23 cases with diagnosis of no FA type abnormality. Auerbach et al. (1986) extended the studies to the first trimester of pregnancy by the study of chromosomal breakage induced by DEB. Baseline chromosomal breakage and breakage after the agent were analyzed in 10 pregnancies: in 2, Fanconi anemia was diagnosed; in 8, FA was excluded even though the fetus was at risk. The results were unambiguous. Poole et al. (1992) described monozygotic twin girls in whom the diagnosis of Fanconi anemia had been made at birth on the basis of limb anomalies and an apparently increased baseline chromosomal breakage frequency in one twin. Over a 13-year follow-up, they had not developed aplastic anemia or other hematologic manifestations of FA. Furthermore, repeat studies in 2 laboratories showed no evidence for increased baseline or DEB-induced chromosomal breakage in either twin. Using the scoring system for FA diagnosis developed by Auerbach et al. (1989), an FA probability coefficient of 0.98 was obtained. Through the International FA Registry, 15 additional patients were identified who had an FA probability score of 0.75 or greater but who had not developed aplastic anemia and were DEB negative. Poole et al. (1992) suggested that these patients should not be considered as instances of FA and that they probably represent a heterogeneous group of disorders with genetic as well as nongenetic causes such as Holt-Oram syndrome (142900), VATER and VACTERL association (192350), and IVIC syndrome (147750). Clinical Management Deeg et al. (1983) performed allogeneic marrow transplantation in 8 patients with Fanconi anemia. Seven were pretreated with cyclophosphamide alone and one with that agent plus procarbazine and antithymocyte globulin. All had engraftment. Three died of graft-versus-host disease (GVHD; see 614395) and one of cerebral hemorrhage. Four were surviving 647 to 3,435 days after grafting. Two were well; 2 had chronic GVHD that was improving. Porfirio et al. (1989) found that the iron chelator desferrioxamine (DFO) partially corrected the chromosome instability in Fanconi anemia. The study was undertaken on the assumption that one of the mechanisms involved in the pathogenesis of Fanconi anemia may be impaired capacity of the cells to remove active oxygen species. There appears to be a relationship between intraleukocyte chelatable iron pool and free radical formation. Porfirio et al. (1989) concluded that it is tempting to envisage a therapeutic trial with DFO. Gluckman et al. (1989) achieved hematopoietic reconstitution in a 5-year-old boy with severe Fanconi anemia by administration of cryopreserved umbilical cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. They used a pretransplantation conditioning procedure developed specifically for the treatment of such patients. This technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that crosslink DNA and to irradiation. Broxmeyer et al. (1989) had proposed that cord blood might be useful for such hematopoietic reconstitution. Gluckman et al. (1992) gave a preliminary report on results of allogeneic bone marrow transplants (BMT) based on the records of the International Bone Marrow Transplant Registry. They suggested that because of the good results of BMT, the adverse effect of previous blood transfusions, the possible toxicity of long-term, high-dose androgen therapy, and the risk of leukemic transformation, it seemed advisable to transplant all patients with an HLA-identical sib as soon as pancytopenia requiring androgen therapy developed. Kohli-Kumar et al. (1994) reported results with bone marrow transplantation from matched sibs in 18 patients. The findings of clastogenic factor in plasma from patients with Fanconi anemia by Emerit et al. (1995) has possible therapeutic implications. As had previously been reported for ataxia-telangiectasia and Bloom syndrome, transferable clastogenic material could be demonstrated in the plasma from patients with Fanconi anemia. While all plasma ultrafiltrates from homozygotes had chromosome damaging properties, the clastogenic material had to be concentrated in most heterozygotes to reach detectable levels. The clastogenic effect was exerted via the intermediacy of superoxide radicals, since it was regularly inhibited by superoxide dismutase. This added further evidence for a prooxidant state in Fanconi anemia. The clastogenic activity possibly plays a role in the progressive impairment of blood cell-producing bone marrow and may predispose patients to develop cancer and leukemia. Prophylactic use of antioxidants may be recommended, using clastogenic plasma activity as a guide. Rackoff et al. (1996) reported that prolonged administration of granulocyte colony stimulating factor (GCSF; 138970) exerts a stimulatory effect on the bone marrow of Fanconi anemia patients and may be used to maintain a clinically adequate absolute neutrophil count in these patients. In some patients GCSF had beneficial effects on multiple hematopoietic lineages and may be used in combination with cytokine protocols for patients with progressive aplastic anemia. Rackoff et al. (1996) also reported that GCSF increases the number of circulating CD34 cells in Fanconi anemia patients. The bone marrow failure associated with Fanconi anemia can be cured by successful allogeneic hematopoietic stem cell (HSC) transplantation. However, with donors other than HLA-identical sibs, this approach is associated with high morbidity and poor survival. Therefore, Grewal et al. (2004) used preimplantation genetic diagnosis (PGD) to select an embryo produced by in vitro fertilization (IVF) that was unaffected by FA and was HLA-identical to the proband. The patient was a 6-year-old girl with FA and myelodysplasia previously treated with oxymetholone and prednisone. After her parents underwent 5 cycles of IVF with intrauterine transfer of 7 embryos over a span of 4 years, successful pregnancy ensued. Twenty-eight days after delivery, the patient underwent transplantation with her newborn sib donor's HLA-identical umbilical cord blood HSCs. Neutrophil recovery occurred on day 17 without subsequent acute or chronic graft-versus-host disease. At the time of report, 2.5 years after transplantation, the patient was well and hematopoiesis was normal. This was said to be the first described successful transplantation, using IVF and PGD, of HSCs from a donor selected on the basis of a specific disorder and HLA characteristics. Grewal et al. (2004) discussed the medical, legal, and ethical issues involved. Farrell et al. (1994) reviewed a patient originally diagnosed by Lewis et al. (1991) with Baller-Gerold syndrome (218600) and changed the diagnosis to Fanconi anemia on the basis of the finding of chronic thrombocytopenia. The pattern of anomalies included bilateral radial ray defects, right renal dysplasia, ventricular septal defect, anteriorly placed anus, persistent cloaca, and congenital hydrocephalus. Diepoxybutane (DEB) chromosome testing in 2 laboratories showed an elevated rate of mean chromosome breaks per cell consistent with that diagnosis. Farrell et al. (1994) pointed out that VACTERL with hydrocephalus (276950) has also been shown to represent Fanconi anemia on the basis of chromosome breakage studies. Rossbach et al. (1996) described 2 brothers with presumed Baller-Gerold syndrome, one of whom had previously been diagnosed with the association of vertebral, cardiac, renal and limb anomalies, anal atresia, and tracheoesophageal fistula (VACTERL) with hydrocephalus, who were evaluated for chromosome breakage because of severe thrombocytopenia in one of them. Spontaneous and clastogen-induced breakage was markedly increased in both patients as compared to controls. Clinical manifestations and chromosome breakage consistent with Fanconi anemia had been reported earlier in patients with a prior diagnosis of Baller-Gerold syndrome by Farrell et al. (1994) and in 3 patients with the VACTERL association with hydrocephalus by Toriello et al. (1991) and Porteous et al. (1992). The authors commented that the observations underscore the clinical heterogeneity of Fanconi anemia and raise the question of whether these syndromes are distinct disorders or phenotypic variants of the same disorder. Raya et al. (2009) showed that, on correction of the genetic defect, somatic cells from Fanconi anemia patients can be reprogrammed to pluripotency to generate patient-specific induced PS (iPS) cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, Raya et al. (2009) demonstrated that corrected Fanconi anemia-specific iPS cells can give rise to hematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, i.e., disease-free. Raya et al. (2009) concluded that their data offered proof of concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications. Raya et al. (2009) were able to induce iPS cells from 3 FA patients, 2 from the FA-A complementation group and 1 from the FA-D2 complementation group. Population Genetics Joenje and Patel (2001) stated that Fanconi anemia has a general, worldwide prevalence of 1-5 per million and is found in all races and ethnic groups, with an estimated heterozygous mutation carrier frequency of between 0.3 and 1%. Rosendorff et al. (1987) estimated that the birth incidence of FA in white, Afrikaans-speaking South Africans is at least 1 in 22,000, the calculated heterozygote prevalence being approximately 1 in 77. They attributed this unusually high gene frequency to founder effect. Founder effect was strongly supported by the demonstration of allelic association between the disease and marker D16S303 in the Afrikaner population (Pronk et al., 1995). Alter (1992) concluded that Fanconi anemia in the Afrikaners represents the most clearly differentiated form of this heterogeneous disorder. She concluded that Fanconi anemia in blacks is clinically indistinguishable from that in other groups with the exception of the Afrikaners. On the basis of complementation analysis of 47 FA patients from Europe and U.S./Canada, the following frequencies of the various subtypes were identified by Buchwald (1995): 31 were group A (66%), 2 were group B (4.3%), 6 were group C (12.7%), 2 were group D (4.3%), and 6 were group E (12.7%). The above data were compiled from several reports. Reporting for the European Fanconi Anaemia Research Group, Joenje (1996) found that among ethnically and clinically unselected FA patients from Germany and the Netherlands, FA-A was most prevalent in Germany (13/22, 59%), whereas in the Netherlands a majority of patients were FA-C (4/6, 67%). Jakobs et al. (1997) determined the complementation group represented by each of 16 unrelated FA patients from North America. The majority of the patients belonged to FA complementation group A (69%), followed by FA-C (18%), FA-D (4%), and FA-B or FA-E (9%). Savoia et al. (1996) found that 11 of 12 Fanconi anemia patients analyzed by complementation belonged to complementation group A. Four and 7 families came from 2 geographic clusters in the Veneto and Campania regions, respectively, which are thought to consist of aggregates of related families in reproductive isolation. The clinical characteristics of the patients showed both intra- and interfamilial heterogeneity, although overall the disease had a relatively mild course. Since the populations of both regions are likely to represent genetic isolates, the findings of Savoia et al. (1996) predicted linkage disequilibrium for markers flanking the FAA gene on chromosome 16. Thus, they concluded that DNAs from these FA families may be useful for positional cloning of the gene through haplotype disequilibrium mapping. Tipping et al. (2001) genotyped 26 Fanconi anemia families of the Afrikaner population of South Africa using microsatellite and single-nucleotide polymorphic markers and detected 5 FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with 4 different mutations. The most common was an intragenic deletion of exons 12-31 (607139.0007), accounting for approximately 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while 2 other mutations accounted for approximately 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected 1 patient from the western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogic investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688; mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogic evidence is consistent with transmission of the major mutation to western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa. In a retrospective study of 145 FA patients from North America, Rosenberg et al. (2003) reported that 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia. The highest ratio of observed to expected solid tumors was 4,317 for vulvar cancer, 2,362 for esophageal cancer, and 706 for head and neck cancer. Kutler et al. (2003) analyzed clinical data from 754 FA patients from North America enrolled in the International Fanconi Anemia Registry, of whom 601 (80%) experienced the onset of bone marrow failure and 173 (23%) had a total of 199 neoplasms. One hundred and twenty (60%) of the neoplasms were hematologic and 79 (40%) were nonhematologic. The risk of developing bone marrow failure and hematologic and nonhematologic neoplasms increased with advancing age, such that by 40 years of age, cumulative incidences were 90%, 33%, and 28%, respectively. Univariate analysis revealed a significantly earlier onset of bone marrow failure and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time of hematologic or nonhematologic neoplasm development between these groups. Levitus et al. (2004) tabulated 11 genetic subtypes of Fanconi anemia, giving a pie diagram of the relative prevalences of the complementation groups based on the first 241 FA families classified by the European Fanconi Anemia Research Programme, 1994-2003. Nomenclature In a review, Alter (1992) pointed out that Fanconi anemia should really be called Fanconi syndrome because the primary defect or defects are not hematopoietic, dermatologic, or orthopedic, but presumably related in some manner to DNA repair. However, the designation Fanconi syndrome was already used to describe a specific constellation of renal tubular dysfunction. Joenje et al. (2000) suggested that future assignments of patients with FA to new complementation groups should conform with stringent criteria. A new group should be based on at least 2 patients with FA whose cell lines are excluded from all known groups and fail to complement each other in fusion hybrids, or, if only one such cell line were available, on a new complementing gene that carries pathogenic mutations in this cell line. Animal Model Cheng et al. (2000) created Fanca-deficient knockout mice and showed that they are viable and have no detectable developmental abnormalities. The hematologic parameters showed a slightly decreased platelet count and a slightly increased erythrocyte mean cell volume in mice at approximately 20 weeks of age, but this did not progress to anemia. Consistent with the clinical phenotype of FA patients, both male and female mice showed hypogonadism and impaired fertility. Furthermore, embryonic fibroblasts of the knockout mice exhibited spontaneous chromosomal instability and were hyperresponsive to the clastogenic effect of the crosslinker mitomycin C. Wong et al. (2003) generated Fanca -/- mice in which Fanca exons 1 through 6 were replaced by a beta-galactosidase reporter construct. Homozygotes displayed FA-like phenotypes including growth retardation, microphthalmia, craniofacial malformations (not found in other Fanca mouse models), and hypogonadism. Homozygous females demonstrated premature reproductive senescence and an increased incidence of ovarian cysts. The fertility defects in homozygotes may be related to a diminished population of primordial germ cells during migration into the gonadal ridges. Homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. The authors suggested that the FA pathway may play a role in the maintenance of reproductive germ cells and in meiotic recombination. Pulliam-Leath et al. (2010) found that Fancc -/- (613899);Fancg -/- (602956) double-mutant mice developed spontaneous hematologic sequelae, including bone marrow failure, acute myeloid leukemia, myelodysplasia, and complex random chromosomal abnormalities, that Fancc -/- mice or Fancg -/- mice did not develop. Studies on cells derived from single-mutant mice showed that loss of Fancg resulted in a more severe defect in multiple hematopoietic compartments than loss of Fancc, suggesting that the 2 genes have nonoverlapping roles in hematopoiesis. However, both single- and double-mutant cells showed similar sensitivity to a DNA crosslinking agent. The phenotype of the double-mutant mice was most consistent with that of human patients with Fanconi anemia. History Guido Fanconi first described this syndrome in 1927 (Fanconi, 1927). The disorder described by Estren and Dameshek (1947) has been referred to as the Estren-Dameshek variant of Fanconi anemia (Nowell et al., 1984). Its characteristics are in all ways identical to full-blown Fanconi anemia except for the absence of the congenital malformations typical of Fanconi anemia. Stevens and Meyer (2002) provided a review of the work of 2 Swiss pioneer hematologists, Eduard Glanzmann (1887-1959) and Guido Fanconi (1892-1979). INHERITANCE \- Autosomal recessive GROWTH Height \- Small stature Weight \- Low birth weight HEAD & NECK Head \- Microcephaly Ears \- Ear anomaly \- Deafness Eyes \- Strabismus \- Microphthalmia CARDIOVASCULAR Heart \- Congenital heart defect GENITOURINARY External Genitalia (Male) \- Cryptorchidism Internal Genitalia (Male) \- Infertility (in some patients) \- Azoospermia, nonobstructive (in some patients) \- Sertoli cell-only syndrome (in some patients) Kidneys \- Kidney malformation \- Absent kidney \- Duplicated kidney \- Duplicated collecting system \- Horseshoe kidney \- Renal ectopia SKELETAL Limbs \- Radial aplasia Hands \- Thumb deformity \- Thumb aplasia \- Thumb hypoplasia \- Duplicated thumb SKIN, NAILS, & HAIR Skin \- Anemic pallor \- Bruisability \- Pigmentary changes \- Hyperpigmentation \- Cafe-au-lait spots NEUROLOGIC Central Nervous System \- Mental retardation ENDOCRINE FEATURES \- Hypergonadotropic hypogonadism HEMATOLOGY \- Anemia \- Neutropenia \- Thrombocytopenia \- Reticulocytopenia \- Pancytopenia \- Bleeding \- Leukemia LABORATORY ABNORMALITIES \- Multiple chromosomal breaks \- Chromosomal breakage induced by diepoxybutane (DEB), and mitomycin C \- Deficient excision of UV-induced pyrimidine dimers in DNA \- Prolonged G2 phase of cell cycle MOLECULAR BASIS \- Caused by mutation in the Fanconi anemia, complementation group A gene (FANCA, 607139.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	FANCONI ANEMIA, COMPLEMENTATION GROUP A	c0015625	4,772	omim	https://www.omim.org/entry/227650	2019-09-22T16:27:57	{"doid": ["0111095"], "mesh": ["D005199"], "omim": ["227650"], "orphanet": ["84"], "synonyms": ["Alternative titles", "FANCONI ANEMIA"], "genereviews": ["NBK1401", "NBK5192"]}
A number sign (#) is used with this entry because of evidence that the phenotype results from a contiguous gene deletion of chromosome 11p13 including the ELP4 (606985) and PAX6 (607108) genes. The deleted region is distal to that involved in the WAGR syndrome (194072). Mutation in the PAX6 gene can cause congenital eye malformations, including aniridia (AN; 106210). Clinical Features Addis et al. (2015) reported 24 patients with a range of neurodevelopmental disorders associated with heterozygous copy number variants (CNVs; 23 deletions and 1 duplication) involving the ELP4 gene on chromosome 11p13. Most had developmental delay with intellectual disability and speech and language disorder. Several had autism or autistic features, including 6 with a primary diagnosis of autism. Several patients had congenital eye malformations. Cytogenetics Addis et al. (2015) provided evidence that heterozygous deletions of the ELP4 gene on chromosome 11p13 may contribute to a range of neurodevelopmental disorders, including general developmental delay, speech and language disorders, and autism spectrum disorders. In the first stage of their study, array CGH testing found that 8 of 4,092 individuals referred for neurodevelopmental disorders had small (less than 1 Mb) deletions disrupting the ELP4 gene. A ninth patient had a 232-kb duplication of the first 7 exons of ELP4 and the PAX6 gene. Four of the patients had CNVs affecting other chromosomes. Only 1 CNV, a microdeletion, involving the ELP4 gene was found in the WTCCC control set of 4,783 individuals (p = 7.5 x 10(-3)). In the second stage of the study, 9 of over 10,000 individuals from the DECIPHER database carried a small (less than 1 Mb) deletion encompassing the ELP4 gene. The phenotype of these individuals included developmental delay, intellectual disability, speech delay, and autism spectrum disorder. Several patients with deletions that disrupted the PAX6 gene or that disrupted a PAX6 enhancer region in intron 9 of the ELP4 gene had congenital eye malformations, such as aniridia. In the third stage of the study, 6 patients with autism from 2 cohorts totaling over 3,000 patients were found to have deletions involving the ELP4 gene. No CNVs involving the ELP4 gene were found in 6,469 controls (p = 2.7 x 10(-3)). In the study overall, the deletions ranged in size from 26 kb to 600 kb, there were no recurrent breakpoints, and several patients had deletions that involved other neighboring genes, including IMMP1L (612323), DCDC1 (608062), and DNAJC24 (611072). In addition, the CNVs were inherited from a presumably unaffected parent in 14 of 24 cases, indicating that the genetic model is clearly not monogenic. Addis et al. (2015) concluded that disruption of the ELP4 gene may contribute to a range of neurodevelopmental phenotypes. No functional studies or studies on patient cells were performed. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Aniridia (in some patients) \- Congenital eye malformations (in some patients) NEUROLOGIC Central Nervous System \- Developmental delay \- Intellectual disability \- Speech and language delay Behavioral Psychiatric Manifestations \- Autism MISCELLANEOUS \- Incomplete penetrance \- Contiguous gene deletion syndrome MOLECULAR BASIS \- Susceptibility conferred by contiguous gene deletion (26-600kb) on chromosome 11p13 ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CHROMOSOME 11p13 DELETION SYNDROME, DISTAL	c4311047	4,773	omim	https://www.omim.org/entry/616902	2019-09-22T15:47:30	{"omim": ["616902"]}
Pigmented villonodular synovitis (PVNS) is a disease in which the tissue lining the joints and tendons in the body (synovium) grows abnormally. It is characterized by a noncancerous mass or tumor. There are two types of PVNS: the local or nodular form (where the tumor involves the tendons that support the joint, or in one area of the joint) and the diffuse form (where the entire lining of the joint is involved). Symptoms might include: pain, limitation of movement, and locking of the joint. In some cases, the normal joint structure can be destroyed. The knee is most commonly affected by this condition, though it can occur in other joints such as the hip, shoulder, elbow, ankle, wrist, and rarely the jaw. The average age of diagnosis for this condition is 35 years. The cause of PVNS is unknown. Treatment involves surgery to remove the tumor and damaged portions of the synovium. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Pigmented villonodular synovitis	c0039106	4,774	gard	https://rarediseases.info.nih.gov/diseases/7396/pigmented-villonodular-synovitis	2021-01-18T17:58:19	{"mesh": ["D013586"], "umls": ["C0039106"], "orphanet": ["66627"], "synonyms": ["Localized pigmented villonodular synovitis", "Diffuse pigmented villonodular synovitis", "Tenosynovial giant cell tumors", "Diffuse-type GCT", "Diffuse-type giant cell tumor", "Tenosynovial giant cell tumor", "TGCT", "TSGCT"]}
CHIME syndrome is a rare ectodermal dysplasia syndrome characterized by ocular colobomas, cardiac defects, ichthyosiform dermatosis, intellectual disability, conductive hearing loss and epilepsy. ## Epidemiology Prevalence is unknown. To date, CHIME syndrome has been described in 8 cases. ## Clinical description CHIME syndrome is characterized by early-onset migratory ichthyosiform dermatosis, bilateral ocular coloboma, conductive hearing loss, seizures, intellectual disability, and characteristic facial features: brachycephaly, mild upslanting of the palpebral fissures, pale blue irides, hypertelorism, flat midface and philtrum, anteverted nostrils, thin upper lip, and excessive creases around a wide mouth. Ears are low-set with thick overfolded helices. Teeth are widely spaced and square in shape. Less constant findings are cleft palate or a less severe equivalent (bifid uvula and/or submucous cleft), cardiac defects (tetralogy of Fallot or transposition of the great vessels), pectus excavatum and supernumerary nipples. ## Etiology CHIME syndrome is caused by mutations in the glycosylphosphatidylinositol gene PIGL located to 17p12-p11.2. ## Genetic counseling Transmission is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CHIME syndrome	c1848392	4,775	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3474	2021-01-23T18:08:18	{"gard": ["310"], "mesh": ["C536729"], "omim": ["280000"], "umls": ["C1848392"], "icd-10": ["Q87.8"], "synonyms": ["Coloboma-congenital heart disease-ichthyosiform dermatosis-intellectual disability-ear anomalies syndrome", "Congenital disorder of glycosylation due to PIGL deficiency", "Neuroectodermal dysplasia, CHIME type", "Neuroectodermal syndrome, Zunich type", "PIGL-CDG", "Zunich-Kaye syndrome"]}
A number sign (#) is used with this entry because X-linked agammaglobulinemia/hypgammaglobulinemia (XLA) is caused by mutation in the gene encoding Bruton tyrosine kinase (BTK; 300300) on chromosome Xq22. Description X-linked agammaglobulinemia is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. The defect in this disorder resides in BTK, also known as BPK or ATK, a key regulator in B-cell development (Rawlings and Witte, 1994). The X-linked form accounts for approximately 85 to 90% of cases of the disorder. Also see 300310. The remaining 15% of cases constitute a heterogeneous group of autosomal disorders (Lopez Granados et al., 2002; Ferrari et al., 2007). ### Genetic Heterogeneity of Agammaglobulinemia/Hypogammaglobulinemia A form of X-linked hypogammaglobulemia (IMD61; 300310) is caused by mutation in the SH3KBP1 gene (300374) on chromosome Xq22. See agammaglobulinemia-1 (AGM1; 601495) for a discussion of genetic heterogeneity of autosomal forms of agammaglobulinemia. Clinical Features X-linked agammaglobulinemia, the first genetic immunodeficiency to be specifically identified, was described by Bruton (1952). Patients are unusually prone to bacterial infection but not to viral infection. A clinical picture resembling rheumatoid arthritis develops in many. Before antibiotics, death occurred in the first decade. In the more usual X-linked form of the disease, plasma cells are lacking. A rarer form of agammaglobulinemia (Hitzig and Willi, 1961), which is inherited as an autosomal recessive (601457), shows marked depression of the circulating lymphocytes, and lymphocytes are absent from the lymphoid tissue. The alymphocytotic type (also see 300400) is even more virulent than the Bruton form, leading to death in the first 18 months after birth from severe thrush, chronic diarrhea, and recurrent pulmonary infections. Seligmann et al. (1968) proposed a classification of immunologic deficiencies. Ament et al. (1973) pointed out that gastrointestinal infestation with Giardia lamblia is frequent in this and other forms of immunodeficiency. Infection with Campylobacter jejuni and Salmonella spp is also frequent (Melamed et al., 1983). Giardiasis may lead to malabsorption, while C. jejuni infection may result in recurrent fever (van der Meer et al., 1986; Kerstens et al., 1992). Geha et al. (1973) showed that males with proven X-linked agammaglobulinemias lacked bone marrow-derived (B) lymphocytes from the circulating blood, whereas progenitor and thymus (T) cells were normal. See 301000 and 308230 for other X-linked deficiencies of immunoglobulins. Although patients have recurrent bacterial infections, they generally have a normal response to viral infection, presumably because cell-mediated immunity is intact. A notable exception is the usually fatal echovirus-induced meningoencephalitis, which is often associated with the 'dermatomyositis-like' syndrome first described by Janeway et al. (1956). Mease et al. (1981) successfully treated a 32-year-old man who developed signs of myopathy and encephalopathy over a period of 3 months. Echo 11 virus was recovered from muscle and spinal fluid. In vitro lymphocyte transformation was temporarily markedly depressed by the infection. High doses of immune globulin given intravenously cured the man of this usually fatal complication. Rosen et al. (1984) reviewed primary immunodeficiencies, giving a classification according to whether the immunodeficiency was predominantly one of antibody formation, was predominantly one of cell-mediated immunity, or was associated with other defects as in ataxia-telangiectasia. Lederman and Winkelstein (1985) collected data from 96 patients cared for in 26 North American medical centers and representing a total experience of almost 1,200 patient-years. Boys with agammaglobulinemia lack circulating B cells. Landreth et al. (1985) described 4 boys with agammaglobulinemia who lacked pre-B lymphocytes. In classic agammaglobulinemia, pre-B cells are present in normal numbers in the bone marrow but appear to be either blocked or aborted in their ability to mature, express surface immunoglobulins, or produce antibody. In the boys who lacked pre-B cells, clinical presentation with recurrent infections was delayed until the second or third year. None of the 4 boys had a history of recurrent infection or similar disease in maternal first cousins or uncles. Two of the patients were brothers. The mode of inheritance is unclear. The immune defect resembled that of the thymoma-agammaglobulinemia syndrome, but thymoma was not present in any of the 4. Thorsteinsson et al. (1990) described studies in 3 brothers with IMD1, the first of whom was diagnosed in 1963 at the age of 9 years and died at the age of 23. Van der Meer et al. (1993) reported the cases of 3 unrelated men with XLA who developed colorectal cancer at the ages of 26, 29, and 36 years. Van der Meer et al. (1993) suggested that there is an increased risk of colorectal cancer in these individuals and that it may be related to intestinal infections. Ochs and Smith (1996) provided a comprehensive review of the clinical and molecular aspects of X-linked agammaglobulinemia. Smith and Witte (1999) provided a comprehensive review of XLA. XLA is characterized by an increased susceptibility mainly to extracellular bacterial infections; however, enteroviral infections frequently run a severe course and often resist therapy (Lederman and Winkelstein, 1985; McKinney et al., 1987; Ochs and Smith, 1996). Rudge et al. (1996) described a patient with XLA who had an enteroviral infection, presumably contracted at 8 years of age. Autopsy performed at 17 years of age, after several years of progressive dementia, showed severe thinning of the cerebral cortex, reduced subcortical and deep white matter, and marked dilatation of the lateral ventricles. Wood et al. (2001) described a 25-year-old man with a selective antipolysaccharide antibody deficiency who was found to have a previously described mutation (300300.0005) in the BTK gene. From the age of 23 years, his IgG level had fallen slightly below the normal range, but he had remained well on antibiotic prophylaxis for 12 years. The authors suggested that male patients with antipolysaccharide antibody deficiency should be evaluated for B-cell lymphopenia and Btk mutations. Biochemical Features Edwards et al. (1978) showed reduced ecto-5-prime-nucleotidase (129190) activity in peripheral blood lymphocytes. This is an ectoenzyme that regulates the uptake of AMP into lymphocytes by converting the nontransportable nucleotide to its readily transported nucleoside, adenosine. Inheritance Lau et al. (1988) discussed the calculation of genetic risks in XLA, including allowance for nonallelic genetic heterogeneity. Hendriks et al. (1989) described a family in which each of 2 sisters had a son with XLA. The 2 sisters with affected sons and another sister all showed exclusive inactivation of the paternal X chromosome in B lymphocytes, indicating that the gene for XLA came from their father, who, however, had no agammaglobulinemia. He was presumed to be an X chromosomal mosaic. RFLP segregation analyses in other XLA pedigrees suggested that this may be a frequent situation. Sakamoto et al. (2001) suggested maternal germinal mosaicism to explain the finding of 2 sibs with XLA who had a single base deletion (563C) in exon 6 of the BTK gene and whose mother had no evidence of the mutation. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient; normal cytoplasmic expression of BTK protein was found in monocytes of the mother. Mapping Race and Sanger (1975) thought that the agammaglobulinemia locus was possibly linked to Xg; the lod scores were positive but low at a recombination fraction of 30%. In 12 families, including an extensively affected Dutch kindred of 8 generations, Mensink et al. (1984) studied linkage with Xg (314700) and the 12E7 polymorphism that is closely linked to Xg. They concluded that XLA and Xg are at least 20 cM apart. Cohen et al. (1985) isolated a cDNA probe recognizing a family of genes, called Xlr (see 300113), on the mouse X chromosome, at least some members of which are closely linked to the xid trait. In accompanying studies, Cohen et al. (1985) presented data which, combined with the RFLP analysis closely linking the Xlr gene family to the xid mutation, suggest that the xid defect resides in a member of this family. From a study of the comparative mapping of the human and mouse X chromosomes, Buckle et al. (1985) predicted that the XLA locus of man may be on Xq between PGK1 (311800) and GLA (300644), i.e., in the segment Xq13-Xq22. This remarkable prediction was borne out by the findings of Kwan et al. (1986). By RFLP studies in 11 families, they showed that XLA is linked to 2 markers, DXS3 and DXS17, both localized in region Xq21.3-q22 (lod = 3.65 at theta = 0.04 and lod = 2.17 at theta = 0.0, respectively). In a single 8-generation Dutch kindred, Mensink et al. (1986) found a maximum lod score of 3.30 at a recombination fraction of 0.06 for linkage of XLA and marker p19-2 (DXS3). In another pedigree, similar linkage to DXS3 was excluded (lod = -3.14 at theta 0.06). This suggested the existence of a second form of X-linked agammaglobulinemia; data obtained by Mensink et al. (1986) from all pedigrees suggested localization of a second XLA gene in the Xp22 band as defined by marker p99-6 (DXS41); see 300310. This is a possible parallel to the historic demonstration of heterogeneity in elliptocytosis (611804) by the linkage principle. Mensink et al. (1986) predicted that more detailed molecular studies 'will ultimately reveal phenotypic differences, reflecting different XLA gene loci, one of them probably coding for a recombinase involved in immunoglobulin heavy-chain rearrangements (Schwaber et al., 1983) and the other(s) being involved in later stages of precursor B cell differentiation (Levitt et al., 1984). 'With a multipoint linkage analysis in 9 families with XLA, Ott et al. (1986) concluded that there was 'clear evidence for heterogeneity of XLA.' The finding of possible linkage to Xg by Race and Sanger (1975) may have been related to their having a mixture of 'Xp' and 'Xq' families. Malcolm et al. (1989) presented further evidence, based on linkage data, for the existence of 2 loci. Mensink et al. (1987) mapped XLA to Xq21.3-q22. No recombination was found between XLA and DXS17 (lod = greater than 6 at theta = 0); no recombinants were found between XLA and DXS17 in this study or in the study by Kwan et al. (1986)--with the exception of the remarkable Z pedigree which may have carried a different form of agammaglobulinemia. Malcolm et al. (1987) demonstrated close linkage to DNA markers in the Xq21.3-q22 region in studies of 15 families. Guioli et al. (1989) found close linkage of IMD1 and DXS178. No recombinants were observed, giving a maximum lod score of 5.92 at theta = 0. Kwan et al. (1990) demonstrated another marker closely linked to XLA, DXS178. Diagnosis Fearon et al. (1987) used a strategy similar to that of Conley et al. (1986) to show that the defect in XLA is intrinsic to B cells as well as to detect the carrier state. According to their strategy, recombinant DNA probes simultaneously detect RFLPs and patterns of methylation of X-chromosome genes. (Different DNA methylation patterns reflect whether the X chromosome is active or inactive and these differences in methylation can be monitored by restriction endonucleases that have the capacity to recognize methylated cytosine residues.) Random X-inactivation patterns were observed in isolated peripheral blood granulocytes, T lymphocytes, and B lymphocytes of women who were not carriers. In contrast, 1 of the 2 X chromosomes was preferentially active in the B cells, but not the T cells or granulocytes, of 3 carriers of the disorder. Fearon et al. (1987) used X-chromosome inactivation analysis to demonstrate that the X chromosome with the wildtype allele at the agammaglobulinemia locus was the active one in all the B cells. Allen et al. (1994) tested carrier status by study of B lymphocytes and T lymphocytes separated by means of antibodies to the B-cell specific antigen CD19 (107265). B lymphocytes were isolated from the mononuclear cell fraction of 20 cc of blood by using anti-CD19 immunomagnetic beads. Quantitative PCR at the androgen-receptor locus was then used to examine patterns of X inactivation in CD19-positive B cells. The trinucleotide repeat at the androgen receptor locus (AR; 313700) is within approximately 100 bp of 2 HpaII restriction-enzyme sites that are methylated on the inactive X chromosome but unmethylated on the active X chromosome. Obligate carriers of XLA demonstrated more than 95% skewing of X inactivation in CD19-positive cells but not in CD19-negative cells. Allen et al. (1994) suggested that refinements in techniques for primary carrier testing and genetic mapping of XLA make possible an ordered approach to prenatal diagnosis and genetic counseling. Schuurman et al. (1988) demonstrated the usefulness of linked RFLP markers in identifying the carrier state and in the early diagnosis of XLA in a newborn son. Journet et al. (1992) demonstrated that the pregnant mother of a boy with XLA but no family history of immune disease was a carrier by demonstrating with a methylation-sensitive probe that the X-inactivation pattern was skewed in the woman's B cells but random in her polymorphonuclear cells. Using RFLP probes flanking the XLA locus on each side, they excluded the diagnosis of XLA in the fetus on the basis of a chorionic villus sample (risk of error less than 0.003). Subsequent studies of the baby confirmed normality. Pathogenesis Pearl et al. (1978) showed that precursor B lymphocytes containing IgM heavy chains can be demonstrated in the bone marrow in XLA. This suggested that an arrest in the differentiation of precursor B lymphocytes into B lymphocytes may be involved. Schwaber et al. (1983) found that about 5% of normal pre-B cells and 100% of XLA pre-B cells produce incomplete mu chains (147020), i.e., C(mu) polypeptide without associated V(H). Thus, XLA represents a block in differentiation secondary to failure to express V(H) genes. (Cytoplasmic mu-chain protein has served as a marker for pre-B cells. Mu-chain gene expression precedes rearrangement and expression of light-chain genes.) Presumably the X chromosome codes for enzyme(s) specific for translocation of V(H) genes or a regulatory mechanism necessary for pre-B cells to differentiate to a stage using these enzymes. In 2 sisters heterozygous for both XLA and G6PD A-/B polymorphism, Conley et al. (1986) found that B cells showed activity of only the A- form of G6PD, whereas T cells and neutrophils had about equal amounts of A- and B enzyme activity. This indicates that the basic defect in XLA is intrinsic to the B cell. Schwaber et al. (1988) found an unusual phenotype of B cells in a patient with XLA, and cellular evidence for lyonization of B cells from the mother and sister. The patient had a failure of B-cell maturation at the stage of early B lymphocytes, associated with production of truncated mu and delta heavy chains composed of D-J(H)-C resulting from abortive rearrangement of variable region genes. There was also delayed expression of L chains. Peripheral blood and B-cell lines from the patient's mother and sister included 50% cells that expressed H chain without L chain. B-cell lines from the mother and sister produced both full-length mu and gamma H chains and truncated mu and delta chains corresponding to the H chains produced by the patient's B cells. Schwaber and Chen (1988) concluded that failure of variable region gene rearrangement may underlie the failure of B lymphoid development in XLA. They observed that immature B cells from a patient produced truncated mu and delta immunoglobulin H chains. In cases of XLA there is variability in the stage at which the arrest of development occurs; the major phenotype is arrested at the stage of pre-B cells, while a minor phenotype is arrested at the stage of immature B lymphocytes. The failure of B lymphoid development is associated in both phenotypes with a failure of Ig heavy chain variable region rearrangement. The immature B cells of a patient with the minor phenotype of XLA produce truncated gamma and delta heavy chains composed of a D-J-constant complex resulting from failure to rearrange a V segment. Schwaber et al. (1988) demonstrated that the fusion of these cells with mouse myeloma complemented the failure of V(H) gene rearrangement. H chains produced by such hybrid cells are composed of V(H)-D-J(H)-C. The genes encoding each of these elements were of human parental origin, indicating that the mouse myeloma provided a trans-acting regulatory element necessary for V(H) rearrangement which the XLA B cells lack. Complementation occurred in all hybrid cells examined, regardless of whether the human X chromosome was retained. Schwaber (1992) presented direct evidence that there is a failure of V(D)J recombination which causes arrest in the transition from pre-B cell to B lymphocyte. He pointed out that the arrest in B-cell development is not absolute: rare B lymphocytes have been identified in peripheral blood of some patients, and B-cell lines have been established from these cells by Epstein-Barr virus transformation. Leakiness of the mutation would not be inconsistent with the proposed mechanism. Molecular Genetics ### X-Linked Agammaglobulinemia Using probes derived for the Southern analysis of DNA from 33 unrelated families and 150 normal X chromosomes, Vetrie et al. (1993) detected restriction pattern abnormalities in 8 families. Five of them had deletions that were shown to be entirely intragenic to BTK, confirming involvement of BTK in XLA. Two single-base missense mutations (300300.0001 and 300300.0002) were identified in XLA patients. The failure of pre-B cells in the bone marrow of XLA males to develop into mature, circulating B cells could be the result of the product of the mutant ATK gene failing to fulfill its role in B-cell signaling. For further information on the molecular genetics of XLA, see 300300. ### X-Linked Hypogammaglobulinemia Kornfeld et al. (1995) described the case of a 16-year-old boy who had recurrent upper respiratory tract infections at 13 months of age and was diagnosed as having transient hypogammaglobulinemia of infancy on the basis of low immunoglobulin levels, normal diphtheria and tetanus antibody responses, normal anterior and posterior cervical nodes, normal tonsillar tissue, and normal numbers of B cells in the blood. IgA levels returned to normal at 15 months of age and remained within normal limits over the next 12 months, and IgG and IgM levels remained relatively unchanged. At age 10, he began receiving intravenous gammaglobulin, which resulted in cessation of infections. The clinical picture was thought to be that of common variable immunodeficiency disease. However, gene studies revealed the deletion of exon 16 of the BTK gene resulting from a splice junction defect. The patient represents an example of the extreme variation that can occur in the XLA phenotype. Animal Model For information on animal models of XLA, including the X-linked immunodeficiency (xid) mouse mutation, see 300300. INHERITANCE \- X-linked recessive HEAD & NECK Ears \- Otitis media \- Hearing loss Eyes \- Conjunctivitis RESPIRATORY Nasopharynx \- Sinusitis \- Rudimentary adenoids \- Rudimentary tonsils Lung \- Pneumonia \- Hypoxemia and cor pulmonale ABDOMEN Liver \- Enteroviral hepatitis Gastrointestinal \- Diarrhea GENITOURINARY Internal Genitalia (Male) \- Epididymitis \- Prostatitis SKELETAL Limbs \- Septic arthritis SKIN, NAILS, & HAIR Skin \- Pyoderma MUSCLE, SOFT TISSUES \- Enteroviral dermatomyositis syndrome NEUROLOGIC Central Nervous System \- Meningitis \- Encephalitis \- Delayed speech acquisition IMMUNOLOGY \- Frequent bacterial infections \- Severe enteroviral infections \- Small lymph nodes \- Absent B-lymphocytes in all organs \- Absent plasma cells in all organs NEOPLASIA \- Increased incidence of rectosigmoid cancer LABORATORY ABNORMALITIES \- Absent or severely reduced levels of serum immunoglobulins MISCELLANEOUS \- Susceptibility to infections start in the first year of life MOLECULAR BASIS \- Caused by mutation in the Bruton agammaglobulinemia tyrosine kinase gene (BTK, 300300.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	AGAMMAGLOBULINEMIA, X-LINKED	c0221026	4,776	omim	https://www.omim.org/entry/300755	2019-09-22T16:19:49	{"doid": ["14179"], "mesh": ["C537409"], "omim": ["300755"], "orphanet": ["47", "229717"], "synonyms": ["Alternative titles", "BRUTON-TYPE AGAMMAGLOBULINEMIA", "AGAMMAGLOBULINEMIA, X-LINKED, TYPE 1", "IMMUNODEFICIENCY 1"], "genereviews": ["NBK1453"]}
A form of craniosynostosis involving multiple sutures (coronal, lambdoidal, sagittal and metopic) characterized by a trilobular skull of varying severity (frontal towering and bossing, temporal bulging and a flat posterior skull), dysmorphic features (downslanting palpebral fissures, midface hypoplasia, and extreme proptosis) and that is complicated by hydrocephalus, cerebral venous hypertension, developmental delay/intellectual disability and hind brain herniation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Isolated cloverleaf skull syndrome	c1860050	4,777	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2343	2021-01-23T17:27:32	{"gard": ["3115"], "omim": ["148800", "600775"], "icd-10": ["Q75.0"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article may be in need of reorganization to comply with Wikipedia's layout guidelines. Please help by editing the article to make improvements to the overall structure. (January 2012) (Learn how and when to remove this template message) This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (January 2012) (Learn how and when to remove this template message) This article contains weasel words: vague phrasing that often accompanies biased or unverifiable information. Such statements should be clarified or removed. (January 2012) This article is in list format, but may read better as prose. You can help by converting this article, if appropriate. Editing help is available. (August 2011) (Learn how and when to remove this template message) Blindisms are stereotyped behaviors sometimes found in visually impaired toddlers or children.[1] Blindism behaviors range from body rocking, head swaying, eye rubbing, head banging, spinning to finger flicking.[1][2] These behaviors are repetitive and serve no specific goals, but can calm or soothe children if they are distressed. As some of these common blindness symptoms overlap with autistic symptoms, and partly because some of its diagnostic criteria depend on vision, it is particularly difficult to diagnose autism among the visually impaired.[3] ## Contents * 1 Causes * 2 Effects * 3 Prevention * 4 References * 5 External links ## Causes[edit] Causes of blindisms[4] include: * The inadequacy of sensory stimulation causes the child to seek stimulation using his own body * Social deprivation due to limited interaction with other people * Limited physical and motor activity, as the child cannot easily move to another place and change his environment to satisfy the basic need for movement and physical activity * Lack of ability to imitate and learn socially acceptable behaviors ## Effects[edit] Blindisms can lead to serious consequences if not corrected. Children displaying blindism behaviors may experience teasing or social isolation by other children. Additionally, the skin around the eye may discolor and become callus-like due to constant poking and rubbing.[1] ## Prevention[edit] Early intervention is often helpful in preventing children from displaying blindism behaviors. In most cases, a qualified teacher arranges an early education program to help develop accurate and effective use of the child's senses. The parents are usually included in such programs together with their visually impaired children, as most parents are unaware of techniques used to teach visually impaired children.[1] ## References[edit] 1. ^ a b c d "Blindisms–What are they? What can be Done to Correct Them?" (PDF). Parent to Parent. Kentucky School for the Blind. Summer 2007. Archived from the original (PDF) on July 17, 2011. 2. ^ "Beating Blindisms". SEE/HEAR News. Texas School for the Blind and Visually Impaired. Spring 2002. Archived from the original on June 22, 2002. 3. ^ Cass H (1998). "Visual impairment and autism: current questions and future research". Autism. 2 (2): 117–38. doi:10.1177/1362361398022002. 4. ^ Geraldine T. Scholl, 1986, Foundations of Education for Blind and Visually Handicapped Children and Youth: Theory and Practice. ## External links[edit] * Blindness, mental retardation and – or autism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Blindism	None	4,778	wikipedia	https://en.wikipedia.org/wiki/Blindism	2021-01-18T18:45:05	{"wikidata": ["Q884329"]}
## Clinical Features Pfeiffer (1966) and Reinhardt and Pfeiffer (1967) studied a kindred with 14 persons affected by hypoplasia of ulna and fibula in the pattern of a regular autosomal dominant. In addition to the shortening and characteristic dysplasia of the ulna and fibula, there were changes of the radius and tibia and of adjacent portions of the skeleton as well. This disorder could be allelic to dyschondrosteosis (127300) which is thought to represent the heterozygous state of Langer mesomelic dwarfism of the hypoplastic ulna, fibula and mandible type (249700). Also see Nievergelt syndrome (163400). Limbs \- Hypoplastic ulna \- Hypoplastic fibula \- Abnormal radius \- Abnormal tibia Growth \- Short-limb dwarfism identifiable at birth Inheritance \- Autosomal dominant \- ? allelic to dyschondrosteosis Head \- Normocephaly Facies \- Normal facies ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ULNA AND FIBULA, HYPOPLASIA OF	c1860616	4,779	omim	https://www.omim.org/entry/191400	2019-09-22T16:32:13	{"mesh": ["C537349"], "omim": ["191400"], "orphanet": ["2634"], "synonyms": ["Alternative titles", "MESOMELIC DWARFISM OF HYPOPLASTIC ULNA AND FIBULA TYPE", "REINHARDT-PFEIFFER MESOMELIC DYSPLASIA"]}
MYH9-related disorder is a condition that can have many signs and symptoms, including bleeding problems, hearing loss, kidney (renal) disease, and clouding of the lens of the eyes (cataracts). The bleeding problems in people with MYH9-related disorder are due to thrombocytopenia. Thrombocytopenia is a reduced level of circulating platelets, which are small cells that normally assist with blood clotting. People with MYH9-related disorder typically experience easy bruising, and affected women have excessive bleeding during menstruation (menorrhagia). The platelets in people with MYH9-related disorder are larger than normal. These enlarged platelets have difficulty moving into tiny blood vessels like capillaries. As a result, the platelet level is even lower in these small vessels, further impairing clotting. Some people with MYH9-related disorder develop hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). Hearing loss may be present from birth or can develop anytime into late adulthood. An estimated 30 to 70 percent of people with MYH9-related disorder develop renal disease, usually beginning in early adulthood. The first sign of renal disease in MYH9-related disorder is typically protein or blood in the urine. Renal disease in these individuals particularly affects structures called glomeruli, which are clusters of tiny blood vessels that help filter waste products from the blood. The resulting damage to the kidneys can lead to kidney failure and end-stage renal disease (ESRD). Some affected individuals develop cataracts in early adulthood that worsen over time. Not everyone with MYH9-related disorder has all of the major features. All individuals with MYH9-related disorder have thrombocytopenia and enlarged platelets. Most commonly, affected individuals will also have hearing loss and renal disease. Cataracts are the least common sign of this disorder. MYH9-related disorder was previously thought to be four separate disorders: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome. All of these disorders involved thrombocytopenia and enlarged platelets and were distinguished by some combination of hearing loss, renal disease, and cataracts. When it was discovered that these four conditions all had the same genetic cause, they were combined and renamed MYH9-related disorder. ## Frequency The incidence of MYH9-related disorder is unknown. More than 200 affected families have been reported in the scientific literature. ## Causes MYH9-related disorder is caused by mutations in the MYH9 gene. The MYH9 gene provides instructions for making a protein called myosin-9. This protein is one part (subunit) of the myosin IIA protein. There are three forms of myosin II, called myosin IIA, myosin IIB and myosin IIC. The three forms are found throughout the body and perform similar functions. They play roles in cell movement (cell motility); maintenance of cell shape; and cytokinesis, which is the step in cell division when the fluid surrounding the nucleus (the cytoplasm) divides to form two separate cells. While some cells use more than one type of myosin II, certain blood cells such as platelets and white blood cells (leukocytes) use only myosin IIA. MYH9 gene mutations that cause MYH9-related disorder typically result in a nonfunctional version of the myosin-9 protein. The nonfunctional protein cannot properly interact with other subunits to form myosin IIA. Platelets and leukocytes, which only use myosin IIA, are most affected by a lack of functional myosin-9. It is thought that a lack of functional myosin IIA leads to the release of large, immature platelets in the bloodstream, resulting in a reduced amount of normal platelets. In leukocytes, the nonfunctional myosin-9 clumps together. These clumps of protein, called inclusion bodies, are a hallmark of MYH9-related disorder and are present in the leukocytes of everyone with this condition. ### Learn more about the gene associated with MYH9-related disorder * MYH9 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Approximately 30 percent of cases result from new mutations in the gene and 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MYH9-related disorder	c0340978	4,780	medlineplus	https://medlineplus.gov/genetics/condition/myh9-related-disorder/	2021-01-27T08:24:33	{"gard": ["180"], "omim": ["155100"], "synonyms": []}
Robin sequence-oligodactyly syndrome is a rare, genetic, developmental defect during embryogenesis syndrome characterized by Robin sequence (i.e. severe micrognathia, retroglossia and U-shaped cleft of the posterior palate) associated with pre- and postaxial oligodactyly. Facial features can include a narrow face and narrow lower dental arch. Clinodactyly, absent phalanx, metacarpal fusions, and hypoplastic carpals have also been reported. There have been no further descriptions in the literature since 1986. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Robin sequence-oligodactyly syndrome	c1868309	4,781	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3104	2021-01-23T17:08:25	{"gard": ["4729"], "mesh": ["C535688"], "omim": ["172880"], "umls": ["C1868309"], "icd-10": ["Q87.0"], "synonyms": ["Pierre Robin sequence-oligodactyly syndrome"]}
Babesiosis refers to a condition caused by microscopic parasites that infect the red blood cells. Many people who are infected with Babesia parasites do not experience any symptoms of the condition. When present, signs and symptoms may include flu-like symptoms such as fever, chills, headache, body aches, nausea and fatigue. In severe cases, babesiosis can be associated with hemolytic anemia. Babesia parasites are primarily spread by infected ticks. Treatment is generally only required in people who develop symptoms of the condition. When necessary, affected people are often prescribed a combination of antimicrobial medications along with supportive care to manage 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Babesiosis	c0004576	4,782	gard	https://rarediseases.info.nih.gov/diseases/5878/babesiosis	2021-01-18T18:01:54	{"mesh": ["D001404"], "orphanet": ["108"], "synonyms": ["Babesia parasite infection", "Human babesiosis"]}
Junctional tachycardia ECG showing junctional tachycardia. Narrow complex QRS. No P waves. Heart rate fast. TreatmentAmiodarone to control the rhythm, electrical cardioversion is not used. Junctional tachycardia is a form of supraventricular tachycardia characterized by involvement of the AV node.[1] It can be contrasted to atrial tachycardia. It is a tachycardia associated with the generation of impulses in a focus in the region of the atrioventricular node due to an A-V disassociation.[2] In general, the AV junction's intrinsic rate is 40-60 bpm so an accelerated junctional rhythm is from 60-100bpm and then becomes junctional tachycardia at a rate of >100 bpm. Junctional tachycardia (rate about 115/min) dissociated from a slightly slower sinus tachycardia (rate about 107/min) producing one form of double tachycardia; pairs of ventricular capture (C) beats (5th, 6th, 19th, and 20th beats); see laddergram. ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Cause[edit] It can be associated with digitalis toxicity.[3] It may also be due to onset of acute coronary syndrome, heart failure, conduction system diseases with enhanced automaticity, or administration of theophylline.[4] ## Diagnosis[edit] On an EKG, junctional tachycardia exhibits the following classic criteria:[2] * P-Waves: The p-wave may be inverted in leads II, III and aVF or may not be visible * Narrow QRS complexes (which is consistent with arrhythmias that conduct through the ventricles using the His-Purkinje system and often originate from the atria or AV junction.) It can coexist with other superventricular tachycardias due to the disassociation between the SA node and the AV node. Forms of junctional tachycardia include junctional ectopic tachycardia (JET) and atrioventricular nodal re-entrant tachycardia (AVNRT) which can be distinguished by performing electrophysiological studies.[5] ## Treatment[edit] Amiodarone is used to control the rhythm. Electrical cardioversion is not used. ## See also[edit] * Junctional rhythm ## References[edit] 1. ^ "junctional tachycardia" at Dorland's Medical Dictionary 2. ^ a b ROSEN, KENNETH (1973). "Junctional Tachycardia: Mechanisms, Diagnosis, Differential Diagnosis, and Management" (PDF). Circulation. 47 (3): 654–664. doi:10.1161/01.CIR.47.3.654. PMID 4571060. Retrieved March 1, 2015. 3. ^ "Junctional Rhythm: Overview - eMedicine". Retrieved 2008-12-21. 4. ^ Aehlert, Barbara (2013). ECGs Made Easy (5th ed.). Elsevier. p. 160. ISBN 9780323170574. 5. ^ Srivathsan K, Gami AS, Barrett R, Monahan K, Packer DL, Asirvatham SJ (January 2008). "Differentiating atrioventricular nodal reentrant tachycardia from junctional tachycardia: novel application of the delta H-A interval". J. Cardiovasc. Electrophysiol. 19 (1): 071004055652013––. doi:10.1111/j.1540-8167.2007.00961.x. PMID 17916156. ## External links[edit] Classification D * ICD-10: I47.1 * ICD-9-CM: xxx * 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 This article about a medical condition affecting the circulatory system 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Junctional tachycardia	c0039235	4,783	wikipedia	https://en.wikipedia.org/wiki/Junctional_tachycardia	2021-01-18T18:49:12	{"mesh": ["D013613"], "wikidata": ["Q6311816"]}
A number sign (#) is used with this entry because of evidence that thrombocytopenia-5 (THC5) is caused by heterozygous mutation in the ETV6 gene (600618) on chromosome 12p13. Description Thrombocytopenia-5 is an autosomal dominant disorder characterized by a decreased number of platelets and a bleeding tendency. Affected individuals have an increased susceptibility to the development of hematologic malignancies, and possibly to solid neoplasms. Thrombocytopenia is usually apparent in early childhood, whereas the development of malignancy can occur throughout life (summary by Zhang et al., 2015). For a discussion of genetic heterogeneity of thrombocytopenia, see 313900. Clinical Features Zhang et al. (2015) reported 3 unrelated families of different ethnicities with thrombocytopenia and various hematologic and solid malignancies. In 1 family, a mother and her 3 children of German and Native American origin all had thrombocytopenia. Two patients had neutropenia and 2 had anemia. The proband was 1 of 2 daughters who presented with easy bruising in infancy and menorrhagia in the teenage years. The proband developed myelodysplastic syndrome at age 17 and underwent hematopoietic stem cell transplant (HSCT). Her sister developed B-cell acute lymphocytic leukemia (ALL) at age 7.5 years, and the mother developed colorectal adenocarcinoma at age 45 and multiple myeloma at age 51. The mother had a history of 5 miscarriages. In a second family, of Scottish descent, 8 patients had thrombocytopenia with petechiae and epistaxis; 1 of these patients developed colon cancer at age 43, and another developed chronic myelomonocytic leukemia (CMML) at age 82. Two patients with thrombocytopenia developed skin cancer, but 2 family members who did not carry the mutation also developed skin cancer. A third patient, of African American descent, had a long history of nosebleeds and menorrhagia. She was found to have thrombocytopenia unresponsive to standard therapies, and she developed T-cell/myeloid mixed-phenotype acute leukemia (MPAL) at age 50 years. She eventually underwent allogeneic HSCT. Noetzli et al. (2015) reported 10 patients from 3 unrelated families with THC5. Patients had thrombocytopenia, increased mean corpuscular volume (MCV), and mild to moderate bleeding. Three of the 10 patients developed B-cell leukemia at ages 3, 37, and 14 years, respectively. Inheritance The transmission pattern of THC5 in the families reported by Zhang et al. (2015) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of 3 unrelated families with autosomal dominant thrombocytopenia, Zhang et al. (2015) identified 3 different heterozygous missense mutations in the ETV6 gene (600618.0003-600618.0005). The mutation in the first family was found by whole-exome sequencing. Functional studies showed that the mutations abrogated DNA binding, altered subcellular localization of ETV6, decreased transcriptional repression in a dominant-negative fashion, and impaired hematopoiesis. These findings identified a central role for ETV6 in hematopoiesis and malignant transformation. In affected members of 3 unrelated families with THC5, Noetzli et al. (2015) identified 2 different heterozygous mutations in the ETV6 gene (P214L, 600618.0005 and R418G, 600618.0006). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent families were found by direct sequencing of the ETV6 gene in 23 families with a similar phenotype. Functional studies showed that all mutations resulted in decreased transcriptional repression, impaired megakaryocyte maturation, and aberrant cellular localization of mutant and wildtype ETV6, consistent with a dominant-negative effect. INHERITANCE \- Autosomal dominant HEAD & NECK Nose \- Epistaxis SKIN, NAILS, & HAIR Skin \- Easy bruising \- Petechiae HEMATOLOGY \- Thrombocytopenia \- Anemia (in some patients) \- Neutropenia (in some patients) NEOPLASIA \- Increased susceptibility to hematologic malignancies MISCELLANEOUS \- Onset of thrombocytopenia in early childhood \- Onset of malignancy can occur throughout life MOLECULAR BASIS \- Caused by mutation in the ETS variant gene 6 (ETV, 600618.0003 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	THROMBOCYTOPENIA 5	c1832388	4,784	omim	https://www.omim.org/entry/616216	2019-09-22T15:49:41	{"mesh": ["C563324"], "omim": ["616216"], "orphanet": ["71290"], "synonyms": ["Alternative titles", "THROMBOCYTOPENIA 5 WITH INCREASED SUSCEPTIBILITY TO MALIGNANCY", "THROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 5"]}
Many types of skin tumors, both benign (noncancerous) and malignant (cancerous), exist. Approximately 20-40% of primary skin tumors are malignant in dogs and 50-65% are malignant in cats. Not all forms of skin cancer in cats and dogs are caused by sun exposure, but it can happen occasionally. On dogs, the nose and pads of the feet contain sensitive skin and no fur to protect from the sun. Also, cats and dogs with thin or light-colored coats are at a higher risk of sun damage over their entire bodies.[1] ## Contents * 1 Diagnosis * 2 Treatment * 3 References * 4 External links ## Diagnosis[edit] Typically, either cytologic or histopathologic analysis of the suspected mass is done prior to initiating treatment. The commonly used diagnostic procedures for skin tumors are fine-needle aspiration cytology and tissue biopsy.[2] Cytology is an important tool that can help the veterinarian distinguish a tumor from inflammatory lesions. The biopsy technique used will largely depend on the tumor's size and location. Small masses are usually completely excised and sent to the pathology lab to confirm that the surrounding healthy tissues that were excised along with the tumor do not contain any cancer cells. If the tumor is larger, a small sample is removed for analysis and depending on the results, appropriate treatment is chosen. Depending on the tumor type and its level of aggressiveness, additional diagnostic tests can include blood tests to assess the pet’s overall health, chest X-rays to check for lung metastasis, and abdominal ultrasound to check for metastasis to other internal organs.[3] ## Treatment[edit] The specific treatment will depend on the tumor's type, location, size, and whether the cancer has spread to other organs. Surgical removal of the tumor remains the standard treatment of choice, but additional forms of therapy such as radiation therapy, chemotherapy, or immunotherapy exist. When detected early, skin cancer in cats and dogs can often be treated successfully. In many cases, a biopsy can remove the whole tumor, as long as the healthy tissues removed from just outside the tumor area do not contain any cancer cells. ## References[edit] 1. ^ "Dogs and Skin Cancer". WebMD. Retrieved 28 September 2011. 2. ^ Withrow SJ, MacEwen EG, eds. (2001). Small Animal Clinical Oncology (3rd ed.). W.B. Saunders Company. 3. ^ "Mast Cell Tumors in Cats". PetCareCenter.com. Retrieved 27 September 2011. ## External links[edit] * Skin Cancer in Cats and Dogs from Pet Cancer Center * Skin Cancer in Dogs from CanineCancer.com' [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Skin cancer in cats and dogs	None	4,785	wikipedia	https://en.wikipedia.org/wiki/Skin_cancer_in_cats_and_dogs	2021-01-18T18:28:02	{"wikidata": ["Q7535378"]}
A rare mitochondrial disease characterized by a variable phenotype comprising delayed psychomotor development or neurodevelopmental regression, hypotonia, seizures, microcephaly, optic atrophy, pyramidal signs, and peripheral neuropathy, among others. Age of onset and disease severity are also variable with some cases taking a fatal course in early infancy. Serum lactate levels may be elevated. Reported brain imaging findings include abnormal signals in the basal ganglia, cerebral and/or cerebellar atrophy, and white matter abnormalities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Encephalopathy due to mitochondrial and peroxisomal fission defect	None	4,786	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=527276	2021-01-23T18:51:16	{"icd-10": ["E88.8"]}
A number sign (#) is used with this entry because of evidence of an association between aspirin-induced asthma and polymorphisms in the TBX21 (604895), PTGER2 (176804), and LTC4S (246530) genes. Clinical Features Lockey et al. (1973) observed 2 families. In 1 family, consanguinity suggested recessive inheritance. The late onset and discordance in a pair of identical twins suggested that environmental factors may be important also. Miller (1971) reported affected sisters. Von Maur et al. (1974) described a family in which autosomal dominant inheritance of aspirin asthma was suggested. In addition to mode of inheritance, differences from prior reports included an earlier age of onset, lack of nasal polyps and sinusitis, and milder asthma. Spector et al. (1979) found that oral challenge with aspirin caused bronchoconstriction in 19% of consecutive adult asthma patients, and other studies involving challenge with nonsteroidal antiinflammatory drugs (NSAIDs) in both adults and children with asthma confirm a prevalence of 10 to 20%. Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene production, probably by removing PGE(2)-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, Cowburn et al. (1998) immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. Counts of cells expressing the terminal enzyme for cysteinyl-leukotriene synthesis, LTC4 synthase (246530), were 5-fold higher in AIA biopsies than in ATA biopsies and 18-fold higher than in N biopsies. Aspirin may remove PGE(2)-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cysteinyl-leukotriene leading to bronchoconstriction. Cowburn et al. (1998) speculated that a polymorphism directed to the regulation of LTC4 synthase expression could be a predisposing factor for the AIA group. Arm and Austen (2002) stated that between 3% and 10% of asthma patients have acute, severe asthma accompanied by rhinorrhea and sometimes associated with hives, flushing, or abdominal pain after the injection of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs). The common feature of drugs that provoke asthma attacks in aspirin-intolerant persons is that they inhibit cyclooxygenase-1 (COX1; 176805); selective inhibition of cyclooxygenase-2 (COX2; 600262) appears not to provoke such a response. Cautious, incremental administration of oral doses of aspirin can lead to a state in which persons with aspirin-sensitive asthma can ingest aspirin without untoward reactions, but daily administration must be continued to maintain this state. Patients with asthma and aspirin sensitivity have greater cysteinyl leukotriene production and greater airway hyperresponsiveness to the effects of inhaled cysteinyl leukotrienes than their aspirin-tolerant counterparts. Sousa et al. (2002) hypothesized that the latter effect reflects elevated expression of the cysteinyl leukotriene receptor CYSLT1 (300201) on inflammatory cells in the target organ and that its expression is downregulated by aspirin desensitization. They found elevated numbers of nasal inflammatory leukocytes expressing the CYSLT1 receptor in aspirin-sensitive patients with chronic rhinosinusitis as compared with their non-aspirin-sensitive counterparts and the downregulation of receptor expression after desensitization to aspirin. Molecular Genetics Sanak et al. (1997) identified a -444A-C promoter polymorphism in the LTC4S gene that was overrepresented among patients with aspirin-intolerant asthma. Six of 11 AIA patients were homozygous for the -444C allele, compared to only 1 individual in the aspirin-tolerant asthmatic and control groups. The frequency of the -444C allele was nearly doubled in AIA (0.436) compared to aspirin-tolerant asthmatics (0.227) and nonasthmatic controls (0.226), yielding a relative risk of 3.89 for the -444C allele. By genotyping 198 Japanese patients with AIA and 274 Japanese controls, Jinnai et al. (2004) found significant association of the phenotype (permutation p = 0.001) with a G/A SNP (uS5) in the 5-prime promoter region of the PTGER2 gene (176804.0001). Analysis of haplotypes constructed according to the linkage disequilibrium pattern showed a significant association with AIA (permutation P = 0.001). The uS5 SNP is located in the regulatory region of the PTGER2 gene in a STAT-binding consensus sequence. Although STAT1 (600555) binding was not observed in gel mobility shift assay with HeLa nuclear extract, an unidentified protein was specifically bound to the allelic sequence. In vitro reporter assay of the site containing the uS5 allele showed reduced transcription activity. Jinnai et al. (2004) hypothesized that the uS5 allele may serve as a target for a transcription repressor protein or that a functional effect of the uS5 allele may decrease transcription, resulting in reduction of the PGE2 braking mechanism of inflammation and contributing to the molecular mechanism underlying AIA. Akahoshi et al. (2005) found a significant association between a promoter SNP of the TBX21 gene (-1993T-C; 604895.0001) and aspirin-induced asthma in a Japanese cohort (p = 0.004), with increased risk associated with a C allele (OR, 1.93; 95% CI, 1.22-3.06). The association was confirmed in additional independent samples from patients with asthma and nasal polyposis (p = 0.008), regardless of aspirin hypersensitivity. ### Associations Pending Confirmation For discussion of a possible association between polymorphism in the ALOX15 gene and protection against nasal polyps and chronic rhinosinusitis, see 152392.0001. Immunologic \- Aspirin intolerance Pulmonary \- Bronchial asthma Nose \- Polyps 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ASTHMA, NASAL POLYPS, AND ASPIRIN INTOLERANCE	c1858067	4,787	omim	https://www.omim.org/entry/208550	2019-09-22T16:30:39	{"mesh": ["C565739"], "omim": ["208550"], "synonyms": ["Alternative titles", "ASA TRIAD"]}
Hanson and Mincy (1975) described 2 brothers with cramps in the legs following strenuous exercise. Symptoms were maximal at adolescence. Both showed elevation of serum creatine phosphokinase. Muscle biopsy showed changes compatible with a myopathy. Five younger children, 2 girls and 3 boys, had elevated CPK levels. The mother had mild elevation of CPK. Muscle \- Leg cramps following strenuous exercise Misc \- Maximal symptoms at adolescence Lab \- Elevated serum creatine phosphokinase 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CRAMPS, FAMILIAL ADOLESCENT	c1857533	4,788	omim	https://www.omim.org/entry/218050	2019-09-22T16:29:17	{"omim": ["218050"]}
Kuhn et al. (1964) described 2 sisters with polymorphic and polytopic ventricular extrasystoles. One had syncopal attacks. A brother died suddenly at age 10 and the mother at age 40, under circumstances suggesting the presence of the same disorder. Cardiac \- Arrhythmia \- Polymorphic and polytopic ventricular extrasystoles Misc \- Sudden death Neuro \- Syncopal attacks 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CARDIAC ARRHYTHMIA	c0003811	4,789	omim	https://www.omim.org/entry/115000	2019-09-22T16:43:45	{"mesh": ["D001145"], "omim": ["115000"], "icd-9": ["427.9", "427"], "icd-10": ["I49.9"], "synonyms": ["Alternative titles", "EXTRASYSTOLES"]}
As indicated in 606933, in the mapping of the tyrosinase locus with a cDNA probe in somatic cell and in situ hybridization, Barton et al. (1988) identified a second site of tyrosinase-related sequences in the region 11p11.2-cen. The primary locus is on 11q14-q21. The functional significance of the second sequence is unknown. Giebel et al. (1991) demonstrated that whereas the tyrosinase gene contains 5 exons, the tyrosinase-like, or tyrosinase-related, 'gene' contains only exons 4 and 5 plus adjacent noncoding regions. The tyrosinase-related segment was found in all human ethnic groups analyzed, and the noncoding nucleotide sequences shared by the 11q tyrosinase gene and the 11p tyrosinase-related segment differed by only 2.6%. This suggested to Giebel et al. (1991) that the 11p segment was duplicated approximately 24 million years ago. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	TYROSINASE-LIKE	c3887993	4,790	omim	https://www.omim.org/entry/191270	2019-09-22T16:32:14	{"omim": ["191270"], "synonyms": ["Alternative titles", "TYROSINASE-RELATED SEGMENT"]}
By histochemistry and electron microscopy, Fardeau et al. (1976) studied muscle biopsy specimens from 2 half brothers with a congenital mild muscle disorder and from their asymptomatic mother. The boys showed numerous fingerprint bodies located at the periphery of the muscle fibers. Fingerprint bodies were not found in the mother, but other slight but definite changes were found. This is the first description of familial occurrence of a fingerprint body myopathy. Muscle \- Congenital mild myopathy Lab \- Fingerprint bodies at the periphery of muscle fibers on EM Inheritance \- X-linked ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	FINGERPRINT BODY MYOPATHY	c1844560	4,791	omim	https://www.omim.org/entry/305550	2019-09-22T16:18:18	{"mesh": ["C564425"], "omim": ["305550"], "orphanet": ["97232"]}
Species of insect "Common greenbottle" redirects here. This phrase may also refer to another species in the Lucilia genus, Lucilia caesar. Common green bottle fly Scientific classification Kingdom: Animalia Phylum: Arthropoda Class: Insecta Order: Diptera Family: Calliphoridae Genus: Lucilia Species: L. sericata Binomial name Lucilia sericata (Meigen, 1826)[1] Synonyms * Phaenicia sericata (Meigen, 1826) * Lucilia nobilis (Meigen, 1826)[2] * Musca nobilis Meigen, 1826[2] * Musca sericata Meigen, 1826[2] The common green bottle fly (Lucilia sericata) is a blowfly found in most areas of the world and is the most well-known of the numerous green bottle fly species. Its body is 10–14 millimetres (0.39–0.55 in) in length – slightly larger than a house fly – and has brilliant, metallic, blue-green or golden coloration with black markings. It has short, sparse black bristles (setae) and three cross-grooves on the thorax. The wings are clear with light brown veins, and the legs and antennae are black. The larvae of the fly may be used for maggot therapy, are commonly used in forensic entomology, and can be the cause of myiasis in livestock and pets. ## Contents * 1 Description * 2 Distribution and habitat * 3 Life history * 4 Food resources * 5 Parental care * 6 Social behavior * 6.1 Mating * 6.1.1 Mate detection * 6.2 Grouping * 7 Importance to humans * 7.1 Forensic importance * 7.2 Veterinary importance * 7.3 Medical importance * 8 Continuing research * 9 References * 10 External links ## Description[edit] Adult L. sericata (Top Left) Macro image of the head The defining characteristic of L. sericata and the one most used when identifying the adult fly is the presence of three bristles on the dorsal mesothorax, located on the middle of the back of the fly. L. sericata is almost identical to its sister species, L. cuprina, and identification between them requires microscopic examination of two main distinguishing characteristics. L. sericata is blue-black, as opposed to L. cuprina, which has a metallic green femoral joint in the first pair of legs. Also, when looking at the occipital setae, L. sericata has one to nine bristles on each side, while L. cuprina has three or less.[3] ## Distribution and habitat[edit] Squirrel carrion (L. sericata in bottom right) Lucilia sericata is common all over the temperate and tropical regions of the planet, including Europe, Africa and Australia. It prefers warm and moist climates and accordingly is especially common in coastal regions, but can also be found in arid areas.[4] The female lays her eggs in carrion of all kinds, sometimes in the skin or hair of live animals, causing myiasis. The larvae feed on decaying organic tissue. The fly favours host species of the genus Ovis, domestic sheep in particular, and sometimes lays eggs in the wet wool of living sheep. This can lead to blowfly strike, causing problems for sheep farmers. L. sericata has been known to prefer lower elevations relative to other Calliphoridae species, such as Calliphora vomitoria. [5] ## Life history[edit] Green bottle fly found in Lodi, California. The life cycle of Lucilia sericata is typical of flies in the family Calliphoridae. After the female deposits the egg, it hatches into a larva that passes through three instars as it grows, then enters prepupal and pupal stages (which can eclose quickly or overwinter depending on temperature) before emerging into the adult stage or imago. To start, the female lays a mass of eggs in carrion. The eggs hatch between nine hours and three days after being deposited on the host, with eggs laid in warmer weather hatching more quickly than those in cooler weather.[6] In this, they differ from the more opportunistic Sarcophagidae, which lay hatching eggs or completely hatched larvae into carrion and cut out the time it takes the eggs to hatch. The flies are extremely prolific; a single female L. sericata typically lays 150−200 eggs per clutch and may produce 2,000 to 3,000 eggs in her lifetime. The pale yellow or grayish conical larvae, like those of most blow flies, have two posterior spiracles through which they respire. The larvae are moderately sized, ranging from 10 to 14 millimeters long. The larva feeds on dead or necrotic tissue for 3 to 10 days, depending on temperature and the quality of the food. During this period the larva passes through three larval instars. At a temperature of 16 °C, the first larval instar lasts about 53 hours, the second about 42 hours and the third about 98 hours. At higher temperatures (27 °C) the first larval instar lasts about 31 hours, the second about 12 hours, and the third about 40 hours.[4] Third-instar larvae enter a "wandering" stage and drop off the host to find an appropriate location with soft enough soil, where they bury themselves to enter a pupal stage, which usually lasts from 6 to 14 days. Burial allows the pupa to more reliably avoid desiccation or predation. The larger the larva, the farther it will be able to travel to find a suitable location to pupate; L. sericata are noted to be remarkably active and can travel over 100 feet before pupating.[7] However, if the temperature is suitably low, a pupa might overwinter in the soil until the temperature rises. After emerging from the pupa, the adult feeds opportunistically on nectar, pollen, feces, or carrion while it matures. Adults usually lay eggs about 2 weeks after they emerge. Their complete life cycle typically ranges from 2 to 3 weeks, but this varies with seasonal and other environmental circumstances. L. sericata usually completes three or four generations each year in cold, temperate climates, and more in warmer regions.[8] ## Food resources[edit] Adult L. sericata feeding on nectar The larvae of L. sericata feed exclusively on dead organic tissue; as the eggs are laid directly into carrion, they are able to feed on the corpse they hatch into until they are ready to pupate. The adults are more varied in their diets, eating carrion and feces as well as pollen and nectar, meaning that they are important pollinators in their native range as well as important agents of decomposition. The pollen (which the flies are capable of digesting, perhaps with the assistance of bacteria in their digestive tracts) may be used as an alternative protein source, especially for gravid females who need large amounts of protein and cannot reliably find carrion. Notably, gravid flies are particularly attracted to sapromyophilous flowers that exude a carrion-like odor, such as the dead horse arum lily. These flowers are tricking the flies into pollinating them by mimicking the scent of a corpse. However, the flies also frequently visit myophilous flowers such as the oxeye daisy, and are attracted to the color yellow as well as to the scent of flowers.[9] This indicates that the flies are attracted to flowers not only because they smell like carrion (in the case of the arum lily), but specifically for the pollen offered by the flower (in the case of myophilous flowers). ## Parental care[edit] L. sericata females lay their eggs on fresh carrion, avoiding older carrion because it can be detrimental to offspring (possibly due to bacterial activity or other factors).[10] Like many blowflies, female L. sericata perform aggregated oviposition, laying their egg masses in carcasses that other flies are also ovipositing in. The presence of female flies eating or ovipositing on a carcass may attract other female flies to do the same, perhaps through chemical cues.[11] Females exhibit preference for certain oviposition conditions over others; they attempt to maximize the survival potential of their offspring by laying eggs in only the best places. They often select natural orifices or wet fur, though they do not tend to oviposit in wounds, as is mistakenly thought by many.[12] Gravid L. sericata prefer warm temperatures for their offspring, since this will decrease development time and therefore increase survival, and they will oviposit faster and with more eggs in warmer carrion. Egg load peaks at 30 degrees C.[6] Research also suggests that sulfur compounds and indole are the major factors attracting gravid flies to carrion, raising the possibility that these compounds could be used to attract flies to traps in order to control them in agricultural settings.[13] ## Social behavior[edit] ### Mating[edit] L. sericata mating The courtship process of L. sericata is complex and consists of several stages of display on the part of the male.[14] First, the male identifies a potential mate and pushes her with his head; he then taps her with his foreleg multiple times. The male then mounts the female and attempts copulation, continuing to tap his foreleg on her body. If the female is receptive the copulation proceeds, genital contact is achieved, and when the process is over both individuals move away. If she is not receptive, the female will kick at the male with her hind legs, but this is not usually successful at dismounting the male and the mating proceeds nevertheless. Some males are left-biased and some males are right-biased in their foreleg tapping, but this bias does not appear to have an effect on their mating success. #### Mate detection[edit] Males are able to recognize potential mates by the frequency at which the light from their iridescent bodies glints through their wings, using the fast and precise visual processing that many flies rely upon for their manoeuverability and agility in flight. They interpret these flashes to assess the age and sex of a potential mate. Under direct sunlight there is a reflected flash at each wingbeat. Males recognise fertile females by light flashing at the frequency at which they flap their wings - slower than young males or old flies of either sex. Eichorn et al. (2017) showed that male L. sericata show a strong preference for a diode flashing alternately on and off at 178 Hz over an immobilized female, 178 Hz being the characteristic wing-beat frequency of a young female L. sericata, over constant light on the same female.[15] This shows that, close-up, sexually active males recognize a flash frequency rather than an attraction by sight or smell. Males preferred a diode flashing at 178 Hz to a diode flashing at other frequencies. L. sericata mate less frequently on cloudy days, suggesting that they rely on direct sunlight flashing through or off or between their wings to recognize potential mates.[15] ### Grouping[edit] The larvae of L. sericata are highly gregarious, to the point that their survival depends upon grouping. The aggregated oviposition behavior of gravid L. sericata females leads to large aggregates of same-age larvae, which have been shown to experience faster development and lower predation as opposed to smaller aggregates or aggregates of variously-aged larvae. The resulting larval masses are able to thermoregulate, raising their own temperature and therefore decreasing their development time, leading to better survival. This thermoregulation may result from the way larvae forage; they are constantly moving and turning over, which could at least in part lead to the temperature rise experienced in larval masses.[16] They also benefit from the digestive power of multiple other larvae. Each larva secretes digestive enzymes and then consumes the resulting dissolved meat around it. If more larvae are present they secrete more digestive enzymes, which dissolve more meat and make food more accessible for the whole group. This easy access to food also contributes to a shorter development time.[17] These benefits are present not only in single-species masses of larvae, but also in mixed-species groupings. Both single-species and mixed groups of larvae have also been shown to have the ability to make collective decisions, perhaps by using signals that are shared between species. In this manner, groups of larvae are able to collectively choose a preferred feeding spot, allowing them all to benefit from their collective digestive abilities and thermoregulation. Similarly, if a group of larvae becomes too large and overcrowding begins to cut into the benefits of heat and collective digestion, larval masses can "decide" to split in two and move to separate areas of a cadaver.[18] These collective larval decisions (and indeed the formation of larval masses themselves) are the result of chemical cues that larvae leave behind them as they crawl along the carrion, which other larvae are predisposed to follow; the result is that the more larvae are in a particular area, the more other larvae will join them.[19] ## Importance to humans[edit] ### Forensic importance[edit] L. sericata is an important species to forensic entomologists. Like most calliphorids, L. sericata has been heavily studied and its life cycle and habits are well documented. Accordingly, the stage of its development on a corpse is used to calculate a minimum post mortem interval, so that it can be used to aid in determining the time of death of the victim. The presence or absence of L. sericata can provide information about the conditions of the corpse. If the insects seem to be on the path of their normal development, the corpse likely has been undisturbed. If, however, the insect shows signs of a disturbed life cycle, or is absent from a decaying body, this suggests post mortem tampering with the body. Because L. sericata is one of the first insects to colonize a corpse, it is preferred to many other species in determining an approximate time of colonization, and thus time of death of the victim. Developmental progress is determined with relative accuracy by measuring the length and weight of larvae at various instars while taking into account the temperature, which can affect development time to a large extent.[20] ### Veterinary importance[edit] Many blow flies have an impact in veterinary science, and L. sericata is no exception. In places such as the UK and Australia, L. sericata is commonly referred to as the "sheep blowfly" since sheep are its primary host in those regions. Although it affects mainly sheep, L. sericata is not host-specific. Sheep, common to Northern Europe In northern Europe, the fly often lays its eggs in sheep wool. The larvae then migrate down the wool where they feed directly on the skin surface in a process called myiasis. This can cause massive lesions and secondary bacterial infections, causing serious problems for sheep farmers. In the UK, blowfly strike affects an estimated 1 million sheep, as well as 80% of sheep farms each year. This causes a huge economic impact in regions affected by blowfly strike. Not only does it cost money to treat infected animals, but measures also must be taken to control L. sericata.[21] A simple and effective way to reduce the incidence of such infection is to shear ewes regularly and to dock their tails, removing areas where thick wool can stay damp for long periods of time. Enacting simple sanitary measures can reduce blowfly strike. For example, timely and proper disposal of carcasses and proper removal of feces are effective measures. Moving sheep from warm, humid, and sheltered areas to more open areas can also help to reduce blowfly strike, for this eliminates conditions conducive to fly development. Trapping systems such as sticky paper may be used to control fly numbers. Treating a flock with chemical agents can be costly, but can aid greatly in maintaining the resistance of the flock to L. sericata. For instance, plunge dipping in diazinon can directly kill the fly on contact. This method works from 3 to 8 weeks in controlling the fly. An alternative chemical method is a pyrethroid pour-on, which lasts 6 to 10 weeks depending on the type of pyrethroid used. Cryomazine and dicylanil, which are insect growth regulators, are also effective and last from 10 to 16 weeks. However, chemical treatment is not ideal, though it can be very effective, because it is costly, tedious, and takes up a lot of time.[21] ### Medical importance[edit] L. sericata has been of medical importance since 1826, when Meigen removed larvae from the eyes and facial cavities of a human patient. L. sericata has shown promise in three separate clinical approaches. First, larvae have been shown to debride wounds with extremely low probability of myiasis upon clinical application. Larval secretions have been shown to help in tissue regeneration. L. sericata has also been shown to lower bacteremia levels in patients infected with MRSA. Essentially, L. sericata larvae can be used as biosurgery agents in cases where antibiotics and surgery are impractical.[22] Larval secretions in vitro enhance fibroblast migration to the wound site, improving wound closure.[22] Larval therapy of L. sericata is highly recommended for the treatment of wounds infected with Gram-positive bacteria, yet is not as effective for wounds infected with Gram-negative bacteria. Also, bacteria from the genus Vagococcus were resistant to the maggot excreta/secreta.[23] Attempts are currently ongoing to extract or synthesize the chymotrypsins found in larval secretions to destroy MRSA without application of the larvae.[24] Myiasis by L. sericata has been reported,[8] including a case of a dual genital infestation of a married couple wherein the larvae were transmitted from the wife's vagina to the husband's penis through sexual intercourse.[25] ## Continuing research[edit] Due to this species' high forensic interest, extensive research on its life cycle has been conducted. The ongoing medical research, however, centered around the secretions produced by L. sericata as an agent against MRSA and VRSA,[26] and the larval applications for maggot therapy. A new antimicrobial agent was isolated from L. sericata secretions and patented under the name Seraticin.[27] Efforts are geared toward making medical professionals more familiar to the current techniques.[28] Like many other ectoparasites, L. sericata has a huge economic impact on farmers, so many studies and research projects have been put in place since the late 1980s to help farmers reduce their impact. Research is also being conducted on less chemical-intensive measures to combat blowfly strike, since chemical dipping and pouring is not only expensive and time-consuming but also toxic. ## References[edit] 1. ^ Meigen, J.W. (1826). Systematische Beschreibung der bekannten europäische n zweiflugeligen Insekten. Hamm: Vierter Theil. Schulz-Wundermann. pp. xii + 412 pp., pls. 42-54. 2. ^ a b c Chandler PJ (2019). "Checklists of Insects of the British Isles (New Series) Part 1: Diptera". Handbooks for the Identification of British Insects. 2. London: Royal Entomological Society of London. 12 (1): 1–234. 3. ^ Bishop D (1991). "Variations in numbers of occipital setae for two species of Lucilia (Diptera: Calliphoridae) in New Zealand" (PDF). New Zealand Entomologist. 14: 29–31. doi:10.1080/00779962.1991.9722609. Archived from the original (PDF) on 2008-10-18. 4. ^ a b "Decompostition: Corpse fauna page". Australian Museum. Archived from the original on 10 February 2009. 5. ^ Baz, Arturo; Cifrián, Blanca; Díaz-äranda, Luisa María; Martín-Vega, Daniel (2007-01-01). "The distribution of adult blow-flies (Diptera: Calliphoridae) along an altitudinal gradient in Central Spain". Annales de la Société Entomologique de France. New Series. 43 (3): 289–296. doi:10.1080/00379271.2007.10697524. ISSN 0037-9271. 6. ^ a b Hans, Krystal Rae; LeBouthillier, R; VanLaerhoven, S L (2019-02-25). "Effect of Temperature on Oviposition Behavior and Egg Load of Blow Flies (Diptera: Calliphoridae)". Journal of Medical Entomology. 56 (2): 441–447. doi:10.1093/jme/tjy173. ISSN 0022-2585. PMID 30295782. S2CID 52926635. 7. ^ Robinson, L.A.; Bryson, D.; Bulling, M.T.; Sparks, N.; Wellard, K.S. (May 2018). "Post-feeding activity of Lucilia sericata (Diptera: Calliphoridae) on common domestic indoor surfaces and its effect on development". Forensic Science International. 286: 177–184. doi:10.1016/j.forsciint.2018.03.010. hdl:10545/622579. PMID 29579718. 8. ^ a b Cetinkaya M, Ozkan H, Köksal N, Coşkun SZ, Hacimustafaoğlu M, Girişgin O (2008). "Neonatal myiasis: a case report" (PDF). The Turkish Journal of Pediatrics. 50 (6): 581–4. PMID 19227424. 9. ^ Brodie BS, Smith MA, Lawrence J, Gries G (2015-12-30). "Effects of Floral Scent, Color and Pollen on Foraging Decisions and Oocyte Development of Common Green Bottle Flies". PLOS ONE. 10 (12): e0145055. Bibcode:2015PLoSO..1045055B. doi:10.1371/journal.pone.0145055. PMC 4696748. PMID 26717311. 10. ^ Brodie, Bekka S.; Babcock, Tamara; Gries, Regine; Benn, Arlan; Gries, Gerhard (January 2016). "Acquired Smell? Mature Females of the Common Green Bottle Fly Shift Semiochemical Preferences from Feces Feeding Sites to Carrion Oviposition Sites". Journal of Chemical Ecology. 42 (1): 40–50. doi:10.1007/s10886-015-0658-7. ISSN 0098-0331. PMID 26637207. S2CID 11387383. 11. ^ Brodie, Bekka S.; Wong, Warren H. L.; VanLaerhoven, Sherah; Gries, Gerhard (2015). "Is aggregated oviposition by the blow flies Lucilia sericata and Phormia regina (Diptera: Calliphoridae) really pheromone-mediated?". Insect Science. 22 (5): 651–660. doi:10.1111/1744-7917.12160. ISSN 1744-7917. PMID 25099558. S2CID 32092326. 12. ^ Charabidze, Damien; Depeme, Aurore; Devigne, Cedric; Hedouin, Valery (Aug 1, 2015). "Do necrophagous blowflies (Diptera: Calliphoridae) lay their eggs in wounds?". Forensic Science International. 253: 71–75. doi:10.1016/j.forsciint.2015.05.025. PMID 26093126. 13. ^ Chaudhury, M. F.; Zhu, J. J.; Skoda, S. R. (July 2017). "Response of Lucilia sericata (Diptera: Calliphoridae) to Screwworm Oviposition Attractant". Journal of Medical Entomology. 52 (4): 527–531. doi:10.1093/jme/tjv054. ISSN 0022-2585. PMID 26335458. 14. ^ Benelli, Giovanni; Romano, Donato (January 2019). "Looking for the right mate—What do we really know on the courtship and mating of Lucilia sericata (Meigen)?". Acta Tropica. 189: 145–153. doi:10.1016/j.actatropica.2018.08.013. PMID 30114395. 15. ^ a b Eichorn, Courtney; Hrabar, Michael; Van Ryn, Emma C.; Brodie, Bekka S.; Blake, Adam J.; Gries, Gerhard (December 2017). "How flies are flirting on the fly". BMC Biology. 15 (1): 2. doi:10.1186/s12915-016-0342-6. ISSN 1741-7007. PMC 5307768. PMID 28193269. 16. ^ Charabidze, Damien; Hedouin, Valery; Gosset, Didier (March 2013). "Discontinuous foraging behavior of necrophagous Lucilia sericata (Meigen 1826) (Diptera Calliphoridae) larvae". Journal of Insect Physiology. 59 (3): 325–331. doi:10.1016/j.jinsphys.2012.12.006. PMID 23333403. 17. ^ Aubernon, Cindy; Hedouin, Valery; Charabidze, Damien (2018-12-08). "The maggot, the ethologist and the forensic entomologist: Sociality and thermoregulation in necrophagous larvae". Journal of Advanced Research. 16: 67–73. doi:10.1016/j.jare.2018.12.001. ISSN 2090-1232. PMC 6413306. PMID 30899590. 18. ^ Boulay, Julien; Deneubourg, Jean-Louis; Hédouin, Valéry; Charabidzé, Damien (2016-02-10). "Interspecific shared collective decision-making in two forensically important species". Proceedings of the Royal Society B: Biological Sciences. 283 (1824): 20152676. doi:10.1098/rspb.2015.2676. ISSN 0962-8452. PMC 4760171. PMID 26865296. 19. ^ Fouche, Quentin; Hedouin, Valery; Charabidze, Damien (December 2018). "Communication in necrophagous Diptera larvae: interspecific effect of cues left behind by maggots and implications in their aggregation". Scientific Reports. 8 (1): 2844. Bibcode:2018NatSR...8.2844F. doi:10.1038/s41598-018-21316-x. ISSN 2045-2322. PMC 5809460. PMID 29434278. 20. ^ Tarone AM, Foran DR (July 2008). "Generalized additive models and Lucilia sericata growth: assessing confidence intervals and error rates in forensic entomology". Journal of Forensic Sciences. 53 (4): 942–8. doi:10.1111/j.1556-4029.2008.00744.x. PMID 18503527. S2CID 8996624. 21. ^ a b Sargison N (27–31 July 2008). The Management of Ectoparasitic Diseases of UK Sheep. World Veterinary Congress. Royal (Dick) School of Veterinary Studies, Easter Bush Veterinary Center, Roslin, Midlothian, Scotland. 22. ^ a b Horobin AJ, Shakesheff KM, Woodrow S, Robinson C, Pritchard DI (May 2003). "Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon interactions between human dermal fibroblasts and extracellular matrix components". The British Journal of Dermatology. 148 (5): 923–33. doi:10.1046/j.1365-2133.2003.05314.x. PMID 12786822. S2CID 23720894. 23. ^ Jaklic D, Lapanje A, Zupancic K, Smrke D, Gunde-Cimerman N (May 2008). "Selective antimicrobial activity of maggots against pathogenic bacteria". Journal of Medical Microbiology. 57 (Pt 5): 617–25. doi:10.1099/jmm.0.47515-0. PMID 18436596. 24. ^ WO application 2007138361, Pritchar DI, Horobin AJ, Brown A, "Chymotrypsin From Lucilia sericata Larvae and its Use for the Treatment of Wounds", published 6 December 2007, assigned to The U.K. Secretary of State for Defense [permanent dead link] 25. ^ Bank EB (1964). "Gleichzeitige Myiasis der Genitalien bei einem Ehepaar". Gynaecologia. 157 (2): 121–122. doi:10.1159/000303880. 26. ^ Cazander G, van Veen KE, Bernards AT, Jukema GN (August 2009). "Do maggots have an influence on bacterial growth? A study on the susceptibility of strains of six different bacterial species to maggots of Lucilia sericata and their excretions/secretions". Journal of Tissue Viability. 18 (3): 80–7. doi:10.1016/j.jtv.2009.02.005. PMID 19362001. 27. ^ WO 2011042684, Exfield A, Bond AE, Dudley E, Newton PR, Nigam Y, Ratcliffe NA, "Antimicrobial Composition and a Method of Controlling Contamination and Infection Using Said Composition", published 14 April 2011, assigned to Department of Research and Innovation Swansea University 28. ^ Jones G, Wall R (October 2008). "Maggot-therapy in veterinary medicine". Research in Veterinary Science. 85 (2): 394–8. doi:10.1016/j.rvsc.2007.12.006. PMID 18237754. ## External links[edit] Wikimedia Commons has media related to Lucilia sericata. * "Common Green Bottle Fly – Lucilia sericata". North American Insects & Spiders. Red Planet Inc. Closeup photographs * "Green Bottle Maggots help cure MRSA patients". BBC News. 2 May 2007. * Monaghan P (1 June 2007). "Rx:Maggots". The Chronicle of Higher Education. LIII (39): A48. * "Lucilia sericata ". Featured Creatures. UF / IFAS. Taxon identifiers * Wikidata: Q603128 * Wikispecies: Lucilia sericata * ADW: Phaenicia_sericata * BioLib: 120151 * BugGuide: 53775 * EoL: 757419 * EPPO: LUCISE * Fauna Europaea: 397109 * Fauna Europaea (new): 29017827-1ba2-4a2f-910c-903bfc66cf36 * GBIF: 5063973 * iNaturalist: 128824 * IRMNG: 10434519 * NBN: NBNSYS0000030351 * NCBI: 13632 * NZOR: 11d71690-c84f-4ada-8c0f-846a7bf94b5a * WoRMS: 987832 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Common green bottle fly	None	4,792	wikipedia	https://en.wikipedia.org/wiki/Common_green_bottle_fly	2021-01-18T18:35:15	{"wikidata": ["Q603128"]}
Hidradenocarcinoma is a rare tumor caused by the abnormal growth of cells in a sweat gland. It is a type of cancer that usually begins as a single spot (lesion) on the skin of the head or neck, but can be been found on other parts of the body. This type of tumor most often develops in people between the ages of 30-60 years old, but has been found in children. Hidradenocarcinoma is usually painless and tends to grow slowly, but may spread into nearby tissues, especially lymph nodes, or to more distant parts of the body (metastasis). The cause of the tumor is unknown. Diagnosis is usually made by careful examination and a series of special skin tests. The main treatment is surgical removal of the tumor often followed by radiation therapy and/or chemotherapy. Long term outlook is best when the cancer is found early. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hidradenocarcinoma	c0334344	4,793	gard	https://rarediseases.info.nih.gov/diseases/10439/hidradenocarcinoma	2021-01-18T18:00:00	{"umls": ["C0334344"], "synonyms": ["Malignant nodular/clear cell hidradenoma", "Malignant acrospiroma", "Malignant clear cell acrospiroma", "Clear cell eccrine carcinoma", "Primary mucoepidermoid cutaneous carcinoma"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (May 2020) (Learn how and when to remove this template message) Hyperreflexia Other namesHyper-reflexia SpecialtyNeurology Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways (disinhibition). See Autonomic dysreflexia. The most common cause of hyperreflexia is spinal cord injury (see autonomic dysreflexia). Standard stimuli like the filling of the bladder can cause excessive responses from the nervous system, such causes are not known. But hyperreflexia can be developed via many other causes, including medication and stimulant side effects, hyperthyroidism, electrolyte imbalance, serotonin syndrome, severe brain trauma, multiple sclerosis, Reye syndrome, and preeclampsia. Treatment depends on diagnosing the specific pathology causing this symptom. Should it be caused by use of stimulants or other substances, then it may involve removing these drugs from use. Recovery of hyperreflexia can occur between several hours to several months after a spinal cord injury; however, the phase of recovery is likely to occur in stages rather than on a continuum.[1] The late stage can be defined as between two weeks and several months.[1] Individuals with a severe spinal cord injury (SCI) mainly present with a later stage of recovery because during the early stages they present with spinal shock.[1] Reflex and motor recovery can sometimes return simultaneously.[1] ## See also[edit] * Hyporeflexia ## References[edit] 1. ^ a b c d Little, J., Ditunno, J. F., Stien, S., A., Harris, R. M. (1999). Incomplete spinal cord injury: Neuronal mechanisms of motor recovery and hyperreflexia. Arch Phys Med Rehabil 80(5): 587-599. ## External links[edit] Classification D * ICD-10: R29.2 * ICD-9-CM: 796.1 * MeSH: D012021 * NIH/Medline * Diseases Database (DDB): 20760 * Arch Phys Med Rehabil * v * t * e Symptoms and signs relating to movement and gait Gait * Gait abnormality * CNS * Scissor gait * Cerebellar ataxia * Festinating gait * Marche à petit pas * Propulsive gait * Stomping gait * Spastic gait * Magnetic gait * Truncal ataxia * Muscular * Myopathic gait * Trendelenburg gait * Pigeon gait * Steppage gait * Antalgic gait Coordination * Ataxia * Cerebellar ataxia * Dysmetria * Dysdiadochokinesia * Pronator drift * Dyssynergia * Sensory ataxia * Asterixis Abnormal movement * Athetosis * Tremor * Fasciculation * Fibrillation Posturing * Abnormal posturing * Opisthotonus * Spasm * Trismus * Cramp * Tetany * Myokymia * Joint locking Paralysis * Flaccid paralysis * Spastic paraplegia * Spastic diplegia * Spastic paraplegia * Syndromes * Monoplegia * Diplegia / Paraplegia * Hemiplegia * Triplegia * Tetraplegia / Quadruplegia * General causes * Upper motor neuron lesion * Lower motor neuron lesion Weakness * Hemiparesis Other * Rachitic rosary * Hyperreflexia * Clasp-knife response [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hyperreflexia	c0151889	4,794	wikipedia	https://en.wikipedia.org/wiki/Hyperreflexia	2021-01-18T18:36:13	{"mesh": ["D012021"], "wikidata": ["Q1429154"]}
Adverse reactions to biologic agents, such as imatinib, occur in more than 80% of patients, and can be characterized by edema and pruritus without dermatitis.[1]: ## See also[edit] * Skin lesion * List of cutaneous conditions ## 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. 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Adverse reaction to biologic agents	c2959665	4,795	wikipedia	https://en.wikipedia.org/wiki/Adverse_reaction_to_biologic_agents	2021-01-18T19:01:36	{"umls": ["C2959665"], "wikidata": ["Q4686719"]}
A number sign (#) is used with this entry because neurodegeneration with brain iron accumulation-1 (NBIA1), also known as Hallervorden-Spatz disease, is caused by homozygous or compound heterozygosity mutation in the pantothenate kinase-2 gene (PANK2; 606157) on chromosome 20p13. HARP syndrome (607236) is a rare allelic disorder with a less severe phenotype and the presence of hypobetalipoproteinemia and acanthocytosis. Description Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are variable (review by Gregory et al., 2009). Panthothenate kinase-associated neurodegeneration has been classified clinically as 'classic,' 'atypical,' or 'intermediate.' In the classic form, patients present within the first decade of life with rapidly progressing disease and loss of ambulation approximately 15 years later. In the atypical form, patients have onset in the second decade with slow progression and maintain independent ambulation after 15 years. In the intermediate form, patients have early onset and slow progression or later onset and rapid progression. Patients with early onset tend to develop pigmentary retinopathy, whereas those with later onset tend to have speech disorders and psychiatric features. All patients have the 'eye of the tiger' sign on brain MRI (Hayflick et al., 2003; Pellecchia et al., 2005). Kumar et al. (2006) noted that the 'eye of the tiger' sign is not pathognomonic for PANK2 mutations. They reported 2 unrelated adult patients with cognitive dysfunction who had the characteristic sign on MRI but did not have mutations in the PANK2 gene. Gregory et al. (2009) provided a detailed review of the different forms of neurodegeneration with brain iron accumulation. In addition, some patients with Kufor-Rakeb syndrome (606693), also known as Parkinson disease-9 (PARK9), have iron deposition in the basal ganglia. ### Genetic Heterogeneity of Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See also NBIA2A (256600) and NBIA2B (610217), both caused by mutation in the PLA2G6 gene (603604); NBIA3 (606159), caused by mutation in the FTL gene (134790); NBIA4 (614298), caused by mutation in the C19ORF12 gene (614297); NBIA5 (300894), caused by mutation in the WDR45 gene (300526); NBIA6 (615643), caused by mutation in the COASY gene (609855); NBIA7 (617916), caused by mutation in the REPS1 gene (614825); and NBIA8 (617917), caused by mutation in the CRAT gene (600184). See review of Schneider and Bhatia (2012) on syndromes of neurodegeneration with brain iron accumulation, including Kufor-Rakeb disease (606693) and aceruloplasminemia (604290). Clinical Features The original description of this syndrome by Hallervorden and Spatz (1922) concerned a sibship of 12 in which 5 sisters showed clinically increasing dysarthria and progressive dementia, and at autopsy brown discoloration of the globus pallidus and substantia nigra. Familial cases have been reported by others as well. About 30 cases were reported by Meyer (1958). Clinically the condition is characterized by progressive rigidity, first in the lower and later in the upper extremities. An equinovarus deformity of the foot has been the first sign in several cases. Involuntary movements of choreic or athetoid type sometimes precede or accompany rigidity. Both involuntary movements and rigidity may involve muscles supplied by cranial nerves, resulting in difficulties in articulation and swallowing. Mental deterioration and epilepsy occur in some. Onset is in the first or second decade and death usually occurs before the age of 30 years. Elejalde et al. (1978) observed 5 affected persons in a kindred and suggested that the condition originated in central Europe. Elejalde et al. (1979) provided a clinical and genetic analysis. This disorder affects the muscular tone and voluntary movements progressively, making coordinated movements and chewing and swallowing almost impossible. Mental deterioration, emaciation, severe feeding difficulties, and visual impairment occur commonly as late manifestations. The mean survival time after diagnosis was 11.18 years (SD = 7.8). The dopamine-neuromelanine system may be involved in the basic pathogenesis. Malmstrom-Groth and Kristensson (1982) reported the cases of 2 second cousins who developed clinical signs of a progressive extrapyramidal motor disorder and mental retardation and died at ages 8 and 11 years. Iron deposits and axonal dystrophy were found in the pallidum. All 5 sibs in the family originally studied by Hallervorden and Spatz (1922) died before age 25. Jankovic et al. (1985) described a kindred ascertained through a 68-year-old man who died after 13 years of progressive dementia, rigidity, bradykinesia, mild tremor, stooped posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of eyelid opening, anarthria, aphonia, and incontinence. At autopsy, he had generalized brain atrophy with large deposits of iron pigment in the globus pallidus, caudate and substantia nigra. Axonal spheroids were found in the globus pallidus, substantia nigra, medulla, and spinal cord. Neurochemical analysis of the brain showed marked loss of dopamine in the nigral-striated areas with relative preservation of dopamine in the limbic areas. Of his 4 sibs, 3 were also affected. The youngest, a sister, had been diagnosed as having Alzheimer disease. The parents, nonconsanguineous, died accidentally at age 46. The diagnosis of Hallervorden-Spatz disease has usually been made postmortem; however, the description of magnetic resonance imaging (MRI) alterations in the basal ganglia (Littrup and Gebarski, 1985; Tanfani et al., 1987; Sethi et al., 1988) suggested the possibility of an in vivo diagnosis. Angelini et al. (1992) presented the clinical and MRI findings of 11 patients diagnosed as having Hallervorden-Spatz disease. Generalized dystonia with predominance of oromandibular involvement, behavioral changes followed by dementia, and retinal degeneration were present in all the patients. MRI pallidal abnormalities consisted of decreased signal intensity in T2-weighted images, compatible with iron deposits, and of a small area of hyperintensity in its internal segment ('eye of the tiger' sign). Casteels et al. (1994) described an 8-year-old girl who presented with 3 years of visual impairment and bilateral optic atrophy before developing dystonia and other typical features of Hallervorden-Spatz disease. The MRI demonstrated extremely low signal intensity of the globus pallitus and in the zona reticularis of the substantia nigra on the T2-weighted images. The red nuclei were spared. The authors suggested that a larger series of patients with Hallervorden-Spatz disease should be studied ophthalmologically to exclude the coincidental occurrence of optic atrophy in a patient with otherwise typical Hallervorden-Spatz disease. Although there is no clinical myopathy associated with Hallervorden-Spatz disease, Malandrini et al. (1995) found similar morphologic changes in skeletal muscle in 2 unrelated patients with typical Hallervorden-Spatz disease. Both of these patients had mild elevation of serum creatine kinase. Histologic analysis of biopsy quadriceps muscle demonstrated subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis, and fiber splitting. Pellecchia et al. (2005) reported 16 patients with PKAN confirmed by genetic analysis. Clinically, 5 patients had classic disease, 4 patients had atypical disease, and 4 had intermediate disease; 3 patients could not be classified. Regardless of clinical type, most patients presented with gait abnormalities or writing difficulty. Two patients presented with psychomotor delay, and 2 presented with motor tics and obsessive-compulsive features similar to Tourette syndrome (137580). The most common features were corticospinal signs, dysarthria, dystonia, and rigidity. Three patients had pigmentary retinopathy, and almost 50% of patients had psychiatric involvement, including hyperactivity and depression. All patients had the characteristic 'eye of the tiger' sign on brain MRI. Diagnosis ### Differential Diagnosis Using single photon emission computed tomography (SPECT), Cossu et al. (2005) found normal striatal presynaptic dopamine activity in 2 sibs with PKAN confirmed by genetic analysis. The authors suggested that these SPECT findings, in combination with the classic MRI findings in PKAN, would aid in the differential diagnosis of the disorder. Mapping Using homozygosity mapping in a large Amish family, Taylor et al. (1996, 1996) mapped Hallervorden-Spatz disease to 20p13-p12.3. Analysis of 9 other families from New Zealand, Australia, Spain, and Italy supported linkage to this region with a total maximum 2-point lod score of 13.75 at theta = 0.0 for 1 polymorphic microsatellite marker. Homozygosity in the Amish family and recombinant haplotypes in 3 of the other families suggested that the gene involved is located in a 4-cM interval between D20S906 and D20S116. Taylor et al. (1996) found locus heterogeneity for the disorder; one Japanese family did not show linkage to this region, indicating the existence of another locus for the disorder. Using linkage analysis of an extended Amish pedigree, Zhou et al. (2001) narrowed the critical interval on chromosome 20p13 to a 1.4-Mb interval that contained 21 known or predicted genes. Molecular Genetics In affected members of an Amish family with Hallervorden-Spatz syndrome, Zhou et al. (2001) identified a homozygous 7-bp deletion (606157.0001) in the coding sequence of the PANK2 gene. Additional missense and null mutations in the PANK2 gene were identified in 32 of 38 individuals with classic Hallervorden-Spatz syndrome. Mutations on both alleles could be accounted for in 22 of these 32 individuals. DNA from individuals with atypical PKAN also demonstrated missense mutations in PANK2. These individuals have later onset, and their diverse phenotypes include early-onset Parkinson disease, severe intermittent dystonia, stuttering with palilalia or facial tics with repetitive hair caressing; all had evidence of increased basal ganglia iron. One consanguineous family with pigmentary retinopathy and late-onset dystonia but without radiographic evidence of brain iron accumulation even into their thirties carried a homozygous missense mutation (606157.0007). In the group studied, most mutations were unique, with a notable exception of the gly411-to-arg mutation (606157.0002), which was present in both classic and atypical individuals. In 16 patients with PKAN, Pellecchia et al. (2005) identified 12 mutations in the PANK2 gene, including 5 novel mutations. Genotype/Phenotype Correlations Hayflick et al. (2003) studied 123 patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome and classified them as having classic disease or atypical disease. All patients with classic Hallervorden-Spatz syndrome and one-third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with classic or atypical PKAN, T2-weighted MRI of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without PANK2 mutations. Predicted levels of pantothenate kinase-2 protein correlated with the severity of the disease. Pellecchia et al. (2005) found no genotype/phenotype correlations among 16 patients with PKAN confirmed by genetic analysis. Hartig et al. (2006) identified homozygous or compound heterozygous PANK2 mutations in 48 of 72 patients with PKAN. Deletions accounted for 4% of mutated alleles. There was a correlation between predicted loss-of-function alleles and earlier age at disease onset. Pathogenesis Drecourt et al. (2018) found that cells derived from NBIA patients with PANK2 mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes (PLA2G6, FA2H (611026), C19ORF12, REPS1, and CRAT). Drecourt et al. (2018) concluded that NBIA results from defective endosomal recycling and should be regarded as a disorder of cellular trafficking, whatever the original genetic defect. Population Genetics In affected members from 4 Dutch families with pantothenate kinase-associated neurodegeneration, Rump et al. (2005) identified a 3-bp deletion in the PANK2 gene (606157.0014). Haplotype analysis suggested a founder effect that arose in Friesland, a northern province of the Netherlands, at the beginning of the ninth century, approximately 38 generations ago. Rump et al. (2005) provided a brief history of the geographic isolation of the region. Animal Model Kuo et al. (2005) generated a mouse knockout of the murine Pank2 gene. Homozygous null mice gradually developed retinal degeneration with progressive photoreceptor decline, significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment, and reduced pupillary constriction response. Homozygous male mutants were infertile due to azoospermia, a condition that was not appreciated in affected humans. In contrast to the human, homozygous null mice exhibited no basal ganglia changes or dystonia. By immunohistochemistry, Pank2 was localized to mitochondria in both retina and spermatozoa. History Julius Hallervorden (1882-1965), whose name, with that of Hugo Spatz, is linked to this disorder, made important contributions to neurologic science (Richardson, 1990). However, as detailed by Shevell (1992), his active involvement in a euthanasia program in Germany during World War II raises serious questions about the moral obligations of medical science. Muller-Hill (1987) reviewed much of this information in his 'Murderous Science.' No euthanasia law was ever enacted in the Third Reich. Rather, physicians were empowered to carry out 'mercy killings' but were never obliged to do so. There was never a direct order to participate, and refusal to cooperate did not result in legal action or professional setback. Active opponents were many and included such prominent physicians as Creutzfeldt, another neuropathologist for whom Creutzfeldt-Jakob disease (123400) is named. Hallervorden's enthusiastic encouragement of the killings and the other aspects that led to dehumanization of both the victims and the participants was detailed by Shevell (1992). In responding to the article by Shevell (1992), several authors (e.g., Gordon, 1993) suggested that Hallervorden's name should be removed from this disorder. Shevell (1992) suggested that the disease might be called 'Martha-Alma disease' for the 2 unfortunate sisters whose brains were first dissected in the original description of the condition (Hallervorden and Spatz, 1922). Zhou et al. (2001) suggested that this disorder be referred to as 'pantothenate kinase-associated neurodegeneration' to avoid the objectionable eponym and to reflect the etiology of the disorder. Shevell (2003) reviewed the unhappy history of Adolf Hitler's 'Aktion T-4' program, which resulted in the deaths of 70,273 individuals 'judged to be incurably ill' and provided Hallervorden with his study material. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial grimacing Eyes \- Pigmentary retinopathy (more common in classic disease) \- Retinal degeneration \- Optic atrophy \- Blepharospasm \- Apraxia of eyelid opening ABDOMEN Gastrointestinal \- Feeding difficulties \- Dysphagia GENITOURINARY Bladder \- Incontinence SKELETAL Feet \- Foot deformity SKIN, NAILS, & HAIR Skin \- Skin pigmentation MUSCLE, SOFT TISSUES \- Decreased muscle mass \- Myopathic changes on pathology NEUROLOGIC Central Nervous System \- Psychomotor delay \- Extrapyramidal syndrome \- Involuntary movements \- Gait abnormalities \- Walking on toes \- Corticospinal signs (87% of patients in 1 report) \- Ataxia \- Choreoathetosis \- Dystonia \- Motor 'tics' \- Difficulty writing \- Rigidity \- Parkinsonism \- Orofacial dyskinesia \- Akinesia \- Spasticity \- Stiffness \- Tremor \- Dysarthria \- Speech abnormalities (palilalia) \- Cognitive decline \- Dementia, progressive \- Generalized brain atrophy \- Neuroaxonal degeneration in the brain \- Axonal swelling or thickening in the CNS \- Axonal 'spheroid' inclusions in the CNS \- Iron deposits in the globus pallidus, caudate, and substantia nigra \- MRI shows decreased signal intensity in the pallidal nuclei with central hyperintensity ('eye of the tiger' sign) Behavioral Psychiatric Manifestations \- Psychiatric abnormalities (more common in patients with atypical disease and slow progression) \- Obsessive-compulsive trait \- Depression \- Hyperactivity \- Behavioral problems VOICE \- Dysphonia MISCELLANEOUS \- Clinically classified into classic, atypical, and intermediate phenotypes \- Classic: onset in first decade, rapid progression, loss of independent ambulation within 15 years \- Atypical: onset in second decade, slow progression, maintenance of independent ambulation up to 40 years later \- Intermediate: onset in first decade with slow progression or onset in second decade with rapid progression \- Allelic to the less severe HARP syndrome ( 607236 ), which is distinguished by the presence of hypobetalipoproteinemia and acanthocytosis \- Similar to infantile neuroaxonal dystrophy (INAD, 256600 ) MOLECULAR BASIS \- Caused by mutation in the pantothenate kinase-2 gene (PANK2, 607157.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1	c0018523	4,796	omim	https://www.omim.org/entry/234200	2019-09-22T16:27:22	{"doid": ["3981"], "mesh": ["D006211"], "omim": ["234200"], "icd-10": ["G23.0"], "orphanet": ["216873", "157850", "216866"], "synonyms": ["PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION", "NBIA1, atypical form", "HALLERVORDEN-SPATZ DISEASE", "Alternative titles", "PKAN, atypical form", "Neurodegeneration with brain iron accumulation type 1, atypical form", "PKAN NEUROAXONAL DYSTROPHY, JUVENILE-ONSET"], "genereviews": ["NBK1490"]}
A number sign (#) is used with this entry because of evidence that familial primary localized cutaneous amyloidosis-1 is caused by heterozygous mutation in the gene encoding oncostatin M receptor-beta (OSMR; 601743) on chromosome 5p13. Description Primary localized cutaneous amyloidosis is characterized clinically by pruritus and skin scratching and histologically by the finding of deposits of amyloid staining on keratinous debris in the papillary dermis (summary by Tanaka et al., 2009). ### Genetic Heterogeneity of Primary Localized Cutaneous Amyloidosis Primary localized cutaneous amyloidosis-2 (PLCA2; 613955) is caused by heterozygous mutation in the IL31RA gene (609510) on chromosome 5q11. Primary localized cutaneous amyloidosis-3 (PLCA3; 617920) is caused by mutation in the GPNMB gene (604368) on chromosome 7p15. Clinical Features Sagher and Shanon (1963) found 3 cases of primary cutaneous amyloidosis in 3 generations of a Russian-Jewish family. Tay (1971) reported affected mother and daughter. Rajagopalan and Tay (1972) reported 19 persons in 4 successive generations of a Chinese family in Malaysia. Onset was around the age of puberty. The extent of cutaneous involvement increased with age but no systemic involvement occurred. There are at least 2 reports of affected sibs. Eng et al. (1976) described brother and sister with amyloid of the skin of a type possibly different from that in the other reports. Newton et al. (1985) described a British family. The subtlety of physical signs contrasted with the severity of the associated pruritus. Transepidermal elimination of amyloid was a characteristic histologic feature. When scratching, patients were able to remove the 'core' of the papules with consequent reduction in pruritus. Four generations and by inference a fifth were affected. ### Primary Cutaneous Amyloidosis Associated with Multiple Endocrine Neoplasia Type IIA PLCA has been described in association with other disorders, including multiple endocrine neoplasia type IIA (MEN2A; 171400). The cutaneous lichen amyloidosis that occurs in MEN2A is associated with pruritus and occurs particularly in the interscapular region. It is thought to be a form of 'friction amyloidosis' and to be related to notalgia paresthetica, a neuropathy of the posterior dorsal nerve rami. A cys634-to-tyr missense mutation in the RET gene (164761.0004) was identified in affected members of one family with MEN2A and cutaneous lichen amyloidosis (Ceccherini et al., 1994). Seri et al. (1997) reported a family in which multiple members with MEN2A and cutaneous lichen amyloidosis had a cys634-to-gly mutation in the RET gene (164761.0003). Tanaka et al. (2009) stated that, despite these reports, there is no evidence to suggest that PLCA in MEN2A results directly from mutations in the RET gene; rather, there is indirect evidence that the amyloid deposition is a secondary phenomenon. Inheritance Most cases of primary localized cutaneous amyloidosis are sporadic. PLCA1 is inherited in an autosomal dominant manner (Arita et al., 2008). Population Genetics Familial primary cutaneous amyloidosis occurs more frequently in certain populations, i.e,, in China, Southeast Asia, and South America (Tanaka et al., 2009). Mapping Genomewide scans for familial PLCA in Taiwan (Lin et al., 2005; Lee et al., 2006) achieved the most significant lod scores for the disease locus on chromosome 5p13.1-q11.2. Arita et al. (2008) mapped the disorder in a large Brazilian family to 5p13.1-q11.2. ### Exclusion Studies Since some patients with multiple endocrine neoplasia type 2A have the clinical picture of primary cutaneous amyloidosis, Lee et al. (1996) carried out linkage analysis in 7 families with cutaneous amyloidosis using 4 dinucleotide repeat markers from the RET region. Negative lod scores and all recombination frequencies were obtained. They thus concluded that there is no evidence for linkage between Chinese families with primary cutaneous amyloidosis of the pericentromeric region of chromosome 10. Molecular Genetics By candidate gene analysis of genes in the PLCA critical mapping region of chromosome 5, Arita et al. (2008) identified heterozygous missense mutations in the OSMR gene (601743.0001-601743.0002) in affected individuals of a large Brazilian family and in 2 other families, one from the United Kingdom and one from South Africa. By whole-exome sequencing of the OSMR gene in Taiwanese patients with PLCA mapping to chromosome 5, Lin et al. (2010) identified 3 novel heterozygous mutations (601743.0003-601743.0005). ### Exclusion Studies Hofstra et al. (1996) screened 3 pedigrees with familial cutaneous lichen amyloidosis for RET mutations and found none in the RET coding and flanking intronic sequences. They interpreted this as indicating that skin amyloidosis found in some MEN2A families and familial cutaneous lichen amyloidosis are different conditions. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Pruritus \- Dry skin \- Scaly skin \- Focal skin lichenification Skin Histology \- Focal deposition of amyloid in dermal papillae \- Pigmentary incontinence \- Amorphous eosinophilic material in the papillary dermis \- Accentuated skin creases MISCELLANEOUS \- Onset may occur in childhood \- Symptoms typically start with severe pruritus on the lower legs MOLECULAR BASIS \- Caused by mutation in the oncostatin-M receptor gene (OSMR, 601743.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1	c4551501	4,797	omim	https://www.omim.org/entry/105250	2019-09-22T16:45:12	{"doid": ["0050639"], "omim": ["105250"], "orphanet": ["353220"], "synonyms": ["PCA", "Alternative titles", "AMYLOIDOSIS IX", "AMYLOIDOSIS, PRIMARY CUTANEOUS, 1", "LICHEN AMYLOIDOSIS, FAMILIAL", "AMYLOIDOSIS, FAMILIAL CUTANEOUS LICHEN", "FPLCA"]}
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. (March 2017) Hypertension and brachydactyly syndrome Other namesBrachydactyly-arterial hypertension syndrome This condition is inherited in an autosomal dominant manner. Hypertension and brachydactyly syndrome (HTNB) also known as Bilginturan syndrome and brachydactyly type E among others is a very rare genetic disorder.[1][2] It was first reported in 1973 by N. Bilginturan et al.[3][4] The estimated prevalence is less than 1 out of 1,000,000.[2] ## Contents * 1 Symptoms * 2 Genetics * 3 Treatment * 4 References * 5 External links ## Symptoms[edit] The disorder is characterized by: * severe salt-independent but age-dependent hypertension * brachydactyly malformations of the hands and fingers * increased fibroblast growth rate * neurovascular contact at the rostral-ventrolateral medulla * altered baroreflex blood pressure regulation * death from stroke before age 50 years when untreated ## Genetics[edit] The disorder is thought to be related to mutations in the PDE3A gene.[1][5] ## Treatment[edit] This section is empty. You can help by adding to it. (January 2018) ## References[edit] 1. ^ a b "HYPERTENSION AND BRACHYDACTYLY SYNDROME; HTNB". www.omim.org. Retrieved 2017-01-19. 2. ^ a b "Brachydactyly arterial hypertension syndrome". www.orpha.net. Retrieved 2017-01-19. 3. ^ Chitayat, D.; Grix, A.; Balfe, J. W.; Abramowicz, J. S.; Garza, J.; Fong, C. T.; Silver, M. M.; Saller, D. N.; Bresnick, G. H. (1997-12-19). "Brachydactyly-short stature-hypertension (Bilginturan) syndrome: report on two families". American Journal of Medical Genetics. 73 (3): 279–285. doi:10.1002/(SICI)1096-8628(19971219)73:3<279::AID-AJMG10>3.0.CO;2-G. ISSN 0148-7299. PMID 9415685. 4. ^ Bilginturan, N.; Zileli, S.; Karacadag, S.; Pirnar, T. (1973-09-01). "Hereditary Brachydactyly Associated with Hypertension". Journal of Medical Genetics. 10 (3): 253–259. doi:10.1136/jmg.10.3.253. ISSN 0022-2593. PMC 1013029. PMID 4774535. 5. ^ Maass, Philipp G.; Aydin, Atakan; Luft, Friedrich C.; Schächterle, Carolin; Weise, Anja; Stricker, Sigmar; Lindschau, Carsten; Vaegler, Martin; Qadri, Fatimunnisa (2015-06-01). "PDE3A mutations cause autosomal dominant hypertension with brachydactyly" (PDF). Nature Genetics. 47 (6): 647–653. doi:10.1038/ng.3302. ISSN 1546-1718. PMID 25961942. ## External links[edit] Classification D * ICD-10: Q73.8 * OMIM: 112410 * MeSH: C537095 External resources * Orphanet: 1276 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hypertension and brachydactyly syndrome	c1862170	4,798	wikipedia	https://en.wikipedia.org/wiki/Hypertension_and_brachydactyly_syndrome	2021-01-18T18:42:11	{"gard": ["967"], "mesh": ["C537095"], "umls": ["C1862170"], "orphanet": ["1276"], "wikidata": ["Q30314087"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Platyspondylic lethal skeletal dysplasia, Torrance type" – news · newspapers · books · scholar · JSTOR (October 2016) (Learn how and when to remove this template message) Platyspondylic lethal skeletal dysplasia, Torrance type Other namesPlatyspondylic dysplasia, Torrance-Luton type Platyspondylic lethal skeletal dysplasia, Torrance type is inherited in an autosomal dominant pattern. Platyspondylic lethal skeletal dysplasia, Torrance type is a severe disorder of bone growth. People with this condition have very short arms and legs, a small chest with short ribs, underdeveloped pelvic bones, and unusually short fingers and toes (brachydactyly). This disorder is also characterized by flattened spinal bones (platyspondyly) and abnormal curvature of the spine (lordosis). As a result of these serious skeletal problems, many infants with platyspondylic lethal skeletal dysplasia, Torrance type are born prematurely, are stillborn, or die shortly after birth from respiratory failure. A few affected people with milder signs and symptoms have lived into adulthood, however. ## Cause[edit] This condition is one of a spectrum of skeletal disorders caused by mutations in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen. This type of collagen is found mostly in cartilage and in the clear gel that fills the eyeball (the vitreous). It is essential for the normal development of bones and other tissues that form the body's supportive framework (connective tissues). ## Genetics[edit] Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, resulting in a reduced amount of this type of collagen in the body. Instead of forming collagen molecules, the abnormal COL2A1 protein builds up in cartilage cells (chondrocytes). These changes disrupt the normal development of bones and other connective tissues, leading to the skeletal abnormalities characteristic of platyspondylic lethal skeletal dysplasia, Torrance type. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. ## External links[edit] * This article incorporates public domain text from The U.S. National Library of Medicine Classification D * ICD-10: Q77.8 * OMIM: 151210 * MeSH: C563627 External resources * Orphanet: 85166 * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Platyspondylic lethal skeletal dysplasia, Torrance type	c1835437	4,799	wikipedia	https://en.wikipedia.org/wiki/Platyspondylic_lethal_skeletal_dysplasia,_Torrance_type	2021-01-18T18:36:41	{"gard": ["4382"], "mesh": ["C563627"], "umls": ["C1835437"], "orphanet": ["85166"], "wikidata": ["Q7202845"]}

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