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Corn allergy, also called maize allergy, is a very rare food allergy.[1] People with a true IgE-mediated allergy to corn develop symptoms such as swelling or hives when they eat corn or foods that contain corn. Corn allergy can be a difficult allergy to manage, due to many food and non-food products that contain various forms of corn, such as corn starch, modified food starch, vinegar, and vanilla extract, among many others. It is an allergy that often goes unrecognized.[medical citation needed] ## Contents * 1 Symptoms * 2 Management * 3 See also * 4 Notes ## Symptoms[edit] Symptoms appear after exposure, and range from mild to severe.[1] As with other food allergies, most people who are allergic to corn have mild symptoms.[2] As a result of a possible immunoglobulin E (IgE) allergy to corn, symptoms can resemble that of any other recognized allergy, including anaphylaxis. Reactions to corn derivatives, such as corn syrup, are also possible.[3] ## Management[edit] As with other food allergies, there is no cure.[2] Most people who are allergic to corn cannot eat corn or anything containing proteins from corn.[1] Many people who are allergic to corn can still eat sugars purified from corn, such as corn syrup.[1] ## See also[edit] * List of allergies * Food intolerance – another cause of illness after eating a particular food ## Notes[edit] 1. ^ a b c d "Corn Allergy". American College of Allergy, Asthma & Immunology. 2019-03-08. Retrieved 2020-09-12. 2. ^ a b Center for Food Safety and Applied Nutrition (2020-07-16). "What You Need to Know about Food Allergies". FDA. 3. ^ Mondello, Wendy (Feb–Mar 2011). "Allergic to Corn". Living Without. This immunology article is a stub. You can help Wikipedia by expanding it. * v * t * e * v * t * e Maize and corn Varieties * Amylomaize * Baby * Blue * Dent * Field * Flint * Flour * Genetically modified * List * MON 810 * MON 863 * Purple * Quality Protein Maize * Shoepeg * Sweet * Varieties * Waxy * By origin * Bolivia * Ecuador * Italy * Peru Parts * Cob * Kernel * Stover Processing * Corn construction * Maize milling * Nixtamalization * Wet-milling * Popcorn maker Pathology * BBCH-scale * Corn allergy * Corn smut * Maize streak virus Production * Biofuel * Cornstalk fiddle * Production in the U.S. * List of popcorn brands * Three Sisters (agriculture) Culture * Corn Palace * Corn School * Field of Corn (1994 sculpture) * National Cornbread Festival * Sweet Corn Festival * Zea (film) Maize dishes Ingredients * Cornmeal * Masa * Mielie-meal * Oil * Samp * Starch * Steep liquor * Syrup * Glucose syrup * High-fructose * Public relations * High-maltose Soups, stews, and porridge * Akple * Banku * Bulz * Cocoloși * Corn chowder * Corn crab soup * Corn pudding * Corn soup * Corn stew * Cou-cou * Creamed corn * Fufu * Ginataang mais * Grits * Hasty pudding * Kačamak * Mămăligă * Mămăligă în pături * Mush * Pashofa * Polenta * Pozole * Sagamite * Ugali * Xarém Tamales * Acaçá * Tamale * Binaki * Guanime * Hallaca * Humita * Nacatamal * Pamonha * Pasteles Fried dishes * Battered sausage * Corn fritter * Corn chip * Corn dog * Corn nut * Cornick * Hushpuppy * Milho frito * Sorullos Other foods * Alivenci * Binatog * Conkies * Corn flakes * Corn on the cob * Corn relish * Corn sauce * Gofio * Hominy * Huitlacoche * Kenkey * Kuymak * Maíz con hielo * Maja maíz * Maque choux * Mote * Pinole * Popcorn * Succotash Beverages * Atole * Bourbon whiskey * Cauim * Champurrado * Chicha * Chicha de jora * Chicha morada * Colada morada * Corn beer * Corn tea * Corn whiskey * Mazamorra * Pinolillo * Pozol * Tejate * Tejuino * Tesgüino [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Corn allergy	None	5,400	wikipedia	https://en.wikipedia.org/wiki/Corn_allergy	2021-01-18T18:29:02	{"wikidata": ["Q5171043"]}
Significant economic disease of cattle caused by two species of Pestivirus Bovine viral diarrhea Immunofluorescence image of BVDV (CP7 type). Nuclei are stained blue with DAPI. The replication complexes of the viruses are marked red by NS3 protein binding antibodies Scientific classification (unranked): Virus Realm: Riboviria Kingdom: Orthornavirae Phylum: Kitrinoviricota Class: Flasuviricetes Order: Amarillovirales Family: Flaviviridae Genus: Pestivirus Groups included * Pestivirus A (formerly Bovine viral diarrhea virus 1) * Pestivirus B (formerly Bovine viral diarrhea virus 2) Cladistically included but traditionally excluded taxa * Pestivirus C * Pestivirus D * Pestivirus E * Pestivirus F * Pestivirus G * Pestivirus H * Pestivirus I * Pestivirus J * Pestivirus K Tongue lesions on confirmed BVD/MD case (mucosal disease form) Bovine viral diarrhea (BVD), bovine viral diarrhoea (UK English) or mucosal disease, and previously referred to as bovine virus diarrhoea (BVD), is an economically significant disease of cattle that is found in the majority of countries throughout the world.[1] Worldwide reviews of the economically assessed production losses and intervention programs (e.g. eradication programs, vaccination strategies and biosecurity measures) incurred by BVD infection have been published.[2] [3] The causative agent, bovine viral diarrhea virus (BVDV), is a member of the genus Pestivirus of the family Flaviviridae.[1] BVD infection results in a wide variety of clinical signs, due to its immunosuppressive effects,[4] as well as having a direct effect on respiratory disease and fertility.[5] In addition, BVD infection of a susceptible dam during a certain period of gestation can result in the production of a persistently infected (PI) fetus.[6] PI animals recognise intra-cellular BVD viral particles as ‘self’ and shed virus in large quantities throughout life; they represent the cornerstone of the success of BVD as a disease. Currently, it was shown in a worldwide review study that the PI prevalence at animal level ranged from low (≤0.8% Europe, North America, Australia), medium (>0.8% to 1.6% East Asia) to high (>1.6% West Asia). Countries that had failed to implement any BVDV control and/or eradication programmes (including vaccination) had the highest PI prevalence.[7] ## Contents * 1 Virus classification and structure * 2 Epidemiology * 3 Pathogenesis * 3.1 Acute, transient infection * 3.2 Intrauterine infections * 3.3 Chronic infections * 4 Clinical signs * 4.1 PI animals * 4.2 Mucosal disease * 5 Diagnosis * 5.1 Virus or antigen detection * 5.2 BVD antibody detection * 6 Eradication and control * 7 Vaccination * 8 See also * 9 References * 10 External links ## Virus classification and structure[edit] BVDVs are a members of the genus Pestivirus, belonging to the family Flaviviridae. Other members of this genus cause Border disease (sheep) and classical swine fever (pigs) which cause significant financial loss to the livestock industry.[8] Pestiviruses are small, spherical, single-stranded, enveloped RNA viruses of 40 to 60 nm in diameter.[9] The genome consists of a single, linear, positive-sense, single-stranded RNA molecule of approximately 12.3 kb.[10] RNA synthesis is catalyzed by the BVDV RNA-dependent RNA polymerase (RdRp). This RdRp can undergo template strand switching allowing RNA-RNA copy choice recombination during elongative RNA synthesis.[11] Two BVDV genotypes are recognised, based on the nucleotide sequence of the 5’untranslated (UTR) region; BVDV-1 and BVDV-2.[12] BVDV-1 isolates have been grouped into 16 subtypes (a –p) and BVDV-2 has currently been grouped into 3 subtypes (a – c).[13] BVDV strains can be further divided into distinct biotypes (cytopathic or non-cytopathic) according to their effects on tissue cell culture; cytopathic (cp) biotypes, formed via mutation of non-cytopathic (ncp) biotypes, induce apoptosis in cultured cells.[14] Ncp viruses can induce persistent infection in cells and have an intact NS2/3 protein. In cp viruses the NS2/3 protein is either cleaved to NS2 and NS3 or there is a duplication of viral RNA containing an additional NS3 region.[15] The majority of BVDV infections in the field are caused by the ncp biotype.[1] ## Epidemiology[edit] BVD is considered one of the most significant infectious diseases in the livestock industry worldwide due to its high prevalence, persistence and clinical consequences.[16] In Europe the prevalence of antibody positive animals in countries without systematic BVD control is between 60 and 80%.[17] Prevalence has been determined in individual countries and tends to be positively associated with stocking density of cattle. BVDV-1 strains are predominant in most parts of the world, whereas BVDV-2 represents 50% of cases in North America.[16] In Europe, BVDV-2 was first isolated in the UK in 2000 and currently represents up to 11% of BVD cases in Europe.[18] Transmission of BVDV occurs both horizontally and vertically with both persistently and transiently infected animals excreting infectious virus. Virus is transmitted via direct contact, bodily secretions and contaminated fomites, with the virus being able to persist in the environment for more than two weeks. Persistently infected animals are the most important source of the virus, continuously excreting a viral load one thousand times that shed by acutely infected animals.[19] ## Pathogenesis[edit] Turbinate cells infected with BVDV ### Acute, transient infection[edit] Following viral entry and contact with the mucosal lining of the mouth or nose, replication occurs in epithelial cells. BVDV replication has a predilection for the palatine tonsils, lymphoid tissues and epithelium of the oropharynx. Phagocytes take up BVDV or virus-infected cells and transport them to peripheral lymphoid tissues; the virus can also spread systemically through the bloodstream. Viraemia occurs 2–4 days after exposure and virus isolation from serum or leukocytes is generally possible between 3–10 days post infection.[20] During systemic spread the virus is able to gain entry into most tissues with a preference for lymphoid tissues. Neutralising antibodies can be detected from 10–14 days post infection with titres continuing to increase slowly for 8–10 weeks. After 2–3 weeks, antibodies effectively neutralise viral particles, promote clearance of virus and prevent seeding of target organs.[21] ### Intrauterine infections[edit] Fetal infection is of most consequence as this can result in the birth of a persistently infected neonate. The effects of fetal infection with BVDV are dependent upon the stage of gestation at which the dam suffers acute infection. BVDV infection of the dam prior to conception, and during the first 18 days of gestation, results in delayed conception and an increased calving to conception interval. Once the embryo is attached, infection from days 29–41 can result in embryonic infection and resultant embryonic death. Infection of the dam from approximately day 30 of gestation until day 120 can result in immunotolerance and the birth of calves persistently infected with the virus. BVDV infection between 80 and 150 days of gestation may be teratogenic, with the type of birth defect dependent upon the stage of fetal development at infection. Abortion may occur at any time during gestation. Infection after approximately day 120 can result in the birth of a normal fetus which is BVD antigen-negative and BVD antibody-positive. This occurs because the fetal immune system has developed, by this stage of gestation, and has the ability to recognise and fight off the invading virus, producing anti-BVD antibodies. ### Chronic infections[edit] BVD virus can be maintained as a chronic infection within some immunoprivileged sites following transient infection. These sites include ovarian follicles, testicular tissues, central nervous system and white blood cells. Cattle with chronic infections elicit a significant immune response, exhibited by extremely high antibody titres. ## Clinical signs[edit] BVDV infection has a wide manifestation of clinical signs including fertility issues, milk drop, pyrexia, diarrhoea and fetal infection.[9] Occasionally, a severe acute form of BVD may occur. These outbreaks are characterized by thrombocytopenia with high morbidity and mortality. However, clinical signs are frequently mild and infection insidious, recognised only by BVDV’s immunosuppressive effects perpetuating other circulating infectious diseases (particularly scours and pneumonias). ### PI animals[edit] Persistently infected animals did not have a competent immune system at the time of BVDV transplacental infection. The virus therefore entered the fetal cells and, during immune system development, was accepted as self. In PIs the virus remains present in a large number of the animal’s body cells throughout its life and is continuously shed. PIs are often ill-thrifty and smaller than their peers, however they can appear normal. PIs are more susceptible to disease, with only 20% of PIs surviving to two years of age.[22] If a PI dam is able to reproduce they always give birth to PI calves.[23] ### Mucosal disease[edit] The PI cattle that do survive ill-thrift are susceptible to mucosal disease. Mucosal disease only develops in PI animals and is invariably fatal.[5] Disease results when a PI animal is superinfected with a cytopathic biotype arising from mutation of the non-cytopathic strain of BVDV already circulating in that animal.[24] The cp BVDV spreads to the gastro-intestinal epithelium, and necrosis of keratinocytes results in erosion and ulceration. Fluid leaks from the epithelial surface of the gastro-intestinal tract causing diarrhoea and dehydration. In addition, bacterial infection of the damaged epithelium results in secondary septicaemia. Death occurs in the ensuing days or weeks. ## Diagnosis[edit] Various diagnostic tests are available for the detection of either active infection or evidence of historical infection. The method of diagnosis used also depends upon whether the vet is investigating at an individual or a herd level. ### Virus or antigen detection[edit] Antigen ELISA and rtPCR are currently the most frequently performed tests to detect virus or viral antigen. Individual testing of ear tissue tag samples or serum samples is performed. It is vital that repeat testing is performed on positive samples to distinguish between acute, transiently infected cattle and PIs. A second positive result, acquired at least three weeks after the primary result, indicates a PI animal. rtPCR can also be used on bulk tank milk (BTM) samples to detect any PI cows contributing to the tank. It is reported that the maximum number of contributing cows from which a PI can be detected is 300. ### BVD antibody detection[edit] Antibody (Ig) ELISAs are used to detect historical BVDV infection; these tests have been validated in serum, milk and bulk milk samples. Ig ELISAs do not diagnose active infection but detect the presence of antibodies produced by the animal in response to viral infection. Vaccination also induces an antibody response, which can result in false positive results, therefore it is important to know the vaccination status of the herd or individual when interpreting results. A standard test to assess whether virus has been circulating recently is to perform an Ig ELISA on blood from 5–10 young stock that have not been vaccinated, aged between 9 and 18 months. A positive result indicates exposure to BVDV, but also that any positive animals are very unlikely to be PI animals themselves. A positive result in a pregnant female indicates that she has previously been either vaccinated or infected with BVDV and could possibly be carrying a PI fetus, so antigen testing of the newborn is vital to rule this out.[5] A negative antibody result, at the discretion of the responsible veterinarian, may require further confirmation that the animal is not in fact a PI. At a herd level, a positive Ig result suggests that BVD virus has been circulating or the herd is vaccinated. Negative results suggest that a PI is unlikely however this naïve herd is in danger of severe consequences should an infected animal be introduced. Antibodies from wild infection or vaccination persist for several years therefore Ig ELISA testing is more valuable when used as a surveillance tool in seronegative herds. ## Eradication and control[edit] The mainstay of eradication is the identification and removal of persistently infected animals. Re-infection is then prevented by vaccination and high levels of biosecurity, supported by continuing surveillance. PIs act as viral reservoirs and are the principal source of viral infection but transiently infected animals and contaminated fomites also play a significant role in transmission.[1] Leading the way in BVD eradication, almost 20 years ago, were the Scandinavian countries. Despite different conditions at the start of the projects in terms of legal support, and regardless of initial prevalence of herds with PI animals, it took all countries approximately 10 years to reach their final stages.[25][26] Once proven that BVD eradication could be achieved in a cost efficient way, a number of regional programmes followed in Europe, some of which have developed into national schemes.[27] Vaccination is an essential part of both control and eradication. While BVD virus is still circulating within the national herd, breeding cattle are at risk of producing PI neonates and the economic consequences of BVD are still relevant. Once eradication has been achieved, unvaccinated animals will represent a naïve and susceptible herd. Infection from imported animals or contaminated fomites brought into the farm, or via transiently infected in-contacts will have devastating consequences. ## Vaccination[edit] Modern vaccination programmes aim not only to provide a high level of protection from clinical disease for the dam, but, crucially, to protect against viraemia and prevent the production of PIs.[28] While the immune mechanisms involved are the same, the level of immune protection required for foetal protection is much higher than for prevention of clinical disease.[29] While challenge studies indicate that killed, as well as live, vaccines prevent foetal infection under experimental conditions, the efficacy of vaccines under field conditions has been questioned.[30] The birth of PI calves into vaccinated herds suggests that killed vaccines do not stand up to the challenge presented by the viral load excreted by a PI in the field.[31] ## See also[edit] * Animal viruses ## References[edit] 1. ^ a b c d Fray; et al. (2000). The effects of bovine viral diarrhoea virus on cattle reproduction in relation to disease control. Animal Reproduction Science 60–61, 615–627. 2. ^ Richter, V; Lebl, K; Baumgartner, W; Obritzhauser, W; Käsbohrer, A; Pinior, B (2017). "A systematic worldwide review of the direct monetary losses due to bovine viral diarrhea virus infection". The Veterinary Journal. 220: 80–87. doi:10.1016/j.tvjl.2017.01.005. PMID 28190502. 3. ^ Pinior, B; Firth, C; Richter, V; Lebl, K; Trauffler, M; Dzieciol, M; Hutter, S; Burgstaller, J; Obritzhauser, W; Winter, P; Käsbohrer, A (2017). "A systematic review of financial and economic assessments of bovine viral diarrhea virus (BVDV) prevention and mitigation activities worldwide". Preventive Veterinary Medicine. 137 (Pt A): 77–92. doi:10.1016/j.prevetmed.2016.12.014. PMID 28040270. 4. ^ Schaut, Robert G.; McGill, Jodi L.; Neill, John D.; Ridpath, Julia F.; Sacco, Randy E. (2015-10-02). "Bovine viral diarrhea virus type 2 in vivo infection modulates TLR4 responsiveness in differentiated myeloid cells which is associated with decreased MyD88 expression". Virus Research. 208: 44–55. doi:10.1016/j.virusres.2015.05.017. ISSN 1872-7492. PMID 26043978. 5. ^ a b c Lanyon; et al. (2014). Bovine Viral Diarrhoea: Pathogenesis and diagnosis. The Veterinary Journal. 6. ^ Grooms (2004). Reproductive consequences of infection with bovine viral diarrhea virus. Veterinary Clinics of North America: Food Animal Practice. 7. ^ Scharnböck, B; Roch, Franz-Ferdinand; Richter, V; Funke, C; Firth, C; Obritzhauser, W; Baumgartner, W; Käsbohrer, A; Pinior, B (2018). "A meta-analysis of bovine viral diarrhoea virus (BVDV) prevalences in the global cattle population". Scientific Reports. 8 (1): 14420. Bibcode:2018NatSR...814420S. doi:10.1038/s41598-018-32831-2. PMC 6158279. PMID 30258185. 8. ^ Hornberg; et al. (2009). Genetic diversity of pestivirus isolates in cattle from Western Austria. Veterinary Microbiology 135 (3–4), 205–213. 9. ^ a b Fenner (2011). Fenners Veterinary Virology. Elsevier, 4th edition. 10. ^ Lindenbach and Rice (2001). Flaviviridae: The viruses and their replication. Fields Virology. 11. ^ Kim MJ, Kao C. Factors regulating template switch in vitro by viral RNA-dependent RNA polymerases: implications for RNA-RNA recombination. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4972-7. doi: 10.1073/pnas.081077198. Epub 2001 Apr 17. PMID: 11309487; PMCID: PMC33148 12. ^ Ridpath; et al. (1994). Segregation of bovine viral diarrhoea virus into genotypes. Virology 205 (1), 66–74. 13. ^ Peterhans; et al. (2010). Cytopathic bovine viral diarrhea viruses (BVDV): emerging pestiviruses doomed to extinction. Veterinary Research 41:44. 14. ^ Gillespie; et al. (1962). Cellular resistance in tissue culture, induced by noncytopathogenic strains, to a cytopathogenic strain of virus diarrhea virus of cattle. Proceedings of the Society for Experimental Biology and Medicine 110, 248–250. 15. ^ Qi; et al. (1998). Insertion of a bovine SMT3B gene in NS4B and duplication of NS3 in a bovine viral diarrhea virus genome correlate with the cytopathogenicity of the virus. Virus Research 57 (1), 1–9. 16. ^ a b Moennig; et al. (2005). BVD control in Europe: current status and perspectives. Animal Health Research Reviews 6 (1): 63–74. 17. ^ Anon (2005). EU Thematic network on control of bovine viral diarrhoea virus (BVDV). Position Paper. 18. ^ Wolfmeyer; et al. (1997). Genomic (50-UTR) and serological differences among German BVDV field isolates. Arch. Virol. 142, 2049–2057. 19. ^ Brownlie; et al. (1987). Pathogenesis and epidemiology of bovine virus diarrhoea virus infection of cattle. Annales de Recherches Veterinaires 18 (2), 157–166. 20. ^ Fray; et al. (1998). Prolonged nasal shedding and viraemia of cytopathogenic bovine virus diarrhoea virus in experimental late-onset mucosal disease. Veterinary Research 143 (22): 608–11. 21. ^ Chase; et al. (2004). The immune response to bovine viral diarrhea virus: a constantly changing picture. Veterinary Clinics of North America Food Animal Practice 20 (1): 95–114. 22. ^ Voges (2006). Direct adverse effects of persistent BVDV infection in dairy heifers – A retrospective case control study. VetScript.19:22–25. 23. ^ Moennig and Liess (1995). Pathogenesis of intrauterine infections with bovine viral diarrhoea virus. Vet. Clin. Food Anim. 11:477–488. 24. ^ Brownlie; et al. (1984). Experimental production of fatal mucosal disease in cattle. Vet Rec 114 (22): 535–536. 25. ^ Hult and Lindberg (2005) Prev Vet Med 72: 143–148 26. ^ Rikula et al. (2005) Prev Vet Med 72: 139–142 27. ^ Rossmanith et al. (2005) Prev Vet Med 72: 133–137 28. ^ Stahl and Alenius (2012) Japanese Journal of Veterinary Research 60 (Supplement) S31–39. 29. ^ Ridpath (2013) Biologicals 41: 14–19. 30. ^ O’Rourke (2002) Journal of the American Veterinary Medical Association 220(12): 1770–1772 31. ^ Graham et al. (2004) Revista Portuguesa de ciencias veterinarias 127: 38. * Bovine Viral Diarrhoea Virus, expert reviewed and published by Wikivet at http://en.wikivet.net/Bovine_Viral_Diarrhoea_Virus, accessed 21/07/2011 ## External links[edit] * New York State Cattle Health Assurance Program BVD Module * Description of the entity on the Merck Veterinary Manual * Animal viruses * Bovine Viral Diarrhea Resource Page * Specialist BVD site, Royal Veterinary College, London Taxon identifiers Bovine viral diarrhea virus 1 * Wikidata: Q18968322 * Wikispecies: Pestivirus A * EoL: 541189 * IRMNG: 11459300 * NCBI: 11099 Bovine viral diarrhea virus 2 * Wikidata: Q18968331 * Wikispecies: Pestivirus B * EoL: 541186 * IRMNG: 11459301 * NCBI: 54315 Pestivirus A * Wikidata: Q51930329 * NCBI: 2170080 Pestivirus B * Wikidata: Q51930337 * NCBI: 2170081 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Bovine viral diarrhea	c0006075	5,401	wikipedia	https://en.wikipedia.org/wiki/Bovine_viral_diarrhea	2021-01-18T19:04:14	{"mesh": ["D001912"], "wikidata": ["Q797128"]}
Isolated congenital vertical talus (CVT) is a rare pedal deformity recognizable at birth by a dislocation of the talonavicular joint, resulting in a characteristic radiographic near-vertical orientation of the talus. ## Clinical description It occurs more commonly in males than females. Some patients have vertical talus in one foot and clubfoot in the other. ## Etiology The etiology and epidemiology of this condition are largely unknown. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance and mutations in HOXD10 gene have been detected in two families. ## Management and treatment Serial manipulation and cast immobilization followed by limited surgery provides excellent results. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital vertical talus	c0240912	5,402	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=178382	2021-01-23T17:08:57	{"gard": ["5488"], "mesh": ["D005413"], "omim": ["192950"], "umls": ["C0240912"], "icd-10": ["Q66.8"], "synonyms": ["Congenital convex foot", "Congenital convex pes valgus", "Congenital rocker-bottom foot"]}
Doping investigation Part of a series on Doping in sport Substances and types * Anabolic steroids * Blood doping * Gene doping * Cannabinoids * Diuretics * Painkillers * Sedatives * Stem cell doping * Stimulants * Beta2-adrenergic agonist * Clenbuterol * Ephedrine * EPO * Human growth hormone * Methylhexanamine * SARMs * Stanozolol * Tetrahydrogestrinone Terminology * Abortion doping * Biological passport * Blood-spinning * Doping test * Performance-enhancing drugs * Repoxygen * Stem cell doping * Whizzinator History * Olympics * Tour de France (1998, 1999, 2007) * Auto racing * BALCO scandal * Clemson University steroid scandal * U of South Carolina steroid scandal * Dubin Inquiry * Association Football * China * East Germany * Russia * United States * Festina affair * Floyd Landis case * Game of Shadows * Juiced * L.A. Confidentiel * Lance Armstrong * History of allegations * Doping case * Operación Puerto * Operation Aderlass * Doping in American football * Steroid use in baseball * Barry Bonds perjury case * Mitchell Report * Biogenesis scandal Doping-related lists * Doping cases in Sport * Athletics * Cycling * Doping at the Olympic Games * Doping at the World Championships in Athletics * Stripped Olympic medals * Stripped European Athletics C'ships medals * Drugs banned from the Olympics * MLB players suspended for doping * MLB players in the Mitchell Report Anti-doping bodies * World Anti-Doping Agency * International Testing Agency * List of national anti-doping organizations * Australian Sports Anti-Doping Authority * French Anti-Doping Agency * National Anti-Doping Agency * Russian Anti-Doping Agency * UK Anti-Doping * United States Anti-Doping Agency * v * t * e Operation Aderlass (English: Operation Bloodletting)[1] is an investigation in Austria and Germany into alleged doping practices carried out by Erfurt-based German physician Mark Schmidt. Athletes from various disciplines have been named as alleged customers of Schmidt's, receiving illegal blood transfusion for the purpose of enhancing performances, with several of them having confessed. ## Contents * 1 History * 1.1 Involved athletes * 1.1.1 Winter sports * 1.1.2 Cycling * 2 Trial * 3 References ## History[edit] Admissions by cross-country skier Johannes Dürr (pictured in 2013) led to the investigations. The case first came to light through admissions by cross-country skier Johannes Dürr in late February 2019. He named Mark Schmidt, a physician based in the German city of Erfurt, as the head of an operation which carried out systematic blood doping.[2] Schmidt had earlier been team doctor at both the Gerolsteiner and Milram cycling teams.[3] In October 2009, Bernhard Kohl, who had been caught in a doping control while riding for Gerolsteiner in 2008, accused Schmidt of having overseen the doping practices. Schmidt denied the accusations.[4] Following Dürr's statements, the police carried out a raid of the Erfurt offices on 27 February 2019. The investigation was carried out by the doping task force of the Munich police.[5] ### Involved athletes[edit] On 20 March 2019, the state prosecutors in Bavaria confirmed that a total of 21 athletes were under suspicion of having been customers of Mark Schmidt. Not all names were initially reported, so as not to disturb investigative measures.[3] #### Winter sports[edit] Following Dürr's statements, Austrian police arrested five athletes at the FIS Nordic World Ski Championships 2019 in Seefeld in Tirol. These were the cross-country skiers Max Hauke and Dominik Baldauf from Austria, Andreas Veerpalu and Karel Tammjärv from Estonia, as well as Alexey Poltoranin from Kazakhstan.[6] Initial reports suggested that a German speed skater was also involved with Schmidt.[5] On 27 May 2019, the media reported that alpine ski racer Hannes Reichelt was interviewed by the police in the preceding week, concerning possible involvement in the affair. Reichelt vehemently denied the accusations.[7] The charges against Reichelt were dropped on 16 October 2019.[8] Max Hauke received a suspended five-month sentence on 30 October 2019 from an Innsbruck court for doping violations reaching back to 2015.[9] Dominik Baldauf also received a suspended five-month sentence on 14 January 2020 from the same court.[10] Both athletes had received four-year bans from competition from the Austrian Anti-Doping Agency on 23 July 2019.[11] On 27 January 2020, Johannes Dürr was given a suspended 15-month jail sentence for his involvement in the affair, after pleading guilty. He did however deny having set up connections between Schmidt and fellow cross-country skiers Hauke and Baldauf, as they had claimed.[12] A report by German newspaper Der Tagesspiegel claimed that Dürr had contemplated taking over the doping operations from Schmidt.[13] The International Ski Federation (FIS) handed four-year bans from competition to Andreas Veerpalu, Karel Tammjärv, and Algo Kärp as well as two Estonian coaches on 29 November 2019.[14] All three athletes had earlier admitted their involvement in the doping practices.[15] Alexey Poltoranin, who had earlier admitted to doping as well, retracted his confession on 8 March 2019.[16] On 12 March, the Kazakh Ministry of Culture and Sports cleared Poltoranin of any charges of having doped, claiming that he only intended to do so and "Fortunately [...] did not use blood doping".[17] He was nevertheless handed a four-year ban from competition from FIS on 6 January 2020.[18] #### Cycling[edit] Alessandro Petacchi pictured in 2012, when he allegedly worked with Schmidt for the purposes of doping On 3 March 2019, Stefan Denifl, who last rode for the Aqua Blue Sport team, confessed to using blood doping under the assistance of Schmidt.[19] One day later, Georg Preidler, riding for Groupama–FDJ at the time, also confessed to having had two blood extractions with Schmidt in late 2018, but denied having actually doped. He nevertheless terminated his contract with the team.[20] Both Denifl and Preidler were provisionally suspended by the sport's governing body, the UCI.[21] Both were handed four-year bans by the Austrian anti-doping organisation on 27 June 2019,[22] and might face charges for commercial sports fraud in addition to their suspensions.[23] On 22 July 2020, Preidler was found guilty of fraud by the Innsbruck Regional Court and handed a twelve-month suspended prison sentence as well as being fined €2,880.[24] On 13 May 2019, Danilo Hondo confessed in an interview with German broadcaster ARD to having used blood doping under Schmidt during 2011, when riding with Lampre–ISD. He was subsequently fired from his job as coach for the Swiss cycling federation.[25] On 14 May 2019, French newspaper Le Monde announced that retired Italian sprinter Alessandro Petacchi had allegedly worked with Schmidt in 2012 and 2013.[26] Petacchi denied the accusations, but was nevertheless provisionally suspended by the UCI one day later.[27] On 24 August 2019, Petacchi was given a two-year period of ineligibility from the UCI.[28] Alongside Petacchi, Kristijan Koren (Bahrain–Merida), Kristijan Đurasek (UAE Team Emirates), and Borut Božič were also implicated and provisionally suspended. Koren and Đurasek were at the time riding the 2019 Giro d'Italia and the 2019 Tour of California respectively, while Božič worked as a directeur sportif for the Bahrain–Merida team.[27] Later the same day, Bahrain–Merida and UAE Team Emirates confirmed that they had pulled their riders from the races.[21] On 9 October, the UCI handed both Koren and Božič two-year bans from competition.[29] On 13 November 2019, Đurasek was given a four-year ban from the UCI for his part in the doping practices.[30] On 19 May 2019, Italian newspaper Corriere della Sera reported links by Slovenian Milan Eržen to Operation Aderlass, while Eržen was serving as managing director of the Bahrain–Merida team.[31] On 22 May, it was announced that the UCI had been following the activities of Eržen and Slovenian cycling in general in several investigations.[32] In May 2019, the UCI suspended mountain biker Christina Kollmann due to blood doping violations in relation to Operation Aderlass.[33] She was subsequently banned from competition for four years and received an eight-month suspended jail sentence from an Austrian court in August 2019.[34] On 27 November 2019, the UCI announced that they had requested anti-doping samples from 2016 and 2017 to be retested, citing information gathered from Austrian authorities.[23] Retired cyclist Pirmin Lang, who last rode for IAM Cycling, admitted to his involvement with Aderlass on 22 February 2020, following investigations by Swiss newspaper Neue Zürcher Zeitung. He was subsequently dismissed by Swiss Racing Academy, a team he had co-founded and where he was employed as manager and directeur sportif.[35] ## Trial[edit] The court trial against Schmidt began on 16 September 2020 at the Oberlandesgericht Munich.[36] In their opening statement, the defense accused the prosecution of procedural errors, including illegal surveillance methods, incomplete paperwork, and undue custody.[37] On 29 September 2020, Schmidt took the stand and gave a confession in almost all of the 150 counts laid out against him. He admitted to having extracted blood from clients for the purposes of doping from as early as 2012. He did however deny to have acted for financial gain, claiming to have only received money to cover his costs, and insisted that the health of his clients had never been in danger.[38] A day later, Johannes Dürr backed up Schmidt's claims. When testifying as a witness, Dürr claimed to have always "felt in safe, professional hands" with Schmidt. He furthermore refused to blame Schmidt for the doping, a decision he claimed to have taken with his coach.[39] Three of the four co-defendants of Schmidt's also confessed, while another accused, a contractor, refused to testify.[40] The contractor, Dirk Q., was sentenced to two years on probation in 2008 for bodily harm resulting in death, following an incident in January 2003, in which he allegedly assaulted two people, one of whom later died. Dirk Q. is said to have been part of Erfurt's neo nazi scene. In this trial, Q. is accused of having worked together with Schmidt, transporting blood as well as doing transfusions.[41] On 10 November 2020, Hondo testified in court, claiming that he doped with blood transfusions under Schmidt's guidance together with Petacchi during 2012. He testified that he had been contacted by Schmidt in late 2011 and then paid €25,000 for doping services over the course of the following year, at the end of which he ended the partnership. Hondo also described the usage of codenames, similar to Operación Puerto, with Hondo being known as "James Bond".[42] On 16 January 2021, Schmidt was sentenced to 4 years and 10 months in prison.[43] ## References[edit] 1. ^ "UCI hopes to secure information on cyclists involved in blood doping investigation". cyclingnews.com. 4 March 2019. Retrieved 15 May 2019. 2. ^ Catuogno, Claudio (1 March 2019). "Der Kronzeuge" (in German). Süddeutsche Zeitung. Retrieved 15 May 2019. 3. ^ a b "'More chapters to be written' in Operation Aderlass, says state prosecutor". cyclingnews.com. 20 March 2019. Retrieved 15 May 2019. 4. ^ Brown, Gregor (12 October 2009). "Kohl accuses former Gerolsteiner doctor of doping involvement". cyclingnews.com. Retrieved 15 May 2019. 5. ^ a b "Deutsche Kunden in Erfurt" (in German). Süddeutsche Zeitung. 24 March 2019. Retrieved 15 May 2019. 6. ^ Rüttenauer, Andreas (27 February 2019). "Mit der Nadel im Arm". Die Tageszeitung: Taz (in German). die tageszeitung. Retrieved 15 May 2019. 7. ^ "Doping-Ermittlung erreicht alpinen Skisport" (in German). kicker. 27 May 2019. Retrieved 27 May 2019. 8. ^ "Verfahren gegen Hannes Reichelt eingestellt". Kleine Zeitung (in German). 16 October 2019. Retrieved 29 January 2020. 9. ^ Beer, Andrea (30 October 2019). "Max Hauke zu Bewährungsstrafe verurteilt". Deutschlandfunk (in German). Retrieved 29 January 2020. 10. ^ "Doping - Bewährungsstrafe gegen Langläufer Baldauf". Sportschau (in German). 14 January 2020. Retrieved 29 January 2020. 11. ^ "Langläufer Baldauf und Hauke für vier Jahre gesperrt". Sportschau (in German). 23 July 2019. Retrieved 29 January 2020. 12. ^ "Johannes Dürr zu 15 Monaten auf Bewährung verurteilt". Der Tagesspiegel (in German). 27 January 2020. Retrieved 29 January 2020. 13. ^ "Diesem „Whistleblower" sollte man keinen Glauben schenken". Der Tagesspiegel (in German). 28 January 2020. Retrieved 29 January 2020. 14. ^ "Estonian skiers, coaches hit with four-year bans after doping investigation". Eesti Rahvusringhääling. 29 November 2019. Retrieved 29 January 2020. 15. ^ "Skier Algo Kärp next to admit to doping". Eesti Rahvusringhääling. 5 March 2019. Retrieved 29 January 2020. 16. ^ "Verhafteter Doper zieht Geständnis zurück". Basler Zeitung (in German). 8 March 2019. Retrieved 29 January 2020. 17. ^ "Kazakh ministry clears skier involved with Veerpalus, Alaver of doping". Eesti Rahvusringhääling. 12 March 2019. Retrieved 29 January 2020. 18. ^ "International ski federation bans 4 in doping case". Associated Press. 6 January 2020. Retrieved 29 January 2020. 19. ^ "Denifl confesses to blood doping in police interview". cyclingnews.com. 3 March 2019. Retrieved 15 May 2019. 20. ^ "Preidler admits to blood extraction as doping investigation widens". cyclingnews.com. 4 March 2019. Retrieved 15 May 2019. 21. ^ a b Ballinger, Alex (15 May 2019). "Riders pulled from Giro d'Italia and Tour of California as UCI publishes names linked to blood doping scandal". Cycling Weekly. Retrieved 15 May 2019. 22. ^ "Denifl and Preidler handed four-year bans after blood doping confessions". cyclingnews.com. 27 June 2019. Retrieved 26 August 2019. 23. ^ a b Ballinger, Alex (28 November 2019). "UCI request anti-doping samples from 2016 and 2017 be re-tested in wake of Operation Aderlass scandal". Cycling Weekly. Retrieved 28 November 2019. 24. ^ Weislo, Laura (22 July 2020). "Georg Preidler found guilty of fraud in Operation Aderlass doping case". cyclingnews.com. Retrieved 24 July 2020. 25. ^ Long, Jonny (13 May 2019). "Danilo Hondo fired from coaching role after confessing to blood doping". Cycling Weekly. Retrieved 15 May 2019. 26. ^ Guillou, Clément (14 May 2019). "L'ancien cycliste italien Alessandro Petacchi, maillot vert du Tour de France, soupçonné de dopage". Le Monde.fr (in French). Le Monde. Retrieved 15 May 2019. 27. ^ a b "Petacchi, Koren, Durasek, Bozic named in Austrian doping ring". cyclingnews.com. 15 May 2019. Retrieved 15 May 2019. 28. ^ "Alessandro Petacchi handed two-year doping ban". cyclingnews.com. 24 August 2019. Retrieved 26 August 2019. 29. ^ "Operation Aderlass: Cyclists Kristijan Koren and Borut Bozic given two-year bans". BBC. 9 October 2019. Retrieved 16 October 2019. 30. ^ "Durasek banned for four years for doping". cyclingnews.com. 13 November 2019. Retrieved 15 November 2019. 31. ^ "Giro d'Italia: il misterioso Erzen, talent scout di Roglic e manovratore della Bahrain di Nibali" (in Italian). Corriere della Sera. 19 May 2019. Retrieved 23 May 2019. 32. ^ "Bahrain-Merida's Milan Erzen under UCI investigation for doping links". cyclingnews.com. 22 May 2019. Retrieved 23 May 2019. 33. ^ "UCI statement on Christina Kollmann-Forstner". Union Cycliste International. 29 May 2019. Retrieved 24 February 2020. 34. ^ Streif, Thomas (2 August 2019). ""Operation Aderlass": Acht Monate bedingt für Mountainbikerin Kollmann". OÖNachrichten (in German). Retrieved 24 February 2020. 35. ^ "Ex-pro Pirmin Lang confesses involvement in Aderlass doping ring". cyclingnews.com. 22 February 2020. Retrieved 24 February 2020. 36. ^ Ostermann, Michael (15 September 2020). "Die Operation Aderlass und der Radsport" [Operation Aderlass and Cycling]. Sportschau (in German). Villard-de-Lans. Retrieved 21 September 2020. 37. ^ Fiedler, Matthias; Neumann, Thilo (17 September 2020). "Anklage nach der Anklage" [Accusation after the Charge]. Der Spiegel (in German). Retrieved 21 September 2020. 38. ^ "Angeklagter Arzt legt in Dopingprozess umfassendes Geständnis ab" [Accused Doctor Gives Comprehensive Confession in Doping Trial]. Der Spiegel (in German). Deutsche Presse-Agentur. 29 September 2020. Retrieved 1 October 2020. 39. ^ "Dopingprozess: Langläufer Dürr verteidigt den Hauptangeklagten" [Doping Trial: Skier Dürr Defends the Defendant]. Bayerischer Rundfunk (in German). 30 September 2020. Retrieved 28 October 2020. 40. ^ Krause, Sebastian (10 October 2020). ""Operation Aderlass": Bizarre Einblicke in ein Doping-Netzwerk" ["Operation Aderlass": Bizarre Insights into a Doping Network]. Bayerischer Rundfunk (in German). Retrieved 28 October 2020. 41. ^ Wozny, Peter (29 October 2020). "Mitangeklagter des Dopingarztes hatte einen Menschen zu Tode geprügelt" [Co-Defendant of Doping Doctor Had Beaten a Man to Death]. Sportschau (in German). Archived from the original on 16 November 2020. Retrieved 16 November 2020. 42. ^ "Hondo tells Aderlass trial he doped with Petacchi". Cyclingnews.com. 11 November 2020. Retrieved 16 November 2020. 43. ^ "Operation Aderlass doctor Mark Schmidt jailed for almost five years". Cyclingnews.com. 16 January 2021. Retrieved 16 January 2021. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Operation Aderlass	None	5,403	wikipedia	https://en.wikipedia.org/wiki/Operation_Aderlass	2021-01-18T18:54:57	{"wikidata": ["Q61977709"]}
Tolmie et al. (1988) described a syndrome of palmoplantar keratoderma, dystrophy of the fingernails, and hereditary motor and sensory neuropathy in 10 members of 4 generations. The nail dystrophy affected both the toenails and the fingernails; it was present at birth or developed during early childhood. Palmoplantar keratoderma became apparent in later childhood. Each subject with nail dystrophy and keratoderma also had clinical or electrophysiologic evidence of axonal neuropathy. The clinical signs were as mild as moderately severe pes cavus, with no symptoms attributable to neuropathy, in a 60-year-old patient, the oldest affected in the pedigree. The combination of palmoplantar keratoderma and Charcot-Marie-Tooth disease was reported in an Italian family by Rabbiosi et al. (1980). The clinical and electrophysiologic findings were thought to indicate an axonal neuropathy. However, nail dystrophy was not noted in that report, whereas it was a constant finding in the affected subjects reported by Tolmie et al. (1988). See 309560 for a possibly X-linked disorder combining keratoderma, spastic paraplegia, and nail dystrophy. Powell et al. (1983) described autosomal dominant inheritance of a distinctive keratoderma with spastic paraplegia. Nail dystrophy was not noted. Both the palmoplantar keratodermas and the hereditary and motor sensory neuropathies show extensive genetic heterogeneity. The syndrome reported by Tolmie et al. (1988) is another example of this heterogeneity. Limbs \- Pes cavus Neuro \- Motor and sensory neuropathy Inheritance \- Autosomal dominant \- heterogeneous Nails \- Nail dystrophy Misc \- Congenital or early childhood onset of nail dystrophy Lab \- Electrophysiologic evidence of axonal neuropathy Skin \- Palmoplantar keratoderma ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	KERATODERMA, PALMOPLANTAR, WITH NAIL DYSTROPHY AND HEREDITARY MOTOR-SENSORY NEUROPATHY	c1835671	5,404	omim	https://www.omim.org/entry/148360	2019-09-22T16:39:17	{"mesh": ["C536153"], "omim": ["148360"], "orphanet": ["538574", "2201"], "synonyms": ["Palmoplantar keratoderma-Charcot-Marie-Tooth syndrome", "Alternative titles", "CHARCOT-MARIE-TOOTH DISEASE WITH PALMOPLANTAR KERATODERMA AND NAIL DYSTROPHY", "AXONAL NEUROPATHY WITH PALMOPLANTAR KERATODERMA"]}
For works entitled "Spring Fever", see Spring Fever (disambiguation). Spring fever is any of a number of mood, physical, or behavioral changes, which may be experienced coinciding with the arrival of spring, particularly restlessness, laziness, and even amorousness.[1] ## Overview[edit] The term spring fever is an auto-antonym (a term with multiple and opposed meanings): On the one hand, the term may refer to an increase in energy, vitality, and sexual appetite, as well as a feeling of restlessness, associated with the end of winter. This concept may have a biological basis.[2] A lift in mood with the arrival of spring, and longer periods of daylight, is often particularly strong in those suffering from seasonal affective disorder (SAD), who experience lows or depression during the winter months.[3] It is this sense that inspires the use of the term as a title for several works of literature and entertainment.[example needed] On the other hand, the term may sometimes be used to describe an opposite effect of springtime lethargy or depression. ## Notes[edit] Look up spring fever in Wiktionary, the free dictionary. 1. ^ "Spring fever". Dictionary.com Unabridged. Retrieved March 26, 2018. 2. ^ Nicholson, Christie. "Fact or Fiction?: 'Spring Fever' Is a Real Phenomenon: Scientific American". Sciam.com. Retrieved 2014-01-01. 3. ^ "Science of Spring Fever". The Times. 2006. Archived from the original on July 27, 2008. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Spring fever	c0034152	5,405	wikipedia	https://en.wikipedia.org/wiki/Spring_fever	2021-01-18T18:49:42	{"mesh": ["D011695"], "wikidata": ["Q30314009"]}
Serious trauma to the cranium See also: Traumatic brain injury "Head trauma" redirects here. It is not to be confused with Mental trauma or Brain trauma. This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Head injury" – news · newspapers · books · scholar · JSTOR (May 2017) (Learn how and when to remove this template message) Head injury Other namesHead trauma Soldier wounded at the Battle of Antietam on September 17, 1862. SymptomsInjury to the brain or skull ComplicationsHydrocephalus, cerebral edema, cerebral hemorrhage, stroke, coma, nervous system damage, paralysis, death TypesConcussion, intracranial hemorrhage, cerebral hemorrhage, cerebral contusion, penetrating head injury, skull fracture, traumatic brain injury A head injury is any injury that results in trauma to the skull or brain. The terms traumatic brain injury and head injury are often used interchangeably in the medical literature.[1] Because head injuries cover such a broad scope of injuries, there are many causes—including accidents, falls, physical assault, or traffic accidents—that can cause head injuries. The number of new cases is 1.7 million in the United States each year, with about 3% of these incidents leading to death. Adults have head injuries more frequently than any age group resulting from falls, motor vehicle crashes, colliding or being struck by an object, or assaults. Children, however, may experience head injuries from accidental falls or intentional causes (such as being struck or shaken) leading to hospitalization.[1] Acquired brain injury (ABI) is a term used to differentiate brain injuries occurring after birth from injury, from a genetic disorder, or from a congenital disorder.[2] Unlike a broken bone where trauma to the body is obvious, head trauma can sometimes be conspicuous or inconspicuous. In the case of an open head injury, the skull is cracked and broken by an object that makes contact with the brain. This leads to bleeding. Other obvious symptoms can be neurological in nature. The person may become sleepy, behave abnormally, lose consciousness, vomit, develop a severe headache, have mismatched pupil sizes, and/or be unable to move certain parts of the body. While these symptoms happen immediately after a head injury occurs, many problems can develop later in life. Alzheimer’s disease, for example, is much more likely to develop in a person who has experienced a head injury.[3] Brain damage, which is the destruction or degeneration of brain cells, is a common occurrence in those who experience a head injury. Neurotoxicity is another cause of brain damage that typically refers to selective, chemically induced neuron/brain damage. ## Contents * 1 Classification * 1.1 Concussion * 1.2 Intracranial bleeding * 1.2.1 Intra-axial bleeding * 1.2.2 Extra-axial bleeding * 1.2.3 Cerebral contusion * 1.2.4 Diffuse axonal injury * 1.2.5 Compound Head Injury * 2 Signs and symptoms * 2.1 Mild brain injuries * 2.2 Moderate/severe brain injuries * 2.3 Symptoms in children * 2.4 Location of brain damage predicts symptoms * 3 Causes * 4 Diagnosis * 5 Management * 6 Prognosis * 7 History * 8 Epidemiology * 9 See also * 10 References * 11 External links ## Classification[edit] Head injuries include both injuries to the brain and those to other parts of the head, such as the scalp and skull. Head injuries can be closed or open. A closed (non-missile) head injury is where the dura mater remains intact. The skull can be fractured, but not necessarily. A penetrating head injury occurs when an object pierces the skull and breaches the dura mater. Brain injuries may be diffuse, occurring over a wide area, or focal, located in a small, specific area. A head injury may cause skull fracture, which may or may not be associated with injury to the brain. Some patients may have linear or depressed skull fractures. If intracranial hemorrhage occurs, a hematoma within the skull can put pressure on the brain. Types of intracranial hemorrhage include subdural, subarachnoid, extradural, and intraparenchymal hematoma. Craniotomy surgeries are used in these cases to lessen the pressure by draining off the blood. Brain injury can occur at the site of impact, but can also be at the opposite side of the skull due to a contrecoup effect (the impact to the head can cause the brain to move within the skull, causing the brain to impact the interior of the skull opposite the head-impact). While impact on the brain at the same site of injury to the skull is the coup effect. If the impact causes the head to move, the injury may be worsened, because the brain may ricochet inside the skull causing additional impacts, or the brain may stay relatively still (due to inertia) but be hit by the moving skull (both are contrecoup injuries). Specific problems after head injury can include[4][5][6] * Skull fracture * Lacerations to the scalp and resulting hemorrhage of the skin * Traumatic subdural hematoma, a bleeding below the dura mater which may develop slowly * Traumatic extradural, or epidural hematoma, bleeding between the dura mater and the skull * Traumatic subarachnoid hemorrhage * Cerebral contusion, a bruise of the brain * Concussion, a loss of function due to trauma * Dementia pugilistica, or "punch-drunk syndrome", caused by repetitive head injuries, for example in boxing or other contact sports * A severe injury may lead to a coma or death * Shaken baby syndrome – a form of child abuse ### Concussion[edit] Main article: Concussion coup bruise A concussion is a form of a mild traumatic brain injury (TBI). This injury is a result due to a blow to the head that could make the person’s physical, cognitive, and emotional behaviors irregular. Symptoms may include clumsiness, fatigue, confusion, nausea, blurry vision, headaches, and others.[7] Mild concussions are associated with sequelae.[8] Severity is measured using various concussion grading systems. A slightly greater injury is associated with both anterograde and retrograde amnesia (inability to remember events before or after the injury). The amount of time that the amnesia is present correlates with the severity of the injury. In all cases, the patients develop post concussion syndrome, which includes memory problems, dizziness, tiredness, sickness and depression. Cerebral concussion is the most common head injury seen in children.[9] ### Intracranial bleeding[edit] Main article: Intracranial hemorrhage Types of intracranial hemorrhage are roughly grouped into intra-axial and extra-axial. The hemorrhage is considered a focal brain injury; that is, it occurs in a localized spot rather than causing diffuse damage over a wider area. #### Intra-axial bleeding[edit] Main article: cerebral hemorrhage Intra-axial hemorrhage is bleeding within the brain itself, or cerebral hemorrhage. This category includes intraparenchymal hemorrhage, or bleeding within the brain tissue, and intraventricular hemorrhage, bleeding within the brain's ventricles (particularly of premature infants). Intra-axial hemorrhages are more dangerous and harder to treat than extra-axial bleeds.[10] #### Extra-axial bleeding[edit] Hematoma type Epidural Subdural * v * t * e Location Between the skull and the inner meningeal layer of the dura mater or between outer endosteal and inner meningeal layer of dura mater Between the meningeal layers of dura mater and the Arachnoid mater Involved vessel Temperoparietal locus (most likely) – Middle meningeal artery Frontal locus – anterior ethmoidal artery Occipital locus – transverse or sigmoid sinuses Vertex locus – superior sagittal sinus Bridging veins Symptoms (depending on the severity)[11] Lucid interval followed by unconsciousness Gradually increasing headache and confusion CT scan appearance Biconvex lens Crescent-shaped Extra-axial hemorrhage, bleeding that occurs within the skull but outside of the brain tissue, falls into three subtypes: * Epidural hemorrhage (extradural hemorrhage) which occur between the dura mater (the outermost meninx) and the skull, is caused by trauma. It may result from laceration of an artery, most commonly the middle meningeal artery. This is a very dangerous type of injury because the bleed is from a high-pressure system and deadly increases in intracranial pressure can result rapidly. However, it is the least common type of meningeal bleeding and is seen in 1% to 3% cases of head injury. * Patients have a loss of consciousness (LOC), then a lucid interval, then sudden deterioration (vomiting, restlessness, LOC) * Head CT shows lenticular (convex) deformity. * Subdural hemorrhage results from tearing of the bridging veins in the subdural space between the dura and arachnoid mater. * Head CT shows crescent-shaped deformity * Subarachnoid hemorrhage, which occur between the arachnoid and pia meningeal layers, like intraparenchymal hemorrhage, can result either from trauma or from ruptures of aneurysms or arteriovenous malformations. Blood is seen layering into the brain along sulci and fissures, or filling cisterns (most often the suprasellar cistern because of the presence of the vessels of the circle of Willis and their branch points within that space). The classic presentation of subarachnoid hemorrhage is the sudden onset of a severe headache (a thunderclap headache). This can be a very dangerous entity and requires emergent neurosurgical evaluation and sometimes urgent intervention. #### Cerebral contusion[edit] Main article: Cerebral contusion Cerebral contusion is bruising of the brain tissue. The piamater is not breached in contusion in contrary to lacerations. The majority of contusions occur in the frontal and temporal lobes. Complications may include cerebral edema and transtentorial herniation. The goal of treatment should be to treat the increased intracranial pressure. The prognosis is guarded. #### Diffuse axonal injury[edit] Main article: Diffuse axonal injury Diffuse axonal injury, or DAI, usually occurs as the result of an acceleration or deceleration motion, not necessarily an impact. Axons are stretched and damaged when parts of the brain of differing density slide over one another. Prognoses vary widely depending on the extent of the damage. #### Compound Head Injury[edit] Overlying scalp laceration and soft tissue disruption in continuity with a skull fracture constitutes “compound head injury”, and has higher rates of infection, unfavorable neurologic outcome, delayed seizures, mortality, and duration of hospital stay.[12] ## Signs and symptoms[edit] Three categories used for classifying the severity of brain injuries are mild, moderate or severe. ### Mild brain injuries[edit] Symptoms of a mild brain injury include headaches, confusion, ringing ears, fatigue, changes in sleep patterns, mood or behavior. Other symptoms include trouble with memory, concentration, attention or thinking. Mental fatigue is a common debilitating experience and may not be linked by the patient to the original (minor) incident. Narcolepsy and sleep disorders are common misdiagnoses.[citation needed] ### Moderate/severe brain injuries[edit] Cognitive symptoms include confusion, aggressive, abnormal behavior, slurred speech, and coma or other disorders of consciousness. Physical symptoms include headaches that do not go away or worsen, vomiting or nausea, convulsions or seizures, abnormal dilation of the eyes, inability to awaken from sleep, weakness in the extremities and loss of coordination. In cases of severe brain injuries, the likelihood of areas with permanent disability is great, including neurocognitive deficits, delusions (often, to be specific, monothematic delusions), speech or movement problems, and intellectual disability. There may also be personality changes. The most severe cases result in coma or even persistent vegetative state.[13] ### Symptoms in children[edit] Symptoms observed in children include changes in eating habits, persistent irritability or sadness, changes in attention, disrupted sleeping habits, or loss of interest in toys.[13] Presentation varies according to the injury. Some patients with head trauma stabilize and other patients deteriorate. A patient may present with or without neurological deficit. Patients with concussion may have a history of seconds to minutes unconsciousness, then normal arousal. Disturbance of vision and equilibrium may also occur. Common symptoms of head injury include coma, confusion, drowsiness, personality change, seizures, nausea and vomiting, headache and a lucid interval, during which a patient appears conscious only to deteriorate later.[14] Symptoms of skull fracture can include: * leaking cerebrospinal fluid (a clear fluid drainage from nose, mouth or ear) is strongly indicative of basilar skull fracture and the tearing of sheaths surrounding the brain, which can lead to secondary brain infection. * visible deformity or depression in the head or face; for example a sunken eye can indicate a maxillar fracture * an eye that cannot move or is deviated to one side can indicate that a broken facial bone is pinching a nerve that innervates eye muscles * wounds or bruises on the scalp or face. * Basilar skull fractures, those that occur at the base of the skull, are associated with Battle's sign, a subcutaneous bleed over the mastoid, hemotympanum, and cerebrospinal fluid rhinorrhea and otorrhea. Because brain injuries can be life-threatening, even people with apparently slight injuries, with no noticeable signs or complaints, require close observation; They have a chance for severe symptoms later on. The caretakers of those patients with mild trauma who are released from the hospital are frequently advised to rouse the patient several times during the next 12 to 24 hours to assess for worsening symptoms. The Glasgow Coma Scale (GCS) is a tool for measuring the degree of unconsciousness and is thus a useful tool for determining the severity of the injury. The Pediatric Glasgow Coma Scale is used in young children. The widely used PECARN Pediatric Head Injury/Trauma Algorithm helps physicians weigh risk-benefit of imaging in a clinical setting given multiple factors about the patient—including mechanism/location of the injury, age of the patient, and GCS score.[15] ### Location of brain damage predicts symptoms[edit] Symptoms of brain injuries can also be influenced by the location of the injury and as a result, impairments are specific to the part of the brain affected. Lesion size is correlated with severity, recovery, and comprehension.[citation needed] Brain injuries often create impairment or disability that can vary greatly in severity. Studies show there is a correlation between brain lesion and language, speech, and category-specific disorders. Wernicke's aphasia is associated with anomia, unknowingly making up words (neologisms), and problems with comprehension. The symptoms of Wernicke’s aphasia are caused by damage to the posterior section of the superior temporal gyrus.[16][17] Damage to the Broca’s area typically produces symptoms like omitting functional words (agrammatism), sound production changes, dyslexia, dysgraphia, and problems with comprehension and production. Broca’s aphasia is indicative of damage to the posterior inferior frontal gyrus of the brain.[18] An impairment following damage to a region of the brain does not necessarily imply that the damaged area is wholly responsible for the cognitive process which is impaired, however. For example, in pure alexia, the ability to read is destroyed by a lesion damaging both the left visual field and the connection between the right visual field and the language areas (Broca's area and Wernicke's area). However, this does not mean one suffering from pure alexia is incapable of comprehending speech—merely that there is no connection between their working visual cortex and language areas—as is demonstrated by the fact that pure alexics can still write, speak, and even transcribe letters without understanding their meaning.[19] Lesions to the fusiform gyrus often result in prosopagnosia, the inability to distinguish faces and other complex objects from each other.[20][medical citation needed][citation needed] Lesions in the amygdala would eliminate the enhanced activation seen in occipital and fusiform visual areas in response to fear with the area intact. Amygdala lesions change the functional pattern of activation to emotional stimuli in regions that are distant from the amygdala.[citation needed] Other lesions to the visual cortex have different effects depending on the location of the damage. Lesions to V1, for example, can cause blindsight in different areas of the brain depending on the size of the lesion and location relative to the calcarine fissure.[21] Lesions to V4 can cause color-blindness,[22] and bilateral lesions to MT/V5 can cause the loss of the ability to perceive motion.[citation needed] Lesions to the parietal lobes may result in agnosia, an inability to recognize complex objects, smells, or shapes, or amorphosynthesis, a loss of perception on the opposite side of the body. ## Causes[edit] Head injuries can be caused by a large variety of reasons. All of these causes can be put into two categories used to classify head injuries; those that occur from impact (blows) and those that occur from shaking.[23] Common causes of head injury due to impact are motor vehicle traffic collisions, home and occupational accidents, falls, assault, and sports related accidents. Head injuries from shaking are most common amongst infants and children.[24] According to the United States CDC, 32% of traumatic brain injuries (another, more specific, term for head injuries) are caused by falls, 10% by assaults, 16.5% by being struck by or against something, 17% by motor vehicle accidents, and 21% by other/unknown ways. In addition, the highest rate of injury is among children ages 0–14 and adults age 65 and older.[25] Brain injuries that include brain damage can also be brought on by exposure to toxic chemicals, lack of oxygen, tumors, infections, and stroke.[26] Possible causes of widespread brain damage include birth hypoxia, prolonged hypoxia (shortage of oxygen), poisoning by teratogens (including alcohol), infection, and neurological illness. Brain tumors can increase intracranial pressure, causing brain damage. ## Diagnosis[edit] See also: Head injury criterion There are a few methods used to diagnose a head injury. A healthcare professional will ask the patient questions revolving around the injury as well as questions to help determine in what ways the injury is affecting function. In addition to this hearing, vision, balance, and reflexes may also be assessed as an indicator of the severity of the injury.[25] A non-contrast CT of the head should be performed immediately in all those who have suffered a moderate or severe head injury. A CT is an imaging technique that allows physicians to see inside the head without surgery in order to determine if there is internal bleeding or swelling in the brain.[27] Computed tomography (CT) has become the diagnostic modality of choice for head trauma due to its accuracy, reliability, safety, and wide availability. The changes in microcirculation, impaired auto-regulation, cerebral edema, and axonal injury start as soon as a head injury occurs and manifest as clinical, biochemical, and radiological changes.[28] An MRI may also be conducted to determine if someone has abnormal growths or tumors in the brain or to determine if the patient has had a stroke.[29] Glasgow Coma Scale (GCS) is the most widely used scoring system used to assess the level of severity of a brain injury. This method is based on objective observations of specific traits to determine the severity of a brain injury. It is based on three traits eye-opening, verbal response, and motor response, gauged as described below. Based on the Glasgow Coma Scale severity is classified as follows, severe brain injuries score 3–8, moderate brain injuries score 9-12 and mild score 13–15. There are several imaging techniques that can aid in diagnosing and assessing the extent of brain damage, such as computed tomography (CT) scan, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single-photon emission tomography (SPECT). CT scans and MRI are the two techniques widely used and are the most effective. CT scans can show brain bleeds, fractures of the skull, fluid build up in the brain that will lead to increased cranial pressure. MRI is able to better detect smaller injuries, detect damage within the brain, diffuse axonal injury, injuries to the brainstem, posterior fossa, and subtemporal and sub frontal regions. However, patients with pacemakers, metallic implants, or other metal within their bodies are unable to have an MRI done. Typically the other imaging techniques are not used in a clinical setting because of the cost, lack of availability. ## Management[edit] See also: Traumatic_brain_injury § Treatment, and Acquired_brain_injury § Treatment Most head injuries are of a benign nature and require no treatment beyond analgesics such as acetaminophen. Non-steroidal painkillers such as ibuprofen are avoided since they could make any potential bleeding worse. Due to the high risk of even minor brain injuries, close monitoring for potential complications such as intracranial bleeding. If the brain has been severely damaged by trauma, a neurosurgical evaluation may be useful. Treatments may involve controlling elevated intracranial pressure. This can include sedation, paralytics, cerebrospinal fluid diversion. Second-line alternatives include decompressive craniectomy (Jagannathan et al. found a net 65% favorable outcomes rate in pediatric patients), barbiturate coma, hypertonic saline, and hypothermia. Although all of these methods have potential benefits, there has been no randomized study that has shown unequivocal benefit. Clinicians will often consult clinical decision support rules such as the Canadian CT Head Rule or the New Orleans/Charity Head injury/Trauma Rule to decide if the patient needs further imaging studies or observation only. Rules like these are usually studied in depth by multiple research groups with large patient cohorts to ensure accuracy given the risk of adverse events in this area.[30] There is a subspecialty certification available for brain injury medicine that signifies expertise in the treatment of brain injury.[31][32] ## Prognosis[edit] Prognosis, or the likely progress of a disorder, depends on the nature, location, and cause of the brain damage (see Traumatic brain injury, Focal and diffuse brain injury, Primary and secondary brain injury). In children with uncomplicated minor head injuries the risk of intracranial bleeding over the next year is rare at 2 cases per 1 million.[33] In some cases transient neurological disturbances may occur, lasting minutes to hours. Malignant post traumatic cerebral swelling can develop unexpectedly in stable patients after an injury, as can post-traumatic seizures. Recovery in children with neurologic deficits will vary. Children with neurologic deficits who improve daily are more likely to recover, while those who are vegetative for months are less likely to improve. Most patients without deficits have full recovery. However, persons who sustain head trauma resulting in unconsciousness for an hour or more have twice the risk of developing Alzheimer's disease later in life.[34] Head injury may be associated with a neck injury. Bruises on the back or neck, neck pain, or pain radiating to the arms are signs of cervical spine injury and merit spinal immobilization via application of a cervical collar and possibly a longboard. If the neurological exam is normal this is reassuring. Reassessment is needed if there is a worsening headache, seizure, one-sided weakness, or has persistent vomiting. To combat overuse of Head CT Scans yielding negative intracranial hemorrhage, which unnecessarily exposes patients to radiation and increase time in the hospital and cost of the visit, multiple clinical decision support rules have been developed to help clinicians weigh the option to scan a patient with a head injury. Among these are the Canadian Head CT rule, the PECARN Head Injury/Trauma Algorithm, and the New Orleans/Charity Head Injury/Trauma Rule all help clinicians make these decisions using easily obtained information and noninvasive practices. Brain injuries are very hard to predict in the outcome. Many tests and specialists are needed to determine the likelihood of the prognosis. People with minor brain damage can have debilitating side effects; not just severe brain damage has debilitating effects. The side- effects of a brain injury depend on location and the body’s response to injury. Even a mild concussion can have long term effects that may not resolve. ## History[edit] The foundation for understanding human behavior and brain injury can be attributed to the case of Phineas Gage and the famous case studies by Paul Broca. The first case study on Phineas Gage’s head injury is one of the most astonishing brain injuries in history. In 1848, Phineas Gage was paving way for a new railroad line when he encountered an accidental explosion of a tamping iron straight through his frontal lobe. Gage observed to be intellectually unaffected but exemplified post-injury behavioral deficits. These deficits include: becoming sporadic, disrespectful, extremely profane, and gave no regard for other workers. Gage started having seizures in February 1860, dying only four months later on May 21, 1860.[35] Ten years later, Paul Broca examined two patients exhibiting impaired speech due to frontal lobe injuries. Broca’s first patient lacked productive speech. He saw this as an opportunity to address language localization. It wasn't until Leborgne, formally known as "tan", died when Broca confirmed the frontal lobe lesion from an autopsy. The second patient had similar speech impairments, supporting his findings on language localization. The results of both cases became a vital verification of the relationship between speech and the left cerebral hemisphere. The affected areas are known today as Broca’s area and Broca’s Aphasia.[36] A few years later, a German neuroscientist, Carl Wernicke, consulted on a stroke patient. The patient experienced neither speech nor hearing impairments but suffered from a few brain deficits. These deficits included: lacking the ability to comprehend what was spoken to him and the words written down. After his death, Wernicke examined his autopsy that found a lesion located in the left temporal region. This area became known as Wernicke's area. Wernicke later hypothesized the relationship between Wernicke's area and Broca's area, which was proven fact.[37] ## Epidemiology[edit] Head injury is the leading cause of death in many countries.[38] ## See also[edit] * Traumatic brain injury * Brain damage * Concussion * Acquired brain injury * Neurodegeneration * Chronic traumatic encephalopathy ## References[edit] 1. ^ a b Hardman S, Rominiyi O, King D, Snelson E (May 2019). "Is cranial computed tomography unnecessary in children with a head injury and isolated vomiting?". BMJ. 365: l1875. doi:10.1136/bmj.l1875. PMID 31123100. S2CID 163165272. 2. ^ Elbaum J (2007-04-13). 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"What we need to know about age-related memory loss". BMJ. 324 (7352): 1502–5. doi:10.1136/bmj.324.7352.1502. PMC 1123445. PMID 12077041. 35. ^ Haas LF (December 2001). "Phineas Gage and the science of brain localisation". Journal of Neurology, Neurosurgery, and Psychiatry. 71 (6): 761. doi:10.1136/jnnp.71.6.761. PMC 1737620. PMID 11723197. 36. ^ Dronkers NF, Plaisant O, Iba-Zizen MT, Cabanis EA (May 2007). "Paul Broca's historic cases: high resolution MR imaging of the brains of Leborgne and Lelong". Brain. 130 (Pt 5): 1432–41. doi:10.1093/brain/awm042. PMID 17405763. 37. ^ Guenther K (November 2013). "The disappearing lesion: sigmund freud, sensory-motor physiology, and the beginnings of psychoanalysis" (PDF). Modern Intellectual History. 10 (3): 569–601. doi:10.1017/S147924431300022X. 38. ^ Debas HT, Donkor P, Gawande A, Jamison DT, Kruk ME, Mock CN (2015). Debas HT, Donkor P, Gawande A, Jamison DT, Kruk ME, Mock CN (eds.). Essential Surgery. Disease Control Priorities. 1 (3rd ed.). Washington, DC: World Bank. doi:10.1596/978-1-4648-0346-8. hdl:10986/21568. ISBN 978-1-4648-0346-8. PMID 26740991. ## External links[edit] Classification D ICD-10: S00.0S09 * ICD-9-CM: 800-879 * MeSH: D006259 * DiseasesDB: 5671 External resources * eMedicine: neuro/153 * Patient UK: Head injury * Brain Injury (journal) * Cochrane Injuries Group: systematic reviews on the prevention, treatment and rehabilitation of traumatic injury * First aid advice for head injuries from the British Red Cross * v * t * e Nonmusculoskeletal injuries of head (head injury) and neck Intracranial * see neurotrauma Extracranial/ facial trauma eye: * Black eye * Eye injury * Corneal abrasion ear: * Perforated eardrum Either/both * Penetrating head injury * v * t * e Trauma Principles * Polytrauma * Major trauma * Traumatology * Triage * Resuscitation * Trauma triad of death Assessment Clinical prediction rules * Revised Trauma Score * Injury Severity Score * Abbreviated Injury Scale * NACA score Investigations * Diagnostic peritoneal lavage * Focused assessment with sonography for trauma Management Principles * Advanced trauma life support * Trauma surgery * Trauma center * Trauma team * Damage control surgery * Early appropriate care Procedures * Resuscitative thoracotomy Pathophysiology Injury * MSK * Bone fracture * Joint dislocation * Degloving * Soft tissue injury * Resp * Flail chest * Pneumothorax * Hemothorax * Diaphragmatic rupture * Pulmonary contusion * Cardio * Internal bleeding * Thoracic aorta injury * Cardiac tamponade * GI * Blunt kidney trauma * Ruptured spleen * Neuro * Penetrating head injury * Traumatic brain injury * Intracranial hemorrhage Mechanism * Blast injury * Blunt trauma * Burn * Penetrating trauma * Crush injury * Stab wound * Ballistic trauma * Electrocution Region * Abdominal trauma * Chest trauma * Facial trauma * Head injury * Spinal cord injury Demographic * Geriatric trauma * Pediatric trauma Complications * Posttraumatic stress disorder * Wound healing * Acute lung injury * Crush syndrome * Rhabdomyolysis * Compartment syndrome * Contracture * Volkmann's contracture * Embolism * air * fat * Chronic traumatic encephalopathy * Subcutaneous emphysema * v * t * e General wounds and injuries Abrasions * Abrasion * Avulsion Blisters * Blood blister * Coma blister * Delayed blister * Edema blister * Fracture blister * Friction blister * Sucking blister Bruises * Hematoma/Ecchymosis * Battle's sign * Raccoon eyes * Black eye * Subungual hematoma * Cullen's sign * Grey Turner's sign * Retroperitoneal hemorrhage Animal bites * Insect bite * Spider bite * Snakebite Other: * Ballistic trauma * Stab wound * Blunt trauma/superficial/closed * Penetrating trauma/open * Aerosol burn * Burn/Corrosion/Chemical burn * Frostbite * Occupational injuries * Traumatic amputation By region * Hand injury * Head injury * Chest trauma * Abdominal trauma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Head injury	c0018674	5,406	wikipedia	https://en.wikipedia.org/wiki/Head_injury	2021-01-18T18:47:57	{"mesh": ["D006259"], "icd-9": ["800", "879"], "icd-10": ["S09"], "wikidata": ["Q2920572"]}
Costeff syndrome is an inherited condition characterized by vision loss, delayed development, and movement problems. Vision loss is primarily caused by degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain. This optic nerve atrophy often begins in infancy or early childhood and results in vision impairment that worsens over time. Some affected individuals have rapid and involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus). Development of motor skills, such as walking, is often delayed in people with Costeff syndrome. Affected individuals may also have speech difficulties (dysarthria). While some people with Costeff syndrome have mild to moderate intellectual disability, many have normal intelligence. Movement problems in people with Costeff syndrome develop in late childhood and include muscle stiffness (spasticity), impaired muscle coordination (ataxia), and involuntary jerking movements (choreiform movements). As a result of these movement difficulties, individuals with Costeff syndrome may require wheelchair assistance. Costeff syndrome is associated with increased levels of a substance called 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria). The amount of this substance does not appear to influence the signs and symptoms of the condition. Costeff syndrome is one of a group of metabolic disorders that can be diagnosed by the presence of 3-methylglutaconic aciduria. People with Costeff syndrome also have high levels of another acid called 3-methylglutaric acid in their urine. ## Frequency Costeff syndrome affects an estimated 1 in 10,000 individuals in the Iraqi Jewish population, in which at least 40 cases have been described. Outside this population, only a few affected individuals have been identified. ## Causes Mutations in a gene called OPA3 cause Costeff syndrome. The OPA3 gene provides instructions for making a protein whose exact function is unknown. The OPA3 protein is found in structures called mitochondria, which are the energy-producing centers of cells. It is thought to play a role in the organization of the shape and structure of mitochondria and in controlled cell death (apoptosis). OPA3 gene mutations that result in Costeff syndrome lead to a loss of OPA3 protein function. Cells without any functional OPA3 protein have abnormally shaped mitochondria. These cells likely have reduced energy production and die prematurely, decreasing energy availability in the body's tissues. Cells in the eyes and brain have high energy demands, and it is likely that they are particularly vulnerable to cell death due to dysfunctional mitochondria and reduced energy production. ### Learn more about the gene associated with Costeff syndrome * OPA3 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Costeff syndrome	c0574084	5,407	medlineplus	https://medlineplus.gov/genetics/condition/costeff-syndrome/	2021-01-27T08:25:30	{"gard": ["5663"], "mesh": ["C535311"], "omim": ["258501"], "synonyms": []}
Urethral hypermobility is a condition of excessive movement of the female urethra due to a weakened urogenital diaphragm. It describes the instability of the urethra in relation to the pelvic floor muscles. A weakened pelvic floor muscle fails to adequately close the urethra and hence can cause stress urinary incontinence. This condition can be measured with anterior compartment descent.[1] It is sometimes treated with urethral bulking injections.[2] ## References[edit] 1. ^ Serdinšek, Tamara; But, Igor (July 2017). "Anterior compartment descent: A new measure in the assessment of urethral hypermobility in women with urinary incontinence". International Journal of Urology. 24 (7): 548–552. doi:10.1111/iju.13370. ISSN 1442-2042. PMID 28556438. 2. ^ Walters, Mark (2015). Urogynecology and reconstructive pelvic surgery, Chapter 22. Philadelphia, PA: Elsevier/Saunders. ISBN 9780323113779; Access provided by the University of Pittsburgh This article about a disease of the genitourinary system is a stub. You can help Wikipedia by expanding it. * v * t * e This women's health related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Urethral hypermobility	c0375380	5,408	wikipedia	https://en.wikipedia.org/wiki/Urethral_hypermobility	2021-01-18T19:04:49	{"umls": ["C0375380"], "wikidata": ["Q25326631"]}
A rare, primary bone dysplasia characterized by proportional short stature, early cessation of bone growth, accelerated skeletal maturation, variable presence of early-onset osteoarthritis and osteochondritis dissecans, and normal endocrine evaluation. The variable dysmorphic features include mild to relative macrocephaly, frontal bossing, midfacial hypoplasia, flat nasal bridge, brachydactyly, broad thumbs, and lordosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Short stature-advanced bone age-early-onset osteoarthritis syndrome	c3665488	5,409	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435804	2021-01-23T17:07:22	{"mesh": ["C580095"], "omim": ["165800"], "icd-10": ["M89.8"]}
Cantu et al. (1974) described a kindred in which 3 brothers and 3 of their maternal uncles had generalized keratosis follicularis, severe growth retardation, and cerebral atrophy. Hair, eyebrows and eyelashes were almost completely absent. Death had occurred at a young age in 2 of the uncles. Microcephaly was present. Dwarfism was severe, congenital and proportionate. Head \- Microcephaly Neuro \- Cerebral atrophy Inheritance \- X-linked Misc \- Early death Hair \- Absent hair, eyebrows and eyelashes Growth \- Severe congenital proportionate dwarfism Skin \- Generalized keratosis follicularis ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	KERATOSIS FOLLICULARIS, DWARFISM, AND CEREBRAL ATROPHY	c1839910	5,410	omim	https://www.omim.org/entry/308830	2019-09-22T16:17:57	{"mesh": ["C536158"], "omim": ["308830"], "orphanet": ["2339"]}
Okamoto et al. (1997) described an apparently new premature aging syndrome in a 15-year-old girl with severe growth and developmental abnormalities. Features also included osteosarcoma, cataracts, diabetes mellitus, osteoporosis, and erythroid macrocytosis. A photograph showed a round face, microcephaly, poor hair growth, flat nasal bridge, and low-set somewhat deformed ears. The parents were healthy and unrelated. Neuro \- Abnormal development Inheritance \- ? Autosomal recessive Head \- Microcephaly Ears \- Low-set ears \- Deformed ears Oncology \- Osteosarcoma Facies \- Round face \- Flat nasal bridge Metabolic \- Diabetes mellitus \- Osteoporosis Heme \- Erythroid macrocytosis Hair \- Poor hair growth Growth \- Premature aging \- Abnormal growth Eyes \- Cataracts ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	PREMATURE AGING SYNDROME, OKAMOTO TYPE	c1866183	5,411	omim	https://www.omim.org/entry/601811	2019-09-22T16:14:24	{"mesh": ["C566621"], "omim": ["601811"]}
A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with short stature, facial anomalies, and speech defects (IDDSFAS) is caused by homozygous mutation in the FBXL3 gene (605653) on chromosome 13q22. Clinical Features Megarbane and Cormier-Daire (2001) described 2 Lebanese sisters, the offspring of first-cousin parents, with short stature, obesity, bulbous nasal tip, microretrognathia, brachydactyly, joint hyperlaxity and dislocations, and severe mental retardation. Radiologic abnormalities included widened mandibular angles, thin temporal processes, hypoplastic clavicles, short distal ends of ulnas, short fourth metacarpals, and dislocation of hips, elbows, and thumbs. Autosomal recessive inheritance was believed to be the most likely mode of inheritance. Ansar et al. (2019) reported 5 affected individuals from a consanguineous Pakistani family (family F145) with global developmental delay, mildly to severely impaired intellectual development, delayed or slurred speech, and short stature. Dysmorphic features included a large bulbous nose and variable microretrognathia. Two patients had strabismus and 1 had microcephaly (-3.1 SD). Two patients had behavioral problems, including aggression or shyness. Detailed radiographic studies revealed no skeletal abnormalities, and none of the patients had a history of joint laxity or dislocations. Brain imaging in 1 patient was normal. Ansar et al. (2019) also reported a 23-year-old Italian man, born of distantly related parents (family M213), with global developmental delay, walking at 30 months, and speech delay with only short sentences and dysarthria at the time of school age. He had moderately impaired intellectual development (IQ of 48 at age 20 years). Additional features included short stature, large bulbous nose, ptosis, an 'odd' and shy personality, and a disturbed sleep/wake cycle. Skeletal anomalies were not reported. (The legend in figure 1 of the article by Ansar et al. (2019) incorrectly stated that the Italian man was from family M039; Ansar (2019) confirmed that the correct family is M213 as stated in the text and table 1.) Inheritance The transmission pattern of IDDSFAS in the families reported by Ansar et al. (2019) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of 2 unrelated consanguineous families (F002 and F145) with IDDSFAS, Ansar et al. (2019) identified a homozygous frameshift or nonsense mutation in the FBXL3 gene (605653.0001 and 605653.0002). The 2 affected sisters in family F002, who were originally reported by Megarbane and Cormier-Daire (2001), also carried homozygous missense variants in 2 other genes, E10A in PPARD (600409) and E511G in LMO7 (604362), that segregated with the phenotype in the family, which included skeletal abnormalities; a role for these variants could not be excluded. An affected patient from a third unrelated family (M213) was homozygous for a missense mutation in FBXL3 (C358R; 605653.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all 3 families. Functional studies of the variants and studies of patient cells were not performed, but the truncating mutations were predicted to result in absence of the FBXL3 C-terminal LRR domain that interacts with CRY2 (603732), causing a loss-of-function effect. The missense mutation C358R affected the same residue as that in the mutant murine model 'after hours' (C358S); see ANIMAL MODEL. In addition to the main features of IDDSFAS, this patient had a disturbed sleep/wake cycle, suggesting involvement of the circadian rhythm system. (In figure 1 of the article by Ansar et al. (2019), the third patient was incorrectly stated to be from family M039; Ansar (2019) confirmed that this patient is from family M213, as stated in the text and table 1 of the article.) Animal Model By screening mutagenized mice for alterations in rhythms of wheel-running activity, Godinho et al. (2007) identified a mutation in the Fbxl3 gene that they termed 'after hours' (Afh). The Afh mutation caused a cys358-to-ser (C358S) substitution in the leucine-rich region of the Fbxl3 protein and resulted in free-running rhythms of about 27 hours in homozygotes. In situ hybridization, immunohistochemistry, and Western blot analyses showed that Afh altered expression of the negative regulators of the circadian clock in the suprachiasmatic nucleus, Per1 (602260), Per2 (603426), and Cry1, as well as the positive regulator, Bmal1. Godinho et al. (2007) concluded that FBXL3 has a central role in mammalian circadian timekeeping. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly (1 patient) Face \- Microretrognathia Eyes \- Strabismus \- Ptosis Nose \- Large nose \- Broad nasal bridge \- Bulbous tip Mouth \- High-arched palate CHEST Ribs Sternum Clavicles & Scapulae \- Hypoplastic clavicles (family A) SKELETAL \- Joint laxity (family A) Skull \- Widened mandibular angles (family A) Limbs \- Joint dislocations (family A) \- Short distal ends of ulnae (family A) Hands \- Short fourth metacarpals (family A) NEUROLOGIC Central Nervous System \- Global developmental delay \- Impaired intellectual development, variable \- Delayed speech \- Poor speech \- Dysarthria \- Delayed walking \- Irregular sleep/wake cycle (in some patients) Behavioral Psychiatric Manifestations \- Shy behavior \- Odd behavior MISCELLANEOUS \- Skeletal manifestations were only observed in 1 family (family A) \- Three unrelated families have been reported (last curated April 2019) MOLECULAR BASIS \- Caused by mutation in the F-box and leucine-rich repeat protein 3 gene (FBXL3, 605653.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	INTELLECTUAL DEVELOPMENTAL DISORDER WITH SHORT STATURE, FACIAL ANOMALIES, AND SPEECH DEFECTS	c1853507	5,412	omim	https://www.omim.org/entry/606220	2019-09-22T16:10:34	{"mesh": ["C565248"], "omim": ["606220"], "synonyms": ["Alternative titles", "MENTAL RETARDATION, SHORT STATURE, FACIAL ANOMALIES, AND JOINT DISLOCATIONS"]}
Heterotaxy is a condition characterized by internal organs that are not arranged as would be expected in the chest and abdomen. Organs are expected to be in a particular orientation inside of the body, known as situs solitus. Heterotaxy occurs when the organs are not in this typical orientation, but are instead in different positions in the body. This most commonly causes complications with the heart, lungs, liver, spleen, and intestines. Specific symptoms include not getting enough oxygen throughout the body, breathing difficulties, increased risk for infection, and problems digesting food. Heterotaxy may be caused by genetic changes (mutations), exposures to toxins while a woman is pregnant causing the baby to have heterotaxy, or the condition may occur sporadically. The condition is typically diagnosed through imaging such as an echocardiogram or an MRI. Treatment depends on the specific symptoms of each person, but typically includes heart surgery and monitoring by a team of specialists. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Heterotaxy	c0266642	5,413	gard	https://rarediseases.info.nih.gov/diseases/10875/heterotaxy	2021-01-18T18:00:00	{"mesh": ["D059446"], "synonyms": ["Heterotaxia", "Heterotaxy syndrome", "Visceral heterotaxy", "Lateralization defect", "Situs ambiguous", "Situs ambiguus"]}
Rare X-linked genetic condition X-linked reticulate pigmentary disorder Other namesFamilial cutaneous amyloidosis,[1] Partington amyloidosis,[1] Partington cutaneous amyloidosis,[1] Partington syndrome type II,[1] reticulate pigmentary disorder,[1] X-linked reticulate pigmentary disorder with systemic manifestations[1] This condition is inherited in an X-linked recessive manner. Carrier females usually only have linear streaks of hyperpigmentation. X-linked reticulate pigmentary disorder with systematic manifestations X-linked reticulate pigmentary disorder is a rare X-linked genetic condition in which males manifest multiple systemic symptoms and a reticulated mottled brown pigmentation of the skin, which, on biopsy, demonstrated dermal deposits of amyloid. Females usually only have linear streaks of hyperpigmentation.[1] The syndrome is also referred to by the acronym X-Linked-PDR or XLPRD.[2] It's a very rare disease, genetically determined, with a chronic course. It was characterized in 1981.[3] Mutation of the POLA1 gene leads to loss of expression of the catalytic subunit of DNA polymerase-α and is responsible for XLPDR.[2] Loss of POLA1 expression results in reduced levels of RNA:DNA hybrids in the cytosol and unexpectedly triggers aberrant immune responses (e.g. type I interferon production) which at least in part can account for the symptoms associated with XLPDR.[2] Another trigger of the immunodeficiency phenotype is a functional deficiency of NK cells, major players of innate antiviral immune system.[4] ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Presentation[edit] Affected males develop generalized reticular hyperpigmentation in early childhood. Hair often looks bedraggled or brushed backward, hanging low on the forehead. Under XLPDR conditions, autoimmune manifestations are developed due to chronically activated anti-viral type I interferon response, connecting XLPDR with disorders like Aicardi-Goutiere syndrome, Systemic Lupus Erythematosus, Psoriasis, etc. 3 Meanwhile, another typical symptom - immunodeficiency - can be developed due to discovering a functional defect in the cytolytic activity of NK cells. Starokadomskyy at al. discovered that POLA1 deficiency is associated with decreased direct cytotoxicity of NK cells due to disturbances in vesicular traffic. Meanwhile, antibody-dependent cell cytotoxicity (ADCC) remains unchanged in XLPDR NK cells.[4] The most common manifestations of XLPDR: * Recurrent respiratory infections * Dyskeratosis corneal * Photophobia * Hypohidrosis (lack of sweat glands) * NK cell functional deficiency * Growth retardation * Gastrointestinal disorders * Kidney disease * Kidney stones * Urinary infections * Webbed feet or hands * Electrolyte imbalance * Retinitis pigmentosa * Lymphoedema * Thyroid abnormalities Not every patient shows all of the listed symptoms. However, skin pathologies, recurrent lung infection, high titer of interferon type I in the blood, and impaired direct cytotoxicity of NK cells are the most common symptoms. In females the disease is characterized by skin rashes linear hyper pigmentation following the Blaschko's lines, morphologically similar to stage 3 pigment incontinence. There are no systemic manifestations associated with XLPDR in females. ## Diagnosis[edit] This section is empty. You can help by adding to it. (April 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (April 2017) ## See also[edit] * Waardenburg syndrome * List of cutaneous conditions ## References[edit] 1. ^ a b c d e f g Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 630. ISBN 1-4160-2999-0. 2. ^ a b c Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, Pokatayev V, Dozmorov I, Khan S, Miyata N, Fraile G, Raj P, Xu Z, Xu Z, Ma L, Lin Z, Wang H, Yang Y, Ben-Amitai D, Orenstein N, Mussaffi H, Baselga E, Tadini G, Grunebaum E, Sarajlija A, Krzewski K, Wakeland EK, Yan N, de la Morena MT, Zinn AR, Burstein E (2016). "DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis". Nature Immunology. 17: 495–504. doi:10.1038/ni.3409. PMC 4836962. PMID 27019227.CS1 maint: uses authors parameter (link) 3. ^ Partington MW, Marriott PJ, Prentice RS, Cavaglia A, Simpson NE (1981). "Familial cutaneous amyloidosis with systemic manifestations in males". Am. J. Med. Genet. 10 (1): 65–75. doi:10.1002/ajmg.1320100109. PMID 6794369. 4. ^ a b Starokadomskyy, Petro; Wilton, Katelynn M.; Krzewski, Konrad; Lopez, Adam; Sifuentes-Dominguez, Luis; Overlee, Brittany; Chen, Qing; Ray, Ann; Gil-Krzewska, Aleksandra; Peterson, Mary; Kinch, Lisa N. (2019-11-01). "NK cell defects in X-linked pigmentary reticulate disorder". JCI Insight. 4 (21). doi:10.1172/jci.insight.125688. ISSN 0021-9738. ## External links[edit] Classification D * ICD-10: E85.0+ L99.0* * OMIM: 301220 * MeSH: C564461 External resources * Orphanet: 85453 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	X-linked reticulate pigmentary disorder	c1845050	5,414	wikipedia	https://en.wikipedia.org/wiki/X-linked_reticulate_pigmentary_disorder	2021-01-18T18:56:10	{"mesh": ["C564461"], "umls": ["C1845050"], "orphanet": ["85453"], "wikidata": ["Q3710164"]}
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND) is caused by homozygous or compound heterozygous mutation in the SPTBN4 gene (606214) on chromosome 19q13. Clinical Features Knierim et al. (2017) reported a boy, born of consanguineous Kurdish parents, with NEDHND. He presented soon after birth with hypotonia, facial weakness, and areflexia. He had delayed motor development and feeding difficulties, and he never achieved head control. At age 10 years, he had myopathic facies, high-arched palate, severe distal muscle weakness, generalized muscle atrophy, scoliosis, ankle contractures, and severely delayed motor and mental development with inability to stand, sit, eat, or speak. Muscle biopsy showed type 1 fiber atrophy, but serum creatine kinase was normal. He also had central deafness with absent brainstem-evoked potentials and a combined axonal and demyelinating motor neuropathy. Wang et al. (2018) reported 6 patients from 5 unrelated families with a severe neurodevelopmental disorder apparent from birth. The patients had congenital hypotonia, profound weakness with areflexia, respiratory and feeding difficulties, and profound developmental delay with no language development. They were unable to sit unsupported and were nonambulatory. Electrophysiologic studies in 3 patients showed a motor neuronopathy/axonopathy that was documented to be progressive in 1 patient. Muscle biopsy showed denervated and atrophic muscle, consistent with a neurogenic disease. Three patients had seizures, including 2 with severe intractable epilepsy. Additional features included cortical visual impairment and deafness due to auditory neuropathy. Wang et al. (2018) concluded that the muscle weakness in these patients was primarily due to severe motor axonal neuropathy and neuronopathy as opposed to a myopathy. Inheritance The transmission pattern of NEDHND in the family reported by Knierim et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In a boy, born of consanguineous Kurdish parents, with NEDHND, Knierim et al. (2017) identified a homozygous truncating mutation in the SPTBN4 gene (Q533X; 606214.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed absence of the SPTBN4 protein, and immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. The phenotype was similar to that of the 'quivering' mouse, which results from a homozygous loss-of-function mutation in the Sptnb4 gene. In 6 patients from 5 unrelated families with NEDHND, Wang et al. (2018) identified homozygous or compound heterozygous mutations in the SPTBN4 gene (see, e.g., 606214.0002-606214.0006). The mutations were found by exome sequencing; confirmed segregation of the mutations with the disorder was only possible in 1 family (family A). All patients except 1 (patient from family C) carried biallelic nonsense or frameshift mutations predicted to result in a complete loss of function. The patient from family C carried compound heterozygous missense mutations (R504Q, 606214.0004 and R2435C, 606214.0005). Five of the 7 variants were located N-terminal to SR10 and were predicted to affect only the longer sigma-1 splice variant; SR15 mediates the interaction with ankyrin-G (ANK3; 600465). The equivalent human variants in mouse Sptbn4 were expressed in cultured rat hippocampal neurons. Most of the truncating variants failed to localize to the axon initial segments (AIS) due to an inability to interact with ANK3, whereas the 2 missense variants and 1 C-terminal frameshift mutation (c.7453delG; 606214.0006) were able to interact with ANK3 and localized properly to the AIS. The c.7453delG mutant was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. Examination of the nodes of Ranvier was possible for 2 patients. Sural nerve biopsy from the patient with a homozygous truncating mutation (W903X; 606214.0003) that affected only the sigma-1 variant showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable nodal immunoreactivity for the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. Sural nerve biopsy from the patient with compound heterozygous missense mutations showed fairly normal structure at the nodes of Ranvier, with a small reduction in potassium channels. Wang et al. (2018) concluded that SPTBN4 mutations disrupt the cytoskeletal machinery that controls proper localization of ion channels and function of axonal domains mainly at the AIS and the nodes of Ranvier, resulting in severe neurologic dysfunction. Animal Model The autosomal recessive mouse mutation 'quivering' (qv), described by Yoon and Les (1957), produces progressive ataxia with hindlimb paralysis, deafness, and tremor. Ear twitch responses (Preyer reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory inflammation, indicating that in contrast to the many mutations causing deafness originating in the cochlea, deafness in qv is central in origin (Deol et al., 1983; Bock et al., 1983). Parkinson et al. (2001) reported that qv mice carry loss-of-function mutations in the Sptnb4 gene that cause alterations in ion channel localization in myelinated nerves. They concluded that this finding provides a rationale for the auditory and motor neuropathies of these mice. Knierim et al. (2017) found absence of Sptbn4 immunostaining at the sarcolemma of muscle from the qv mouse, as well as complete absence of type 1 muscle fibers. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Absent head control Face \- Facial weakness \- Myopathic facies Ears \- Deafness, central \- Auditory neuropathy \- Absent brainstem evoked potentials Eyes \- Cortical visual impairment Mouth \- High-arched palate ABDOMEN Gastrointestinal \- Feeding difficulties SKELETAL Spine \- Scoliosis Feet \- Ankle contractures MUSCLE, SOFT TISSUES \- Hypotonia, severe \- Generalized muscle atrophy \- Type 1 fiber atrophy \- Neurogenic pattern seen on EMG \- Denervation atrophy NEUROLOGIC Central Nervous System \- Delayed psychomotor development, profound \- Hypotonia, profound \- Inability to sit or stand \- Absent speech \- Seizures (in some patients) Peripheral Nervous System \- Areflexia \- Axonal and demyelinating peripheral neuropathy LABORATORY ABNORMALITIES \- Normal serum creatine kinase MISCELLANEOUS \- Onset at birth MOLECULAR BASIS \- Caused by mutation in the nonerythrocytic beta-spectrin 4 gene (SPTBN4, 606214.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS	c4479603	5,415	omim	https://www.omim.org/entry/617519	2019-09-22T15:45:45	{"omim": ["617519"], "synonyms": ["Alternative titles", "MYOPATHY, CONGENITAL, WITH NEUROPATHY AND DEAFNESS"]}
Rare genetic disorder causing lack of fingerprints Adermatoglyphia Other namesImmigration delay disease Adermatoglyphia is inherited in an autosomal dominant manner Adermatoglyphia is an extremely rare genetic disorder that prevents the development of fingerprints. Five extended families worldwide are known to be affected by this condition.[1][2] The disorder was informally nicknamed "immigration delay disease" by Professor Peter Itin after his first patient had trouble traveling to the U.S. without any fingerprints for identification.[3] ## Contents * 1 Case study * 2 References * 3 External links ## Case study[edit] In 2007 an isolated finding was published regarding the description of a person from Switzerland who lacked fingerprints.[4] The phenotype was mapped to chromosome 4q22\. In the splice-site of a 3' exon of the gene for SMARCAD1-helicase, a point mutation was detected. It results in a shortened form of the skin-specific protein.[5] The heterozygous expression of the mutation suggests an autosomal dominant mode of inheritance.[6] The Swiss patient, and eight of her relatives who also had the mutation, all had "flat finger pads and a reduced number of sweat glands in the hands".[7] Other conditions can cause a lack of fingerprints, but unlike them, adermatoglyphia has no side effects.[8] Mutations in helicases are involved in other rare genetic diseases, such as Werner syndrome.[9] ## References[edit] 1. ^ Reference, Genetics Home. "Adermatoglyphia". Genetics Home Reference. Retrieved 2020-07-07. 2. ^ "Adermatoglyphia disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials". www.malacards.org. Retrieved 2020-07-07. 3. ^ "The family with no fingerprints". BBC News. 2020-12-26. Retrieved 2020-12-27. 4. ^ Burger B, Fuchs D, Sprecher E, Itin P (May 2011). "The immigration delay disease: adermatoglyphia-inherited absence of epidermal ridges". J. Am. Acad. Dermatol. 64 (5): 974–80. doi:10.1016/j.jaad.2009.11.013. PMID 20619487. 5. ^ Stromberg, Joseph. "Adermatoglyphia: The Genetic Disorder Of People Born Without Fingerprints". Smithsonian Magazine. Retrieved 2020-07-07. 6. ^ Nousbeck J, Burger B, Fuchs-Telem D, et al. (August 2011). "A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant adermatoglyphia". Am. J. Hum. Genet. 89 (2): 302–7. doi:10.1016/j.ajhg.2011.07.004. PMC 3155166. PMID 21820097. 7. ^ The family with no fingerprints, by Mir Sabbir; at BBC.com; published December 26, 2020; retrieved December 28, 2020 8. ^ Kaufman, Rachel (August 9, 2011). "Mutated DNA Causes No-Fingerprint Disease". National Geographic News. 9. ^ Sarfraz, Nuraiz; N, Sarfraz (2019-02-08). "Adermatoglyphia: Barriers to Biometric Identification and the Need for a Standardized Alternative". Cureus Journal of Medical Science. 11 (2): e4040. doi:10.7759/cureus.4040. PMC 6456356. PMID 31011502. ## External links[edit] * The dictionary definition of adermatoglyphia at Wiktionary Classification D * ICD-10: Q82.8 * OMIM: 136000 * MeSH: C565010 External resources * Orphanet: 289465 * v * t * e Metabolic disease: DNA replication and DNA repair-deficiency disorder DNA replication * Separation/initiation: RNASEH2A * Aicardi–Goutières syndrome 4 * Termination/telomerase: DKC1 * Dyskeratosis congenita DNA repair Nucleotide excision repair * Cockayne syndrome/DeSanctis–Cacchione syndrome * Thymine dimer * Xeroderma pigmentosum * IBIDS syndrome MSI/DNA mismatch repair * Hereditary nonpolyposis colorectal cancer * Muir–Torre syndrome * Mismatch repair cancer syndrome MRN complex * Ataxia telangiectasia * Nijmegen breakage syndrome Other * RecQ helicase * Bloom syndrome * Werner syndrome * Rothmund–Thomson syndrome/Rapadilino syndrome * Fanconi anemia * Li-Fraumeni syndrome * Severe combined immunodeficiency This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Adermatoglyphia	c1852150	5,416	wikipedia	https://en.wikipedia.org/wiki/Adermatoglyphia	2021-01-18T18:31:33	{"gard": ["12550"], "mesh": ["C565010"], "umls": ["C1852150", "C1851080"], "icd-10": ["Q82.8"], "orphanet": ["289465"], "wikidata": ["Q356410"]}
## Summary ### Clinical characteristics. WT1 disorder is characterized by congenital/infantile- or childhood-onset of a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful. ### Diagnosis/testing. The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing. ### Management. Treatment of manifestations: Glomerulopathy: Avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition. Disorder of testicular development: Management is often by a multidisciplinary team (medical geneticist, endocrinologist, urologist, and psychologist). Treat Wilms tumor with standard oncology protocols an, when applicable, nephron-sparing surgery. Treat CAKUT as per standard care. Prevent whenever possible gonadoblastoma by prophylactic gonadectomy. Surveillance: Monitor for first appearance of the following: (1) proteinuria every six months until age ten years, yearly thereafter; (2) Wilms tumor every three months until age seven years. For ongoing issues with disorder of testicular development as per treating multidisciplinary team and for CAKUT as per treating nephrologist and/or urologist. Agents/circumstances to avoid: Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with a WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance. ### Genetic counseling. WT1 disorder is inherited in an autosomal dominant manner. Most individuals diagnosed with WT1 disorder have the disorder as the result of an apparent de novo WT1 pathogenic variant; in rare instances, a parent of an individual with WT1 disorder is heterozygous for the WT1 pathogenic variant. If a parent of the proband is affected and/or is known to have the WT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the WT1 pathogenic variant is 50%. If the proband's WT1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Once the WT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis Formal diagnostic criteria for WT1 disorder have not been established. Note: This chapter on WT1 disorder excludes WAGR syndrome (Wilms tumor-aniridia-genital anomalies-retardation), caused by a contiguous gene deletion of PAX6 and WT1 (see PAX6-Related Aniridia). ### Suggestive Findings A WT1 disorder should be suspected in an individual with the following clinical findings. #### Clinical Findings Progressive glomerulopathy (also known as a podocytopathy; i.e., a condition caused by dysfunction of the podocytes): * Onset from infancy to the second to third decade of life * Manifestations in the order in which they typically (but not invariably) appear: * Persistent proteinuria, defined as any one of the following lasting >3 months: 24-hour protein excretion >100 mg/m2/day OR urine protein:creatinine ratio ≥0.2 mg/mg (0.5 if age <2 yrs) OR urine protein:creatinine ratio >20 mg/mmol (50 if age <2 yrs) [Hogg et al 2003] * Steroid-resistant nephrotic syndrome (SRNS). Nephrotic syndrome (defined as hypoalbuminemia, edema, and hyperlipidemia) that does not respond to standard steroid therapy. Note: "Congenital nephrotic syndrome" is nephrotic syndrome manifesting in the first three months of life. * Chronic kidney disease (CKD), defined as glomerular filtration rate <60 mL/min/1.73 m2) [Hogg et al 2003] Wilms tumor, especially in children with: * Early-onset Wilms tumor (i.e., median age 15-19 months vs median age of 36 months in children without a WT1 pathogenic variant) OR * Bilateral Wilms tumors Disorder of testicular development (See Nonsyndromic Disorders of Testicular Development.) * 46,XY disorder of sex development (46,XY DSD) * External genitalia that can range over the following spectrum: * Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee * Microphallus * Abnormalities of scrotal formation * Normal-appearing female * Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: * Absent * Fully developed uterus and fallopian tubes * Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) ranging over the following spectrum: * Normal testis * Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) * Streak gonad * 46,XY complete gonadal dysgenesis (46,XY CGD) * External genitalia. Normal female * Müllerian structures. Uterus and fallopian tubes present * Gonadal findings. Streak gonads or dysgenetic testes Note: 46,XX individuals with a WT1 disorder may have abnormalities of the müllerian structures such as bicornuate uterus and typically do not have a disorder of gonadal development. Gonadoblastoma (germ cell tumor). Most commonly in 46,XY individuals with a disorder of testicular development Congenital anomalies of the kidney and urinary tract (CAKUT) including: * Duplex kidney; horseshoe kidney; kidney malrotation * Vesico-urinary reflux; pelviureteric junction stenosis; urogenital sinus Other. Diaphragmatic hernia #### Supportive Laboratory Findings Normal 46,XX karyotype or normal 46,XY karyotype determined by either: * Chromosome analysis with FISH to determine the integrity of SRY, or * Chromosomal microarray analysis ### Establishing the Diagnosis The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing (see Table 1). Note: Identification of a heterozygous WT1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of WT1 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 Single-gene testing. Sequence analysis of WT1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Sequence analysis of the entire gene is typically performed first; however, some laboratories may choose to sequence exons 8, 9, and their intronic junctions first because more than 90% of pathogenic variants are in that region [Lipska et al 2014]. If no pathogenic variant is found, gene-targeted deletion/duplication analysis can be performed to detect intragenic deletions or duplications. A multigene panel (for any of the following, depending on the clinical manifestations at the time of the evaluation: SRNS; hereditary [pediatric] cancers; 46,XY disorders of testicular development [see Table 2]; CAKUT) that includes WT1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in WT1 Disorder View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method WT1Sequence analysis 3>90% 4 Gene-targeted deletion/duplication analysis 5<10% 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lipska et al [2014], Sadowski et al [2015] 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\. Several exon and multiexon deletions have been reported (e.g., Finken et al [2015]). ## Clinical Characteristics ### Clinical Description A WT1 disorder is characterized by congenital/infantile- or childhood-onset of a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma (see Table 2). While various combinations of renal and other findings associated with a WT1 pathogenic variant have in the past been designated as certain syndromes, those combinations are now recognized to be part of a phenotypic continuum and their designations are no longer clinically helpful (see Nomenclature) [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015, Ahn et al 2017]. ### Table 2. WT1 Disorder: Select Clinical Findings View in own window Clinical findingPresent in % of WT1 DisordersComment Glomer- ulopathyPersistent proteinuria>95%Renal hallmark of WT1 disorder; degree may vary over time. SRNS80%Criteria for diagnosis of SRNS 1 may not be met initially. CNS15%Nephrotic syndrome within 1st 3 mos of life External genitaliaMüllerian structuresGonadal findings Disorder of testicular development46,XX DSD or CGDSee footnote 2.Normal femaleBicornus uterus, polypose uterusStreak gonads, hypertrophic ovaries, or normal ovaries 46,XY DSD63%-79% of 46,XY individuals 3Range: microphallus, hypospadias & cryptorchidism, ambiguous, normal-appearing femaleRange: absent to normal uterus & fallopian tubesRange: normal testis, ovotestis, dysgenetic testis, streak gonad 46,XY CGD18%-33% of 46,XY individuals 3Normal femaleUterus & fallopian tubes presentStreak gonads or dysgenetic testes Wilms tumor38%-43% 3 * Median age at diagnosis: 1.3-1.6 yrs * Significant fraction is bilateral synchronous &/or metachronous CAKUT~11% 3 * Kidney: duplex, horseshoe; malrotation * Urinary tract: vesico-urinary reflux, pelviureteric junction stenosis, urinary sinus Gonadoblastoma5% * To date, reported only in individuals w/a disorder of testicular development * See Genotype-Phenotype Correlations for WT1 variants assoc w/highest risk. 46,XY CGD = 46,XY complete gonadal dysgenesis; 46,XY DSD = 46,XY disorder of sex development; CAKUT = congenital anomalies of the kidney and urinary tract; CGD = complete gonadal dysgenesis; CNS = congenital nephrotic syndrome; DSD = disorders of sex development; SRNS = steroid-resistant nephrotic syndrome 1\. Nephrotic syndrome (proteinuria, hypoalbuminemia, edema, and hyperlipidemia) that does not respond to standard steroid therapy 2\. Two instances of 46,XX complete gonadal dysgenesis have been reported [Ahn et al 2017, Roca et al 2019]. 3\. Lipska et al [2014], Lehnhardt et al [2015] #### Progressive Glomerulopathy Persistent proteinuria is the most common initial finding of the glomerulopathy. While the degree of proteinuria may fluctuate at the onset of renal involvement, it becomes progressively worse over time. The severity of the proteinuria varies among affected individuals, even within the same family. Note that individuals with end-stage renal disease (ESRD) may be anuric, and thus will not have proteinuria. Steroid-resistant nephrotic syndrome (SRNS) – proteinuria, hypoalbuminemia, edema, and hyperlipidemia that does not respond to standard steroid therapy – is the characteristic renal finding. SRNS can precede Wilms tumor by as much as four years, present at the time of Wilms tumor diagnosis, or develop after Wilms tumor (as much as 10 years after completion of the oncology treatment) [Lipska et al 2014, Lehnhardt et al 2015]. SRNS results in irreversible and progressive decline of renal function and inevitably leads to ESRD. Congenital nephrotic syndrome (nephrotic syndrome that presents in the first 3 months of life) is more rapidly progressive, resulting in ESRD within weeks to months. Typical findings of the glomerulopathy on renal biopsy are diffuse mesangial sclerosis reported primarily in children younger than age two years and focal segmental glomerulosclerosis in older individuals (usually as either isolated SRNS or SRNS in association with 46,XY complete gonadal dysgenesis). Of note, because the histologic findings do not correlate with the clinical findings and because remarkable histopathologic heterogeneity is observed even among individuals with the same WT1 pathogenic variant [Lipska et al 2014, Lehnhardt et al 2015, Trautmann et al 2017], renal biopsy is no longer considered a first-tier diagnostic measure for patients of any age. #### Wilms Tumor Wilms tumor (nephroblastoma) is one of the most common pediatric malignant solid tumors. The estimated risk to heterozygotes who have an exonic WT1 pathogenic variant of developing Wilms tumor is one tumor per nine years at risk. Calculation of the exact penetrance is hampered because a significant number of individuals with a WT1 pathogenic variant undergo prophylactic nephrectomy at the time of transplantation or placement of a peritoneal dialysis catheter). The median age at Wilms tumor diagnosis in WT1 disorder is significantly younger (median age 1.3-1.6 years (range 0-4.5 years) compared to Wilms tumor of unknown cause. Bilateral tumors are more frequent in individuals with a truncating WT1 variant compared to individuals with other variants (>50% vs <15%) [Lipska et al 2014, Lehnhardt et al 2015] (see Genotype-Phenotype Correlations). The survival rates for individuals with Wilms tumor caused by a WT1 disorder do not differ significantly from those in individuals with Wilms tumor of unknown cause. #### Genital Findings 46,XY individuals have a disorder of testicular development that is either a disorder of sex development (DSD) or complete gonadal dysgenesis (CGD) (see Table 2). 46,XY individuals with normal testes, normal male external genitalia, and normal fertility have been reported anecdotally. 46,XX individuals typically have normal ovaries, normal female external genitalia, müllerian structures that are usually normal (however, on occasion bicornuate uterus has been observed), and normal fertility (see Table 2 for details). To date, two instances of 46,XX CGD have been reported [Ahn et al 2017, Roca et al 2019]. #### Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) CAKUT are observed in about 10% of individuals with a WT1 disorder. The most common kidney abnormalities are duplex kidney, horseshoe kidney, kidney malrotation. The most commonly reported urinary tract anomalies are vesico-urinary reflux, ureteropelvic junction stenosis, and urogenital sinus (in a 46,XX individual in whom both the urethra and vagina open into a common channel). #### Gonadoblastoma Individuals with 46,XY disorder of testicular development (either 46,XY DSD or 46,XY CGD) are at increased risk for germ cell tumors, particularly gonadoblastoma. The observed incidence is one gonadal tumor per 30 years at risk [Lipska et al 2014]. Because of the lack of long-term follow-up data, exact penetrance and long-term outcome are unknown. The survival rates for gonadoblastoma are excellent; however, if not treated it may result in malignant transformation of germ cells. A few cases of Sertoli tumor or other malignant testicular germ cell tumors have been reported [Kitsiou-Tzeli et al 2012]. #### Other Diaphragmatic defect or herniation is a rare finding in WT1 disorder, reported in fewer than ten infants [Denamur et al 2000, Suri et al 2007, Ahn et al 2017]. Post-transplant lymphoproliferative disorder (PTLD) was reported in 7%-17% of individuals with a WT1 disorder following kidney transplantation [Lipska et al 2014, Ahn et al 2017]. In all children undergoing kidney transplantation, the 25-year cumulative incidence of PTLD, adjusted for the competing risk of death, is 3.6% (95% CI 2.7-4.8). Due to small numbers and lack of standardized follow-up data, it is not yet possible to determine if the frequency of PTLD is higher for WT1 disorder than for all other children undergoing renal transplantation. ### Genotype-Phenotype Correlations Recent developments have allowed delineation of genotype-phenotype correlations for the following subgroups of WT1 variants. Truncating pathogenic variants (all nonsense, frameshift, or splice-site variants that are not KTS intron variants; see Molecular Genetics) are associated with the following [Lipska et al 2014, Lehnhardt et al 2015]: * Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower. * Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely. * The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4). * One in five individuals has congenital anomalies of the kidney and urinary tract. Missense variants affecting nucleotides coding for amino acid residues in the DNA-binding region in exons 8 and 9 (see Molecular Genetics) are associated with the following [Lipska et al 2014]: * The highest risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS. By age two and a half years, 50% of affected children have ESRD. * Of 46,XY individuals, approximately 80% had 46,XY DSD and 20% 46,XY CGD [Author, personal observation]. Missense pathogenic variants in exons 8 and 9 outside the DNA-binding region are associated with an intermediate glomerulopathy phenotype that manifests before age five years and progresses to ESRD by about age ten years [Lipska et al 2014]. Certain donor splice-site pathogenic variants in intron 9 (see Molecular Genetics) are associated with the following [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015]: * Later-onset and relatively slow progression of glomerulopathy that typically leads to ESRD in adolescence * 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals ### Penetrance The penetrance of WT1 disorder is high. It is age dependent, reaching about 90% by the end of puberty. A few asymptomatic parents heterozygous for the same germline WT1 variant in their affected offspring have been reported [Fencl et al 2012, Lipska et al 2014, Kaneko et al 2015, Boyer et al 2017]. The penetrance appears to depend on the gender of the affected parent, with higher penetrance associated with paternal origin of the WT1 variant [Kaneko et al 2015]. However, current data on penetrance are limited because the variable expressivity of WT1 pathogenic variants was not recognized until recently, as the asymptomatic parents of a child with a WT1 pathogenic variant were not routinely tested. ### Nomenclature Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant. Given the extensive clinical overlap between these clinical diagnoses and molecular characterization of their shared genetic etiology, Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome are no longer useful clinical diagnoses. However, these terms may still be used in the medical literature to refer to the following general phenotypic constellations: * Frasier syndrome. SRNS, 46,XY CGD, and gonadoblastoma * Denys-Drash syndrome. SRNS with diffuse mesangial sclerosis on renal biopsy, Wilms tumor, and 46,XY DSD * Meacham syndrome. Diaphragmatic hernia, pulmonary dysplasia, complex congenital heart defects, and genitourinary abnormalities including ambiguous genitalia and gonadal dysgenesis; in most reports, the condition was lethal early in infancy prior to development of other possible manifestations of WT1 disorder, such as SRNS or Wilms tumor. So far, none of the reported individuals with a confirmed WT1 pathogenic variant and a diaphragmatic defect had a complex congenital heart defect. A multigenic cause of this syndrome, with another as-yet-unknown gene responsible for the more severe cardio-pulmonary phenotype, has been suggested [Suri et al 2007]. Male pseudohermaphroditism. The spectrum of clinical manifestations related to 46,XY disorders of testicular development with a WT1 pathogenic variant was previously referred to using outdated terms such as "male pseudohermaphroditism." ### Prevalence The prevalence of WT1 disorder is not known. Fewer than 500 affected individuals have been reported to date. There are no WT1 founder variants or biased geographic distribution in specific populations. ## Differential Diagnosis For the differential diagnosis of: * Wilms tumor, see Wilms Tumor Predisposition; * 46,XY disorders of testicular development, see Nonsyndromic Disorders of Testicular Development; * Diaphragmatic hernia, see Congenital Diaphragmatic Hernia Overview. Steroid-resistant nephrotic syndrome (SRNS) is a podocytopathy (i.e., a condition caused by dysfunction of the podocytes). To date, approximately 60 genes have been associated with hereditary podocytopathy. Up to 30% of individuals with SRNS who undergo molecular genetic testing have a heterozygous pathogenic variant or biallelic pathogenic variants in a hereditary podocytopathy gene [Trautmann et al 2018]. * The two most commonly involved genes, NPHS1 (OMIM 256300) and NPHS2 (OMIM 600995), encode components of the slit diaphragm and are selectively expressed in the podocyte. * A subset of genes encode proteins that are not tissue/organ specific: these include cell signaling pathways, mitochondrial energy provision (see Primary Coenzyme Q10 Deficiency) and nuclear transcription factors such as SMARCAL1 (see Schimke Immunoosseous Dysplasia), LMX1B (see Nail-Patella Syndrome), and WT1. Pathogenic variants in these genes can cause a range of phenotypes from largely kidney-limited disease to severe syndromic disorders. Note: Among individuals with isolated SRNS, WT1 is among the top three most commonly mutated genes accounting for approximately 5% of cases [Sadowski et al 2015, Trautmann et al 2015]. * Other genes associated with hereditary podocytopathy are involved in sustaining proper functioning of the cytoskeleton and membrane protein complex linking these structures (e.g., the COL4A3/4/5 gene family; see Alport Syndrome). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a WT1 disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in an Individual with a WT1 Disorder View in own window System/ConcernEvaluationComment Glomer- ulopathyPersistent proteinuriaUrine protein:creatinine ratioFor evidence of proteinuria SRNS CKD CNS * 24-hour urine protein test * Serum protein, albumin, creatinine, cholesterol, IgG, C3 * Blood pressure measurements For evidence of proteinuria, hypertension, & CKD Disorder of testicular developmentKaryotype w/FISH for SRY or CMA (to determine chromosomal sex)To be performed in all individuals w/ambiguous genitalia & all prepubertal phenotypic females Pelvic USEval of gonadal localization & character Hormonal studiesFor children who have not undergone gonadectomy: hormonal studies as directed by a pediatric endocrinologist Wilms tumorAbdominal USMetachronous & synchronous tumors may be unilateral or bilateral. CAKUTAbdominal USTo identify duplex kidney, horseshoe kidney, kidney malrotation, &/or signs of obstructive nephropathy due to vesicoureteral reflux & ureteropelvic junction stenosis Diaphragmatic herniaAP & lateral chest x-ray to detect a small diaphragmatic hernia; larger ones would probably be clinically apparent due to respiratory distressEval for diaphragmatic defect especially prior to start of peritoneal dialysis Genetic counselingBy genetics professionals 1To inform patients & families re nature, MOI, & implications of WT1 disorder in order to facilitate medical & personal decision making Family support/ ResourcesAssess: * Use of community or online resources such as Parent to Parent * Need for social work involvement for parental support CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CMA = chromosomal microarray analysis; CNS = congenital nephrotic syndrome; MOI = mode of inheritance; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound 1\. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with a WT1 Disorder View in own window Manifestation/ConcernTreatmentConsiderations/Other Glomer- ulopathyPersistent proteinuriaConsider renin-angiotensin-aldosterone system (RAAS) inhibition: ACE inhibitor, AT1 receptor blocker. * Avoid immunosuppressants, which are ineffective & potentially toxic. * Nephropathy does not recur post renal transplantation. 1 SRNS CKD CNS Disorder of testicular developmentSee Nonsyndromic Disorders of Testicular Development.Management is often by a multidisciplinary team incl medical geneticist, endocrinologist, urologist, & psychologist. Wilms tumorStandard oncology protocols; surgery w/nephron-sparing approach whenever applicableBilateral prophylactic nephrectomy after reaching ESRD (i.e., at time of kidney transplantation or placement of a peritoneal dialysis catheter) 2 CAKUTUrologic intervention may be applicable.Per treating nephrologist &/or urologist GonadoblastomaGonadectomy per DSD teamNo consensus re timing of surgery Diaphragmatic herniaAs per treating surgeonRepair to be performed prior to start of peritoneal dialysis CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; DSD = disorders of sex development; ESRD = end-stage renal disease; SRNS = steroid-resistant nephrotic syndrome 1\. For a child to be eligible for kidney transplantation, most centers require that children weigh 10 kg and/or be at least one year post-completion of treatment for Wilms tumor. 2\. Gariépy-Assal et al [2018] ### Surveillance ### Table 5. Recommended Surveillance for Individuals with a WT1 Disorder View in own window System/ConcernEvaluationFrequency Glomer- ulopathyPersistent proteinuria / SRNSMonitor for 1st appearance of proteinuria.Every 6 mos until age 10 yrs; annually after age 10 yrs CNSMonitor for 1st appearance of proteinuria.During first 3 mos of life CKDMonitor progression of known CKD.Every 2 yrs Disorder of testicular developmentMonitor timing & progression of puberty.Per treating multidisciplinary team (medical geneticist, endocrinologist, urologist, psychologist) Wilms tumorMonitor for 1st appearance of Wilms tumor.Abdominal US every 3 mos until age 7 yrs 1 CAKUTFollow up of known kidney &/or urinary tract anomaliesPer treating nephrologist &/or urologist CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound 1\. Mussa et al [2019] ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual with a WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Because renal disease may progress during pregnancy, a pregnant woman with a WT1 disorder should be referred promptly to a perinatal center experienced in the care of pregnant women with chronic kidney disease. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	WT1 Disorder	None	5,417	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK556455/	2021-01-18T20:49:49	{"synonyms": []}
A number sign (#) is used with this entry because desmosterolosis is caused by homozygous or compound heterozygous mutation in the DHCR24 gene (606418) on chromosome 1p32. Description Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001). Clinical Features FitzPatrick et al. (1998) reported the case of an infant with multiple lethal congenital malformations and osteosclerosis in whom there was generalized accumulation of an abnormal neutral sterol and a relative deficiency of cholesterol. The sterol was identified by gas chromatography-mass spectrometry (GC-MS) as desmosterol, a biosynthetic precursor of cholesterol. The infant had macrocephaly, hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalized osteosclerosis. FitzPatrick et al. (1998) compared the phenotype to that of Smith-Lemli-Opitz syndrome (270400), which is a defect in the synthesis of cholesterol, and Raine syndrome (259775), which is characterized by generalized osteosclerosis, nasal hypoplasia, and gingival nodules. The abnormal accumulations of desmosterol occurred in the kidney, liver, and brain. Higher than normal levels of the same sterol were detected in plasma samples obtained from both parents. The biochemical phenotype was highly suggestive of a novel inborn error of cholesterol biosynthesis caused by an autosomal recessive deficiency of 3-beta-hydroxysterol-delta-24-reductase. Because of the phenotypic overlap with Raine syndrome, postmortem tissue samples from the patient with Raine syndrome described by Kan and Kozlowski (1992) were analyzed; however, desmosterol accumulation was not found in the tissues of that case, suggesting that it represented a distinct disorder. FitzPatrick et al. (1998) stated that there are 2 general mechanisms by which aberrant cholesterol synthesis may cause malformations: a relative deficiency of cholesterol and a relative excess of sterol precursor. These are not mutually exclusive. Furthermore, the hedgehog family of proteins, mutations in which have been identified in malformations (e.g., SHH; 600725), have been shown to undergo posttranslational modification by covalent attachment of a cholesterol molecule to the biologically active N-terminal fragment of these peptides (Porter et al., 1996). Zolotushko et al. (2011) reported a consanguineous Bedouin kindred in which 6 individuals had desmosterolosis confirmed by genetic analysis. Four living individuals were examined. All had a severe neurologic phenotype with psychomotor retardation, microcephaly, spasticity, severe convulsions, nystagmus, and strabismus. Brain MRI showed ventriculomegaly, decreased white matter, and partial or complete agenesis of the corpus callosum. Other features included failure to thrive, microretrognathia, and contractures of the hands. Dysmorphic facial features were not observed. Biochemical studies of 2 affected boys showed significantly increased desmosterol levels compared to controls. Desmosterol accounted for 3.4% and 10%, respectively, of the total sterols compared to less than 0.04% in controls. Their unaffected fathers had increased levels compared to controls (0.1%), but not as high as their affected sons. Schaaf et al. (2011) reported a female infant with desmosterolosis confirmed by genetic analysis (606418.0005 and 606418.0006). The patient was born prematurely at 34 weeks' gestation and showed macrocephaly, hydrocephalus, hypoplasia of the corpus callosum, and generalized arthrogryposis. Dysmorphic features included prominent forehead, telecanthus, short nose with anteverted nares, retrognathia, and low-set ears. She also had rhizomesomelia, fifth finger clinodactyly, mild cutaneous 2-4 toe syndactyly, and proximal placement of the big toes. She had developmental delay associated with enlarged and abnormal ventricles and an effaced gyral pattern, and radiographs showed eventration of the right anterior medial diaphragm. Molecular Genetics In 2 patients with desmosterolosis described by FitzPatrick et al. (1998) and Andersson et al. (2000, 2002), Waterham et al. (2001) identified mutations in the DHCR24 gene (606418.0001-606418.0003). Andersson et al. (2000, 2002) described a boy with desmosterolosis who was born at term with microcephaly, agenesis of the corpus callosum, downslanting palpebral fissures, bilateral epicanthal folds, submucous cleft palate, micrognathia, mild contractures of the hands, bilateral clubfeet, cutis aplasia, and persistent patent ductus arteriosus. At 40 months of age, he was severely developmentally delayed but was learning to walk, used 5 words, and followed simple commands. Height and weight were less than the 2nd centile. Radiologic examination disclosed neither rhizomelic shortness nor osteosclerosis. Plasma sterol quantification when the patient was 2 years old demonstrated a normal cholesterol level but a 100-fold increase in desmosterol. Both parents had mildly increased levels of desmosterol in plasma, consistent with heterozygosity for DHCR24 deficiency. Analysis of sterol metabolism in cultured transformed lymphoblasts showed a 100-fold increased level of desmosterol and a moderately decreased level of cholesterol in the patient's cells and a 10-fold elevation of desmosterol in the mother's cells. DNA analysis of the patient and his parents identified a homozygous and heterozygous mutation, respectively, in the DHCR24 gene that when expressed in yeast had a residual activity of 20%. By genomewide linkage analysis followed by candidate gene sequencing of a consanguineous Bedouin family with desmosterolosis, Zolotushko et al. (2011) identified a homozygous mutation in the DHCR24 gene (R103C; 606418.0004). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly \- Macrocephaly, relative Face \- Frontal bossing \- Micrognathia Ears \- Posteriorly rotated ears \- Low-set ears Eyes \- Strabismus \- Nystagmus Nose \- Hypoplastic nasal bridge \- Short nose \- Anteverted nares Mouth \- Thick alveolar ridges \- Gingival nodules \- Cleft palate CARDIOVASCULAR Heart \- Total anomalous pulmonary venous drainage (1 patient) GENITOURINARY External Genitalia (Male) \- Ambiguous genitalia External Genitalia (Female) \- Ambiguous genitalia SKELETAL \- Arthrogryposis \- Osteosclerosis Limbs \- Rhizomelic shortening Hands \- Contractures of the hands NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Spasticity \- Seizures \- Ventriculomegaly \- Hydrocephalus \- Decreased white matter \- Partial or complete agenesis of the corpus callosum \- Effaced gyral pattern LABORATORY ABNORMALITIES \- Elevated plasma desmosterol MISCELLANEOUS \- Patients from 4 unrelated families have been reported (as of October 2011) \- Variable phenotype \- Dysmorphic facial features may not be present MOLECULAR BASIS \- Caused by mutation in the 24-dehydrocholesterol reductase gene (DHCR24, 606418.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DESMOSTEROLOSIS	c1865596	5,418	omim	https://www.omim.org/entry/602398	2019-09-22T16:13:49	{"mesh": ["C566555"], "omim": ["602398"], "orphanet": ["35107"]}
## Clinical Features Prakash et al. (2003) described an Asian Indian family with autosomal dominant progressive nephropathy, with features of both focal segmental glomerulosclerosis (see 603278) and Alport syndrome (104200). Seven members of the family were affected, and there was male-to-male transmission. Two members had end-stage renal disease (ESRD). Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the 7 affected individuals also had sensorineural deafness that involved both low and high frequencies in some members. Mapping In a genomewide scan of an Asian Indian family with autosomal dominant progressive nephropathy, Prakash et al. (2003) observed significant evidence of linkage for chromosome 11q24, with a multipoint lod score of 3.2 for marker D11S4464 at theta = 0.0. Linkage was excluded to the region 2q36-q37, where the genes COL4A3 (120070) and COL4A4 (120131), mutant in autosomal recessive Alport syndrome (203780), reside. Linkage was also excluded to 22q11.2, the location of the MYH9 gene (160775), which is mutant in some cases of Fechtner syndrome (see 155100). Linkage was further excluded to FSGS loci FSGS1 (603278) on 19q13 and FSGS3 (607832) on 11q22. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEPHROPATHY, PROGRESSIVE, WITH DEAFNESS	c1836119	5,419	omim	https://www.omim.org/entry/609469	2019-09-22T16:06:02	{"mesh": ["C563713"], "omim": ["609469"], "synonyms": ["Alternative titles", "NEDE", "ALPORT/FOCAL SEGMENTAL GLOMERULOSCLEROSIS-LIKE SYNDROME"]}
Vacuolar interface dermatitis, with lymphocytes in the dermis and epidermis (black arrow indicates one), and vacuolization (white arrow) at the dermoepidermal junction. Micrograph of a vacuolar interface dermatitis with dermal mucin, as may be seen in lupus. H&E stain. Vacuolar interface dermatitis (VAC, also known as liquefaction degeneration, vacuolar alteration or hydropic degeneration) is a dermatitis with vacuolization at the dermoepidermal junction, with lymphocytic inflammation at the epidermis and dermis.[1] ## Causes[edit] Causes of vacuolar interface dermatitis edit Main conditions[2] Characteristics Micrograph Photograph Generally/Not otherwise specified Typical findings, called "vacuolar interface dermatitis":[2] * Mild inflammatory cell infiltrate along the dermoepidermal junction (black arrow in image) * Vacuolization within the basal keratinocytes (white arrow in image) * Often necrotic, predominantly basal, individual keratinocytes, manifesting as colloid or Civatte bodies Acute graft-versus-host-disease * Vacuolar alteration of various severity, from focal or diffuse vacuolation of the basal keratinocytes (grade I), to separation at the dermoepidermal junction (grade III) * Involvement of the hair follicle[2] * Rarely eosinophils[2] Allergic drug reaction * Rarely involvement of hair follicles.[2] * Frequently eosinophils[2] Lichen sclerosus Hyperkeratosis, atrophic epidermis, sclerosis of dermis and dermal lymphocytes.[3] Erythema multiforme Lupus erythematosis Typical findings in systemic lupus erythematosus:[4] * Fibrinoid necrosis at the dermoepidermal junction * Liquefactive degeneration and atrophy of the epidermis * Mucin deposition in the reticular dermis * Edema, small hemorrhages * Mild and mainly lymphocytic infiltrate in the upper dermis * Fibrinoid material in the dermis around capillary blood vessels, on collagen and in the interstitium * In non-bullous cases, perivascular and interstitial neutrophils are sometimes present in the upper dermis, with damage to blood vessels An interface dermatitis with vacuolar alteration, not otherwise specified, may be caused by viral exanthems, phototoxic dermatitis, acute radiation dermatitis, erythema dyschromicum perstans, lupus erythematosus and dermatomyositis.[2] ## References[edit] 1. ^ Bolognia, Jean L.; et al. (2007). Dermatology. St. Louis: Mosby. p. 11. ISBN 1-4160-2999-0. 2. ^ a b c d e f g Unless else specified in boxes, reference is: Alsaad, K O (2005). "My approach to superficial inflammatory dermatoses". Journal of Clinical Pathology. 58 (12): 1233–1241. doi:10.1136/jcp.2005.027151. ISSN 0021-9746. 3. ^ Lisa K Pappas-Taffer. "Lichen Sclerosus". Medscape. Updated: May 17, 2018 4. ^ Mowafak Hamodat. "Skin inflammatory (nontumor) > Lichenoid and interface reaction patterns > Lupus: systemic lupus erythematosus (SLE)". PathologyOutlines. Topic Completed: 1 August 2011. Revised: 26 March 2019 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Vacuolar interface dermatitis	c0262982	5,420	wikipedia	https://en.wikipedia.org/wiki/Vacuolar_interface_dermatitis	2021-01-18T19:05:13	{"umls": ["C0262982"], "wikidata": ["Q7908029"]}
Desbuquois syndrome (DBQD) is an osteochondrodysplasia characterized by severe micromelic dwarfism, facial dysmorphism, joint laxity with multiple dislocations, vertebral and metaphyseal abnormalities and advanced carpotarsal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. A variant form of DBQD, Kim variant (see these terms), has also been described and is characterized by short stature and articular, minor facial and significant hand anomalies. ## Epidemiology To date, less than 50 cases have been described in the literature. ## Clinical description DBQD is characterized by severe micromelic dwarfism, facial dysmorphism (round flat face, prominent eyes, midface hypoplasia, short nose, microstomia, long upper lip with flat philtrum, microretrognathia, often resulting in isolated Pierre Robin syndrome (see this term)), thoracic hypoplasia, kyphoscoliosis, severe joint laxity with dislocation, and osteopenia. Additional features include glaucoma, cardiac septal defects, lung hypoplasia, obesity and clubbed feet with rocker bottom appearance. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies (accessory ossification center distal to the second metacarpal, bifid distal phalanx, or thumb with delta-shaped phalanx). A variant form of DBQD, Kim variant, has been described in 7 patients originating from Korea and Japan, and is characterized by short stature, articular and minor facial anomalies, together with significant hand anomalies including short metacarpals and elongated phalanges with advanced carpal bone age. ## Etiology DBQD type 1 and Kim variant are caused by mutation in the gene CANT1 (17q25.3). However, the function of CANT1 is still unknown. Mutations in the gene XYLT1 (16p12) has been reported to cause DBQD type 2. XYLT1 encodes xylosyltransferase 1 which is involved in proteoglycan synthesis. However not all DBQD type 2 have XYLT1 mutations supporting the involvement of other disease causing genes. ## Diagnostic methods 'Diagnosis relies upon recognition of clinical and radiological features which include an advanced carpal and tarsal bone age; broad femoral neck with a spur-like projection and prominent lesser trochanter, producing characteristic ''monkey wrench'' (Swedish key) appearance; narrow thorax; coronal or sagittal clefting of the vertebrae and typical hand changes for DBQD type 1 that consist of small delta-shaped extraphalangeal bone, distal to the second metacarpal, leading to radial deviation of the index fingers (delta phalanx or bifid thumb),and horizontal acetabular roofs with dislocation of femoral heads. Diagnosis is confirmed by the genetic screening of CANT1 in type 1 and XYLT1 in type 2DBQD.' ## Differential diagnosis Differential diagnosis includes autosomal dominant or recessive Larsen syndrome, Reunion island's Larsen syndrome, Catel-Manzke syndrome, chondrodysplasia with joint dislocations, gPAPP type, CHST3-related skeletal dysplasia, spondyloepiphyseal dysplasia, Omani type, diastrophic dwarfism and humerospinal dysostosis (see these terms). ## Antenatal diagnosis Antenatal diagnosis is achieved by ultrasound during the second trimester of pregnancy, by the detection of hydramnios, hydrops fetalis (see this term), intrauterine growth retardation, vertebral abnormalities and characteristic dysmorphic features. ## Genetic counseling Transmission is autosomal recessive and genetic counseling is recommended. ## Management and treatment Management includes regular orthopedic survey with often a need for multiple surgeries (scoliosis, hip and knee dislocation), and eye and ear follow up. ## Prognosis Type 1 DBQD displays a high lethality rate of >33% due to respiratory failure. Survivors may have intellectual disability, developmental delay, generalized and progressive joint laxity with dislocated knees. Orthopedic complications often limit the ambulation in DBQD. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Desbuquois syndrome	c0432242	5,421	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1425	2021-01-23T19:03:20	{"gard": ["1818"], "mesh": ["C535943"], "omim": ["251450", "300881", "615777"], "umls": ["C0432242"], "icd-10": ["Q78.8"], "synonyms": ["DBQD", "Desbuquois dysplasia"]}
6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases. ## Clinical description When left untreated, the deficiency causes neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include psychomotor retardation, tonus disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation and difficulty swallowing. ## Diagnostic methods PTPS deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. The most effective way to diagnose the disorder is to measure pteridine levels in urine and to confirm the result by measuring neurotransmitters 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg). ## Genetic counseling PTPS deficiency is an autosomal recessive genetic disorder. ## Management and treatment Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	6-pyruvoyl-tetrahydropterin synthase deficiency	c0878676	5,422	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=13	2021-01-23T19:06:51	{"gard": ["5682"], "mesh": ["C535325"], "omim": ["261640"], "umls": ["C0878676"], "icd-10": ["E70.1"], "synonyms": ["Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Polymelia" – news · newspapers · books · scholar · JSTOR (December 2016) (Learn how and when to remove this template message) Polymelia Other namesHydra syndrome Radiograph of a human child with polymelia SpecialtyMedical genetics Polymelia is a birth defect in which an affected individual has more than the usual number of limbs. It is a type of dysmelia. In humans and most land-dwelling animals, this means having five or more limbs. The extra limb is most commonly shrunken and/or deformed. The term is from Greek πολυ- "many", μέλεα "limbs". Sometimes an embryo started as conjoined twins, but one twin degenerated completely except for one or more limbs, which end up attached to the other twin. Sometimes small extra legs between the normal legs are caused by the body axis forking in the dipygus condition. Notomelia (from Greek for "back-limb-condition") is polymelia where the extra limb is rooted along or near the midline of the back.[1] Notomelia has been reported in Angus cattle often enough to be of concern to farmers.[2] Cephalomelia (from Greek for "head-limb-condition") is polymelia where the extra limb is rooted on the head.[3] ## Contents * 1 Origin * 2 Notable cases * 2.1 Humans * 2.2 Other animals * 3 In mythology * 4 In popular culture * 5 See also * 6 References * 7 Sources * 8 External links ## Origin[edit] Tetrapod legs evolved in the Devonian or Carboniferous geological period from the pectoral fins and pelvic fins of their crossopterygian fish ancestors. Fish fins develop along a "fin line", which runs from the back of the head along the midline of the back, round the end of the tail, and forwards along the underside of the tail, and at the cloaca splits into left and right fin lines which run forwards to the gills. In the paired ventral part of the fin line, normally only the pectoral and pelvic fins survive (but the Devonian acanthodian fish Mesacanthus developed a third pair of paired fins); but along the non-paired parts of the fin line, other fins develop. In tetrapods, only the four paired fins normally persisted, and became the four legs. Notomelia and cephalomelia are atavistic reappearances of dorsal fins. Some other cases of polymelia are extra development along the paired part of the fin lines, or along the ventral posterior non-paired part of the fin line. ## Notable cases[edit] ### Humans[edit] A six-month old child with an extra leg * In the summer of 2005, a baby girl named Destiny was born with a fully formed extra leg in Detroit. This was the result of a conjoined twin scenario. * In March 2006, a baby boy identified only as Jie-jie was born in Shanghai with a fully formed third arm: he had two full-sized left arms, one ventral to the other. This is the only documented case of a child born with a fully formed supernumerary arm. It is an example of an extra limb on a normal body axis.[4] * In July 2007 a child was born with four legs at the Lebowakgomo hospital outside Polokwane (South Africa) * On November 6, 2007, doctors at Bangalore's Sparsh Hospital in Bangalore, India successfully completed surgery on a two-year-old girl named Lakshmi Tatma who was born with four arms and four legs; this was not true polymelia but a case of ischiopagus Siamese twinning where one twin's head had disappeared during development. * Frank Lentini had a third leg, as well as a fourth foot and two sets of genitals. * A boy named Gaurav, born in Tanahun district in Nepal with an extra arm growing out of his upper back between his shoulder blades, two years ago was published on 2016. * 1995: Somali baby girl born with three right arms.[5] ### Other animals[edit] A grown steer with five legs. Piglet with dipygus at Ukrainian National Chernobyl Museum in Kiev * A four-legged chicken was born at Brendle Farms in Somerset, Pennsylvania, in 2005.[6] The story was carried on the major TV network news programs and USA Today. The bird was found living normally among the rest of the chickens after 18 months. She was adopted and named Henrietta by the farm owner's 13-year-old daughter, Ashley, who refuses to sell the chicken.[7] The second (hind) legs are fully formed but non-functional. * Four-legged ducks are occasionally hatched, such as 'Stumpy', an individual born in February 2007 on a farm in Hampshire, England.[8] * Frogs in the US sometimes are affected by polymelia when attacked in the tadpole stage by the Ribeiroia parasite. * A puppy, known as Lilly, was born in the United States[9] with a fully formed fifth leg jutting out between her hind legs. She was initially set to be sold to a freak show, but was instead bought by a dog lover who had the extra leg removed. * For a vertebrate with 3 pairs of paired fins/limbs, see the early Devonian acanthodian fish Mesacanthus. ## In mythology[edit] Many mythological creatures like dragons, winged horses, and griffins have six limbs: four legs and two wings. The dragon's science is discussed in Dragons: A Fantasy Made Real. In Greek Mythology: * The Hekatonkheires were said to each have one hundred hands. * The Gegenees were a race of giants with six arms. * The centaurs had six limbs: four horse legs and two human arms. Sleipnir, Odin's horse in Norse mythology, has eight normal horse legs, and is usually depicted with limbs twinned at the shoulder or hip. Several Hindu deities are depicted with multiple arms and sometimes also multiple legs. ## In popular culture[edit] * Edward Albee's stage play The Man Who Had Three Arms tells the story of a fictional individual who was normal at birth but eventually sprouted a third functional arm, protruding from between his shoulder blades. After several years of living with three arms, the extra limb was reabsorbed into his body and the man became physically normal again. In Albee's play, the title character is extremely angry that we (the audience) seem to be much more interested in the period of his life when he had three arms, rather than his normal life before and after that interval. * Monty Python's Flying Circus performed a skit about a man with three buttocks. He believes that he has been invited to be interviewed on television because he is a nice person, and is dismayed to learn that he has only been invited because the interviewer is curious about his unusual condition. * The Dark Backward is a 1991 comedy film directed and written by Adam Rifkin, which features Judd Nelson as an unfunny garbage man who pursues a stand-up comedy career. When the "comedian" grows a third arm out of his back, he becomes an overnight hit. * Justice, the main antagonist in the cartoon Afro Samurai, has a fully formed extra arm protruding from his right shoulder. * * Paco, a playable character in Brawlout, is a four-armed frog\- and shark-like creature. * Spiral, character in the X-Men stories of Marvel Comics, has six arms. * A 6-armed Spider-Man frequently appears as an alternate reality incarnation of the character, and is sometimes referred to as "Polymelian". * In the Mortal Kombat series, the Shokan is a race of humanoids known to have four arms. * Ibid: A Life is a fictional biography of Jonathan Blashette, a man with three legs. * Zaphod Beeblebrox, a character in Douglas Adams' Hitchhiker's Guide to the Galaxy, has a third arm as well as a second head. ## See also[edit] * Dipygus * Dysmelia * Polydactyly * Polysyndactyly * Supernumerary body parts ## References[edit] 1. ^ Google search 2. ^ "Polymelia". 3. ^ Kelani, A. Bariath; Moumouni, H.; Younsa, H.; James Didier, L.; Hima, A. M.; Guemou, A.; Issa, A. W.; Ibrahim, A.; Sanda, M. A.; Sani, R.; Sanoussi, S.; Catala, M. (2015). "A case of cephalomelia discovered in a baby born in Niger". Child's Nervous System. 32 (1): 205–208. doi:10.1007/s00381-015-2831-2. PMID 26227339. S2CID 28169410. 4. ^ Sommerville, Quentin (2006-07-06). "Three-armed boy 'recovering well'". BBC News. Retrieved 2016-12-22. 5. ^ Mennen, U.; Deleare, O.; Matime, A. (1997). "Upper Limb Triplication with Radial Dimelia". Journal of Hand Surgery. 22 (1): 80–83. doi:10.1016/S0266-7681(97)80025-3. PMID 9061534. S2CID 35811842. 6. ^ "Pennsylvania farm discovers a four-legged chicken". Associated Press. 2006-09-22. Retrieved 2006-09-22. 7. ^ "This quadruped has feathers and clucks - US news - Weird news - Animal weirdness \| NBC News". NBC News. 2006-09-22. Retrieved 2016-12-22. 8. ^ "Xinhua - English". News.xinhuanet.com. 2006-07-07. Archived from the original on 2016-12-23. Retrieved 2016-12-22. 9. ^ "Five-Legged Dog Saved From Coney Island Freakshow". Huffington Post. 2009-08-20. Retrieved 2015-03-12. ## Sources[edit] * Avian Diseases, 1985 Jan-Mar; 29(1): pp. 244-5. Polymelia in a broiler chicken., Anderson WI, Langheinrich KA, McCaskey PC.: "A polymelus monster was observed in a 7-week-old slaughterhouse chicken. The supernumerary limbs were smaller than the normal appendages but contained an equal number of digits.". * Kim C, Yeo S, Cho G, Lee J, Choi M, Won C, Kim J, Lee S (2001). "Polymelia with two extra forelimbs at the right scapular region in a male Korean native calf". J. Vet. Med. Sci. 63 (10): 1161–4. doi:10.1292/jvms.63.1161. PMID 11714039. * "Polymelia in the toad Bufo melanostictus" (PDF). Ias.ac.in. Retrieved 2016-12-22. ## External links[edit] * 2013: child with two left legs * Youtube video of child with notomelia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Polymelia	c0265546	5,423	wikipedia	https://en.wikipedia.org/wiki/Polymelia	2021-01-18T18:46:05	{"wikidata": ["Q661933"]}
A number sign (#) is used with this entry because this form of hereditary renal disease, referred to here as nephrotic syndrome type 3 (NPHS3), is caused by homozygous or compound heterozygous mutation in the PLCE1 gene (608414) on chromosome 10q23. Description Nephrotic syndrome, a malfunction of the glomerular filter, is characterized clinically by proteinuria, edema, and end-stage renal disease (ESRD). Renal histopathology may show diffuse mesangial sclerosis (DMS) or focal segmental glomerulosclerosis (FSGS) (Hinkes et al., 2006). Most patients with NPHS3 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen (Gbadegesin et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300). Clinical Features Hinkes et al. (2006) described 14 patients from 7 unrelated families with nephrotic syndrome. Five families were of Turkish origin and consanguineous, 1 was of Israeli origin and consanguineous, and the last was of Turkish and Russian origin with unknown consanguinity. The age at onset ranged from 2 months to 4 years, except for 1 child who had onset at age 8.5 years, and ESRD occurred within several months. One child had ESRD as early as 5 months of age. Most patients showed steroid resistance, but 1 had steroid-sensitive disease and another had favorable response to cyclophosphamide. Others were not treated. None had extrarenal manifestations. Renal biopsies of most patients showed diffuse mesangial sclerosis, although biopsies from 2 sibs with a slightly later age at onset and less rapid progression showed focal segmental glomerulosclerosis. Gbadegesin et al. (2008) reported 7 patients from 6 families with genetically confirmed NPHS3. They were ascertained from a larger group of patients on the basis of having early-onset proteinuria, edema, and hypoalbuminemia associated with diffuse mesangial sclerosis on renal biopsy, resulting in rapid progression to end-stage renal failure. None of the patients in this report who were treated responded to steroid therapy. Boyer et al. (2010) reported 18 patients from 12 families with NPHS3 confirmed by genetic analysis. Renal biopsies showed FSGS in 6 and DMS in 5; 1 family did not have biopsy results. Age at onset was reported as ranging from 3 months to 5 years, but most with later onset had already reach end-stage renal disease, suggesting that the disorder had been present for some time. Age at end-stage renal disease was always before age 7 years, and as early as 8 months. All patients had steroid-resistant disease. Three sporadic patients with similar clinical characteristics were also identified. The patients were of multiple ethnic origins, including Moroccan, Pakistani, French, Turkish, Bosnian, Serbian, and Greek. Inheritance Consanguinity and affected sibs in the families segregating nephrotic syndrome reported by Hinkes et al. (2006) indicated autosomal recessive inheritance. Clinical Management Most patients with NPHS3 do not respond to steroid treatment (Hinkes et al., 2006; Gbadegesin et al., 2008) and are thus classified as having steroid nonresponsive nephrotic syndrome. However, Hinkes (2008) emphasized the finding of Hinkes et al. (2006) who reported 2 patients with genetically confirmed NPHS3 who did show a sustained response to steroid treatment. Both had homozygous truncating mutations in the PLCE1 gene and onset of nephrotic syndrome at ages 2 and 12 months, respectively. An Israeli child, treated with cyclosporin A for 2.5 years, was free of proteinuria at age 13 years. A Turkish patient responded to an 8-month course of steroid therapy and had normal serum albumin and creatinine and a near-normal protein/creatinine ratio at age 6 years. Hinkes (2008) noted that these were the first examples of complete therapeutic response patients with a severe form of hereditary nephrotic syndrome. Mapping Hinkes et al. (2006) generated whole-genome haplotype data for 26 consanguineous families with idiopathic nephrotic syndrome, 22 with 1 affected child and 4 with 2 affected children, all of whom were negative for mutations in the nephrin (NPHS1; 602716), podocin (NPHS2; 604766), WT1 (607102), and laminin-beta-2 (LAMB2; 150325) genes. Parametric multipoint analysis of the 4 multiplex families yielded a maximum lod score of 5.1 on chromosome 10q23.32-q24.1, defining a new gene locus for nephrotic syndrome that the authors designated NPHS3. Haplotype analysis revealed a continuous segment of homozygosity in 3 of the multiplex families and 2 of the simplex families; microsatellite analysis of these 5 families delimited a 4.0-Mb critical region between markers A1717632 and A1715598. Candidate genes in the region included PLCE1 (608414), which was found to have 10- to 11-fold higher expression in glomeruli compared with renal cortex or medulla and approximately 6-fold higher expression in podocyte-containing glomeruli compared with podocyte-depleted glomeruli. Molecular Genetics Hinkes et al. (2006) analyzed the PLCE1 gene in 7 consanguineous kindreds with early-onset nephrotic syndrome and homozygosity for microsatellites at the NPHS3 locus on chromosome 10q23.32-q24.1 and identified 7 different homozygous mutations. All 12 affected individuals from 6 kindreds with truncating mutations (608414.0001-608414.0006, respectively) presented with proteinuria by age 4 and developed gross proteinuria and edema; 9 of the 12 progressed to end-stage renal disease by 5 years of age. Renal histopathology was performed in 8 individuals with truncating mutations and all had diffuse mesangial sclerosis. In contrast, renal biopsy in the 2 sibs with a homozygous missense mutation (608414.0007) showed focal segmental glomerulosclerosis; in these patients, the onset of proteinuria was comparatively late (8.8 years and 2.0 years, respectively), as was the age of onset for ESRD (12.0 years and 4.0 years, respectively). Including the patients reported by Hinkes et al. (2006), Gbadegesin et al. (2008) found homozygous PLCE1 mutations in 10 (28.6%) of 35 families with NPHS3 and diffuse mesangial sclerosis. Three (8.5%) of the families had mutations in the WT1 gene (see NPHS4, 256370). Boyer et al. (2010) identified homozygous or compound heterozygous mutations in the PLCE1 gene (see, e.g., 608414.0008-608414.0010) in affected individuals from 12 (18%) of 68 families with early-onset steroid-resistant nephrotic syndrome and 3 (7%) of 44 patients with sporadic disease. Among the 12 families, renal biopsy showed FSGS in 6 and DMS in 5; 1 family had no biopsy results. Among the whole cohort, PLCE1 mutations were found in 12% of families with FSGS and 50% of families with DMS. There were no apparent genotype/phenotype correlations, but patients with DMS had a worse prognosis compared to those with FSGS. However, 3 unrelated individuals who were not affected were found to carry homozygous mutations that caused disease in their respective families, suggesting that additional factors are necessary to disease to occur. Nomenclature In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic terms 'focal segmental glomerulosclerosis' (FSGS) and 'diffuse mesangial sclerosis' have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. INHERITANCE \- Autosomal recessive GENITOURINARY Kidneys \- Nephrotic syndrome \- Diffuse mesangial sclerosis \- Focal segmental glomerulosclerosis MUSCLE, SOFT TISSUES \- Edema LABORATORY ABNORMALITIES \- Proteinuria \- Hypoalbuminemia MISCELLANEOUS \- Onset in infancy or childhood \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the phospholipase C, epsilon-1 gene (PLCE1, 608414.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEPHROTIC SYNDROME, TYPE 3	c1868672	5,424	omim	https://www.omim.org/entry/610725	2019-09-22T16:04:11	{"doid": ["0080382"], "mesh": ["C536404"], "omim": ["610725"], "orphanet": ["656"], "synonyms": ["Alternative titles", "NEPHROTIC SYNDROME, EARLY-ONSET, TYPE 3"]}
Cytomegalovirus esophagitis SpecialtyGastroenterology, Infectious disease Cytomegalovirus esophagitis is a form of esophagitis associated with cytomegalovirus.[1] Symptoms include dysphagia, upper abdominal pain, diarrhea, nausea, vomiting, and sometimes hematemesis. This condition occurs in the setting of patients with a weakened immune system who are susceptible to both infections by CMV and the manifestation of symptoms. A large majority of patient that have CMV Esophagitis are diagnosed with HIV. Another significant segment of the population have weakened immune systems through transplant surgery, diabetes, or due to medication. Diagnosis is done primarily by endoscopy with biopsy, as CMV Esophagitis has a distinctive pathology pattern of linear ulcers.[2] ## Contents * 1 Signs and Symptoms * 2 Transmission * 3 Diagnosis * 4 Pathology * 5 Treatment * 6 References * 7 External links ## Signs and Symptoms[edit] 1. Dysphagia: Difficulty or pain while swallowing 2. Hematemesis: Blood while vomiting 3. Abdominal Pain: Pain in the upper abdominal area, usually exacerbated by swallowing. Pain can also manifest as heartburn symptoms 4. Nausea/vomiting 5. Fever [3] ## Transmission[edit] There are multiple ways cytomegalovirus can be transmitted. Mother to child transmission is common after childbirth. It can also be spread through blood or sex. Transmission via salvia, tears, or skin contact is rare.[4] ## Diagnosis[edit] The most effective diagnostic tool for CMV is endoscopy with biopsy. Generally on inspection of the esophagus large punched out lesions are seen in the middle part of the esophagus. Further histological evaluation of the lesions demonstrates enlarged cells in the sub-epithelial layer with inclusions within the cell's nucleus and its cytoplasm. In addition to the histological examination fluorescent staining with an immunoperoxidase stain is highly specific. Radiologic imaging techniques such as X-Rays or CT Scans are not effective in diagnosing CMV Esophagitis but can identify any resulting strictures or fistulas.[5] ## Pathology[edit] Marcoscopy On a macroscopic basis CMV Esophagitis may appear to be punched out lesions Microscopy Histology of CMV Esophagitis demonstrates enlarged cells with inclusions within both the cytoplasm and the nucleus of the cell. Also aggregates of macrophage cells are common on microscopic examination.[5] ## Treatment[edit] Treatment revolves around intravenous treatment of ganciclovir. Alternate treatments involve valganciclovir, or foscarnet. All of these medication can cause nausea, diarrhea, fever, loss of appetite. Rarer side effects include anemia and tremors.[6] ## References[edit] 1. ^ Meinhard Classen; G. N. J. Tytgat; Charles J. Lightdale (2010). Gastroenterological Endoscopy. Thieme. pp. 490–. ISBN 978-3-13-125852-6. Retrieved 3 November 2010. 2. ^ Robbins and Cotran pathologic basis of disease. Kumar, Vinay, 1944-, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A. (Ninth ed.). Philadelphia, PA. 2014. ISBN 9781455726134. OCLC 879416939.CS1 maint: others (link) 3. ^ Marques, Susana; Carmo, Joana; Pinto, Daniel; Bispo, Miguel; Ramos, Sância; Chagas, Cristina (2017). "Cytomegalovirus Disease of the Upper Gastrointestinal Tract: A 10-Year Retrospective Study". GE - Portuguese Journal of Gastroenterology. 24 (6): 262–268. doi:10.1159/000479232. ISSN 2341-4545. PMC 5731150. PMID 29255766. 4. ^ "About Cytomegalovirus and Congenital CMV Infection \| CDC". www.cdc.gov. 2019-11-04. Retrieved 2019-11-19. 5. ^ a b Zaidi, Syed Ali; Cervia, Joseph S. (April 2002). "Diagnosis and Management of Infectious Esophagitis Associated with Human Immunodeficiency Virus Infection". Journal of the International Association of Physicians in AIDS Care. 1 (2): 53–62. doi:10.1177/154510970200100204. ISSN 1545-1097. PMID 12942677. S2CID 38823534. 6. ^ Parente, F.; Porro, Bianchi (March 1998). "Treatment of Cytomegalovirus Esophagitis in Patients With Acquired Immune Deficiency Syndrome: A Randomized Controlled Study of FoscarnetVersusGanciclovir". American Journal of Gastroenterology. 93 (3): 317–322. ISSN 0002-9270. PMID 9517631. ## External links[edit] Classification D External resources * eMedicine: article/1952121 * v * t * e Infectious diseases – viral systemic diseases Oncovirus DNA virus HBV Hepatocellular carcinoma HPV Cervical cancer Anal cancer Penile cancer Vulvar cancer Vaginal cancer Oropharyngeal cancer KSHV Kaposi's sarcoma EBV Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin lymphoma Follicular dendritic cell sarcoma Extranodal NK/T-cell lymphoma, nasal type MCPyV Merkel-cell carcinoma RNA virus HCV Hepatocellular carcinoma Splenic marginal zone lymphoma HTLV-I Adult T-cell leukemia/lymphoma Immune disorders * HIV * AIDS Central nervous system Encephalitis/ meningitis DNA virus Human polyomavirus 2 Progressive multifocal leukoencephalopathy RNA virus MeV Subacute sclerosing panencephalitis LCV Lymphocytic choriomeningitis Arbovirus encephalitis Orthomyxoviridae (probable) Encephalitis lethargica RV Rabies Chandipura vesiculovirus Herpesviral meningitis Ramsay Hunt syndrome type 2 Myelitis * Poliovirus * Poliomyelitis * Post-polio syndrome * HTLV-I * Tropical spastic paraparesis Eye * Cytomegalovirus * Cytomegalovirus retinitis * HSV * Herpes of the eye Cardiovascular * CBV * Pericarditis * Myocarditis Respiratory system/ acute viral nasopharyngitis/ viral pneumonia DNA virus * Epstein–Barr virus * EBV infection/Infectious mononucleosis * Cytomegalovirus RNA virus * IV: Human coronavirus 229E/NL63/HKU1/OC43 * Common cold * MERS coronavirus * Middle East respiratory syndrome * SARS coronavirus * Severe acute respiratory syndrome * SARS coronavirus 2 * Coronavirus disease 2019 * V, Orthomyxoviridae: Influenza virus A/B/C/D * Influenza/Avian influenza * V, Paramyxoviridae: Human parainfluenza viruses * Parainfluenza * Human orthopneumovirus * hMPV Human digestive system Pharynx/Esophagus * MuV * Mumps * Cytomegalovirus * Cytomegalovirus esophagitis Gastroenteritis/ diarrhea DNA virus Adenovirus Adenovirus infection RNA virus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNA virus HBV (B) RNA virus CBV HAV (A) HCV (C) HDV (D) HEV (E) HGV (G) Pancreatitis * CBV Urogenital * BK virus * MuV * Mumps * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Cytomegalovirus esophagitis	c0877119	5,425	wikipedia	https://en.wikipedia.org/wiki/Cytomegalovirus_esophagitis	2021-01-18T18:41:22	{"wikidata": ["Q5201362"]}
## Description Hydroxyproline is an imino acid normally present in human plasma. It is derived primarily from endogenous collagen turnover and the breakdown of dietary collagen. The finding of elevated (5- to 10-fold increase from the normal of less than 50 micromoles) serum hydroxyproline is thought to be an inherited defect in the catabolism of hydroxyproline. Clinical Features Elevated serum hydroxyproline appears not to cause any significant clinical symptoms. Pelkonen and Kivirikko (1970) described hydroxyprolinemia in a brother and sister. No clinical abnormality was present and the authors suggested that hydroxyprolinemia, like cystathioninuria, is a 'non-disease.' Phang and Scriver (1989) stated that 'there is no evidence that the metabolic phenotype is a cause of clinical manifestation.' Bias of ascertainment is introduced by the fact that the hyperhydroxyprolinemia is found in patients investigated because of abnormality. They knew of reports of 6 probands. Kim et al. (1997) prospectively studied a girl with untreated hydroxyprolinemia identified on neonatal screening and compared her with her unaffected dizygotic twin sister. In the affected twin, plasma and urine hydroxyproline were increased 10-fold and 100-fold, respectively. Both girls had normal growth. On neuropsychologic testing, the affected twin was within normal limits, performing slightly better than her sister on verbal achievement but less well on visual perceptual testing. Kim et al. (1997) concluded that hydroxyprolinemia caused no physical or cognitive deficits. They could not rule out a possible effect on visual perceptual functioning. Inheritance Even when only 1 case, in a female, was reported, this condition was thought to be an autosomal recessive because of its nature as an inborn error of metabolism and because the parents were thought to have been sibs (Scriver and Efron, 1972). Pathogenesis In vivo studies indicate a deficiency of hydroxy-L-proline oxidase, the enzyme that catalyzes the first step in the catabolic pathway, oxidizing hydroxyproline to delta(1)-pyrroline-3-hydroxy-5-carboxylic acid (Scriver and Efron, 1972; Phang et al., 2001). History Hydroxyprolinemia was originally thought to result in mental retardation. Efron et al. (1965) described a clinical syndrome in which mental retardation and microscopic hematuria were present. A defect in hydroxyproline oxidase was proposed (Efron et al., 1965). Scriver and Efron (1972) described another case with mental retardation observed by Noel Raine in Birmingham, England. However, the authors admitted that there may be no relation between the 2 findings, as the mother had mental retardation with normal hydroxyproline levels, and the child was believed to be born of related parents. Roesel et al. (1979) reported affected sisters. The proband was a 51-year-old mentally retarded woman with episodic psychotic behavior. She had shown regression after meningitis at age 15 months and was institutionalized at age 30. One sister died in a psychiatric institution. The second sister with documented hydroxyprolinemia was seemingly not retarded. The sisters excreted 33 and 21% of an oral hydroxyproline load; their mother excreted 5.4%. Deficiency of hydroxyproline oxidase was indicated by the lack of delta-1-pyrroline-3-hydroxy-5-carboxylic acid excretion. Urinary glycolate and oxalate did not increase during the loading test. Misc \- Clinical disease association unproved GU \- Microscopic hematuria Neuro \- Mental retardation \- Episodic psychotic behavior Lab \- 4-hydroxy-L-proline oxidase deficiency \- Hydroxyprolinemia Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYDROXYPROLINEMIA	c0268531	5,426	omim	https://www.omim.org/entry/237000	2019-09-22T16:26:54	{"mesh": ["C562669"], "omim": ["237000"], "icd-10": ["E72.59"], "synonyms": ["Alternative titles", "4-HYDROXY-L-PROLINE OXIDASE DEFICIENCY"]}
Lenz microphthalmia syndrome is one of a group of genetic disorders known as syndromic microphthalmia. These conditions involve abnormal development of the eyes and several other parts of the body. Eye symptoms may include underdeveloped (small)or absent eyes, clouding of the lens (cataracts), uncontrolled eye movements (nystagmus),a gap or split in structures that make up the eye (coloboma) and glaucoma. These symptoms may affect one or both eyes and may cause vision loss or blindness. Other signs and symptoms may include abnormalities of the ears, teeth, hands, skeleton, urinary system, brain and heart. Around 60% of people with this condition have delayed development or intellectual disability ranging from mild to severe. There are at least 10 different types of syndromic microphthalmia that are caused by mutations in different genes. Most cases of Lenz microphthalmia are caised by mutations of the BCOR gene and are inherited in an X-linked recessive pattern. Other forms of syndromic microphthalmia are inherited in different patterns depending on the gene involved. There is no specific treatment for Lenz microphthalmia, and the long term outlook is based on the symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lenz microphthalmia syndrome	c0796016	5,427	gard	https://rarediseases.info.nih.gov/diseases/87/lenz-microphthalmia-syndrome	2021-01-18T17:59:28	{"mesh": ["C537464"], "omim": ["309800"], "umls": ["C0796016"], "orphanet": ["568"], "synonyms": ["Microphthalmia syndromic 1", "MCOPS1", "Lenz dysplasia", "Syndromic microphthalmia type 1", "MAA (formerly)", "Microphthalmia or anophthalmos with associated anomalies (formerly)", "Microphthalmia Lenz type"]}
Tyrosinemia type 3 is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine, a building block of most proteins. This condition is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase, one of the enzymes required for the multi-step process that breaks down tyrosine. This enzyme shortage is caused by mutations in the HPD gene. Characteristic features include intellectual disability, seizures, and periodic loss of balance and coordination (intermittent ataxia). Tyrosinemia type 3 is inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tyrosinemia type 3	c0268623	5,428	gard	https://rarediseases.info.nih.gov/diseases/10332/tyrosinemia-type-3	2021-01-18T17:57:14	{"mesh": ["D020176"], "omim": ["276710"], "umls": ["C0268623"], "orphanet": ["69723"], "synonyms": ["Tyrosinemia type III", "4-alpha hydroxyphenylpyruvic acid oxidase deficiency", "4-alpha hydroxyphenylpyruvate dioxygenase deficiency", "4-hydroxyphenylpyruvate dioxygenase deficiency"]}
A mild subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a variable onset (ranging from infancy to adolescence) of progressive proximal upper and lower limb muscle weakness and atrophy. Mild scapular winging, calf hypertrophy, and lack of respiratory and cardiac involvement are also observed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Telethonin-related limb-girdle muscular dystrophy R7	c1866008	5,429	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=34514	2021-01-23T17:53:36	{"gard": ["10471"], "mesh": ["C566599"], "omim": ["601954"], "umls": ["C1866008"], "icd-10": ["G71.0"], "synonyms": ["Autosomal recessive limb-girdle muscular dystrophy type 2G", "LGMD due to telethonin deficiency", "LGMD type 2G", "LGMD2G", "Limb-girdle muscular dystrophy due to telethonin deficiency", "Limb-girdle muscular dystrophy type 2G", "Telethonin-related LGMD R7"]}
Morse et al. (1987) reported the prenatal diagnosis of a characteristic abnormality in 2 fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. The knees were in extension. Both were male; the parents were normal and not related. The disorder resembled the Neu-Laxova syndrome (256520) in intrauterine growth retardation, multiple joint contractures, severe microcephaly, and recurrence in families. However, the lack of hyperkeratosis or ichthyosis and the resulting characteristic facial appearance, the lack of distal extremity swelling, and the presence of holoprosencephaly distinguished the disorder from the Neu-Laxova syndrome. The validity of the syndrome and the probable X-linked recessive inheritance suggested by Morse et al. (1987) were indicated by the report of Hockey et al. (1988): single cases in each of 3 sibships connected through females were affected with what appeared to be precisely the same disorder. Joints \- Congenital multiple joint contractures Head \- Microcephaly \- Holoprosencephaly Growth \- Intrauterine growth retardation Neuro \- Markedly decreased fetal movement 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HOLOPROSENCEPHALY WITH FETAL AKINESIA/HYPOKINESIA SEQUENCE	c1844016	5,430	omim	https://www.omim.org/entry/306990	2019-09-22T16:18:11	{"mesh": ["C564409"], "omim": ["306990"], "orphanet": ["2570"]}
Not to be confused with Cinchonism. Neuropsychiatric quinism is a chronic encephalopathy due to intoxication by mefloquine, quinacrine, chloroquine. It is associated with brain dysfunction and brainstem dysfunction. It may be confused as posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). In the opinion of one medical author it "may have been widely unrecognized in veteran populations, and its symptoms misattributed to other causes."[1] Symptoms include, but are not limited to, limbic encephalopathy and neurotoxic vestibulopathy.[2] ## Contents * 1 Symptoms * 1.1 Very high probability * 1.2 Moderate probability * 1.3 Prodromal * 2 References ## Symptoms[edit] This neuropsychiatric syndrome is defined by several symptoms that distinguish it from others:[2] ### Very high probability[edit] * delirium * confusion * disorientation ### Moderate probability[edit] * dementia * amnesia * seizures ### Prodromal[edit] * anxiety * depression * sleep disturbance * abnormal dreams * dizziness * vertigo * paresthesias ## References[edit] 1. ^ Nevin, Remington L. (2019). "Neuropsychiatric Quinism: Chronic Encephalopathy Caused by Poisoning by Mefloquine and Related Quinoline Drugs". Veteran Psychiatry in the US. pp. 315–331. doi:10.1007/978-3-030-05384-0_20. ISBN 978-3-030-05383-3. 2. ^ a b Nevin, Remington L.; Leoutsakos, Jeannie-Marie (2017). "Identification of a Syndrome Class of Neuropsychiatric Adverse Reactions to Mefloquine from Latent Class Modeling of FDA Adverse Event Reporting System Data". Drugs in R&D. 17: 199–210. doi:10.1007/s40268-016-0167-3. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Quinism	None	5,431	wikipedia	https://en.wikipedia.org/wiki/Quinism	2021-01-18T18:39:25	{"wikidata": ["Q85795345"]}
Neurological symptom of lack of will or initiative This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Abulia" – news · newspapers · books · scholar · JSTOR (August 2018) In neurology, abulia, or aboulia (from Greek: βουλή, meaning "will"),[1] refers to a lack of will or initiative and can be seen as a disorder of diminished motivation (DDM). Abulia falls in the middle of the spectrum of diminished motivation, with apathy being less extreme and akinetic mutism being more extreme than abulia.[2] The condition was originally considered to be a disorder of the will,[3][4] and aboulic individuals are unable to act or make decisions independently; and their condition may range in severity from subtle to overwhelming. It is also known as Blocq's disease (which also refers to abasia and astasia-abasia).[5] ## Contents * 1 Symptoms and signs * 1.1 Differentiation from other disorders * 2 Causes * 2.1 Damage to the basal ganglia * 2.2 Damage to the capsular genu * 2.3 Damage to anterior cingulate circuit * 2.4 Acute caudate vascular lesions * 3 Diagnosis * 3.1 Illnesses where abulia may be present * 3.2 Alzheimer's disease * 4 Current treatment * 5 Society and culture * 6 See also * 7 References * 8 External links ## Symptoms and signs[edit] The clinical condition denoted abulia was first described in 1838; however, since that time, a number of different, some contradictory, definitions have emerged.[6] Abulia has been described as a loss of drive, expression, behavior and speech output, with slowing and prolonged speech latency, and reduction of spontaneous thought content and initiative.[7] The clinical features most commonly associated with abulia are:[6] * Difficulty in initiating and sustaining purposeful movements * Lack of spontaneous movement * Reduced spontaneous speech * Increased response-time to queries * Passivity * Reduced emotional responsiveness and spontaneity * Reduced social interactions * Reduced interest in usual pastimes Especially in patients with progressive dementia, it may affect feeding.[8] Patients may continue to chew or hold food in their mouths for hours without swallowing it.[8] The behavior may be most evident after these patients have eaten part of their meals and no longer have strong appetites. ### Differentiation from other disorders[edit] Both neurologists and psychiatrists recognize abulia to be a distinct clinical entity, but its status as a syndrome is unclear. Although abulia has been known to clinicians since 1838, it has been subjected to different interpretations – from 'a pure lack of will', in the absence of motor paralysis to, more recently, being considered 'a reduction in action emotion and cognition'.[6] As a result of the changing definition of abulia, there is currently a debate on whether or not abulia is a sign or a symptom of another disease, or its own disease that seems to appear in the presence of other more well-researched diseases, such as Alzheimer's disease.[6] A 2002 survey of two movement disorder experts, two neuropsychiatrists, and two rehabilitation experts, did not seem to shed any light on the matter of differentiating abulia from other DDMs. The experts used the terms "apathy" and "abulia" interchangeably and debated whether or not abulia was a discrete entity, or just a hazy gray area on a spectrum of more defined disorders.[6] Four of the experts said abulia was a sign and a symptom, and the group was split on whether or not it was a syndrome.[6] Another survey, which consisted of true and false questions about what abulia is distinct from, whether it is a sign, symptom, or syndrome, where lesions are present in cases of abulia, what diseases are commonly associated with abulia, and what current treatments are used for abulia, was sent to 15 neurologists and 10 psychiatrists. Most experts agreed that abulia is clinically distinct from depression, akinetic mutism, and alexithymia.[6] However, only 32% believed abulia was different from apathy, while 44% said they were not different, and 24% were unsure. Yet again, there was disagreement about whether or not abulia is a sign, symptom, or syndrome.[6][citation needed] The study of motivation has been mostly about how stimuli come to acquire significance for animals. Only recently has the study of motivational processes been extended to integrate biological drives and emotional states in the explanation of purposeful behavior in human beings. Considering the number of disorders attributed to a lack of will and motivation, it is essential that abulia and apathy be defined more precisely to avoid confusion.[6] ## Causes[edit] Many different causes of abulia have been suggested. While there is some debate about the validity of abulia as a separate disease, experts mostly agree that abulia is the result of frontal lesions and not with cerebellar or brainstem lesions.[6] As a result of more and more evidence showing that the mesolimbic and the mesocortical dopamine system are key to motivation and responsiveness to reward, abulia may be a dopamine-related dysfunction.[7] Abulia may also result from a variety of brain injuries which cause personality change, such as dementing illnesses, trauma, or intracerebral hemorrhage (stroke), especially stroke causing diffuse injury to the right hemisphere.[9][10] ### Damage to the basal ganglia[edit] Injuries to the frontal lobe and/or the basal ganglia can interfere with an individual's ability to initiate speech, movement, and social interaction. Studies have shown that 5-67% of all patients with traumatic brain injuries and 13% of patients with lesions on their basal ganglia suffer from some form of diminished motivation.[2] It may complicate rehabilitation when a stroke patient is uninterested in performing tasks like walking despite being capable of doing so. It should be differentiated from apraxia, when a brain injured patient has impairment in comprehending the movements necessary to perform a motor task despite not having any paralysis that prevents performing the task; that condition can also result in lack of initiation of activity. ### Damage to the capsular genu[edit] A case study involving two patients who suffered from acute confusional state and abulia was conducted to see if these symptoms were the result of an infarct in the capsular genu. Using clinical neuropsychological and MRI evaluations at baseline and one year later showed that the cognitive impairment was still there one year after the stroke. Cognitive and behavioral alterations due to a genu infarct are most likely because the thalamo-cortical projection fibers that originate from the ventral-anterior and medial-dorsal nuclei traverse the internal capsule genu. These tracts are part of a complex system of cortical and subcortical frontal circuits through which the flow of information from the entire cortex takes place before reaching the basal ganglia. Cognitive deterioration could have occurred through the genu infarcts affecting the inferior and anterior thalamic peduncles. The interesting thing about this case study was that the patients did not show any functional deficit at the follow-up one year after the stroke and were not depressed but did show diminished motivation. This result supports the idea that abulia may exist independently of depression as its own syndrome.[11] ### Damage to anterior cingulate circuit[edit] The anterior cingulate circuit consists of the anterior cingulate cortex, also referred to as Brodmann area 24, and its projections to the ventral striatum which includes the ventromedial caudate. The loop continues to connect to the ventral pallidum, which connects to the ventral anterior nucleus of the thalamus. This circuit is essential for the initiation of behavior, motivation and goal orientation, which are the very things missing from a patient with a disorder of diminished motivation. Unilateral injury or injury along any point in the circuit leads to abulia regardless of the side of the injury, but if there is bilateral damage, the patient will exhibit a more extreme case of diminished motivation, akinetic mutism.[9] ### Acute caudate vascular lesions[edit] It is well documented that the caudate nucleus is involved in degenerative diseases of the central nervous system such as Huntington disease. In a case study of 32 acute caudate stroke patients, 48% were found to be experiencing abulia. Most of the cases where abulia was present were when the patients had a left caudate infarct that extended into the putamen as seen through a CT or MRI scan.[12] ## Diagnosis[edit] Diagnosis for abulia can be quite difficult because it falls between two other disorders of diminished motivation, and one could easily see an extreme case of abulia as akinetic mutism or a lesser case of abulia as apathy and therefore, not treat the patient appropriately. If it were to be confused with apathy, it might lead to attempts to involve the patient with physical rehabilitation or other interventions where a source of strong motivation would be necessary to succeed but would still be absent. The best way to diagnose abulia is through clinical observation of the patient as well as questioning of close relatives and loved ones to give the doctor a frame of reference with which they can compare the patient's new behavior to see if there is in fact a case of diminished motivation.[7] In recent years, imaging studies using a CT or MRI scan have been shown to be quite helpful in localizing brain lesions which have been shown to be one of the main causes of abulia.[6] ### Illnesses where abulia may be present[edit] * Normal Pressure Hydrocephalus * Depression * Schizophrenia * Frontotemporal dementia * Parkinson's disease * Huntington's disease * Pick's disease * Progressive supranuclear palsy * Traumatic brain injury * Stroke ### Alzheimer's disease[edit] A lack of motivation has been reported in 25–50% of patients with Alzheimer's disease. While depression is also common in patients with this disease, abulia is not a mere symptom of depressions because more than half of the patients with Alzheimer's disease with abulia do not suffer from depression. Several studies have shown that abulia is most prevalent in cases of severe dementia which may result from reduced metabolic activity in the prefrontal regions of the brain. Patients with Alzheimer's disease and abulia are significantly older than patients with Alzheimer's who do not lack motivation. Going along with that, the prevalence of abulia increased from 14% in patients with a mild case Alzheimer's disease to 61% in patients with a severe case of Alzheimer's disease, which most likely developed over time as the patient got older.[8] ## Current treatment[edit] Most current treatments for abulia are pharmacological, including the use of antidepressants. However, antidepressant treatment is not always successful and this has opened the door to alternative methods of treatment. The first step to successful treatment of abulia, or any other DDM, is a preliminary evaluation of the patient's general medical condition and fixing the problems that can be fixed easily. This may mean controlling seizures or headaches, arranging physical or cognitive rehabilitation for cognitive and sensorimotor loss, or ensuring optimal hearing, vision, and speech. These elementary steps also increase motivation because improved physical status may enhance functional capacity, drive, and energy and thereby increase the patient's expectation that initiative and effort will be successful.[2] There are 5 steps to pharmacological treatment:[2] 1. Optimize medical status. 2. Diagnose and treat other conditions more specifically associated with diminished motivation (e.g., apathetic hyperthyroidism, Parkinson's disease). 3. Eliminate or reduce doses of psychotropics and other agents that aggravate motivational loss (e.g., SSRIs, dopamine antagonists). 4. Treat depression efficaciously when both DDM and depression are present. 5. Increase motivation through use of stimulants, dopamine agonists, or other agents such as cholinesterase inhibitors. ## Society and culture[edit] A case of abulia after a transient ischemic attack in the frontal lobes is depicted in the episode "House Training" of the drama series House, M.D.. ## See also[edit] * Avolition ## References[edit] 1. ^ Bailly, A. (2000). Dictionnaire Grec Français, Éditions Hachette. 2. ^ a b c d Marin, R. S., & Wilkosz, P. A. (2005). Disorders of diminished motivation Archived 2012-11-22 at the Wayback Machine. Journal of Head Trauma Rehabilitation, 20(4), 377-388. 3. ^ Berrios G.E. and Gili M. (1995) Will and its disorders. A conceptual history. History of Psychiatry 6: 87-104 4. ^ Berrios G.E. and Gili M. (1995) Abulia and impulsiveness revisited. Acta Psychiatrica Scandinavica 92: 161-167 5. ^ Robinson, Victor, ed. (1939). "Bloq's disease, abulia, defined and described under the entry for abasia". The Modern Home Physician, A New Encyclopedia of Medical Knowledge. WM. H. Wise & Company (New York)., page 1. 6. ^ a b c d e f g h i j k Vijayaraghavan, L., Krishnamoorthy, E. S., Brown, R. G., & Trimble, M. R. (2002). Abulia: A Delphi survey of British neurologists and psychiatrists. [Article]. Movement Disorders, 17(5), 1052-1057. 7. ^ a b c Jahanshahi, M., & Frith, C. D. (1998). Willed action and its impairments. [Review]. Cognitive Neuropsychology, 15(6-8), 483-533.. 8. ^ a b c Starkstein, S. E., & Leentjens, A. F. G. (2008). The nosological position of apathy in clinical practice. [Review]. Journal of Neurology, Neurosurgery, and Psychiatry, 79(10), 1088-1092. 9. ^ a b Grunsfeld, A. A., & Login, I. S. (2006). Abulia following penetrating brain injury during endoscopic sinus surgery with disruption of the anterior cingulate circuit: Case report. [Article]. Bmc Neurology, 6, 4. 10. ^ Kile, S. J., Camilleri, C. C., Latchaw, R. E., & Tharp, B. R. (2006). Bithalamic lesions of butane encephalopathy. [Article]. Pediatric Neurology, 35(6), 439-441. 11. ^ Pantoni, L., Basile, A. M., Romanelli, M., Piccini, C., Sarti, C., Nencini, P., et al. (2001). Abulia and cognitive impairment in two patients with capsular genu infarct. [Article]. Acta Neurologica Scandinavica, 104(3), 185-190. 12. ^ Kumral, E., Evyapan, D., & Balkir, K. (1999). Acute caudate vascular lesions. [Article]. Stroke, 30(1), 100-108. ## External links[edit] * The dictionary definition of abulia at Wiktionary * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Abulia	c0919974	5,432	wikipedia	https://en.wikipedia.org/wiki/Abulia	2021-01-18T18:44:32	{"wikidata": ["Q335941"]}
A rare parenchymal liver disease characterized by progressive fibrosis of the portal tracts due to arrest of maturation of the ductal plate of the intrahepatic bile ducts. Clinically, it may manifest as a portal hypertensive, cholangitic, mixed, or latent form. Onset of symptoms is mostly in adolescence or young adulthood. Hepatocellular function is relatively well preserved. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Isolated congenital hepatic fibrosis	None	5,433	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=485426	2021-01-23T17:27:33	{"synonyms": ["Isolated CHF"]}
A number sign (#) is used with this entry because of evidence that palmoplantar keratoderma and woolly hair (PPKWH) is caused by homozygous mutation in the KANK2 gene (614610) on chromosome 19p13. Clinical Features Ramot et al. (2014) studied 2 consanguineous Arab families with keratoderma and woolly hair, 1 of which (family 1) had previously been reported (family B) by Djabali et al. (2002). All 7 patients presented with a variable degree of striate palmoplantar keratoderma, which was generally more severe on the soles. Leukonychia was more pronounced on the fingernails than toenails. Scalp hair, body hair, eyebrows, and eyelashes were sparse, and 2 patients also exhibited woolly hair. The fifth toes showed variable degrees of pseudoainhum, ranging from external rotation to a deep sulcus at the digitoplantar fold, accompanied by a bulbous appearance of the distal toe. Symptoms appeared to be more severe with advancing age, suggesting a progressive course of the disease. The patients reported no dyspnea, syncope, or weakness, and there was no family history of early sudden death. Electrocardiography was normal in all patients, and echocardiography in the oldest patient from each family was also normal. Skin biopsy from 1 patient showed nonepidermolytic keratoderma with regular acanthosis and a normal granular layer. Molecular Genetics In a consanguineous Arab family with palmoplantar keratoderma and woolly hair, originally reported by Djabali et al. (2002), Ramot et al. (2014) performed exome sequencing and identified homozygosity for a missense mutation in the KANK2 gene (A670V; 614610.0001). The mutation segregated with disease in this family as well as in a second Arab family that had a similar phenotype and came from the same geographic region. Screening of 100 ethnically and geographically matched controls revealed 1 individual who was heterozygous for the mutation, which was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Sparse scalp hair \- Woolly scalp hair Eyes \- Sparse eyebrows \- Sparse eyelashes SKIN, NAILS, & HAIR Skin \- Keratoderma, striated, on palms \- Keratoderma of soles at pressure points \- Pseudoainhum of fifth toes Skin Histology \- Nonepidermolytic keratoderma \- Regular acanthosis \- Normal granular layer Nails \- Leukonychia, more pronounced on fingernails than toenails Hair \- Sparse scalp hair \- Woolly scalp hair (in some patients) \- Sparse body hair MISCELLANEOUS \- Progressive disorder, with older patients exhibiting more severe symptoms \- Based on report of 2 consanguineous Arab families (last curated November 2014) MOLECULAR BASIS \- Caused by mutation in the KN motif- and ankyrin repeat domain-containing protein 2 gene (KANK2, 614610.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	PALMOPLANTAR KERATODERMA AND WOOLLY HAIR	c4015202	5,434	omim	https://www.omim.org/entry/616099	2019-09-22T15:49:55	{"omim": ["616099"], "orphanet": ["420686"], "synonyms": ["KWWH type IV", "Keratoderma with woolly hair type IV", "Woolly hair-palmoplantar hyperkeratosis syndrome"]}
17q12 duplication occurs when a person has an extra copy of a portion of chromosome 17. Our genetic information is organized in structures called chromosomes. People with 17q12 duplication have an extra piece of genetic information from chromosome 17. Some people with this duplication do not have any signs or symptoms. Other people may have symptoms including intellectual disability, developmental delay, and behavioral challenges. Some people with 17q12 duplication may also have vision problems. Rarely, people with 17q12 duplication may also have other health problems, such as problems with the heart or kidneys. 17q12 duplication occurs when a portion of chromosome 17 is duplicated. When the duplication is inherited from a parent, it is inherited in an autosomal dominant manner. The duplication may be suspected if a doctor sees signs and symptoms such as developmental delay, behavioral problems, and intellectual disability. Genetic testing using chromosomal microarray (CMA) may confirm the diagnosis. Treatment options may include physical, occupational, and speech therapies, as well as management by a psychiatrist or psychologist to assist with any behavioral challenges. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	17q12 duplication	c3281137	5,435	gard	https://rarediseases.info.nih.gov/diseases/13296/17q12-duplication	2021-01-18T18:02:26	{"omim": ["614526"], "orphanet": ["261272"], "synonyms": ["Chromosome 17q12 duplication syndrome", "Recurrent duplication of 17q12", "Dup(17)(q12)", "17q12 microduplication syndrome", "17q12 microduplication", "Trisomy 17q12"]}
HIV/AIDS in Bhutan remains a relatively rare disease among its population. It has, however, grown into an issue of national concern since Bhutan's first reported case in 1993. Despite preemptive education and counseling efforts, the number of reported HIV/AIDS cases has climbed since the early 1990s. This prompted increased government efforts to confront the spread of the disease through mainstreaming sexually transmitted disease (STD) and HIV prevention, grassroots education, and the personal involvement of the Bhutanese royal family in the person of Queen Mother Sangay Choden.[1] ## Contents * 1 Infection rates and patterns * 2 Treatment * 3 History * 4 See also * 5 References ## Infection rates and patterns[edit] In 2011, there were 246 reported cases of HIV in Bhutan, representing just over 0.03% of the population.[2] In July 2010, there were a total of 217 cases detected, however Health Ministry sources indicated actual numbers were estimated at more than 500 by UNAIDS.[3] Infection rates had remained modest though increasing, climbing from 185 reported cases, or 0.026% of the population, in early 2010. The Ministry of Health attributed climbing numbers to promiscuity, drug use, and the prevalence of HIV/AIDS in neighbouring countries.[4]:4 In 2010, almost 91% of HIV infections among Bhutanese were attributed to multiple partners and lack of condom use.[3] As of 2010, Bhutan had not implemented any needle and syringe programs.[1]:19 Persons living with HIV/AIDS in Bhutan include all social groups, including government employees, businessmen, farmers, soldiers, monks, sex workers and housewives. In 2010, housewives presented 61 of 217 known cases, while sex workers presented 10.[3] Persons between the ages of 15 and 29 accounted for half of those reportedly living with HIV/AIDS in 2010. In Bhutan, HIV/AIDS is detections come about primarily through contact tracing and routine medical checks.[3] Urban areas such as Thimphu, home to bars, karaoke, discos, and hotels, show the greatest propensity for the spread of HIV/AIDS. Kuensel estimated there were some 266 sex workers in Thimphu alone.[5] Through 2010, 40 people died due to HIV/AIDS-related causes, and one committed suicide.[3]:6 ## Treatment[edit] HIV/AIDS treatment and counseling are available exclusively under the Bhutanese universal health care system.[1]:27 In 2010, 46 of the known 217 living with HIV/AIDS were receiving treatment.[3] Issues of treatment, counseling, and behavioral compliance among HIV-positive persons have become a matter of public debate.[6] Unlike most of its neighbors, Bhutan has never conducted any serological or behavioral surveillance of its at-risk populations.[1]:35 Persons living with HIV/AIDS in Bhutan carry a social stigma and often face discrimination, including disowning and unemployment, because it is a sexually-transmitted disease.[7][8][9][10] Despite the prevalence of promiscuity in Bhutanese society, those infected often remain silent for fear discrimination in an otherwise conservative society. Both the government[3][4][11] and media in Bhutan[9][12] have recognized the need to address social stigma, which hampers prevention, by educating and counseling the general population. Lhak-sam, a non-governmental organization, was founded in Thimphu in 2009 by HIV-positive Bhutanese to further education and prevention of HIV/AIDS. A large number of its members are unemployed.[7][13] ## History[edit] Although there were no reported cases of acquired immune deficiency syndrome (AIDS) through the early 1990s, the Department of Public Health set up a public awareness program in 1987. With the encouragement of the WHO, a "reference laboratory" was established at the Thimphu General Hospital to test for AIDS and human immunodeficiency virus (HIV) as a precautionary measure. To further enhance awareness, representatives of the National Institute of Family Health were sent to Bangladesh in 1990 for training in AIDS awareness and treatment measures.[14] Bhutan's first HIV/AIDS case was detected in 1993.[3][11] In 1999, Queen Mother Sangay Choden assumed the Bhutanese UNFPA ambassadorship, and has been Bhutan's most visible public education campaigner on HIV/AIDS. She has given numerous presentations at public gatherings, at schools and to dropouts, to the military, at monasteries, and in rural communities. The Queen is also responsible for Bhutan's observance of World AIDS Day.[1] On 24 May 2004, the Fourth Druk Gyalpo, King Jigme Singye Wangchuck, promulgated the Royal Decree on HIV Prevention. In it, he called for citizens to participate in HIV prevention while respecting the rights of those living with HIV/AIDS. This was followed by another Royal Edict in 2004 on HIV/AIDS. Before ascending the throne, future Fifth Druk Gyalpo Jigme Khesar Namgyal Wangchuck advocated abstinence by rejecting "undesirable activities" and demonstrate compassion to those living with the disease.[1] ## See also[edit] * Health in Bhutan * HIV/AIDS in Asia ## References[edit] 1. ^ a b c d e f HIV/AIDS in the South-East Asia Region: progress report 2010 (PDF) (Report). World Health Organization, Regional Office for South-East Asia. 2010. pp. 43–45. ISBN 978-92-9022-389-4. Archived from the original (PDF) on 2011-07-06. Retrieved 2011-11-21. 2. ^ "The Ministry of Health has Detected…". Bhutan Observer online. 2011-08-01. Retrieved 2011-11-21. 3. ^ a b c d e f g h "An Update on Human Immuno Deficiency Virus/Acquired Immuno Deficiency Syndrome (HIV/AIDS)" (PDF). Bhutan Ministry of Health. 2010-07-01. Archived from the original (PDF) on 2012-05-08. Retrieved 2011-11-22. 4. ^ a b Annual Health Bulletin 2010 (PDF) (Report). Ministry of Health (Government of Bhutan). 2010. ISBN 978-99936-767-2-0. Archived from the original (PDF) on 2011-07-06. Retrieved 2011-03-10. 5. ^ Pokhrel, Nirmala (2011-02-26). "Thimphu Survey Shows High Risk Sexual Conduct". Kuensel online. Retrieved 2011-11-21.[permanent dead link] 6. ^ Wangchuk, Sonam (2011-08-19). "Sex, Disease, and Criminality". Bhutan Observer online. Archived from the original on 2011-11-19. Retrieved 2011-11-21. 7. ^ a b "Lhaksam ལྷག་བསམ། Bhutan Network of Positive People". Retrieved 2011-11-21. 8. ^ Pelden, Sonam (2011-02-21). "A – The covert status of this support group NGO reflects the society it exists in". Kuensel online. Retrieved 2011-11-21.[permanent dead link] 9. ^ a b Pelden, Sonam (2011-11-21). "To Come out of the Closet or Not?". Kuensel online. Retrieved 2011-11-21.[permanent dead link] 10. ^ Pelden, Sonam (2011-10-15). "No Law in Place to Protect Their Rights". Archived from the original on 2011-10-22. Retrieved 2011-11-21. 11. ^ a b "History: National STI and HIV/AIDS" (PDF). Bhutan Ministry of Health. p. 2. Archived from the original (PDF) on 2012-05-08. Retrieved 2011-11-21. 12. ^ "Editorial: Living with HIV/AIDS". Kuensel online. 2011-02-23. Retrieved 2011-11-21.[permanent dead link] 13. ^ Pelgen, Ugyen (2011-10-01). "IMS Builds Capacity for Lhaksam (HIV – NGO)". Bhutan Times online. Archived from the original on 2012-04-20. Retrieved 2011-11-21. 14. ^ Robert L. Worden (September 1991). Andrea Matles Savada (ed.). Bhutan: A country study. Federal Research Division. Health. This article incorporates text from this source, which is in the public domain. * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal 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δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HIV/AIDS in Bhutan	None	5,436	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Bhutan	2021-01-18T19:05:45	{"wikidata": ["Q5629821"]}
Galton et al. (1974) described patients with obesity resulting from a defect in triglyceride breakdown. In the form of triglyceride storage disease they called type II, both the beta-adrenergic receptor and adenyl cyclase were intact as judged by a normal increment in tissue levels of cyclic AMP on treatment with isoprenaline. However, cyclic AMP did not activate triglyceride-lipase with the expected release of glycerol from the tissues. The defect was found in a 60-year-old woman, her daughter and her eldest sister, whereas her nonidentical twin sister and brother responded the same as did obese control subjects. In type I disease (190420), noradrenaline poorly stimulated the activity of adenyl cyclase in tissues, suggesting a defect either in the beta-adrenergic receptor or in adenyl cyclase itself. Type III disease is Wolman disease (278000). In 2 Nigerian sibs, Galton et al. (1976) described a different type of triglyceride storage disease manifested by microcephaly, nystagmus, deafness and hepatomegaly in addition to triglyceride deposits in peripheral adipose tissue despite severe malnutrition. Growth \- Obesity Lab \- Defect in triglyceride breakdown \- Intact beta-adrenergic receptor and adenyl cyclase Inheritance \- ? Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	TRIGLYCERIDE STORAGE DISEASE, TYPE II	c1860820	5,437	omim	https://www.omim.org/entry/190430	2019-09-22T16:32:17	{"mesh": ["C566030"], "omim": ["190430"]}
Kowarski syndrome Other namesShort stature due to growth hormone qualitative anomaly This condition is inherited in an autosomal recessive manner. Kowarski syndrome[1] describes cases of growth failure (height and bone age two standard deviations below the mean for age), despite the presence of normal or slightly high blood growth hormone by radioimmunoassay (RIA-GH) and low serum IGF1 (formerly called somatomedin), and who exhibit a significant increase in growth rate following recombinant GH therapy.[2] ## Contents * 1 Cause * 2 Diagnosis * 2.1 Diagnostic criteria * 2.2 Reliability of testing * 3 References * 4 External links ## Cause[edit] Allen Avinoam Kowarski et al.[3] described the first two cases of the Kowarski syndrome in 1978. The group speculated that their patients' growth impairment was caused by a mutation in the growth hormone gene, which altered the structure of their secreted growth hormone, reducing its biological activity while retaining its ability to bind the antibodies used in the RIA-GH. Their RIA-GH measured growth hormone of reduced bioactivity. The children retained the ability to respond to treatment with active growth hormone.[citation needed] The speculation of Kowarski et al. was confirmed by Valenta et al in 1985, Takahshi et al in 1996 and 1997 and Besson et al in 2005. Valenta et al[4] studied a case of Kowarski syndrome where they confirmed a structural abnormality of the growth hormone molecule. 60 to 90% of circulating growth hormone of the patient was in the form of tetramers and dimers (normal, 14% to 39% in plasma) and the patients' growth hormone polymers were abnormally resistant to conversion into monomers by urea. Takahashi et al.[5] reported a case of a boy with short stature who was heterozygous for a mutation in the GH1 gene. In this child, growth hormone not only could not activate the GH receptor (GHR) but also inhibited the action of wild type GH because of its greater affinity for GHR and GH-binding protein (GHBP) that is derived from the extracellular domain of the GHR. Thus, a dominant-negative effect was observed.[citation needed] Takahashi et al.[6] demonstrated in a girl with short stature, a biologically inactive growth hormone resulting from a heterozygous mutation in the GH1 gene. At age 3 years, the girl's height was 3.6 standard deviations below the mean for age and sex. Bone age was delayed by 1.5 years. She had a prominent forehead and a hypoplastic nasal bridge with normal body proportions. She showed lack of growth hormone action despite high immunoassayable GH levels in serum and marked catch-up growth to exogenous GH administration. Results of other studies were compatible with the production of a bioinactive GH, which prevented dimerization of the growth hormone receptor, a crucial step in GH signal transduction.[citation needed] Besson et al[7] described in 1955 a Serbian patient with Kowarski syndrome who was homozygous for a mutation in the GH1 gene that disrupted the first disulfide bridge in growth hormone. The parents were each heterozygous for the mutation and were of normal stature.[citation needed] ## Diagnosis[edit] ### Diagnostic criteria[edit] The discovery of the Kowarski syndrome created a dilemma. The first diagnostic test for the syndrome was subjecting the suspected children to six month of growth hormone therapy. Kowarski syndrome was assumed to be a very rare disorder (officially recognized as an “orphan disease”). Researchers could not justify subjecting children to a trial period of growth hormone therapy to confirm the diagnosis of a rare syndrome. There is a need for a reliable and practical diagnostic procedure for the syndrome.[citation needed] ### Reliability of testing[edit] The standard test for growth hormone deficiency is the growth hormone stimulation test. Peak levels of growth hormone below normal are considered confirmation of a growth hormone deficiency. Growth-impaired children with a normal stimulation test were considered suspect for having the Kowarski syndrome that may benefit from treatment with growth hormone.[citation needed] Zadik et al.[8] reported in 1990 that the growth hormone stimulation test is not reliable, suggesting the use of the more reliable 24-hour integrated concentration of growth hormone (IC-GH) as a better test. In 1995, it was also suggested[9] that some cases of the neurosecretory growth failure syndrome might have the Kowarski syndrome. Albertsson-Wikland Kerstin confirmed in 1992[10] that the IC-GH test is a reproducible test for growth hormone deficiency and Carel et al. confirmed in 1997[11] that the reliability of the growth hormone stimulation tests was poor. A 1987 study by Bistrizer et al [12] suggested a diagnostic procedure that may be used to diagnose the Kowarski syndrome. Their study was based on the requirement for the growth hormone molecule to bind a specific binding molecule on the wall of the responsive cells to elicit its activity. Their study demonstrated a decrease ability of the growth hormone from children with the Kowarski syndrome to bind with living IM-9 cells. The test involved measuring the ratio between the levels of growth hormone by a radioreceptor assay (RRA-GH) to the level of growth hormone determined by the established radioimmunoassay (RIA-GH). The study found that the RRA-GH/RIA-GH ratio in NS subjects was normal but significantly below normal (P<0.005) in the Kowarski syndrome patients. The authors proposed the use of their test for the diagnosis of the Kowarski syndrome. Bistrizer, Chalew and Kowarski demonstrated in 1995 [9] that a modified RRA-GH/RIA-GH ratio test was a predictor for the responsiveness of growth-impaired children to growth hormone therapy. The RRA-GH/RIA-GH ratio assay proposed by Bistrizer et al.[9] can be used for screening of patients who may have the Kowarski syndrome thus more likely to respond to Growth Hormone therapy. Advances in the methodology for identifying spot mutations in the DNA of individuals demonstrated that the "Kowarski Syndrome is caused by various mutations in the GH1 gene (17q22-q24) that result in structural GH anomalies and a biologically inactive molecule." Testing individual patient for such mutation is offered on the Internet.[13] ## References[edit] 1. ^ OMIM Database entry for Kowarski syndrome 2. ^ Mullis, 6th ESPE Advanced Seminar in Developmental Endocrinology, Bern, May 10–11, 2012; volume editor, Primus-E. Developmental biology of GH secretion, growth, and treatment. Basel: Karger. p. 75. ISBN 9783318022445. 3. ^ Kowarski AA, Schneider J, Ben-Galim E, Weldon VV, Daughaday WH (August 1978). "Growth failure with normal serum RIA-GH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH". J. Clin. Endocrinol. Metab. 47 (2): 461–4. doi:10.1210/jcem-47-2-461. PMID 263308. 4. ^ Valenta LJ, Sigel MB, Lesniak MA, Elias AN, Lewis UJ, Friesen HG, Kershnar AK (January 1985). "Pituitary dwarfism in a patient with circulating abnormal growth hormone polymers". N. Engl. J. Med. 312 (4): 214–7. doi:10.1056/NEJM198501243120405. PMID 3965948. 5. ^ Takahashi, Yutaka; Kaji, Hidesuke; Okimura, Yasuhiko; Goji, Katsumi; Abe, Hiromi; Chihara, Kazuo (1996). "Short Stature Caused by a Mutant Growth Hormone". New England Journal of Medicine. 334 (7): 432–436. doi:10.1056/NEJM199602153340704. ISSN 0028-4793. PMID 8552145. 6. ^ Takahashi Y, Shirono H, Arisaka O, Takahashi K, Yagi T, Koga J, Kaji H, Okimura Y, Abe H, Tanaka T, Chihara K (September 1997). "Biologically inactive growth hormone caused by an amino acid substitution". J. Clin. Invest. 100 (5): 1159–65. doi:10.1172/JCI119627. PMC 508291. PMID 9276733. 7. ^ Besson A, Salemi S, Deladoëy J, Vuissoz JM, Eblé A, Bidlingmaier M, Bürgi S, Honegger U, Flück C, Mullis PE (May 2005). "Short stature caused by a biologically inactive mutant growth hormone (GH-C53S)". J. Clin. Endocrinol. Metab. 90 (5): 2493–9. doi:10.1210/jc.2004-1838. PMID 15713716. 8. ^ Zadik Z, Chalew SA, Gilula Z, Kowarski AA (November 1990). "Reproducibility of growth hormone testing procedures: a comparison between 24-hour integrated concentration and pharmacological stimulation". J. Clin. Endocrinol. Metab. 71 (5): 1127–30. doi:10.1210/jcem-71-5-1127. PMID 2229276. 9. ^ a b c Bistritzer T, Chalew SA, Kowarski AA (1995). "Growth failure with plasma GH that is normal by RIA but low by radioreceptor assay: responsiveness to exogenous GH". Horm. Res. 43 (6): 261–5. doi:10.1159/000184306. PMID 7607611. 10. ^ Albertsson-Wikland K, Rosberg S (February 1992). "Reproducibility of 24-h growth hormone profiles in children". Acta Endocrinol. 126 (2): 109–12. doi:10.1530/acta.0.1260109. PMID 1543014. 11. ^ Carel JC, Tresca JP, Letrait M, Chaussain JL, Lebouc Y, Job JC, Coste J (July 1997). "Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study". J. Clin. Endocrinol. Metab. 82 (7): 2117–21. doi:10.1210/jcem.82.7.4106. PMID 9215281. 12. ^ Bistritzer, Tzvy; Chalew, Stuart A; Lovohik, Judith C; Kowarski, A Avlnoam (1987). "Decreased Growth Hormone (Gh) Binding to Im-9 Cells in Children with Biologically Inactive Gh Syndrome (Bi)". Pediatric Research. 21 (4): 244A. doi:10.1203/00006450-198704010-00461. ISSN 0031-3998. 13. ^ "Short stature due to growth hormone qualitative anomaly". orphanet. ## External links[edit] Classification D * ICD-10: E23.0 * OMIM: 262650 * MeSH: C537505 External resources * Orphanet: 629 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Kowarski syndrome	c1849779	5,438	wikipedia	https://en.wikipedia.org/wiki/Kowarski_syndrome	2021-01-18T19:00:43	{"gard": ["408"], "mesh": ["C537505"], "orphanet": ["629"], "wikidata": ["Q17082044"]}
A rare inflammatory optic neuropathy characterized by recurrent episodes of idiopathic inflammation of the optic nerve head with optic disc edema associated with macular exudate in a star-shaped pattern. Patients present with acute visual loss, most typically in the form of a large central scotoma. Pain is mild or absent. Bilateral involvement is frequent and usually sequential. The interval between attacks is highly variable, ranging from months to several years. Visual loss is cumulative with each attack and often severe. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Recurrent idiopathic neuroretinitis	None	5,439	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=499103	2021-01-23T17:20:15	{"synonyms": ["RINR"]}
This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (September 2020) Abortion in Vermont is legal. 70% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases. ## Contents * 1 Terminology * 2 Context * 3 History * 3.1 Legislative history * 3.2 Judicial history * 3.3 Clinic history * 4 Statistics * 5 Abortion financing * 6 Women's abortion experiences * 7 Abortion rights views and activities * 7.1 Protests * 8 Anti-abortion views and activities * 8.1 Violence * 9 Footnotes * 10 References ## Terminology[edit] Main article: Abortion The abortion debate most commonly relates to the "induced abortion" of an embryo or fetus at some point in a pregnancy, which is also how the term is used in a legal sense.[note 1] Some also use the term "elective abortion", which is used in relation to a claim to an unrestricted right of a woman to an abortion, whether or not she chooses to have one. The term elective abortion or voluntary abortion describes the interruption of pregnancy before viability at the request of the woman, but not for medical reasons.[1] Anti-abortion advocates tend to use terms such as "unborn baby", "unborn child", or "pre-born child",[2][3] and see the medical terms "embryo", "zygote", and "fetus" as dehumanizing.[4][5] Both "pro-choice" and "pro-life" are examples of terms labeled as political framing: they are terms which purposely try to define their philosophies in the best possible light, while by definition attempting to describe their opposition in the worst possible light. "Pro-choice" implies that the alternative viewpoint is "anti-choice", while "pro-life" implies the alternative viewpoint is "pro-death" or "anti-life".[6] The Associated Press encourages journalists to use the terms "abortion rights" and "anti-abortion".[7] ## Context[edit] See also: Abortion in the United States Free birth control correlates to teenage girls having a fewer pregnancies and fewer abortions. A 2014 New England Journal of Medicine study found such a link. At the same time, a 2011 study by Center for Reproductive Rights and Ibis Reproductive Health also found that states with more abortion restrictions have higher rates of maternal death, higher rates of uninsured pregnant women, higher rates of infant and child deaths, higher rates of teen drug and alcohol abuse, and lower rates of cancer screening.[8] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[9] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] ## History[edit] ### Legislative history[edit] By the end of the 1800s, all states in the Union except Louisiana had therapeutic exceptions in their legislative bans on abortions.[10] In the 19th century, bans by state legislatures on abortion were about protecting the life of the mother given the number of deaths caused by abortions; state governments saw themselves as looking out for the lives of their citizens.[10] As of 2017, California, Oregon, Montana, Vermont, and New Hampshire allow qualified non-physician health professionals, such as physicians' assistants, nurse practitioners, and certified nurse midwives, to do first-trimester aspiration abortions and to prescribe drugs for medical abortions.[11] In February 2019, Vermont House Human Services and Judiciary committees held public hearings about abortion in relation to H.57. As a way to try to stop passage, Vermont Republican Party urged people to come and speak in opposition to it.[12] In early 2019, an amendment was passed called Proposal 5. The amendment to the state constitution would "ensure that every Vermonter is afforded personal reproductive liberty." Before the amendment becomes law, it needs to pass the state legislature a second time and then be voted on in a ballot box measure during a 2022 special election.[13][14][15] Vermont's Republican Governor Phil Scott has promised not to veto Proposal 5.[9] As of May 2019, there was no law that clearly addressed abortion in the state's law, with abortion rights not clearly defined.[13] ### Judicial history[edit] In 1972, the Vermont Supreme Court made a ruling that effectively ended abortion restrictions in the state.[12] The US Supreme Court's decision in 1973's Roe v. Wade ruling meant the state could no longer regulate abortion in the first trimester.[10] ### Clinic history[edit] Number of abortion clinics in Vermont by year. See also: Abortion clinic Between 1982 and 1992, the number of abortion clinics in the state declined by three, going from nineteen in 1982 to sixteen in 1992.[16] In 2014, there were six abortion clinics in the state.[17] 64% of the counties in the state did not have an abortion clinic. That year, 38% of women in the state aged 15 – 44 lived in a county without an abortion clinic.[18] In March 2016, there were twelve Planned Parenthood clinics in the state.[19] In 2017, there were twelve Planned Parenthood clinics in a state with a population of 136,459 women aged 15 – 49 of which six offered abortion services.[20] ## Statistics[edit] In the period between 1972 and 1974, there were zero recorded illegal abortion deaths in the state.[21] In 1990, 67,000 women in the state faced the risk of an unintended pregnancy.[16] In 2013, among white women aged 15–19, there were abortions 190, 0 abortions for black women aged 15–19, 10 abortions for Hispanic women aged 15–19, and 10 abortions for women of all other races.[22] In 2014, 70% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases.[23] In 2017, the state had an infant mortality rate of 4.8 deaths per 1,000 live births.[9] Number of reported abortions, abortion rate and percentage change in rate by geographic region and state in 1992, 1995 and 1996[24] Census division and state Number Rate % change 1992–1996 1992 1995 1996 1992 1995 1996 Total 1,528,930 1,363,690 1,365,730 25.9 22.9 22.9 –12 New England 78,360 71,940 71,280 25.2 23.6 23.5 –7 Connecticut 19,720 16,680 16,230 26.2 23 22.5 –14 Maine 4,200 2,690 2,700 14.7 9.6 9.7 –34 Massachusetts 40,660 41,190 41,160 28.4 29.2 29.3 3 New Hampshire 3,890 3,240 3,470 14.6 12 12.7 –13 Rhode Island 6,990 5,720 5,420 30 25.5 24.4 –19 Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents, US CDC estimates Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate^ Ratio^^ No. Rate^ Ratio^^ Vermont 1,161 10.0 189 1,235 10.6 201 6.8 2014 [25] Vermont 1,121 9.7 190 1,265 10.9 214 12.4 2015 [26] Vermont 1,131 9.9 196 1,298 11.3 226 14.1 2016 [27] ^number of abortions per 1,000 women aged 15-44; ^^number of abortions per 1,000 live births ## Abortion financing[edit] State Medicaid coverage of medically necessary abortion services.Navy blue: Medicaid covers medically necessary abortion for low-income women through legislationRoyal blue: Medicaid covers medically necessary abortions for low-income women under court order Gray: Medicaid denies abortion coverage for low-income women except for cases of rape, incest, or life endangerment. 17 states including Vermont use their own funds to cover all or most "medically necessary" abortions sought by low-income women under Medicaid, 13 of which are required by State court orders to do so.[28] In 2010, the state had 699 publicly funded abortions, of which were zero federally funded and 699 were state funded.[29] ## Women's abortion experiences[edit] Dotty Kyle of Warren was a teenager in 1953 who found herself pregnant. After talking to her parents, Kyle and her parents decided getting an abortion would be the best option. They located a doctor who would perform an illegal abortion after their regular office hours ended. According to Kyle, the abortion "allowed me to graduate high school, go to college, marry and have three lovely children. Without access to abortion, I would have struggled to support a child as a single mother."[12] ## Abortion rights views and activities[edit] ### Protests[edit] Women from the state participated in marches supporting abortion rights as part of a #StoptheBans movement in May 2019.[30] ## Anti-abortion views and activities[edit] ### Violence[edit] In 1977, there were four arson attacks on abortion clinics in the United States. These took place in Minnesota, Vermont, Nebraska and Ohio. Combined, they caused over US$1.1 million in damage.[31] ## Footnotes[edit] 1. ^ According to the Supreme Court's decision in Roe v. Wade: > (a) For the stage prior to approximately the end of the first trimester, the abortion decision and its effectuation must be left to the medical judgement of the pregnant woman's attending physician. (b) For the stage subsequent to approximately the end of the first trimester, the State, in promoting its interest in the health of the mother, may, if it chooses, regulate the abortion procedure in ways that are reasonably related to maternal health. (c) For the stage subsequent to viability, the State in promoting its interest in the potentiality of human life may, if it chooses, regulate, and even proscribe, abortion except where it is necessary, in appropriate medical judgement, for the preservation of the life or health of the mother. Likewise, Black's Law Dictionary defines abortion as "knowing destruction" or "intentional expulsion or removal". ## References[edit] 1. ^ Watson, Katie (December 20, 2019). "Why We Should Stop Using the Term "Elective Abortion"". AMA Journal of Ethics. 20: E1175-1180. doi:10.1001/amajethics.2018.1175. PMID 30585581. Retrieved May 17, 2019. 2. ^ Chamberlain, Pam; Hardisty, Jean (2007). "The Importance of the Political 'Framing' of Abortion". The Public Eye Magazine. 14 (1). 3. ^ "The Roberts Court Takes on Abortion". New York Times. November 5, 2006. Retrieved January 18, 2008. 4. ^ Brennan 'Dehumanizing the vulnerable' 2000 5. ^ Getek, Kathryn; Cunningham, Mark (February 1996). "A Sheep in Wolf's Clothing – Language and the Abortion Debate". Princeton Progressive Review. 6. ^ "Example of "anti-life" terminology" (PDF). Archived from the original (PDF) on July 27, 2011. Retrieved November 16, 2011. 7. ^ Goldstein, Norm, ed. The Associated Press Stylebook. Philadelphia: Basic Books, 2007. 8. ^ Castillo, Stephanie (October 3, 2014). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved May 27, 2019. 9. ^ a b c d e "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved May 25, 2019. 10. ^ a b c Buell, Samuel (January 1, 1991). "Criminal Abortion Revisited". New York University Law Review. 66: 1774–1831. 11. ^ "Study: Abortions Are Safe When Performed By Nurse Practitioners, Physician Assistants, Certified Nurse Midwives". Retrieved January 25, 2017. 12. ^ a b c Walters, John. "Walters: Vermont Abortion Bill Hearing Features Emotional Testimony". Seven Days. Retrieved May 28, 2019. 13. ^ a b "Are there any states working to protect abortion rights?". Well+Good. May 17, 2019. Retrieved May 25, 2019. 14. ^ "SENATE CHAMBER PROPOSED AMENDMENT TO THE CONSTITUTION OF THE STATE OF VERMONT" (PDF). legislature.vermont.gov. 2019. Retrieved July 6, 2019. 15. ^ Lou, Michelle. "Vermont lawmakers are trying to pass a constitutional amendment to protect the right to an abortion". CNN. Retrieved May 25, 2019. 16. ^ a b Arndorfer, Elizabeth; Michael, Jodi; Moskowitz, Laura; Grant, Juli A.; Siebel, Liza (December 1998). A State-By-State Review of Abortion and Reproductive Rights. DIANE Publishing. ISBN 9780788174810. 17. ^ Gould, Rebecca Harrington, Skye. "The number of abortion clinics in the US has plunged in the last decade — here's how many are in each state". Business Insider. Retrieved May 23, 2019. 18. ^ businessinsider (August 4, 2018). "This is what could happen if Roe v. Wade fell". Business Insider (in Spanish). Retrieved May 24, 2019. 19. ^ Bohatch, Emily. "27 states with the most Planned Parenthood clinics". thestate. Retrieved May 24, 2019. 20. ^ "Here's Where Women Have Less Access to Planned Parenthood". Retrieved May 23, 2019. 21. ^ Cates, Willard; Rochat, Roger (March 1976). "Illegal Abortions in the United States: 1972–1974". Family Planning Perspectives. 8 (2): 86. doi:10.2307/2133995. JSTOR 2133995. PMID 1269687. 22. ^ "No. of abortions among women aged 15–19, by state of residence, 2013 by racial group". Guttmacher Data Center. Retrieved May 24, 2019. 23. ^ "Views about abortion by state - Religion in America: U.S. Religious Data, Demographics and Statistics \| Pew Research Center". Retrieved May 23, 2019. 24. ^ "Abortion Incidence and Services in the United States, 1995-1996". Guttmacher Institute. June 15, 2005. Retrieved June 2, 2019. 25. ^ Jatlaoui, Tara C. (2017). "Abortion Surveillance — United States, 2014". MMWR. Surveillance Summaries. 66 (24): 1–48. doi:10.15585/mmwr.ss6624a1. ISSN 1546-0738. PMID 29166366. 26. ^ Jatlaoui, Tara C. (2018). "Abortion Surveillance — United States, 2015". MMWR. Surveillance Summaries. 67 (13): 1–45. doi:10.15585/mmwr.ss6713a1. ISSN 1546-0738. PMC 6289084. PMID 30462632. 27. ^ Jatlaoui, Tara C. (2019). "Abortion Surveillance — United States, 2016". MMWR. Surveillance Summaries. 68. doi:10.15585/mmwr.ss6811a1. ISSN 1546-0738. 28. ^ Francis Roberta W. "Frequently Asked Questions". Equal Rights Amendment. Alice Paul Institute. Archived from the original on April 17, 2009. Retrieved September 13, 2009. 29. ^ "Guttmacher Data Center". data.guttmacher.org. Retrieved May 24, 2019. 30. ^ Bacon, John. "Abortion rights supporters' voices thunder at #StopTheBans rallies across the nation". USA TODAY. Retrieved May 25, 2019. 31. ^ Jacobson, Mireille; Royer, Heather (December 2010). "Aftershocks: The Impact of Clinic Violence on Abortion Services". American Economic Journal: Applied Economics. 3: 189–223. doi:10.1257/app.3.1.189. Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Abortion in Vermont	None	5,440	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Vermont	2021-01-18T18:47:20	{"wikidata": ["Q64876958"]}
## Clinical Features Huizing et al. (1994, 1996) reported a boy with macrosomia, mild dysmorphic features, severe psychomotor retardation, delayed myelination, and polymicrogyria. Mild dysmorphic features included prominent forehead, depressed nasal bridge, mild hypertelorism, high-arched palate, widely spaced nipples, and umbilical hernia. He had 2/3 toe syndactyly and hypoplastic nails. Due to intrapartum asphyxia, he needed oxygen support for 10 days. He also developed neonatal seizures and hypothalamic hypothyroidism. He had lack of psychomotor development, hypotonia, head lag, poor visual fixation, and failure to thrive. Brain MRI at age 5 months showed mildly dilated and disfigured lateral ventricles, focal cortical dysplasia, and diffusely delayed myelination. At age 4 years, he showed psychomotor retardation; he died at age 6 years (Messina et al., 1999). De Pinto et al. (2000) reported a patient with recurrent infections, fatigue, and hypotonia since age 1 year. He had isolated glycosuria at age 18 months. At age 3 years, he was hospitalized for continuous vomiting and loss of consciousness, and was found to have metabolic lactic acidosis, ketonuria, electrolyturia, massive bicarbonaturia, and aminoaciduria, consistent with progressive tubular insufficiency. He also showed poor physical growth. Bone marrow biopsy showed hypocellularity with lack of erythroblasts. He developed thrombocytopenia, anemia, and neutropenia, and died 1 month after admission. Biochemical Features Laboratory studies of the patient reported by Huizing et al. (1994, 1996) showed lactic acidosis, suggesting a defect in mitochondrial energy metabolism. Skeletal muscle biopsy showed normal patterns and normal mitochondria, but biochemical studies showed impaired rates of pyruvate oxidation and ATP production in muscle mitochondria. There were no specific deficiencies of the respiratory chain enzymes. Western blot analysis with a monoclonal antibody against human voltage-dependent anion channel-1 (VDAC1; 604492), a mitochondrial membrane channel, showed almost complete deficiency of VDAC1 protein in skeletal muscles and moderately decreased levels in fibroblasts. VDAC1 is a transporter for metabolites directly involved in oxidative phosphorylation. The findings suggested that VDAC1 deficiency could cause an abnormal composition and/or altered osmolarity within the mitochondrial matrix, leading to impaired mitochondrial energy metabolism in this patient. Coding sequences of the VDAC1 gene were not affected in this patient, suggesting that a defect in structures controlling gene expression were responsible for the defect. Huizing et al. (1996) noted that a defect in other mitochondrial membrane carriers had been reported: defects in ANT (SLC25A4; 103220) causing PEOA2 (609283); defects in a malate-aspartate shuttle in a patient with a myopathy (254960); and defects in SLC25A20 (613698) causing metabolic defects (212138). Laboratory studies of the patient reported by De Pinto et al. (2000) showed progressive tubular insufficiency, elevated transaminases, aminoaciduria, and persistent lactic acidosis. Leukocytes showed mitochondrial DNA deletion, and skeletal muscle biopsy showed lack of reactivity with a monoclonal antibody against VDAC1. Studies of skeletal muscle showed that a mitochondrial channel had low conductance compared to VDAC1 in controls, was cation selective, and lacked voltage-dependent activity, all of which was different from normal VDAC1. De Pinto et al. (2000) suggested that the mitochondrial channel identified in the skeletal muscle of this patient may represent a different porin isoform. INHERITANCE \- Isolated cases GROWTH Other \- Macrosomia (1 patient) \- Failure to thrive HEAD & NECK Head \- Prominent forehead Eyes \- Hypertelorism, mild \- Poor visual fixation Nose \- Depressed nasal bridge Mouth \- High-arched palate CHEST Breasts \- Widely spaced nipples ABDOMEN External Features \- Umbilical hernia GENITOURINARY Kidneys \- Renal tubular insufficiency (1 patient) SKELETAL Feet \- Syndactyly, 2/3 SKIN, NAILS, & HAIR Nails \- Hypoplastic nails MUSCLE, SOFT TISSUES \- Hypotonia \- Skeletal muscle biopsy shows impaired respiratory oxidation \- Decreased expression of the VDAC1 protein \- Normal mitochondrial morphology (1 patient) \- Mitochondrial DNA deletion (1 patient) NEUROLOGIC Central Nervous System \- Lack of psychomotor development (1 patient) \- Seizures (1 patient) \- Delayed myelination (1 patient) \- Dilated lateral ventricles (1 patient) \- Cortical dysplasia, focal (1 patient) \- Polymicrogyria (1 patient) METABOLIC FEATURES \- Lactic acidosis HEMATOLOGY \- Bone marrow failure (1 patient) \- Anemia \- Thrombocytopenia \- Neutropenia LABORATORY ABNORMALITIES \- Aminoaciduria (1 patient) \- Ketonuria (1 patient) \- Electrolyturia (1 patient) \- Abnormal transaminases (1 patient) MISCELLANEOUS \- Two unrelated patients with different phenotypes have been reported (as of March 2012) \- Dysmorphic features were only reported in 1 patient \- One patient died at age 7 years \- A second patient died at age 3 years ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ENCEPHALOMYOPATHY, MITOCHONDRIAL, DUE TO VOLTAGE-DEPENDENT ANION CHANNEL DEFICIENCY	c3281106	5,441	omim	https://www.omim.org/entry/614520	2019-09-22T15:54:54	{"omim": ["614520"]}
A number sign (#) is used with this entry because of evidence that multicentric carpotarsal osteolysis syndrome (MCTO) is caused by heterozygous mutation in the MAFB gene (608968) on chromosome 20q12. Description Multicentric carpotarsal osteolysis syndrome is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. Autosomal dominant inheritance has been documented in many families (Pai and Macpherson, 1988). See also Torg-Winchester syndrome (259600), an autosomal recessive multicentric osteolysis syndrome. Clinical Features Shurtleff et al. (1964) observed a family in which 11 persons in 3 generations had osteolysis of the carpal bones with nephropathy. Osteolysis of the carpal bones led to disappearance of these bones in older subjects. Deformity of the hands suggesting arthritis also occurred in severe cases. Hypertension and renal failure resulting from arteriolar thickening were internal complications. Caffey (1961) described affected father and son. The father died of uremia (McKusick, 1970). Torg et al. (1969) suggested that sporadic cases such as that of Lagier and Rutishauer (1965) and that of Torg and Steel (1968) represent a separate disorder. It seems that they are indistinguishable (except quantitatively in terms of severity of renal disease) from the inherited cases and may represent new dominant mutations. Gluck and Miller (1972) reported a family with males affected with osteolysis in 3 successive generations. Nephropathy and hypertension were not present. Kohler et al. (1973) described a father and 3 sibs with hereditary osteolysis. The osteolysis was most severe in the carpal and tarsal bones. The osteolysis was also present and spreading in adjacent areas. All the affected showed arthritic symptoms in childhood, painless deformities of the wrists and feet, and a Marfan-like appearance. Mild deterioration of the elbow was present in the children. No hypertension or renal involvement was seen. These patients demonstrated an elevated alkaline phosphatase reflecting the process of bone destruction. Whyte et al. (1978) described affected father and son. Both had micrognathia and hypotelorism and were exceptionally tall during the symptomatic stage of their disease. Urinary hydroxyproline was increased. Whyte et al. (1978) suggested that multicentric osteolysis with nephropathy is an entity separate from hereditary multicentric osteolysis. Bennett et al. (1980) described a female patient with onset of puffy and tender feet and wrists at age 21 months. She was 135 cm tall at the age of 13. At age 14 cloudiness of the lower portion of both corneas was discovered. Proteinuria and white cells in the urine with no bacteria were discovered at age 16. Then and at age 18 and 20, blood pressure was normal. At the age of 22, the patient presented with a blood pressure of 240/140; however, hypertensive retinopathy was not seen. The patient died soon afterwards with azotemia. The kidneys weighed 55 grams each. Microscopy showed proliferation of vascular intima and medial hypertrophy of renal vessels of all sizes. Nephropathy in this condition typically appears several years after osteolysis has occurred, and the reverse sequence has, it seems, not been seen. After diagnosing carpotarsal osteolysis in a man hospitalized for nephropathy, Fryns (1982) diagnosed the same disorder in his 6-month-old son. Hardegger et al. (1985) reported an isolated case and reviewed the various forms of osteolysis including the monocentric massive osteolysis which goes by the name of Gorham (Gorham and Stout, 1955) and appears to be nonmendelian. Carnevale et al. (1987) pointed out that clinical manifestations begin in early childhood with arthritis-like episodes involving ankles and wrists, progressive deformities, radiologic osteolytic changes, and variable degrees of disability. They emphasized the triangular shape of the face, protruding eyes, and micrognathia. Pai and Macpherson (1988) reported 2 sporadic cases. One of the patients was described as having a 'peculiar, chubby cheek, doll-like facial appearance' in spite of a generally cachectic appearance. Similar facial changes were noted in the review by Carnevale et al. (1987). The second patient of Pai and Macpherson (1988) was an 11-year-old black boy referred for the management of end-stage renal disease. Proteinuria had first been detected during a preschool examination at age 5. Patients with onset of symptoms in adulthood may represent a subgroup in which ribs, clavicles, sternum, and mandible may be involved (Renie and Pyeritz, 1981; Tookman et al., 1985). It is not clear whether this is genetically determined or whether it is the same disorder as the childhood-onset condition. Shinohara et al. (1991) described a 5-year-old girl with osteolysis of the carpal bones as well as other parts of the skeleton and nephropathy. She also had corneal clouding and valvular pulmonary stenosis, leading Shinohara et al. (1991) to conclude that the disorder was distinctive. Urlus et al. (1993) reported the cases of affected father and daughter and provided an extensive review of the literature. Zankl et al. (2012) studied 11 simplex probands and 2 multigenerational pedigrees with multicentric carpotarsal osteolysis. Each affected individual had classic radiographic features of MCTO, with complete destruction of carpal bones but relatively well-preserved metacarpals and phalanges. Of the 11 simplex cases, 5 had undergone renal transplantation and 3 had markedly impaired renal function but did not yet require dialysis; the remaining 3 patients, who showed no evidence of renal dysfunction, were all under 7 years of age. The affected individuals from the 2 families with MCTO showed no evidence of renal dysfunction, with the exception of 1 patient who 'at a very old age' developed renal dysfunction of unknown etiology. Inheritance Male-to-male transmission in several cases of osteolysis of carpal bones with nephropathy (e.g., Caffey, 1961, Whyte et al., 1978, Fryns, 1982) confirmed autosomal dominant inheritance. Molecular Genetics In 5 probands with multicentric carpotarsal osteolysis, Zankl et al. (2012) performed whole-exome sequencing followed by quality filtering and identified heterozygosity for missense mutations in the MAFB gene (see, e.g., 608968.0001-608968.0003 and 608968.0005) in all 5 patients. Analysis of MAFB in an additional 6 unrelated simplex cases revealed heterozygosity for missense mutations in all of them (see, e.g., 608968.0003 and 608968.0004). In 2 families with autosomal dominant inheritance of MCTO, Zankl et al. (2012) identified heterozygosity for another missense mutation that segregated with disease in both families (608968.0006). Noting that affected individuals from these 2 families, many of whom were adults, did not manifest renal disease, the authors concluded that MAFB mutations are also responsible for MCTO in the absence of renal disease. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Maxillary hypoplasia \- Micrognathia Eyes \- Exophthalmos GENITOURINARY Kidneys \- Nephropathy \- Hypertension \- Renal failure SKELETAL \- Osteopenia Hands \- Ulnar deviation of hands \- Wrist swelling \- Wrist arthralgia \- Carpal bone osteolysis \- Metacarpal osteolysis Feet \- Pes cavus \- Ankle swelling \- Ankle arthralgia \- Tarsal bone osteolysis \- Metatarsal osteolysis MUSCLE, SOFT TISSUES \- Ankle swelling \- Wrist swelling LABORATORY ABNORMALITIES \- Proteinuria MISCELLANEOUS \- Onset in infancy-early childhood MOLECULAR BASIS \- Caused by mutation in the v-MAF musculoaponeurotic fibrosarcoma oncogene family, protein B gene (MAFB, 608968.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MULTICENTRIC CARPOTARSAL OSTEOLYSIS SYNDROME	c2674705	5,442	omim	https://www.omim.org/entry/166300	2019-09-22T16:37:01	{"mesh": ["C567171"], "omim": ["166300"], "orphanet": ["2774"], "synonyms": ["Alternative titles", "OSTEOLYSIS, HEREDITARY, OF CARPAL BONES WITH OR WITHOUT NEPHROPATHY", "MULTICENTRIC OSTEOLYSIS, AUTOSOMAL DOMINANT"]}
## Clinical Features Aryl hydrocarbon hydroxylase (AHH, CYP1A1) is one of the mixed function oxidases in the microsomal fraction. Busbee et al. (1972) found 3 distinct groups--low, intermediate, and high--in regard to inducibility of AHH measured in cultured lymphocytes 24 hours after introduction of 3-methylcholanthrene. Family studies indicated diallelic determination at a single locus. Using the same inducer, Kellermann et al. (1973) found polymorphic inducibility of lymphocyte AHH. Since AHH is an enzyme involved in metabolism of carcinogens, the genetic difference might be relevant to the occurrence of cancer. In a normal white US population, Kellermann et al. (1973) found low, intermediate and high inducibility in the following proportions: 44.7%, 45.9%, 9.4%, respectively. Among 50 patients with bronchogenic cancer, they found the following proportions: 4.0%, 66.0%, and 30.0%, respectively. Genetically determined high inducibility of AHH may be associated with enhanced risk of cancer in cigarette smokers (Kouri et al., 1982). Fletcher et al. (1978) emphasized the poor reproducibility of AHH inducibility in lymphocytes. As discussed by Price Evans (1993), the aryl hydrocarbon receptor, which is encoded by a gene (AHR; 600253) located on 7p, combines with the aryl hydrocarbon that is inducer. The resulting inducer-receptor complex is transported to the nucleus where it binds to the regulatory region of the CYP1A1 gene (108330), located on 15q. Induction of synthesis of enzyme in the cytoplasm leads to oxidation of the hydrocarbon. The AHH inducibility phenotype is due to characteristics of the CYP1A1 and CYP1A3 (124060) genes. Inheritance From studies of AHH in twins, Paigen et al. (1978) concluded that AHH inducibility may be determined by a single or a few polymorphic genes. From a twin study, Borresen et al. (1981) concluded that inducibility (but not basal level) is heritable (heritability = 0.7). Major control of inducibility by one locus was considered possible. Animal Model In the mouse it was shown by Shichi et al. (1978) that homozygotes and heterozygotes for the Ah(b) allele (which renders the mouse susceptible to AHH induction by 3-methylcholanthrene) developed an irreversible opacity of the anterior portion of the lens, resembling a senile cataract, within 6 hours after a large intraperitoneal dose of acetaminophen. Whether the same occurs in man is not known. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ARYL HYDROCARBON HYDROXYLASE INDUCIBILITY	c1862463	5,443	omim	https://www.omim.org/entry/108340	2019-09-22T16:44:44	{"mesh": ["C566250"], "omim": ["108340"], "synonyms": ["Alternative titles", "AHH INDUCIBILITY"]}
A number sign (#) is used with this entry because of evidence that factor XII deficiency is caused by mutation in the F12 gene (610619) on chromosome 5q35. Clinical Features Factor XII deficiency was usually discovered because of the practice in some hospitals of routinely performing whole blood clotting times before surgical operations (McCain et al., 1959). Ratnoff and Steinberg (1962) analyzed data on 55 cases in 37 families. Parental consanguinity was present in at least 2 instances. Some heterozygotes show partial deficiency of Hageman factor. The Japanese case reported by Miwa et al. (1968) had first-cousin parents. Egeberg (1970) described 4 Norwegian families with deficient factor XII (about half normal). Unlike the usual experience of no abnormality, they showed a slight to moderate bleeding tendency and a high incidence of cerebral apoplexy occurring at a relatively early age. Some of the patients had attacks of local edema, severe headache, abdominal pain, and various forms of allergy. Braulke et al. (1993) presented data suggesting that reduced levels of factor XII activity may be a risk factor for repeated spontaneous abortions. Gordon et al. (1981) showed that both the clot-promoting activity and the antigenic properties of Hageman factor are lower in Orientals than in American whites. Factor XII deficiency seemingly inherited as an autosomal dominant was reported by Bennett et al. (1972). The authors hypothesized that the gene could be allelic with that responsible for the autosomal recessive form. Superficial migratory thrombophlebitis (Samlaska et al., 1990) and leg ulcer (Goodnough et al., 1983; Lammle et al., 1991) have been documented as skin manifestations of factor XII deficiency. Sato-Matsumura et al. (2000) reported 2 individuals with factor XII deficiency presenting with livedo and painful leg ulcers who improved dramatically after anticoagulant therapy. They suggested that factor XII deficiency may lead to a hypercoagulative state in some individuals, predisposing them to painful ulcers and livedo. In a study of 150 consecutive patients with retinal vein occlusion (RVO) compared with age- and gender-matched controls, Kuhli et al. (2004) found that factor XII deficiency was highly prevalent in RVO patients 45 years of age or younger. By contrast, the prevalence of factor XII deficiency in RVO patients older than 45 years appeared similar to that seen in healthy individuals. Koster et al. (1994) and Girolami et al. (2004) concluded that severe (homozygous) factor XII deficiency is not a cause of deep-vein thrombosis. In a study of myocardial infarction and arterial thrombosis in severe (homozygous) factor XII deficiency, Girolami et al. (2005) likewise concluded that the role of the coagulation factor deficiency in the pathogenesis of arterial thrombosis is minor. Mapping The F12 gene, site of defects resulting in factor XII deficiency, maps to chromosome 5q33-qter (Royle et al., 1988). Soria et al. (2002) conducted a genomewide linkage screen to localize genes that influence variation in F12 levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (lod scores 4.73 and 3.53, respectively). On chromosome 5, the peak lod score occurred in the 5q33-qter region, where the F12 gene is located. Addition of the 46C/T polymorphism (610619.0004) in the F12 gene increased the multipoint lod score to 10.21. A bivariate linkage analysis of F12 activity and thrombosis further improved the linkage signal (lod = 11.73) and provided strong evidence that this quantitative trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P = 0.004). Linkage analysis conditional on 46C/T indicated that this polymorphism alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represented the first direct genetic evidence that a QTL in or near the F12 gene influences both F12 activity and susceptibility to thrombosis and suggested the presence of one or more functional variants in F12. Molecular Genetics Bernardi et al. (1987) found that the factor XII gene alteration in the Hageman trait was detected by the TaqI restriction enzyme in 2 affected brothers and 11 members of the paternal lineage. Gene deletion was excluded. The TaqI polymorphic site was located within the 5-prime portion of the gene and the mutation in the polymorphic site was judged to be the cause of the factor XII deficiency. This may represent a CpG mutation of the sort that is found in a number of other genes such as F8 (300841) in hemophilia A (306700). In 5 of 12 unrelated patients with low factor XII activity detected by chance during presurgery screening, Schloesser et al. (1995) found heterozygosity for a splice site mutation in the F12 gene (610619.0003). The mutation was not found in 74 healthy control subjects. Both compound heterozygous patients and a homozygous patient lacked immunologic reactive protein. Animal Model Renne et al. (2005) found that F12-deficient mice, like F12-deficient humans, had normal bleeding times and no spontaneous bleeding. However, in vivo fluorescence microscopy showed that, even though initial adhesion of platelets at sites of injury was unaffected in F12-deficient mice, subsequent formation and stabilization of 3-dimensional thrombi was severely impaired. This defect was observed in several locations in the vascular system in response to different types of injury and was completely reversed by infusion of human F12. Renne et al. (2005) concluded that F12-induced intrinsic coagulation is important for clotting in vivo, suggesting that F12 may be a target for antithrombotic therapy. History Roberts (2003) gave an account of the medical and scientific career of Oscar Ratnoff (born in 1916), who discovered both Hageman factor (factor XII) and Fitzgerald factor (612358). Ratnoff is credited with recruiting Earl Davie to the field of blood coagulation, to which Davie introduced modern biochemical and molecular biologic techniques. Davie and Ratnoff (1964) and, independently and simultaneously, Macfarlane (1964) proposed the waterfall hypothesis of blood coagulation. Ratnoff was long resistant to the use of a system of Roman numerals for the various clotting factors. Inheritance \- Autosomal recessive Misc \- No symptoms Heme \- Whole-blood clotting time prolonged \- Partial thromboplastin time prolonged \- Hageman factor deficiency \- Factor XII deficiency ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	FACTOR XII DEFICIENCY	c0015526	5,444	omim	https://www.omim.org/entry/234000	2019-09-22T16:27:19	{"doid": ["2231"], "mesh": ["D005175"], "omim": ["234000"], "orphanet": ["330"], "synonyms": ["Alternative titles", "F12 DEFICIENCY", "HAGEMAN FACTOR DEFICIENCY", "HAF DEFICIENCY"]}
A number sign (#) is used with this entry because of evidence that variants in the SMAD7 gene (602932) influence susceptibility to colorectal cancer. For a phenotypic description and a discussion of genetic heterogeneity of colorectal cancer, see 114500. Mapping To identify risk variants for colorectal cancer, Broderick et al. (2007) conducted a genomewide association study, genotyping 550,163 SNPs in 940 individuals with familial colorectal tumors including 627 with colorectal cancer and 313 with advanced adenomas, and 965 controls. They evaluated selected SNPs in 3 replication sample sets (7,473 cases, 5,984 controls) and identified 3 SNPs in the SMAD7 gene associated with colorectal cancer. Across 4 sample sets, the association between rs4939827 and colorectal cancer was highly statistically significant (P = 1.00 x 10(-12)). All 3 SNPs identified in the study mapped to a linkage disequilibrium block within intron 3 of SMAD7. In the first phase of a genomewide association study to identify colorectal cancer susceptibility alleles, Tomlinson et al. (2008) genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 colorectal cancer cases, 313 high-risk adenoma) and 965 controls. They identified strong association at the same 3 SNPs in intron 3 of the SMAD7 gene identified by Broderick et al. (2007). In a genomewide association study to identify loci associated with colorectal cancer risk, Tenesa et al. (2008) genotyped 555,510 SNPs in 1,012 early-onset Scottish colorectal cancer cases and 1,012 controls for phase 1. In phase 2, the authors genotyped 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. The authors then genotyped the 5 highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from 7 populations. They replicated the association of the SNP rs4939827 (odds ratio = 1.2; P = 7.8 x 10(-28)). The risk of rectal cancer was greater than that for colonic cancer for rs4939827. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	COLORECTAL CANCER, SUSCEPTIBILITY TO, 3	c2677123	5,445	omim	https://www.omim.org/entry/612229	2019-09-22T16:02:06	{"omim": ["612229"], "synonyms": ["Alternative titles", "COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 18"]}
Megarbane et al. (2004) described what they considered to be a newly recognized autosomal recessive syndrome in a 4-year-old girl, the offspring of healthy first-cousin Lebanese parents. The features were severe pre- and postnatal short stature, low pitched voice, retinitis pigmentosa, photophobia, short neck, broad thorax, platyspondyly, rhizomelic shortening of the long bones, bilateral subluxation of the hips, advanced maturation of the epiphyses, and apparently normal intellectual development. Two subsequent pregnancies had ended in spontaneous abortion with polyhydramnios and severe growth retardation. Another daughter was alive and in good health. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	SKELETAL DYSPLASIA, RHIZOMELIC, WITH RETINITIS PIGMENTOSA	c1836898	5,446	omim	https://www.omim.org/entry/609047	2019-09-22T16:06:46	{"mesh": ["C563806"], "omim": ["609047"]}
Heart-hand syndrome type 2 is an extremely rare heart-hand syndrome (see this term) described in two families to date, that is characterized by upper limb malformations (brachytelephalangy type D, hypoplastic deltoids, mild shortening of the fourth and fifth metacarpals in some individuals, skeletal anomalies in the humerus, radius, ulnae, and thenar bones) and cardiac arrhythmias (junctional rhythms and atrial fibrillation). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Heart-hand syndrome type 2	c2931323	5,447	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1350	2021-01-23T18:24:06	{"gard": ["9847"], "mesh": ["C536784"], "umls": ["C2931323"], "icd-10": ["Q87.2"], "synonyms": ["Atriodigital dysplasia type 2", "Tabatznik syndrome"]}
In this disorder the thumb is adducted and flexed across the palm due to a defect in the extensors of the thumb. Weckesser et al. (1968) described an American black family in which 7 males in 4 sibships were affected. The pattern was entirely consistent with X-linked recessive inheritance. Findings in children and grandchildren of affected males were not described. White and Jensen (1952) observed the anomaly in mother and 2 children, and Namba et al. (1965) described it in brother and sister. A preponderance of affected males (27 out of 42) is consistent with X-linkage, especially when the likely heterogeneity of congenital clasped thumb is taken into account. Weckesser et al. (1968) classified their cases into 4 groups. Clasped thumb occurs in some families with X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius (307000). Anderson and Breed (1981) suggested that the Moro reflex may be a useful way to detect congenital clasped thumb early. The thumb normally extends during the Moro reflex. Also see 201550. Tsuyuguchi et al. (1985) reviewed 43 cases and presented a revision of the classification by Weckesser et al. (1968). They provided no genetic information. Limbs \- Thumb adducted and flexed \- Thumb extensor defect Neuro \- Thumb extension failure during Moro reflex Inheritance \- X-linked recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	THUMBS, CONGENITAL CLASPED	c0431886	5,448	omim	https://www.omim.org/entry/314100	2019-09-22T16:17:09	{"mesh": ["C562949"], "omim": ["314100"], "synonyms": ["Alternative titles", "ADDUCTED THUMBS SYNDROME"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Disorders of calcium metabolism" – news · newspapers · books · scholar · JSTOR (September 2010) (Learn how and when to remove this template message) Disorders of calcium metabolism Calcium SpecialtyEndocrinology Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body. In a healthy physiology, extracellular calcium levels are maintained within a tight range through the actions of parathyroid hormone, vitamin D and the calcium sensing receptor.[1] Disorders in calcium metabolism can lead to hypocalcemia, decreased plasma levels of calcium or hypercalcemia, elevated plasma calcium levels. ## Contents * 1 Hypocalcemia * 2 Hypercalcemia * 3 Plasma Calcium * 4 See also * 5 References * 6 External links ## Hypocalcemia[edit] Hypocalcemia is common and can occur unnoticed with no symptoms or, in severe cases, can have dramatic symptoms and be life-threatening.[1] Hypocalcemia can be parathyroid related or vitamin D related. Parathyroid related hypocalcemia includes post-surgical hypoparathyroidism, inherited hypoparathyroidism, pseudohypoparathyroidism, and pseudo-pseudohypoparathyroidism.[1] Post-surgical hypoparathyroidism is the most common form, and can be temporary (due to suppression of tissue after removal of a malfunctioning gland) or permanent, if all parathyroid tissue has been removed.[1] Inherited hypoparathyroidism is rare and is due to a mutation in the calcium sensing receptor. Pseudohypoparathyroidism is maternally inherited and is categorized by hypocalcemia and hyperphosphatemia. Finally, pseudo-pseudohypoparathyroidism is paternally inherited. Patients display normal parathyroid hormone action in the kidney, but exhibit altered parathyroid hormone action in the bone.[1] Vitamin D related hypocalcemia may be associated with a lack of vitamin D in the diet, a lack of sufficient UV exposure, or disturbances in renal function. Low vitamin D in the body can lead to a lack of calcium absorption and secondary hyperparathyroidism (hypocalcemia and raised parathyroid hormone).[1] Symptoms of hypocalcemia include numbness in fingers and toes, muscle cramps, irritability, impaired mental capacity and muscle twitching.[1] ## Hypercalcemia[edit] Hypercalcemia is suspected to occur in approximately 1 in 500 adults in the general adult population.[2] Like hypocalcemia, hypercalcemia can be non-severe and present with no symptoms, or it may be severe, with life-threatening symptoms. Hypercalcemia is most commonly caused by hyperparathyroidism and by malignancy, and less commonly by vitamin D intoxication, familial hypocalciuric hypercalcemia and by sarcoidosis.[2] Hyperparathyroidism occurs most commonly in postmenopausal women. Hyperparathyroidism can be caused by a tumor, or adenoma, in the parathyroid gland or by increased levels of parathyroid hormone due to hypocalcemia.[2] Approximately 10% of cancer sufferers experience hypercalcemia due to malignancy.[2] Hypercalcemia occurs most commonly in breast cancer, lymphoma, prostate cancer, thyroid cancer, lung cancer, myeloma, and colon cancer.[2] It may be caused by secretion of parathyroid hormone-related peptide by the tumor (which has the same action as parathyroid hormone), or may be a result of direct invasion of the bone, causing calcium release.[2] Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, abdominal pain, lethargy, depression, confusion, polyuria, polydipsia and generalized aches and pains.[2] ## Plasma Calcium[edit] The amount of biologically active calcium varies with the level of serum albumin, a protein to which calcium is bound, and therefore levels of ionized calcium are better measures than a total calcium; however, one can correct a total calcium if the albumin level is known. * A normal ionized calcium is 1.12-1.45 mmol/L (4.54-5.61 mg/dL). * A normal total calcium is 2.2-2.6 mmol/L (9-10.5 mg/dl). * Total calcium of less than 8.0 mg/dL is hypocalcaemia, with levels below 1.59 mmol/L (6 mg/dL) generally fatal. * Total calcium of more than 10.6 mg/dL is hypercalcaemia, with levels over 3.753 mmol/L (15.12 mg/dL) generally fatal. ## See also[edit] * calcium metabolism * Pseudohypoparathyroidism * Milk-alkali syndrome ## References[edit] 1. ^ a b c d e f g Murphy, E; Williams (2009). "Hypocalcemia". Medicine. 37 (9): 465–468. doi:10.1016/j.mpmed.2009.06.003. 2. ^ a b c d e f g Waters, M (2009). "Hypercalcemia". InnovAiT. 2 (12). doi:10.1093/innovait/inp143. ## External links[edit] * Fong J, Khan A (February 2012). "Hypocalcemia: updates in diagnosis and management for primary care". Can Fam Physician. 58 (2): 158–62. PMC 3279267. PMID 22439169. * Cooper MS, Gittoes NJ (June 2008). "Diagnosis and management of hypocalcaemia". BMJ. 336 (7656): 1298–302. doi:10.1136/bmj.39582.589433.BE. PMC 2413335. PMID 18535072. * Žofková I (2016). "Hypercalcemia. Pathophysiological aspects". Physiol Res. 65 (1): 1–10. doi:10.33549/physiolres.933059. PMID 26596315. Classification D * MeSH: D002128 Classification D * ICD-10: E83.5 * ICD-9-CM: 275.4 * MeSH: D002128 * v * t * e Metal deficiency and toxicity disorders Iron excess: * Iron overload * Hemochromatosis * Hemochromatosis/HFE1 * Juvenile/HFE2 * HFE3 * African iron overload/HFE4 * Aceruloplasminemia * Atransferrinemia * Hemosiderosis deficiency: * Iron deficiency Copper excess: * Copper toxicity * Wilson's disease deficiency: * Copper deficiency * Menkes disease/Occipital horn syndrome Zinc excess: * Zinc toxicity deficiency: * Acrodermatitis enteropathica Other * Inborn errors of metabolism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Disorders of calcium metabolism	c0006705	5,449	wikipedia	https://en.wikipedia.org/wiki/Disorders_of_calcium_metabolism	2021-01-18T18:57:14	{"mesh": ["D002128"], "umls": ["C0006705"], "wikidata": ["Q5282519"]}
Congenital anomaly of rotation of the midgut Intestinal malrotation SpecialtyMedical genetics Intestinal malrotation is a congenital anomaly of rotation of the midgut. It occurs during the first trimester as the fetal gut undergoes a complex series of growth and development. Malrotation can lead to a dangerous complication called volvulus. Malrotation can refer to a spectrum of abnormal intestinal positioning, often including:[citation needed] * The small intestine found predominantly on the right side of the abdomen * The cecum displaced from its usual position in the right lower quadrant into the epigastrium or right hypochondrium * An absent or displaced ligament of Treitz * Fibrous peritoneal bands called bands of Ladd running across the vertical portion of the duodenum * An unusually narrow, stalk-like mesentery The position of the intestines, narrow mesentery and Ladd's bands can contribute to several severe gastrointestinal conditions. The narrow mesentery predisposes some cases of malrotation to midgut volvulus, a twisting of the entire small bowel that can obstruct the mesenteric blood vessels leading to intestinal ischemia, necrosis, and death if not promptly treated. The fibrous Ladd's bands can constrict the duodenum, leading to intestinal obstruction. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Signs and symptoms of malrotation vary depending on if the patient is suffering from an acute volvulus or experiencing chronic symptoms.[citation needed] * If the patient, most often an infant, presents acutely with midgut volvulus, it is usually manifested by bilious vomiting, crampy abdominal pain, abdominal distention, and in late cases, the passage of blood and mucus in their stools. * Patients with chronic, uncorrected or undiagnosed malrotation can have recurrent abdominal pain and vomiting. * Malrotation may be asymptomatic. ### Complications[edit] Intestinal malrotation can lead to a number of disease manifestations and complications such as:[citation needed] * Acute midgut volvulus * Chronic midgut volvulus * Acute duodenal obstruction * Chronic duodenal obstruction * Short bowel syndrome, in cases of volvulus with intestinal necrosis * Death, in cases of volvulus with pan-necrosis of the bowel, severe septic shock or hypovolemic shock * Malabsorption * Chronic motility issues * Internal herniation * Superior mesenteric artery syndrome ## Causes[edit] Diagram showing the process by which the intestine rotates and herniates during normal development. From panel A to B (left-sided views), the midgut loop rotates 90° in a counterclockwise direction, so that its position changes from midsagittal (A) to transverse (B1). The small intestine forms loops (B2) and slides back into the abdomen (B3) during resolution of the hernia. Meanwhile, the cecum moves from the left to the right side, which represents the additional 180° counterclockwise rotation of the intestine (C, central view).[1] The exact cause of intestinal malrotation is unknown. It is not definitively associated with a particular gene, but there is some evidence of recurrence in families.[2] ## Diagnosis[edit] Malrotation is most often diagnosed during infancy, however, some cases are not discovered until later in childhood or even adulthood.[3] With acutely ill patients, consider emergency surgery laparotomy if there is a high index of suspicion.[citation needed] In cases of volvulus, plain radiography may demonstrate signs of duodenal obstruction with dilatation of the proximal duodenum and stomach but it is often non-specific. Ultrasonography may be useful in some cases of volvulus, depicting a "whirlpool sign" where the superior mesenteric artery and Superior mesenteric vein have twisted.[4] Upper gastrointestinal series is the modality of choice for the evaluation of malrotation, as it will often show an abnormal position of the duodenum and duodeno-jejunal flexure (ligament of Treitz). In cases of malrotation complicated with volvulus, upper GI demonstrates a corkscrew appearance of the distal duodenum and jejunum. In cases of obstructing Ladd's bands, upper GI may reveal a duodenal obstruction. Although upper GI series is regarded as the most reliable diagnostic test for intestinal malrotation, false negatives may occur in 5% of cases.[4] False negatives are most frequently attributed to radiographer error, uncooperative pediatric patients, or variations in intestinal positioning. In equivocal cases physicians may wish to repeat the upper GI or consider additional diagnostic modalities. Lower gastrointestinal series, may be helpful in some patients by showing the caecum at an abnormal location. CT scan and Magnetic resonance imaging may also aide in the diagnosis of equivocal cases.[citation needed] The incidence of intestinal malrotation in infants with omphalocoele is low. Therefore, there is little evidence to support the screening for intestinal malrotation in infants with omphalocoele.[5] ## Treatment[edit] Prompt surgical treatment is necessary for intestinal malrotation when volvulus has occurred: * First, the patient is resuscitated with fluids to stabilize them for surgery * The volvulus is corrected (counterclockwise rotation of the bowel), * The fibrous Ladd's bands over the duodenum are cut, * The mesenteric pedicle is widened by separation of the duodenum and cecum, * The small and large bowels are placed in a position that reduces their risk of future volvulus With this condition the appendix is often on the wrong side of the body and therefore removed as a precautionary measure during the surgical procedure. This surgical technique is known as the "Ladd's procedure", after Dr. William Ladd.[6][7] Long-term research on the Ladd's procedure indicates that even after surgery, some patients are susceptible to GI issues and may need further surgery.[8] ## See also[edit] * Situs inversus, a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. ## References[edit] 1. ^ Soffers JH, Hikspoors JP, Mekonen HK, Koehler SE, Lamers WH (August 2015). "The growth pattern of the human intestine and its mesentery". BMC Developmental Biology. 15 (1): 31. doi:10.1186/s12861-015-0081-x. PMC 4546136. PMID 26297675. 2. ^ Stalker HJ, Chitayat D (September 1992). "Familial intestinal malrotation with midgut volvulus and facial anomalies: a disorder involving a gene controlling the normal gut rotation?". American Journal of Medical Genetics. 44 (1): 46–7. doi:10.1002/ajmg.1320440111. PMID 1519649. 3. ^ Dietz DW, Walsh RM, Grundfest-Broniatowski S, Lavery IC, Fazio VW, Vogt DP (October 2002). "Intestinal malrotation: a rare but important cause of bowel obstruction in adults". Diseases of the Colon and Rectum. 45 (10): 1381–6. doi:10.1007/s10350-004-6429-0. PMID 12394439. S2CID 23269321. 4. ^ a b Yeh WC, Wang HP, Chen C, Wang HH, Wu MS, Lin JT (June 1999). "Preoperative sonographic diagnosis of midgut malrotation with volvulus in adults: the "whirlpool" sign". Journal of Clinical Ultrasound. 27 (5): 279–83. doi:10.1002/(SICI)1097-0096(199906)27:5<279::AID-JCU8>3.0.CO;2-G. PMID 10355892. 5. ^ Lauriti, Giuseppe; Miscia, Maria Enrica; Cascini, Valentina; Chiesa, Pierluigi Lelli; Pierro, Agostino; Zani, Augusto (March 2019). "Intestinal malrotation in infants with omphalocele: A systematic review and meta-analysis". Journal of Pediatric Surgery. 54 (3): 378–382. doi:10.1016/j.jpedsurg.2018.09.010. ISSN 0022-3468. PMID 30309732. 6. ^ Ladd WE (1936). "Surgical Diseases of the Alimentary Tract in Infants". N Engl J Med. 215 (16): 705–8. doi:10.1056/NEJM193610152151604. 7. ^ Bass KD, Rothenberg SS, Chang JH (February 1998). "Laparoscopic Ladd's procedure in infants with malrotation". Journal of Pediatric Surgery. 33 (2): 279–81. doi:10.1016/S0022-3468(98)90447-X. PMID 9498402. 8. ^ Murphy FL, Sparnon AL (April 2006). "Long-term complications following intestinal malrotation and the Ladd's procedure: a 15 year review". Pediatric Surgery International. 22 (4): 326–9. doi:10.1007/s00383-006-1653-4. PMID 16518597. S2CID 22816456. ## External links[edit] Classification D * ICD-10: Q43.3 * ICD-9-CM: 751.4 * OMIM: 193250 * MeSH: C562456 C562456, C562456 External resources * eMedicine: ped/1200 * v * t * e Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Intestinal malrotation	c0221210	5,450	wikipedia	https://en.wikipedia.org/wiki/Intestinal_malrotation	2021-01-18T18:56:13	{"mesh": ["C562456"], "umls": ["C0345255", "C0221210"], "icd-9": ["751.4"], "icd-10": ["Q43.3"], "orphanet": ["2454"], "wikidata": ["Q448023"]}
Transient neonatal diabetes mellitus (TNDB) is a type of diabetes that appears within the first few weeks of life but is transient; affected infants go into remission within a few months, with possible relapse to permanent diabetes in adolescence or adulthood. Affected individuals have slow growth before birth followed by hyperglycemia, dehydration and failure to thrive in infancy. Approximately 70% of cases are caused by the overactivity of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. These cases are referred to as 6q24-related TNDB; most (but not all) of these cases are not inherited. Other genetic causes include mutations in the KCNJ11 and ABCC8 genes, which usually cause permanent neonatal diabetes. Treatment may include rehydration and intravenous insulin at the time of diagnosis, followed by subcutaneous insulin. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Transient neonatal diabetes mellitus	c1832386	5,451	gard	https://rarediseases.info.nih.gov/diseases/1839/transient-neonatal-diabetes-mellitus	2021-01-18T17:57:19	{"mesh": ["C563322"], "omim": ["601410", "610374", "610582"], "umls": ["C1832386"], "orphanet": ["99886"], "synonyms": ["TNDM1", "TNDM", "DMTN", "Diabetes mellitus, transient neonatal", "Chromosome 6-associated transient diabetes mellitus", "Diabetes mellitus, 6q24-related transient neonatal"]}
A number sign (#) is used with this entry because of evidence that this form of renal disease, referred to here as nephrotic syndrome type 4 (NPHS4), is caused by mutation in the Wilms tumor suppressor gene (WT1; 607102) on chromosome 11p13. Mutation in the WT1 gene can also cause isolated Wilms tumor (194070), as well as Denys-Drash syndrome (DDS; 194080), which is characterized by nephrotic syndrome and the additional features of male pseudohermaphroditism, with or without Wilms tumor. Description Nephrotic syndrome, a malfunction of the glomerular filter, leads to proteinuria, edema, and, in steroid-resistant nephrotic syndrome, end-stage renal disease (ESRD). Renal histopathology in NPHS4 due to WT1 mutations most often shows diffuse mesangial sclerosis (DMS), but can also show focal segmental glomerulosclerosis (FSGS). Both of these terms refer to pathologic findings and may be associated with the same clinical phenotype, namely nephrotic syndrome (review by Schumacher et al., 1998). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300). Clinical Features Mendelsohn et al. (1982) reported 5 children in 2 related Israeli Arab families with a clinical picture characterized by onset in infancy of asymptomatic proteinuria with subsequent development of the nephrotic syndrome and progression to renal failure and death before the age of 3 years. The clinical picture and renal histopathology were those described by Habib and Bois (1973) as infantile mesangial sclerosis. Familial occurrence had been noted by Habib and Bois (1973), Rossenbeck et al. (1966), and Gonzales et al. (1977). Jeanpierre et al. (1998) studied 10 patients with nephrotic syndrome and renal insufficiency associated with diffuse mesangial sclerosis on renal biopsy. These patients were selected on the basis of the presence of renal mesangial sclerosis in the absence of structural urogenital abnormalities and Wilms tumor. Three of the patients were male. One male and 3 female patients underwent normal pubertal development, whereas the other patients were still too young. Follow-up examinations had not demonstrated Wilms tumor, and there were no other congenital abnormalities and no family history of developmental or renal abnormalities. The parents of 1 patient were consanguineous. Jeanpierre et al. (1998) also reported 10 other patients with diffuse mesangial sclerosis on renal biopsy in the context of DDS. Nine of the patients had the 46,XY karyotype and genital abnormalities ranging from testicular ectopia to female phenotype. One patient had the 46,XX karyotype and streaked ovaries. Unilateral WT was diagnosed in 2 patients, and gonadoblastoma was diagnosed in 2 other patients. For all 20 patients, the age at which the first symptoms of nephrotic syndrome were observed varied from birth to 4.3 years. The age at end-stage renal disease was 18 days to 4.5 years, except for 1 patient who developed ESRD at age 11 years 6 months. Two patients died of ESRD during the first month of life. Two patients, aged 6 years and 2.9 years, had not yet developed ESRD. Schumacher et al. (1998) identified WT1 mutations in 10 children with early-onset nephrotic syndrome. Two genotypically female girls had isolated congenital/infantile nephrotic syndrome. Seven other patients, all of whom were genotypic males, had additional urogenital features consistent with DDS, such as uterus/vagina, ambiguous genitalia, or micropenis. The eighth child, a genotypic female, developed Wilms tumor at age 18 months, and was thus classified as having incomplete DDS. Renal biopsy showed diffuse mesangial sclerosis in 8 and focal segmental glomerulosclerosis in 2 cases. End-stage renal disease was reached either concomitantly or within 4 months after onset of nephrotic syndrome in 7 patients. Four children developed Wilms tumor either before or concomitant with nephrotic syndrome. No WT1 mutations were found in 7 other children with isolated nephrotic syndrome who appeared to have a slower progression than the first group and who did not have Wilms tumor. Schumacher et al. (1998) proposed that patients with early-onset, rapidly progressive nephrotic syndrome and diffuse mesangial or focal segmental glomerulosclerosis on renal biopsy should be tested for WT1 mutations to identify those at risk for developing Wilms tumor. Molecular Genetics Of 10 patients with nephrotic syndrome associated with diffuse mesangial sclerosis on renal biopsy, 10 with DDS, and 4 with only urogenital abnormalities and/or Wilms tumor, Jeanpierre et al. (1998) identified heterozygous mutations in the WT1 gene in 16, 4 of whom presented with renal dysfunction. Two of the 4 mutations had previously been identified in patients with DDS (607102.0006 and 607102.0012), one had previously been identified in patients with Frasier syndrome (607102.0018), and one was novel (607102.0022). An analysis of genotype/phenotype correlations showed an association between mutations in exons 8 and 9 of the WT1 gene and nephrotic syndrome; among patients with nephrotic syndrome and diffuse mesangial sclerosis, there was a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype. There was also statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. Ito et al. (2001) described 7 Japanese patients with nephrotic syndrome associated with diffuse mesangial sclerosis. WT1 mutations were detected in 2 of these patients. Nomenclature In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic terms 'focal segmental glomerulosclerosis' (FSGS) and 'diffuse mesangial sclerosis' (DMS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. INHERITANCE \- Autosomal dominant GENITOURINARY Kidneys \- Nephrotic syndrome \- Renal failure \- Diffuse mesangial sclerosis \- Focal segmental glomerulosclerosis (less common) MISCELLANEOUS \- Onset in early childhood \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the Wilms tumor 1 gene (WT1, 607102.0022 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEPHROTIC SYNDROME, TYPE 4	c1868672	5,452	omim	https://www.omim.org/entry/256370	2019-09-22T16:24:24	{"doid": ["0080383"], "mesh": ["C536404"], "omim": ["256370"], "orphanet": ["656"]}
A rare genetic cerebral small vessel disease characterized by an adult-onset primary microangiopathy with severe atherosclerosis of arterioles and secondary leukoencephalopathy. Patients may present with migraine, transient ischemic attacks, stroke with central facial palsy, cognitive dysfunction with impaired concentration, dementia, depression, movement disorder, vertigo, dysphagia, dysarthria, sicca syndrome, impaired REM sleep, and therapy-resistant hypertension, among others. Brain MRI typically shows a leukoencephalopathy that is disproportionately severe and extensive compared to the clinical disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Cathepsin A-related arteriopathy-strokes-leukoencephalopathy	None	5,453	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=575553	2021-01-23T18:53:19	{"synonyms": ["CARASAL"]}
Hyperprolinemia type 2 is an autosomal recessive proline metabolism disorder due to pyroline-5-carboxylate dehydrogenase deficiency. The condition is often benign but clinical signs may include seizures, intellectual deficit and mild developmental delay. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hyperprolinemia type 2	c2931835	5,454	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79101	2021-01-23T18:51:30	{"gard": ["1798", "6710"], "mesh": ["C538385"], "omim": ["239510"], "umls": ["C0268530", "C2931835"], "icd-10": ["E72.5"], "synonyms": ["Delta-1-pyrroline-5-carboxylate dehydrogenase deficiency"]}
Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, is a progressive condition that causes many tissues and organs to enlarge and become inflamed or scarred. Skeletal abnormalities are also common in this condition. The rate at which symptoms worsen varies among affected individuals. People with MPS VI generally do not display any features of the condition at birth. They often begin to show signs and symptoms of MPS VI during early childhood. The features of MPS VI include a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), distinctive-looking facial features that are described as "coarse," and a large tongue (macroglossia). Affected individuals also frequently develop heart valve abnormalities, an enlarged liver and spleen (hepatosplenomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). The airway may become narrow in some people with MPS VI, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). The clear covering of the eye (cornea) typically becomes cloudy, which can cause significant vision loss. People with MPS VI may also have recurrent ear infections and hearing loss. Unlike other types of mucopolysaccharidosis, MPS VI does not affect intelligence. MPS VI causes various skeletal abnormalities, including short stature and joint deformities (contractures) that affect mobility. Individuals with this condition may also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Carpal tunnel syndrome develops in many children with MPS VI and is characterized by numbness, tingling, and weakness in the hands and fingers. People with MPS VI may develop a narrowing of the spinal canal (spinal stenosis) in the neck, which can compress and damage the spinal cord. The life expectancy of individuals with MPS VI depends on the severity of symptoms. Without treatment, severely affected individuals may survive only until late childhood or adolescence. Those with milder forms of the disorder usually live into adulthood, although their life expectancy may be reduced. Heart disease and airway obstruction are major causes of death in people with MPS VI. ## Frequency The exact incidence of MPS VI is unknown, although it is estimated to occur in 1 in 250,000 to 600,000 newborns. ## Causes Mutations in the ARSB gene cause MPS VI. The ARSB gene provides instructions for producing an enzyme called arylsulfatase B, which is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. Mutations in the ARSB gene reduce or completely eliminate the function of arylsulfatase B. The lack of arylsulfatase B activity leads to the accumulation of GAGs within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions such as MPS VI that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. The accumulation of GAGs within lysosomes increases the size of the cells, which is why many tissues and organs are enlarged in this disorder. Researchers believe that the buildup of GAGs may also interfere with the functions of other proteins inside lysosomes, triggering inflammation and cell death. ### Learn more about the gene associated with Mucopolysaccharidosis type VI * ARSB ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Mucopolysaccharidosis type VI	c0026709	5,455	medlineplus	https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-vi/	2021-01-27T08:24:56	{"gard": ["7095"], "mesh": ["D009087"], "omim": ["253200"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by homozygous mutation in the gene encoding glutamate decarboxylate-1 (GAD1; 605363) on chromosome 2q31. One such family has been reported. Description Cerebral palsy (CP) is defined as a nonprogressive but not unchanging disorder of posture or movement, caused by an abnormality of the brain and first evident at the stage of rapid brain development (Hughes and Newton, 1992). The most common forms result from factors surrounding difficulties before or at birth, such as severe perinatal asphyxia, congenital infection, prematurity, and multiple pregnancy (Blair and Stanley, 1988; Stanley, 1994). More rarely, familial clustering or absence of pre- or postpartum events indicate that there are genetic forms of the disorder (Lynex et al., 2004). Cerebral palsy can be classified according to the type of movement disorder: spastic cerebral palsy accounts for approximately 60% of cases and can be subdivided into hemiplegic, diplegic, quadriplegic, and monoplegic types, whereas other forms include athetoid/dyskinetic, ataxic (605388), and mixed (Gustavson et al., 1969). ### Genetic Heterogeneity of Spastic Quadriplegic Cerebral Palsy See also CPSQ2 (612900), caused by deletion of the ANKRD15 gene (KANK1; 607704) inherited on the paternal allele, and CPSQ3 (617008), caused by mutation in the ADD3 gene (601568) on 10q24. Related phenotypes that were formerly classified in the CPSQ series include spastic paraplegia-47 (SPG47; 614066), spastic paraplegia-50 (SPG50; 612936), spastic paraplegia-51 (SPG51; 613744), and spastic paraplegia-52 (614067). Clinical Features Mitchell and Bundey (1997) and McHale et al. (1999) reported a consanguineous family of Pakistani origin in which 4 sibs had spastic cerebral palsy with onset in infancy. All had moderate to severe mental retardation. All had spasticity affecting predominantly the lower limbs, although 2 also had mild hypertonia and ataxia of the upper limbs. Spastic features included hypertonicity, hyperreflexia, and extensor plantar responses. Two older sibs had contractures. One patient had bilateral dislocated hips and another had microcephaly and scoliosis. Cranial nerve abnormalities, nystagmus, and seizures were not present. Inheritance Spastic cerebral palsy is the most common CP subtype and has a low overall recurrence risk. However, inherited spastic cerebral palsy has a recurrence risk in sibs of approximately 1 in 8 (Bundey and Griffiths, 1977). Most cases are autosomal recessive. Population Genetics The common forms of cerebral palsy have an incidence of 1 in 250 to 1,000 births (Pharoah et al., 1987; Bundey and Alam, 1993). However, approximately 2% of all CP cases in Swedish and English children are believed to be due to a genetic cause because most of these cases have no recognizable adverse pre- or postpartum events (Gustavson et al., 1969; Bundey and Griffiths, 1977). Mapping McHale et al. (1999) identified consanguineous families with multiple cases affected by symmetric spastic CP and performed a genomewide search for linkage using 290 polymorphic DNA markers. In 3 families, a region of homozygosity was identified on chromosome 2q21-q31 between markers D2S124 and D2S148 (maximum combined multipoint lod score for the 3 families was 5.75). The minimum region of homozygosity was approximately 5 cM between D2S124 and D2S2284. Molecular Genetics In 4 affected sibs of a consanguineous Pakistani family with autosomal recessive spastic cerebral palsy reported by Mitchell and Bundey (1997), Lynex et al. (2004) identified a homozygous mutation in the GAD1 gene (605363.0001). INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly SKELETAL Spine \- Scoliosis Limbs \- Contractures NEUROLOGIC Central Nervous System \- Mental retardation \- Spastic diplegia, symmetric \- Spastic quadriplegia \- Hyperreflexia \- Hypertonia \- Extensor plantar responses MISCELLANEOUS \- Genetic heterogeneity \- Onset in infancy MOLECULAR BASIS \- Caused by mutation in the glutamate decarboxylase 1 gene (GAD1, 605363.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 1	c2751938	5,456	omim	https://www.omim.org/entry/603513	2019-09-22T16:13:04	{"doid": ["10970"], "mesh": ["C567853"], "omim": ["603513"], "orphanet": ["210141"], "synonyms": ["Inherited congenital spastic quadriplegia", "Spastic quadriplegic cerebral palsy"]}
A number sign (#) is used with this entry because distal hereditary motor neuronopathy type VIIB (dHMN7B or HMN7B) is caused by heterozygous mutation in the dynactin-1 gene (601143) on chromosome 2p13. See also HMN7A (158580), which is caused by mutation in the SLC5A7 gene (608761) on chromosome 2q14. For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN type I (HMN1; 182960). Clinical Features Puls et al. (2003) identified a family with a slowly progressive, autosomal dominant form of motor neuron disease without sensory symptoms. Onset of the disorder was in early adulthood with breathing difficulty due to vocal fold paralysis, progressive facial weakness, and weakness and muscle atrophy in the hands. Weakness and muscle atrophy in the distal lower extremities developed later. There is some phenotypic overlap between this disorder and amyotrophic lateral sclerosis (ALS; 105400). Mapping Puls et al. (2003) performed a genomewide screen in their family with lower motor neuron disease and demonstrated linkage to 2p13 with a maximum lod score of 4.05 at D2S2109 at recombination fraction theta = 0.0. Multipoint linkage analysis gave a maximum lod score of 5.6. Molecular Genetics Puls et al. (2003) found a gly59-to-ser mutation in the DCTN1 gene (G59S; 601143.0001) in all affected individuals of the family they studied with lower motor neuron disease. Among 250 patients with a putative diagnosis of amyotrophic lateral sclerosis, Munch et al. (2004) identified a woman with a mutation in the DCTN1 gene (T1249I; 601143.0002). She had onset at age 56 years of distal lower limb weakness and atrophy without involvement of the upper limbs or bulbar muscles. Munch et al. (2004) considered the phenotype in this patient to be different from that reported by Puls et al. (2003); they stated that 'one of the main differences' was 'the lack of upper motor neuron signs in patients with the G59S mutation,' but specific clinical details were lacking. INHERITANCE \- Autosomal dominant RESPIRATORY Larynx \- Breathing difficulty due to vocal cord paralysis NEUROLOGIC Central Nervous System \- Lower motor neuron disease \- Facial weakness \- Hand muscle weakness \- Hand muscle atrophy \- Breathing difficulty due to vocal cord paralysis \- Lower limb muscle weakness (occurs later) \- Lower limb muscle atrophy \- No sensory symptoms MISCELLANEOUS \- Onset in early adulthood \- Slowly progressive MOLECULAR BASIS \- Caused by mutation in the dynactin-1 gene (DCTN1, 601143.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VIIB	c1843315	5,457	omim	https://www.omim.org/entry/607641	2019-09-22T16:08:58	{"doid": ["0111202"], "mesh": ["C564362"], "omim": ["607641"], "orphanet": ["139589"], "synonyms": ["Alternative titles", "NEUROPATHY, DISTAL HEREDITARY MOTOR, WITH VOCAL CORD PARALYSIS, TYPE VIIB", "NEUROPATHY, DISTAL HEREDITARY MOTOR, TYPE VIIB", "Distal spinal muscular atrophy with vocal cord paralysis", "DHMN7B", "dHMN7", "HMN VIIB", "LOWER MOTOR NEURON DISEASE, DYNACTIN TYPE"]}
## Description Total ophthalmoplegia involves total paralysis of all extra- and intraocular muscles. If one or more of the external muscles, including the levator palpebrae, is not affected, the condition is known as incomplete or partial ophthalmoplegia. If only 1 nerve is affected, the palsy is named after that nerve (see, e.g., abducens palsy, 100200) (Waardenburg, 1963). Clinical Features Waardenburg (1963) discussed familial cases of total ophthalmoplegia including those described by Li (1923) and Waardenburg (1924). Waardenburg (1924) had observed a large, 6-generation, consanguineous pedigree in which 3 of 10 sibs in one sibship and 2 of 3 sibs in another sibship had total ophthalmoplegia, with only a very small abduction effect, associated with extreme miosis and reflexless pupils. Waardenburg (1963) also cited a report by Suzuki in 1926 in which 3 brothers were affected and 2 other sibs and the parents were normal. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Ophthalmoplegia \- Ptosis \- Miosis \- Decreased pupillary accommodation \- Strabismus \- Amblyopia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	OPHTHALMOPLEGIA TOTALIS WITH PTOSIS AND MIOSIS	c1850314	5,458	omim	https://www.omim.org/entry/258400	2019-09-22T16:24:06	{"mesh": ["C564927"], "omim": ["258400"]}
Athletic pubalgia SpecialtySports medicine Athletic pubalgia, also called sports hernia,[1] core injury,[2] hockey hernia,[3] hockey groin,[1] Gilmore's groin,[1] or groin disruption[4] is a medical condition of the pubic joint affecting athletes.[5] It is a syndrome characterized by chronic groin pain in athletes and a dilated superficial ring of the inguinal canal. Football and ice hockey players are affected most frequently. Both recreational and professional athletes may be affected. ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 Incidence * 5 References * 6 External links ## Presentation[edit] Symptoms include pain during sports movements, particularly hip extension, and twisting and turning. This pain usually radiates to the adductor muscle region and even the testicles, although it is often difficult for the patient to pin-point the exact location. Following sporting activity the person with athletic pubalgia will be stiff and sore. The day after a match, getting out of bed or a car will be difficult. Any exertion that increases intra-abdominal pressure, such as coughing, sneezing, or sporting activity can cause pain. In the early stages, the person may be able to continue playing their sport, but the problem usually gets progressively worse. As pain in the groin and pelvis can be referred from a number of problems, including injuries to the lumbar spine, the hip joint, the sacro-iliac joint, the abdomen, and the genito-urinary system, diagnosis of athletic pubalgia requires skillful differentiation and pubic examination in certain cases where there is intense groin pain. ## Diagnosis[edit] The diagnosis is based on the patient's history, clinical signs, and, increasingly, an MRI exam.[6] Symptoms can often be reproduced by maneuvers such as performing sit-ups or crunches. Pain can also be elicited with the patient in a "frog position", in which the patient is supine with knees bent and heels together.[7] The exact lesion may differ, but common pathologic findings at operation are: * torn external oblique aponeurosis * tear in the conjoint tendon * conjoint tendon torn from pubic tubercle * dehiscence between conjoined tendon and inguinal ligament * tear in the fascia transversalis[8] * abnormal insertion of the rectus abdominis muscle * tear of the abdominal internal oblique muscle from the pubic tubercle * entrapment of the ilioinguinal nerve or genitofemoral nerve[9] Several of these lesions may occur simultaneously. Also, many athletes have concomitant weakness or tearing of the adductor muscles or labral tears of the hip. When the adductor muscles are tight post injury, that can be enough to trigger symptoms. ## Treatment[edit] Conservative therapies (gentle stretching and a short period of rest[10]) may temporarily alleviate the pain, but definitive treatment consists of surgical repair followed by a structured rehabilitation.[9][11] The first conservative treatment option should be to restore normal motion after the adductor has begun to heal (usually 6–8 weeks post injury). Sleeping in a prone position with the hip on the affected side flexed and externally rotated can be a cure in some individuals.[citation needed] ## Incidence[edit] The exact incidence of these entities is unknown: some believe it is the most common cause of chronic groin pain in athletes, while others argue that it is only rare.[12] ## References[edit] 1. ^ a b c Meyers, William C.; Yoo, Edward; Devon, Octavia N.; Jain, Nikhil; Horner, Marcia; Lauencin, Cato; Zoga, Adam (October 2007). "Understanding "Sports Hernia" (Athletic Pubalgia): The Anatomic and Pathophysiologic Basis for Abdominal and Groin Pain in Athletes". Operative Techniques in Sports Medicine. 15 (4): 165–177. doi:10.1053/j.otsm.2007.09.001. ISSN 1060-1872. 2. ^ Ross, James R.; Stone, Rebecca M.; Larson, Christopher M. (December 2015). "Core Muscle Injury/Sports Hernia/Athletic Pubalgia, and Femoroacetabular Impingement". Sports Medicine and Arthroscopy Review. 23 (4): 213–220. doi:10.1097/JSA.0000000000000083. PMID 26524557. S2CID 11850885. 3. ^ Omar IM, Zoga AC, Kavanagh EC, et al. (2008). "Athletic pubalgia and "sports hernia": optimal MR imaging technique and findings". Radiographics. 28 (5): 1415–38. doi:10.1148/rg.285075217. PMID 18794316. 4. ^ "Gimore's Groin, Symptoms, Diagnosis, Treatment" (PDF). thegilmoregroinandherniaclinic.co.uk. 2013. Archived from the original (PDF) on 2013-12-03. Retrieved April 30, 2013. 5. ^ Ahumada LA, Ashruf S, Espinosa-de-los-Monteros A, Long JN, de la Torre JI, Garth WP, Vasconez LO (2005). "Athletic pubalgia: definition and surgical treatment". Ann Plast Surg. 55 (4): 393–6. doi:10.1097/01.sap.0000181344.22386.fa. PMID 16186706. S2CID 24007081. 6. ^ "Sports Hernia". Orthopedics.about.com. 2005-12-16. Retrieved 2011-11-13. 7. ^ Le Blanc, E; LeBlanc KA (2003). "Groin pain in athletes". Hernia. 7 (2): 68–71. doi:10.1007/s10029-002-0105-x. PMID 12820026. S2CID 24609449. 8. ^ Joesting DR (2002). "Diagnosis and treatment of sportsman's hernia". Curr Sports Med Rep. 1 (2): 121–4. doi:10.1249/00149619-200204000-00010. PMID 12831721. 9. ^ a b sports/162 at eMedicine 10. ^ "athletic pubalgia". GPnotebook. 11. ^ "The Gilmore Groin & Hernia Clinic Archived 2007-07-06 at the Wayback Machine". Retrieved November 24, 2006. 12. ^ Fredberg U, Kissmeyer-Nielsen P (1996). "The sportsman's hernia—fact or fiction?". Scand J Med Sci Sports. 6 (4): 201–4. doi:10.1111/j.1600-0838.1996.tb00091.x. PMID 8896091. ## External links[edit] Classification D * ICD-9-CM: 848.8 * v * t * e Dislocations/subluxations, sprains and strains Joints and ligaments Head and neck * Dislocation of jaw * Whiplash Shoulder and upper arm * GH (Dislocated shoulder) * AC (Separated shoulder) * ALPSA lesion * SLAP tear * Bankart lesion Elbow and forearm * Pulled elbow * Gamekeeper's thumb Hip and thigh * Hip dislocation Knee and leg * Tear of meniscus * Anterior cruciate ligament injury * Unhappy triad * Patellar dislocation * Knee dislocation Ankle and foot * Sprained ankle (High ankle sprain) * Turf toe Muscles and tendons Shoulder and upper arm * Rotator cuff tear Hip and thigh * Pulled hamstring Knee and leg * Patellar tendon rupture * Achilles tendon rupture * Shin splints [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Athletic pubalgia	None	5,459	wikipedia	https://en.wikipedia.org/wiki/Athletic_pubalgia	2021-01-18T18:47:08	{"icd-9": ["848.8"], "wikidata": ["Q3099702"]}
A number sign (#) is used with this entry because GM1-gangliosidosis is caused by mutation in the gene encoding beta-galactosidase-1 (GLB1; 611458). Description GM1-Gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. Clinically, patients show variable degrees of neurodegeneration and skeletal abnormalities. There are 3 main clinical variants categorized by severity and variable residual beta-galactosidase activity. Type I, or infantile form, shows rapid psychomotor deterioration beginning within 6 months of birth, generalized central nervous system involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death. Type II, or late-infantile/juvenile form (230600), has onset between 7 months and 3 years, shows generalized central nervous system involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present. Type III, or adult/chronic form (230650), shows onset from 3 to 30 years and is characterized by localized skeletal involvement and localized central nervous system involvement, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity (Suzuki et al., 2001). See also Morquio B disease (253010), an allelic disorder with skeletal anomalies and no neurologic involvement. The GM2-gangliosidoses include Tay-Sachs disease (272800) and Sandhoff disease (268800). Clinical Features Landing et al. (1964) gave the first definitive description of this entity, which had variously been called 'Hurler variant,' 'pseudo-Hurler disease,' and 'Tay-Sachs disease with visceral involvement.' O'Brien et al. (1965) suggested the designation 'generalized gangliosidosis.' Clinical features of the infantile form include severe cerebral degeneration leading to death within the first 2 years of life; accumulation of ganglioside in neurons, hepatic, splenic and other histiocytes, and in renal glomerular epithelium; and the presence of skeletal deformities resembling Hurler disease (607014). Scott et al. (1967) described affected sibs. Renal biopsy showed storage of an acid mucopolysaccharide rather than a glycolipid in vacuoles of the glomerular epithelium. The vacuoles were thought to represent lysosomes. The authors suggested that generalized gangliosidosis, which they also called 'neurovisceral lipidosis,' may be closely related to the Hurler syndrome, which it resembles clinically and radiologically. Grossman and Danes (1968) demonstrated x-ray features resembling those of Hurler syndrome, increased synthesis and storage of mucopolysaccharides by skin fibroblasts, and marked metachromasia of fibroblasts in both parents. Autosomal recessive inheritance was suggested. Singer and Schafer (1972) reported a patient who presented at age 3 months due to poor psychomotor development and hepatosplenomegaly. He was later found to have dysplastic changes in the long bones and vertebrae and cherry-red spot on the macula. He died at age 18 months. A female sib had died at age 18 months with autopsy findings consistent with generalized gangliosidosis. Detailed biochemical studies on beta-galactosidase obtained from liver tissue of this patient and a patient with juvenile type II disease suggested that the 2 disorders are related and likely allelic. Fricker et al. (1976) reported a 3-month-old girl with rapidly progressive psychomotor retardation, hepatomegaly, vacuolated lymphocytes, minimal bone dysplasia, and decreased beta-galactosidase activity. She died at age 16 months. Postmortem examination showed generalized GM1-gangliosidosis. Giugliani et al. (1985) found that GM1-gangliosidosis was the inborn error of metabolism most often diagnosed on the Pediatrics Service in Porto Alegre, Brazil. From a study of 8 families, they suggested that increased fetal loss and macrosomy are features and that vacuolated lymphocytes are a useful diagnostic clue. Almost all patients had alteration in the lumbar vertebrae and cherry spots on the retina. Yoshida et al. (1991) reported 4 unrelated Japanese patients with the infantile form of GM1-gangliosidosis. Age at onset ranged from 3 to 5 months. All patients had psychomotor retardation or deterioration, macular cherry-red spots, hepatosplenomegaly, and dysostosis multiplex. Beta-galactosidase activity in leukocytes ranged from 0.65 to 1.58% of control values. ### GM1-Gangliosidosis with Cardiac Involvement Hadley and Hagstrom (1971) reported cardiomyopathy in an infant with GM1-gangliosidosis. EKG showed an incomplete bundle branch block and pathology showed vacuolated and hypertrophied myofibers. The mitral valve leaflets were thick and nodular with vacuolated histiocytes and fibrous tissue. The right coronary artery was partially occluded by an atherosclerotic plaque containing ballooned cells. Benson et al. (1976) reported cardiomegaly in association with GM1-gangliosidosis. Kohlschutter et al. (1982) reported cardiomyopathy in an infant with beta-glucosidase deficiency who died of heart failure at age 8 months. Rosenberg et al. (1985) also described cardiac abnormalities in patients with beta-galactosidase deficiency. Other Features Beratis et al. (1989) described angiokeratoma corporis diffusum appearing before the age of 10 months in a boy with GM1-gangliosidosis. The angiokeratomas did not form clusters but were scattered widely over the body and proximal extremities. No angiokeratomas were observed on the penis and scrotum. Hanson et al. (2003) described 2 infants with extensive dermal melanocytosis in association with GM1-gangliosidosis type I and Hurler syndrome, respectively. Clinically, dermal melanocytosis associated with lysosomal storage disease is characterized by extensive blue cutaneous pigmentation with dorsal and ventral distribution, indistinct borders, and persistent and/or 'progressive' behavior. A literature analysis revealed 37 additional cases. The most common lysosomal storage disease associated with dermal melanocytosis was Hurler syndrome (24 of 39 cases), followed by GM1-gangliosidosis (11 of 39 cases). Hanson et al. (2003) concluded that in the appropriate clinical setting, an unusual presentation of dermal melanocytosis in an infant may be a cutaneous sign of an underlying lysosomal storage disease. Biochemical Features O'Brien et al. (1965) identified the ganglioside stored in this disorder as a GM1 ganglioside distinct from that seen in Tay-Sachs disease. Okada and O'Brien (1968) demonstrated that beta-galactosidase deficiency is the fundamental defect in generalized gangliosidosis. O'Brien (1969) found that all 3 isoenzymes of acid beta-galactosidase, A, B and C, were grossly deficient in all tissues. Galjaard et al. (1975, 1975) studied complementation in cell hybrids between 4 types of Gm(1)-gangliosidosis. They concluded that types I and II involved the same locus. Complementation studies suggested that types III and IV may result from mutation at a second and separate locus. Horst et al. (1975) demonstrated transfer of E. coli beta-galactosidase to gangliosidosis fibroblasts by phage transduction. O'Brien (1975) suggested that the pleiotropic effects of mutations affecting a single locus for beta-galactosidase can be explained by the principle of one gene/one polypeptide/many substrates. Accordingly, different mutations in the same enzyme may have variable phenotypic effects since different mutations may impair one or more substrate specificities much more than others. Sixteen patients with beta-galactosidase deficiency and various phenotypes (i.e., types I, II, or III) were studied and all were found to have cross-reacting positive material to anti-beta-galactosidase antibody. However, all had decreased enzymatic activity. The findings suggested that the various forms of the disorder are due to a mutation at a common locus (reviewed by O'Brien and Norden, 1977). Hoogeveen et al. (1986) showed that the mutations in the infantile and adult forms of GM1-gangliosidosis interfere with the phosphorylation of precursor beta-galactosidase. As a result, the precursor is secreted instead of being compartmentalized into the lysosomes and further processed. Molecular Genetics Yoshida et al. (1991) and Nishimoto et al. (1991) independently identified mutations in the GLB1 gene in Japanese patients with various forms of GM1 gangliosidosis. Those with the infantile form had specific mutations (611458.0001; 611458.0002; 611458.0005-611458.0007). Residual enzyme activity in these patients ranged from 0.65 to 1.58% of control values (Yoshida et al., 1991). In several Italian patients with infantile GM1-gangliosidosis with cardiac involvement, Morrone et al. (2000) identified homozygous mutations in the GLB1 gene (611458.0023-611458.0026). Cardiac involvement took the form of dilated and/or hypertrophic cardiomyopathy. All of these mutations were located in the GLB1 region common to the beta-galactosidase-1 lysosomal protein and ts nonlysosomal splice variant, elastin-binding protein (EBP) or S-Gal, and were shown to impair elastogenesis (Hinek et al., 2000). Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations. Genotype/Phenotype Correlations Hinek et al. (2000) performed expression studies on 2 nonsense GLB1 mutations resulting in GM1-gangliosidosis with cardiac involvement (see, e.g., R351X; 611458.0019). Both mutations resulted in impairment of the lysosomal and EBP protein regions and showed no EBP expression. Functional studies indicated that mutants showed impaired secretion of tropoelastin and did not assemble elastic fibers, resulting in impaired elastogenesis. In these mutants, coculturing with Chinese hamster ovary cells transfected with S-Gal cDNA resulted in improved deposition of elastic fibers. In contrast, cells from patients with missense mutations resulting in lysosomal beta-galactosidase deficiency, but not in S-Gal deficiency, assembled normal elastic fibers. The study provided validating functional roles of S-Gal in elastogenesis and elucidated an association between impaired elastogenesis and the development of connective tissue disorders in patients with infantile GM1-gangliosidosis with cardiac involvement. History Caffey (1951) probably described the first cases, interpreting them as gargoylism with prenatal onset. Animal Model O'Brien et al. (1990) performed allogeneic bone marrow transplantation early in life in a case of canine GM1-gangliosidosis. Despite successful engraftment, no benefit was found. Prieur et al. (1991) described GM1-gangliosidosis in sheep in which deficiency of beta-galactosidase was coupled with a deficiency of alpha-neuraminidase. Skelly et al. (1995) described a new form of ovine GM1-gangliosidosis in which there was a specific deficiency of lysosomal beta-D-galactosidase only. INHERITANCE \- Autosomal recessive GROWTH Height \- Dwarfism HEAD & NECK Face \- Coarse facies \- Full forehead \- Flat nose Eyes \- Hypertelorism \- Clear cornea \- Cherry-red spot in half the patients Mouth \- Gingival hyperplasia Neck \- Short neck CARDIOVASCULAR Heart \- Dilated cardiomyopathy (in a subset of patients) \- Hypertrophic cardiomyopathy (in a subset of patients) \- Congestive heart failure (in a subset of patients) \- Valvular heart disease (in a subset of patients) CHEST Ribs Sternum Clavicles & Scapulae \- Thick ribs ABDOMEN External Features \- Inguinal hernia Liver \- Hepatomegaly Spleen \- Splenomegaly GENITOURINARY Kidneys \- Glomerular epithelial cytoplasmic vacuolization SKELETAL Spine \- Kyphosis \- Scoliosis \- Hypoplastic vertebral bodies \- Beaked vertebral bodies Limbs \- Joint stiffness SKIN, NAILS, & HAIR Skin \- Angiokeratoma corporis diffusum \- Dermal melanocytosis Hair \- Hypertrichosis NEUROLOGIC Central Nervous System \- Mental retardation \- Cerebral degeneration METABOLIC FEATURES \- No mucopolysacchariduria \- Beta-galactosidase-1 deficiency IMMUNOLOGY \- Vacuolated lymphocytes MISCELLANEOUS \- Death in infancy \- Allelic to mucopolysaccharidosis IVB MOLECULAR BASIS \- Caused by mutation in the beta-1 galactosidase gene (GLB1, 611458.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	GM1-GANGLIOSIDOSIS, TYPE I	c0085131	5,460	omim	https://www.omim.org/entry/230500	2019-09-22T16:27:39	{"doid": ["0080502"], "mesh": ["D016537"], "omim": ["230500"], "orphanet": ["79255", "354"], "synonyms": ["GANGLIOSIDOSIS, GENERALIZED GM1, INFANTILE FORM", "Alternative titles", "GLB1 DEFICIENCY", "BETA-GALACTOSIDASE-1 DEFICIENCY", "Infantile GM1 gangliosidosis", "GANGLIOSIDOSIS, GENERALIZED GM1, TYPE 1", "Norman-Landing disease", "GANGLIOSIDOSIS, GENERALIZED GM1, TYPE I"], "genereviews": ["NBK164500"]}
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Find sources: "Syndrome of inappropriate antidiuretic hormone secretion" – news · newspapers · books · scholar · JSTOR (January 2019) Syndrome of inappropriate antidiuretic hormone secretion Other namesSchwartz-Bartter syndrome, syndrome of inappropriate antidiuresis (SIAD) SpecialtyEndocrinology SymptomsLack of appetite, nausea, vomiting, abdominal pain, seizures and coma[1] Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source.[1] Unsuppressed ADH causes an unrelenting increase in solute-free water being returned by the tubules of the kidney to the venous circulation. The causes of SIADH are grouped into six categories: 1) central nervous system diseases that directly stimulate the hypothalamus, the site of control of ADH secretion; 2) various cancers that synthesize and secrete ectopic ADH; 3) various lung diseases; 4) numerous drugs that chemically stimulate the hypothalamus; 5) inherited mutations; and 6) miscellaneous largely transient conditions.[2] ADH is derived from a preprohormone precursor that is synthesized in cells in the hypothalamus and stored in vesicles in the posterior pituitary. Appropriate ADH secretion is regulated by osmoreceptors on the hypothalamic cells that synthesize and store ADH: plasma hypertonicity activates these receptors, ADH is released into the blood stream, the kidney increases solute-free water return to the circulation, and the hypertonicity is alleviated. Inappropriate (increased) ADH secretion causes an unrelenting increase in solute-free water ("free water") absorption by the kidneys, with two consequences. First, in the extracellular fluid (ECF) space, there is a dilution of blood solutes, causing hypoosmolality, including a low sodium concentration - hyponatremia. Then virtually simultaneously, in the intracellular space, cells swell, i.e. intracellular volume increases. Swelling of brain cells causes various neurological abnormalities which in severe or acute cases can result in convulsions, coma, and death. Potential treatments of SIADH include restriction of fluid intake, correction of an identifiable reversible underlying cause, and/or medication which promotes solute-free water excretion by the kidney. The presence of cerebral edema may necessitate intravenous isotonic or hypertonic saline administration.[2] SIADH was originally described in 1957 in two people with small-cell carcinoma of the lung.[3] ## Contents * 1 Signs and symptoms * 1.1 Gastro-intestinal * 1.2 Musculoskeletal * 1.3 Neuro-muscular * 1.4 Respiratory * 1.5 Neurological * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 Epidemiology * 7 History * 8 Society and culture * 9 References * 10 External links ## Signs and symptoms[edit] ### Gastro-intestinal[edit] * Anorexia * Nausea ### Musculoskeletal[edit] * Muscle aches * Generalized muscle weakness[4] ### Neuro-muscular[edit] * Myoclonus[4] * Decreased reflexes[4] * Ataxia[4] * Pathological reflexes[4] * Tremor[4] * Asterixis[4] ### Respiratory[edit] * Cheyne-Stokes respiration[4] ### Neurological[edit] * Dysarthria[4] * Lethargy * Confusion[4] * Delirium[4] * Seizures[4] * Coma (from brain swelling)[4] * Death[4] ## Causes[edit] Causes of SIADH include conditions that dysregulate ADH secretion in the central nervous system, tumors that secrete ADH, drugs that increase ADH secretion, and many others. A list of common causes is below:[2] * Central nervous system-related causes * Infections * Meningitis, encephalitis, brain abscess, rocky mountain spotted fever, AIDS * Perinatal asphyxia * Mass / bleed * Trauma, subarachnoid hemorrhage, subdural hematoma, cavernous sinus thrombosis * Hydrocephalus * Guillain–Barré syndrome * Acute porphyria (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) * Multiple system atrophy * Multiple sclerosis * Cancers * Carcinomas * Lung cancers (small-cell lung cancer, mesothelioma) * Gastrointestinal cancers (stomach, duodenum, pancreas) * Genitourinary cancers (bladder, urethral, prostate, endometrial) * Lymphoma * Sarcomas (Ewing's sarcoma) * Pulmonary causes * Infection * Pneumonia * Lung abscess * Asthma * Cystic fibrosis * Drugs * Chlorpropamide * Clofibrate * Phenothiazine * Ifosfamide * Cyclophosphamide * Carbamazepine * Oxcarbazepine * Valproic acid * Selective serotonin reuptake inhibitors (SSRIs, a class of antidepressants) * 3,4-Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy. SIADH due to taking ecstasy was cited as a factor in the deaths of Anna Wood and Leah Betts) * Oxytocin * Vincristine * Morphine * Amitriptyline * Transient causes * Endurance exercise * General anesthesia * Hereditary causes * Sarcoidosis ## Pathophysiology[edit] Normally there are homeostatic processes in the body which maintain the concentration of body solutes within a narrow range, both inside and outside cells. The process occurs as follows: in some hypothalamic cells there are osmoreceptors which respond to hyperosmolality in body fluids by signalling the posterior pituitary gland to secrete ADH.[5] This keeps serum sodium concentration - a proxy for solute concentration - at normal levels, prevents hypernatremia and turns off the osmoreceptors.[6] Specifically, when the serum sodium rises above 142 mEq/L, ADH secretion is maximal (and thirst is stimulated as well); when it is below 135 mEq/L, there is no secretion.[7] ADH activates V2 receptors on the basolateral membrane of principal cells in the renal collecting duct, initiating a cyclic AMP-dependent process that culminates in increased production of water channels (aquaporin 2), and their insertion into the cells’ luminal membranes.[8] Excessive ADH causes an inappropriate increase in the reabsorption in the kidneys of solute-free water ("free water"): excess water moves from the distal convoluted tubules (DCT)s and collecting tubules of the nephrons \- via activation of aquaporins, the site of the ADH receptors \- back into the circulation. This has two consequences. First, in the extracellular fluid (ECF) space, there is a dilution of blood solutes, causing hypoosmolality, including a low sodium concentration - hyponatremia. [There is no expansion of the ECF volume because as it attempts to expand, aldosterone is suppressed and atrial natriuretic peptide (ANP) is stimulated: both of these hormones cause isotonic ECF fluid to be excreted by the kidneys sufficient to keep ECF volume at a normal level.] Also, virtually simultaneously to these ECF events, the intracellular space (ICF) volume expands. This is because the osmolality of the ECF is (transiently) less than that of the ICF; and since water is readily permeable to cell membranes, solute-free water moves from the ECF to the ICF compartment by osmosis: all cells swell. Swelling of brain cells \- cerebral edema \- causes various neurological abnormalities which in acute and/or severe cases can result in convulsions, coma, and death.[citation needed] The normal function of ADH on the kidneys is to control the amount of water reabsorbed by kidney nephrons. ADH acts in the distal portion of the renal tubule (Distal Convoluted Tubule) as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium), causing hyponatremia; this is compounded by the fact that the body responds to water retention by decreasing aldosterone, thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion concern individuals where vasopressin release and response are normal but where abnormal renal expression and translocation of aquaporin 2, or both are found.[9] It has been suggested that this is due to abnormalities in the secretion of secretin in the brain and that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades."[9] There are no abnormalities in total body sodium metabolism.[10] Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L) are seen[11] ## Diagnosis[edit] Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium.[12] Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium).[13] A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality - <275 mOsm/kg of water; 2) urinary sodium concentration high - over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume - cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma).[1] There are nine supplemental features: 1) a low BUN; 2) a low uric acid; 3) a normal creatinine; 4) failure to correct hyponatremia with IV normal saline; 5) successful correction of hyponatremia with fluid restriction; 6) a fractional sodium excretion >1%; 7) a fractional urea excretion >55%; 8) an abnormal water load test; and 9) an elevated plasma AVP.[2] ### Differential diagnosis[edit] Antidiuretic hormone (ADH) is released from the posterior pituitary for a number of physiologic reasons. The majority of people with hyponatremia, other than those with excessive water intake (polydipsia) or renal salt wasting, will have elevated ADH as the cause of their hyponatremia. However, not every person with hyponatremia and elevated ADH has SIADH. One approach to a diagnosis is to divide ADH release into appropriate (not SIADH) or inappropriate (SIADH). Appropriate ADH release can be a result of hypovolemia, a so-called non-osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water. It can also be perceived hypovolemia, as in the conditions of congestive heart failure (CHF) and cirrhosis in which the kidneys perceive a lack of intravascular volume. The hyponatremia caused by appropriate ADH release (from the kidneys' perspective) in both CHF and cirrhosis have been shown to be an independent poor prognostic indicator of mortality. Appropriate ADH release can also be a result of non-osmotic triggers. Symptoms such as nausea/vomiting and pain are significant causes of ADH release. The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of people who are hospitalized with acute illness and are found to have mild to moderate hyponatremia. SIADH is less common than appropriate release of ADH. While it should be considered in a differential, other causes should be considered as well.[14] Cerebral salt wasting syndrome (CSWS) also presents with hyponatremia, there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage.[15] Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause.[16] ## Treatment[edit] How to manage SIADH depends on whether symptoms are present, the severity of the hyponatremia, and the duration. Management of SIADH includes:[2] * Removing the underlying cause when possible. * Mild and asymptomatic hyponatremia is treated with adequate solute intake (including salt and protein) and fluid restriction starting at 500 ml per day of water with adjustments based on serum sodium levels. Long-term fluid restriction of 1,200–1,800 mL/day may maintain the person in a symptom free state.[17] * Moderate and symptomatic hyponatremia is treated by raising the serum sodium level by 0.5 to 1 mmol per liter per hour for a total of 8 mmol per liter during the first day with the use of furosemide and replacing sodium and potassium losses with 0.9% saline. * For people with severe symptoms (severe confusion, convulsions, or coma) hypertonic saline (3%) 1–2 ml/kg IV in 3–4 h should be given.[citation needed] * Drugs * Demeclocycline can be used in chronic situations when fluid restrictions are difficult to maintain; demeclocycline is the most potent inhibitor of Vasopressin (ADH/AVP) action. However, demeclocycline has a 2–3 day delay in onset with extensive side effect profile, including skin photosensitivity, and nephrotoxicity.[18] * Urea: oral daily ingestion has shown favorable long-term results with protective effects in myelinosis and brain damage.[18] Limitations noted to be undesirable taste and is contraindicated in people with cirrhosis to avoid initiation or potentiation of hepatic encephalopathy. * Conivaptan – an antagonist of both V1A and V2 vasopressin receptors.[18] * Tolvaptan – an antagonist of the V2 vasopressin receptor. Raising the serum sodium concentration too rapidly may cause central pontine myelinolysis.[19] Avoid correction by more than 12 mEq/L/day. Initial treatment with hypertonic saline may abruptly lead to a rapid dilute diuresis and fall in ADH.[citation needed] ## Epidemiology[edit] The incidence of SIADH rises with increasing age. Residents of nursing homes are at highest risk.[20] ## History[edit] The condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with lung cancer.[21][3] Criteria were developed by Schwartz and Bartter in 1967 and have remained unchanged since then.[21][22] ## Society and culture[edit] The condition is occasionally referred to by the names of the authors of the first report: Schwartz-Bartter syndrome.[23] Because not all people with this syndrome have elevated levels of vasopressin, the term "syndrome of inappropriate antidiuresis" (SIAD) has been proposed as a more accurate description of this condition.[24] ## References[edit] 1. ^ a b c Babar SM (October 2013). "SIADH associated with ciprofloxacin". The Annals of Pharmacotherapy. 47 (10): 1359–63. doi:10.1177/1060028013502457. PMID 24259701. S2CID 36759747. 2. ^ a b c d e Ellison, David H.; Berl, Tomas (2007). "The Syndrome of Inappropriate Antidiuresis". New England Journal of Medicine. 356 (20): 2064–72. doi:10.1056/NEJMcp066837. PMID 17507705. [needs update] 3. ^ a b Schwartz, William B.; Bennett, Warren; Curelop, Sidney; Bartter, Frederic C. (1957). "A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone". The American Journal of Medicine. 23 (4): 529–42. doi:10.1016/0002-9343(57)90224-3. PMID 13469824. reproduced as a Milestone in Nephrology with author commentary in Schwartz, William B.; Bennett, Warren; Curelop, Sidney; Bartter, Frederic C. (2001). "A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 1957" (PDF). Journal of the American Society of Nephrology. 12 (12): 2860–70. PMID 11729259. 4. ^ a b c d e f g h i j k l m n Thomas, Christie P (Jul 30, 2018). "Syndrome of Inappropriate Antidiuretic Hormone Secretion". Medscape. Retrieved Oct 30, 2018. 5. ^ Antunes-Rodrigues, J; de Castro, M; Elias, LL; Valença, MM; McCann, SM (January 2004). "Neuroendocrine control of body fluid metabolism". Physiological Reviews. 84 (1): 169–208. doi:10.1152/physrev.00017.2003. PMID 14715914. [needs update] 6. ^ Baylis, PH; Thompson, CJ (November 1988). "Osmoregulation of vasopressin secretion and thirst in health and disease". Clinical Endocrinology. 29 (5): 549–76. doi:10.1111/j.1365-2265.1988.tb03704.x. PMID 3075528. S2CID 10897593. [needs update] 7. ^ Sterns, RH; Silver, SM; Hicks, JK (2013). "44: Hyponatremia". In Alpern, Robert J.; Moe, Orson W.; Caplan, Michael (eds.). Seldin and Giebisch's The Kidney Physiology & Pathophysiology (5th ed.). Burlington: Elsevier Science. ISBN 9780123814630. 8. ^ Kwon, TH; Hager, H; Nejsum, LN; Andersen, ML; Frøkiaer, J; Nielsen, S (May 2001). "Physiology and pathophysiology of renal aquaporins". Seminars in Nephrology. 21 (3): 231–8. doi:10.1053/snep.2001.21647. PMID 11320486. [needs update] 9. ^ a b Chu, J. Y. S.; Lee, L. T. O.; Lai, C. H.; Vaudry, H.; Chan, Y. S.; Yung, W. H.; Chow, B. K. C. (2009). "Secretin as a neurohypophysial factor regulating body water homeostasis". Proceedings of the National Academy of Sciences. 106 (37): 15961–6. Bibcode:2009PNAS..10615961C. doi:10.1073/pnas.0903695106. JSTOR 40484830. PMC 2747226. PMID 19805236. 10. ^ Onitilo, A. A.; Kio, E.; Doi, S. A. R. (2007). "Tumor-Related Hyponatremia". Clinical Medicine & Research. 5 (4): 228–37. doi:10.3121/cmr.2007.762. PMC 2275758. PMID 18086907. 11. ^ Adrogué, Horacio J.; Madias, Nicolaos E. (2000). "Hyponatremia". New England Journal of Medicine. 342 (21): 1581–9. doi:10.1056/NEJM200005253422107. PMID 10824078. 12. ^ Gross, P (April 2012). "Clinical management of SIADH". Therapeutic Advances in Endocrinology and Metabolism. 3 (2): 61–73. doi:10.1177/2042018812437561. PMC 3474650. PMID 23148195. 13. ^ Thomas, Christie P (22 April 2017). "Syndrome of Inappropriate Antidiuretic Hormone Secretion: Practice Essentials, Background, Pathophysiology". Medscape. Retrieved 16 September 2017. 14. ^ Pillai, Binu P.; Unnikrishnan, Ambika Gopalakrishnan; Pavithran, Praveen V. (September 2011). "Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder". Indian Journal of Endocrinology and Metabolism. 15 (Suppl3): S208–S215. doi:10.4103/2230-8210.84870. ISSN 2230-8210. PMC 3183532. PMID 22029026. 15. ^ Sen J, Belli A, Albon H, et al. (2003). "Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage". The Lancet Neurology. 2 (10): 614–621. doi:10.1016/s1474-4422(03)00531-3. PMID 14505583. S2CID 38149776. 16. ^ Rivkees, Scott A (2008). "Differentiating appropriate antidiuretic hormone secretion, inappropriate antidiuretic hormone secretion and cerebral salt wasting: the common, uncommon, and misnamed". Current Opinion in Pediatrics. 20 (4): 448–52. doi:10.1097/MOP.0b013e328305e403. PMID 18622203. S2CID 41194368. 17. ^ Schürer, Ludwig; Wolf, Stefan; Lumenta, Christianto B. (2010). "Water and Electrolyte Regulation". In Lumenta, Christianto B.; Di Rocco, Concezio; Haase, Jens; et al. (eds.). Neurosurgery. European Manual of Medicine. pp. 611–5. doi:10.1007/978-3-540-79565-0_40. ISBN 978-3-540-79565-0. 18. ^ a b c Zietse, R.; van der Lubbe, N.; Hoorn, E. J. (2009). "Current and future treatment options in SIADH". Clinical Kidney Journal. 2 (Suppl_3): iii12–iii19. doi:10.1093/ndtplus/sfp154. PMC 2762827. PMID 19881932. 19. ^ Ashrafian, H.; Davey, P. (2001). "A review of the causes of central pontine myelinosis: yet another apoptotic illness?". European Journal of Neurology. 8 (2): 103–9. doi:10.1046/j.1468-1331.2001.00176.x. PMID 11430268. S2CID 37760332. 20. ^ Upadhyay, A; Jaber, BL; Madias, NE (July 2006). "Incidence and prevalence of hyponatremia". The American Journal of Medicine. 119 (7 Suppl 1): S30-5. doi:10.1016/j.amjmed.2006.05.005. PMID 16843082. [needs update] 21. ^ a b Verbalis, JG; Goldsmith, SR; Greenberg, A; Korzelius, C; Schrier, RW; Sterns, RH; Thompson, CJ (October 2013). "Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations". The American Journal of Medicine. 126 (10 Suppl 1): S1-42. doi:10.1016/j.amjmed.2013.07.006. PMID 24074529. 22. ^ Bartter, Frederic C.; Schwartz, William B. (1967). "The syndrome of inappropriate secretion of antidiuretic hormone". The American Journal of Medicine. 42 (5): 790–806. doi:10.1016/0002-9343(67)90096-4. PMID 5337379. 23. ^ Schwartz-Bartter syndrome at Who Named It? 24. ^ Feldman, BJ; Rosenthal, SM; Vargas, GA; Fenwick, RG; Huang, EA; Matsuda-Abedini, M; Lustig, RH; Mathias, RS; Portale, AA; Miller, WL; Gitelman, SE (5 May 2005). "Nephrogenic syndrome of inappropriate antidiuresis". The New England Journal of Medicine. 352 (18): 1884–90. doi:10.1056/NEJMoa042743. PMC 5340184. PMID 15872203. ## External links[edit] Classification D * ICD-10: E22.2 * ICD-9-CM: 253.6 * MeSH: D007177 * DiseasesDB: 12050 * SNOMED CT: 55004003 External resources * MedlinePlus: 003702 * eMedicine: emerg/784 med/3541 ped/2190 * v * t * e Pituitary disease Hyperpituitarism Anterior * Acromegaly * Hyperprolactinaemia * Pituitary ACTH hypersecretion Posterior * SIADH General * Nelson's syndrome * Hypophysitis Hypopituitarism Anterior * Kallmann syndrome * Growth hormone deficiency * Hypoprolactinemia * ACTH deficiency/Secondary adrenal insufficiency * GnRH insensitivity * FSH insensitivity * LH/hCG insensitivity Posterior Neurogenic diabetes insipidus General * Empty sella syndrome * Pituitary apoplexy * Sheehan's syndrome * Lymphocytic hypophysitis * Pituitary adenoma * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Syndrome of inappropriate antidiuretic hormone secretion	c0021141	5,461	wikipedia	https://en.wikipedia.org/wiki/Syndrome_of_inappropriate_antidiuretic_hormone_secretion	2021-01-18T18:28:57	{"gard": ["10306"], "mesh": ["D007177"], "umls": ["C0021141"], "icd-9": ["253.6"], "wikidata": ["Q959457"]}
## Clinical Features Type A3 brachydactyly is shortening of the middle phalanx of the fifth finger. Slanting of the distal articular surface of the middle phalanx leads to radial deflection of the distal phalanx. Because of rhomboid or triangular shape of the rudimentary middle phalanx, radial curvature (clinodactyly) of the fifth finger results (Temtamy and McKusick, 1978). Bauer (1907) described this anomaly in 4 generations. Dutta (1965) described 'simple radial deviation of the distal phalanx' without bony deformity of the middle or distal phalanx and with normal length of the digit. Whether this is a separate trait is not certain. Type A3 brachydactyly is variable and may encompass the cases described by Dutta (1965) (Temtamy and McKusick, 1978). Hertzog (1967) defined shortened fifth medial phalanges as those less than half the length of the fourth medial phalanx. Hertzog (1967) studied 296 children in Philadelphia, 200 Black and 96 Chinese, and found the trait in 12 of the Chinese children and in none of the Black children. The trait occurred more frequently in females. Two of the affected Chinese children had clinodactyly. X-rays showed well-proportioned diaphyses and cone-shaped epiphyses with early union. In a study of BDA3 among youth in the Jiral population in Nepal, Williams et al. (2007) found that the incidence of cone-shaped epiphyses with BDA3 was nearly double for females compared to males. They suggested that BDA3 with cone-shaped epiphyses is transmitted differently, and separately, from BDA3 and that the former has a strong sex-bias (female:male, 5:2). Inheritance Hersh et al. (1953) studied 5 pedigrees with brachydactyly-clinodactyly (type A3 brachydactyly) and suggested autosomal dominant transmission with incomplete penetrance. Population Genetics Buschang and Malina (1980) noted that 2 indices had been used in previous studies of brachymesophalangy V in various populations: Index 1, based on the ratio of the width to the length of the fifth mid-phalanx, and Index 2, based on the ratio of the length of the fifth to the length of the fourth mid-phalanges. They used both indices to identify the trait among 2,012 individuals from 5 samples of children of different ethnic backgrounds. Index 1 consistently produced higher frequencies than index 2. However, both indices indicated highest relative frequencies among Mexican children, moderate frequencies among children of European ancestry (Pennsylvania White, Canadian, West German), and lower frequencies in Pennsylvania Black children. Buschang and Malina (1980) suggested that Index 2 provides a more accurate indicator within a population as well as a measure that is more comparable between different populations. Their Table 1 listed the results of previous population studies of brachymesophalangy V along with the index used in each study. Williams et al. (2007) noted that as part of a genetic epidemiologic study of the growth and development of children in rural Nepal (Jiri Growth Study), hand-wrist radiographs were taken annually of children of the Jirel ethnic group. From a study of the latest radiographs of 1,357 Jirel youths (676 boys, 681 girls), aged 3 to 20 years, for the presence or absence of BDA3 (based on length, width, and shape of the bone), they found an overall prevalence of BDA3 of 10.5% (12.9% of males and 8.9% of females). Their Table 2 listed the results of previous population studies of 'a short, broad middle phalanx of the fifth digit.' Radiology \- Cone-shaped epiphyses \- Rhomboid or triangular shaped fifth finger middle phalanx Limbs \- Brachydactyly \- Hypoplastic fifth finger middle phalanx \- Fifth finger clinodactyly \- Clinomicrodactyly Growth \- Normal Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	BRACHYDACTYLY, TYPE A3	c1862140	5,462	omim	https://www.omim.org/entry/112700	2019-09-22T16:44:07	{"mesh": ["C537090"], "omim": ["112700"], "synonyms": ["Alternative titles", "BRACHYMESOPHALANGY V", "BRACHYDACTYLY-CLINODACTYLY"]}
## Clinical Features Ohdo et al. (1987) described a 1-year-old child born to second-cousin parents who had tetraamelia, hypotrichosis, upward slanting palpebral fissures, lack of lacrimal openings, hypoplastic lacrimal ducts and sacs opening toward the exterior, prominent and bulbous nose, large downturned mouth (carp mouth), high narrow palate, bilateral preauricular pits, sacral dimple, bilateral undescended testes, and developmental retardation. Since the next fetus conceived by the mother was found on ultrasonography to have no limbs, abortion was induced. The facies of the abortus resembled that of the proband. Ohdo et al. (1994) provided follow-up information on the proband, who had been admitted into an institution for severely mentally and physically handicapped children. His temperature increased when the ambient temperature was high and he suffered from persistent constipation. He never developed eyebrows, eyelashes, or hair on his head. EEG was within normal limits. A CT scan of the brain showed ventriculomegaly and increased subarachnoid space. At 8 years 5 months of age his mental age was evaluated as being 5 months. He suffered frequently from dehydration. At death at the age of 8 years 7 months, his crown-to-rump measurement was 49.0 cm, weight 4.96 kg, and head circumference 48.2 cm. At necropsy, regurgitant esophagitis, a poorly developed small intestine, and small, thick-walled urinary bladder were found. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Preauricular pits Eyes \- Upslanting palpebral fissures \- Absent lacrimal openings \- Hypoplastic lacrimal duct Nose \- Bulbous nose Mouth \- Large mouth \- Downturned mouth \- High, narrow palate ABDOMEN External Features \- Umbilical hernia Gastrointestinal \- Constipation GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL Limbs \- Tetramelia SKIN, NAILS, & HAIR Skin \- Sacral dimple Hair \- Hypotrichosis NEUROLOGIC Central Nervous System \- Mental retardation METABOLIC FEATURES \- Susceptible to hyperthermia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	TETRAAMELIA WITH ECTODERMAL DYSPLASIA AND LACRIMAL DUCT ABNORMALITIES	c2931214	5,463	omim	https://www.omim.org/entry/273390	2019-09-22T16:21:51	{"mesh": ["C536496"], "omim": ["273390"]}
## Description Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003). For additional information and a discussion of genetic heterogeneity of restless legs syndrome, see RLS1 (102300). Clinical Features Bonati et al. (2003) reported an Italian family in which at least 15 members spanning 3 generations had restless legs syndrome inherited in an autosomal dominant pattern. The mean age at onset was 26 years, and was characterized by an irresistible desire to move the lower extremities associated with paresthesias. Episodes occurred at rest and most often at night, resulting in insomnia and chronic sleep deprivation. Several patients complained of leg cramps during the day with exercise. One woman reported exacerbation of symptoms during pregnancy. Some family members demonstrated a less severe phenotype designated 'periodic leg movements in sleep,' which the authors considered to be a precursor to the full disorder. Mapping In a large Italian family with autosomal dominant restless legs syndrome, Bonati et al. (2003) found linkage to a 9.1-cM region between markers D14S70 and D14S1068 on chromosome 14q13-q21 (maximum 2-point lod score of 3.23 at D14S288). Levchenko et al. (2004) found support for this locus in a French Canadian population. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 2	c1837285	5,464	omim	https://www.omim.org/entry/608831	2019-09-22T16:07:06	{"omim": ["608831"]}
Signet ring cell carcinoma A signet ring cell carcinoma of the stomach. Signet ring cells are seen in the lower half of the image. Gastric epithelium is seen in the upper half of the image. H&E stain. SpecialtyOncology Signet ring cell carcinoma (SRCC) is a rare form of highly malignant adenocarcinoma[1] that produces mucin. It is an epithelial malignancy characterized by the histologic appearance of signet ring cells. Primary SRCC tumors are most often found in the glandular cells of the stomach (SRCC originates in the stomach in 56 percent of patients),[2] and less frequently in the breast, gallbladder, urinary bladder, and pancreas.[3] SRCCs do not normally form in the lungs, though a few incidences have been reported.[1] Among colorectal cancers, the prevalence of SRCC is less than one percent. Though incidence and mortality of gastric cancer has declined in many countries over the past 50 years, there has been an increase in occurrences of gastric SRCC-type cancers.[4] SRCC tumors grow in characteristic sheets, which makes diagnosis using standard imaging techniques, like CT and PET scans, less effective.[5][6] ## Contents * 1 Causes * 2 Mechanism of formation * 3 Metastasis * 4 Histology * 5 Treatment * 6 Prognosis by organ * 6.1 Bladder * 6.2 Colorectal * 6.3 Stomach * 7 Additional images * 8 References * 9 External links ## Causes[edit] Some cases are inherited, and these cases are often caused by mutations in the CDH1 gene, which encodes the important cell–cell adhesion glycoprotein E-cadherin.[7][8] Somatic mutations of the APC gene have also been implicated in the development of gastric SRCCs.[9] The role of other risk factors in gastric cancer such as salt-preserved food, smoking, auto-immune gastritis are not well studied in SRCC.[10] ## Mechanism of formation[edit] SRCCs are dedifferentiated adenocarcinomas that lose the capability for cell–cell interaction.[citation needed] Highly differentiated adenocarcinomas form SRCCs via a loss of adherens and tight junctions that typically separate MUC4, a mucin protein, and ErbB2, an oncogenic receptor. When MUC4 and ErbB2 are able to interact, they trigger an activation loop. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell–cell interactions are lost and signet carcinomas are formed. Constitutive action of the ErbB2/ErbB3 complex also enhances cell growth.[11] The mechanism of this malignant cancer is still unclear; however, it has been found that a colon carcinoma cell known as HCC2998 causes an increase in differentiated tumor production. The reason for this increase is due to active PI3K that are converted to a SRCC-like cells.[12] ## Metastasis[edit] The pattern of metastasis is different for gastric signet cell carcinoma than for intestinal-type gastric carcinoma. The SRCC tumor is often seen in the peritoneum and has also been known to spread to lymphatic permeation of the lungs and to the ovaries, creating Krukenberg tumors.[13] Cases of gastric carcinomas metastasizing to the breast and forming signet-ring cells have also been reported. One study suggests that when signet-ring cells are found in a breast tumor, the presence of gastric cancer should also be considered.[14] ## Histology[edit] Main article: signet ring cell SRCCs are named due to their resemblance to signet rings, which result from the formation of large vacuoles full of mucin that displace the nucleus to the cell's periphery.[15] Stomach cancers with both adenocarcinoma and some SRC (known as mixed-SRCC) exhibit more aggressive behavior than purely SRCC or non-SRCC histologies.[16] A study of SRCC colorectal cancers compared mucin-rich SRCC tumors and mucin-poor SRCC tumors. They concluded that the latter more frequently demonstrated adverse histologic features such as lymphatic invasion, venous invasion and perineural invasion.[17] ## Treatment[edit] Chemotherapy has relatively poor curative efficacy in SRCC patients and overall survival rates are lower compared to patients with more typical cancer pathology. SRCC cancers are usually diagnosed during the late stages of the disease, so the tumors generally spread more aggressively than non-signet cancers, making treatment challenging.[18] In the future, case studies indicate that bone marrow metastases will likely play a larger role in the diagnosis and management of signet ring cell gastric cancer.[19] In SRCC of the stomach, removal of the stomach cancer is the treatment of choice. There is no combination of chemotherapy which is clearly superior to others, but most active regimens include 5-Fluorouracil (5-FU), Cisplatin, and/or Etoposide. Some newer agents, including Taxol and Gemcitabine (Gemzar) are under investigation.[20] In a single case study of a patient with SRCC of the bladder with recurrent metastases, the patient exhibited a treatment response to palliative FOLFOX-6 chemotherapy.[21] There are reports of occasional pulmonary tumour thrombotic microangiopathy leading to pulmonary hypertension and coagulation problems that could be successfully treated with Imatinib. ## Prognosis by organ[edit] These aggressive tumors are generally diagnosed at advanced stages and survival is generally shorter. The prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage.[22] One study suggests that its dismal prognosis seems to be caused by its intrinsic tumor biology, suggesting an area for further research.[23] ### Bladder[edit] Primary signet-ring cell carcinoma of the urinary bladder is extremely rare and patient survival is very poor and occurs mainly in men ages 38 to 83. However, one such patient treated with a radical cystectomy followed by combined S-1 and Cisplatin adjuvant chemotherapy did demonstrate promising long-term survival of 90 months.[24] ### Colorectal[edit] Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, with a reported incidence of less than 1 percent. It has a poor prognosis because symptoms often develop late and it is usually diagnosed at an advanced stage. Five-year survival rates in previous studies ranged from nine to 30 percent. Average survival was between 20 and 45 months.[25] It tends to affect younger adults with higher likelihood of lymphovascular invasion. It is worth noting that the overall survival rate of patients with SRCC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma.[26] In advanced gastric cancers, the prognosis for patients with the SRCCs was significantly worse than for the other histological types, which can be explained by the finding that advanced SRCC gastric cancers have a larger tumor size, more lymph node metastasis, a deeper invasive depth and more Borrmann type 4 lesions than other types.[27] ### Stomach[edit] When compared to adenocarcinoma stomach, SRCC in the stomach occurs more often in women and younger patients.[28] Patients with SRCC of the stomach show similar clinicopathological features to patients with undifferentiated histology. A recent study found that patients with SRCC had a better prognosis than patients with undifferentiated gastric carcinoma. However, when narrowed to patients with only advanced stage gastric cancer, those with SRCC had a worse prognosis than other cell types.[29] ## Additional images[edit] * Gastric signet ring cell carcinoma. H&E stain. ## References[edit] 1. ^ el-Zimaity HM, Itani K, Graham DY (October 1997). "Early diagnosis of signet ring cell carcinoma of the stomach: role of the Genta stain". J. Clin. Pathol. 50 (10): 867–8. doi:10.1136/jcp.50.10.867. PMC 500272. PMID 9462273. 2. ^ Benesch, Matthew; Mathieson, Alexander (June 2020). "Epidemiology of Signet Ring Cell Adenocarcinomas". Cancers. 12 (6): E1544. doi:10.3390/cancers12061544. PMC 7352645. PMID 32545410. 3. ^ Belli, Sedat; Aytac, Huseyin Ozgur; Karagulle, Erdal; Yabanoglu, Hakan; Kayaselcuk, Fazilet; Yildirim, Sedat (2014-01-01). "Outcomes of Surgical Treatment of Primary Signet Ring Cell Carcinoma of the Colon and Rectum: 22 Cases Reviewed With Literature". International Surgery. 99 (6): 691–698. doi:10.9738/INTSURG-D-14-00067.1. ISSN 0020-8868. PMC 4254225. PMID 25437572. 4. ^ Henson, Donald Earl; Dittus, Christopher; Younes, Mamoun; Nguyen, Hong; Albores-Saavedra, Jorge (July 2004). "Differential Trends in the Intestinal and Diffuse Types of Gastric Carcinoma in the United States, 1973–2000: Increase in the Signet Ring Cell Type". Archives of Pathology & Laboratory Medicine. 128 (7): 765–770. doi:10.1043/1543-2165(2004)128<765:DTITIA>2.0.CO;2 (inactive 2021-01-16). PMID 15214826.CS1 maint: DOI inactive as of January 2021 (link) 5. ^ Shah, Rajal B.; Zhou, Ming (2011-09-29). Prostate Biopsy Interpretation: An Illustrated Guide. Springer Science & Business Media. ISBN 978-3-642-21369-4. 6. ^ Shen, Steven S.; Zhai, Qihui Jim; Ayala, Alberto G. (2012-04-20). Advances in Surgical Pathology: Prostate Cancer. Lippincott Williams & Wilkins. ISBN 978-1-60831-434-8. 7. ^ "Office of Rare Diseases Research: Diffuse Gastric Cancer". National Institute of Health. National Institute of Health. pp. 84–85. Retrieved 2012-11-21. 8. ^ Muta, Hiromi; Noguchi, Masayuki; Kanai, Yae; Ochiai, Atsushi; Nawata, Hajime; Hirohashi, Setsuo (1996-08-01). "E-Cadherin Gene Mutations in Signet Ring Cell Carcinoma of the Stomach". Japanese Journal of Cancer Research. 87 (8): 843–848. doi:10.1111/j.1349-7006.1996.tb02109.x. ISSN 1349-7006. PMC 5921174. PMID 8797891. 9. ^ Nakatsuru, Shuichi; Yanagisawa, Akio; Ichii, Shigetoshi; Tahara, Eiichi; Kato, Yo; Nakamura, Yusuke; Horii, Akira (1992-10-01). "Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma". Human Molecular Genetics. 1 (8): 559–563. doi:10.1093/hmg/1.8.559. ISSN 0964-6906. PMID 1338691. 10. ^ Pernot, Simon; Voron, Thibault; Perkins, Geraldine; Lagorce-Pages, Christine; Berger, Anne; Taieb, Julien (2015-10-28). "Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge". World Journal of Gastroenterology. 21 (40): 11428–11438. doi:10.3748/wjg.v21.i40.11428. ISSN 1007-9327. PMC 4616218. PMID 26523107. 11. ^ Fukui, Yasuhisa (2014-08-08). "Mechanisms behind signet ring cell carcinoma formation". Biochemical and Biophysical Research Communications. 450 (4): 1231–1233. doi:10.1016/j.bbrc.2014.07.025. ISSN 1090-2104. PMID 25019985. 12. ^ Fukui Y (2014). "Mechanism behind signet ring cell carcinoma formation". Biochemical and Biophysical Research Communications. 450 (4): 1231–1233. doi:10.1016/j.bbrc.2014.07.025. PMID 25019985. 13. ^ Duarte, Ignacio; Llanos, Osvaldo (1981). "Patterns of metastases in intestinal and diffuse types of carcinoma of the stomach". Human Pathology. 12 (3): 237–242. doi:10.1016/S0046-8177(81)80124-4. PMID 7228019. 14. ^ Iesato, Asumi; Oba, Takaaki; Ono, Mayu; Hanamura, Toru; Watanabe, Takayuki; Ito, Tokiko; Kanai, Toshiharu; Maeno, Kazuma; Ishizaka, Katsuhiko (2014-12-29). "Breast metastases of gastric signet-ring cell carcinoma: a report of two cases and review of the literature". OncoTargets and Therapy. 8: 91–97. doi:10.2147/OTT.S67921. ISSN 1178-6930. PMC 4284042. PMID 25565869. 15. ^ Portnoy, L. M. (2006-05-05). Radiologic Diagnosis of Gastric Cancer: A new Outlook. Springer Science & Business Media. ISBN 9783540294214. 16. ^ Huh, Cheal Wung; Jung, Da Hyun; Kim, Jie-Hyun; Lee, Yong Chan; Kim, Hyunki; Kim, Hoguen; Yoon, Sun Och; Youn, Young Hoon; Park, Hyojin (2013-02-01). "Signet ring cell mixed histology may show more aggressive behavior than other histologies in early gastric cancer". Journal of Surgical Oncology. 107 (2): 124–129. doi:10.1002/jso.23261. ISSN 1096-9098. PMID 22991272. S2CID 206174013. 17. ^ Hartman, Douglas J.; Nikiforova, Marina N.; Chang, Daniel T.; Chu, Edward; Bahary, Nathan; Brand, Randall E.; Zureikat, Amer H.; Zeh, Herbert J.; Choudry, Haroon; Pai, Reetesh K. (2013). "Signet ring cell colorectal carcinoma: A distinct subset of mucin-poor microsatellite-stable signet ring cell carcinoma associated with dismal prognosis". The American Journal of Surgical Pathology. 37 (7): 969–977. doi:10.1097/PAS.0b013e3182851e2b. PMID 23681075. S2CID 19107084. 18. ^ Nitsche, Ulrich; Zimmermann, Anina; Späth, Christoph; Müller, Tara; Maak, Matthias; Schuster, Tibor; Slotta-Huspenina, Julia; Käser, Samuel A.; Michalski, Christoph W.; Janssen, Klaus-Peter; Friess, Helmut; Rosenberg, Robert; Bader, Franz G. (2013). "Mucinous and Signet-Ring Cell Colorectal Cancers Differ from Classical Adenocarcinomas in Tumor Biology and Prognosis". Annals of Surgery. 258 (5): 775–783. doi:10.1097/SLA.0b013e3182a69f7e. PMC 3888475. PMID 23989057. 19. ^ Dittus, Christopher; Mathew, Hannah; Malek, Anita; Negroiu, Andreea (2014-09-14). "Bone marrow infiltration as the initial presentation of gastric signet ring cell adenocarcinoma". Journal of Gastrointestinal Oncology. 5 (6): E113–E116. doi:10.3978/j.issn.2078-6891.2014.050. PMC 4226827. PMID 25436133. 20. ^ "Signet Ring Cell Cancer \| Oncolink - Cancer Resources". www.oncolink.org. Retrieved 2016-04-20. 21. ^ Pugashetti, Neil; Yap, Stanley A.; Lara, Primo N.; Gandour-Edwards, Regina; Dall’Era, Marc A. (2015-01-01). "Metastatic signet-ring cell carcinoma of the urinary bladder: A novel management approach to a rare tumour". Canadian Urological Association Journal. 9 (3–4): E204–E207. doi:10.5489/cuaj.2447. ISSN 1911-6470. PMC 4455640. PMID 26085880. 22. ^ Pernot, Simon; Voron, Thibault; Perkins, Geraldine; Lagorce-Pages, Christine; Berger, Anne; Taieb, Julien (2015-10-28). "Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge". World Journal of Gastroenterology. 21 (40): 11428–11438. doi:10.3748/wjg.v21.i40.11428. ISSN 1007-9327. PMC 4616218. PMID 26523107. 23. ^ Nitsche, Ulrich; Zimmermann, Anina; Späth, Christoph; Müller, Tara; Maak, Matthias; Schuster, Tibor; Slotta-Huspenina, Julia; Käser, Samuel A.; Michalski, Christoph W.; Janssen, Klaus-Peter; Friess, Helmut; Rosenberg, Robert; Bader, Franz G. (2013). "Mucinous and Signet-Ring Cell Colorectal Cancers Differ from Classical Adenocarcinomas in Tumor Biology and Prognosis". Annals of Surgery. 258 (5): 775–783. doi:10.1097/SLA.0b013e3182a69f7e. PMC 3888475. PMID 23989057. 24. ^ Takashi Hamakawa; Yoshiyuki Kojima; Taku Naiki; Yasue Kubota; Takahiro Yasui; Keiichi Tozawa; Yutaro Hayashi; Kenjiro Kohri (April 2013). "Case Report: Long-Term Survival of a Patient with Invasive Signet-Ring Cell Carcinoma of the Urinary Bladder Managed by Combined S-1 and Cisplatin Adjuvant Chemotherapy". Case Reports in Urology. 2013: 915874. doi:10.1155/2013/915874. PMC 3664482. PMID 23738191. 25. ^ Belli, Sedat; Aytac, Huseyin Ozgur; Karagulle, Erdal; Yabanoglu, Hakan; Kayaselcuk, Fazilet; Yildirim, Sedat (2014-01-01). "Outcomes of Surgical Treatment of Primary Signet Ring Cell Carcinoma of the Colon and Rectum: 22 Cases Reviewed With Literature". International Surgery. 99 (6): 691–698. doi:10.9738/INTSURG-D-14-00067.1. ISSN 0020-8868. PMC 4254225. PMID 25437572. 26. ^ Lee WS, Chun HK, Lee WY, et al. (September 2007). "Treatment outcomes in patients with signet ring cell carcinoma of the colorectum". The American Journal of Surgery. 194 (3): 294–298. doi:10.1016/j.amjsurg.2006.12.041. PMID 17693269. 27. ^ Kim, J. P.; Kim, S. C.; Yang, H. K. (1994-08-01). "Prognostic significance of signet ring cell carcinoma of the stomach". Surgical Oncology. 3 (4): 221–227. doi:10.1016/0960-7404(94)90037-x. ISSN 0960-7404. PMID 7834113. 28. ^ Shah, Rajal B.; Zhou, Ming (2011-09-29). Prostate Biopsy Interpretation: An Illustrated Guide. Springer Science & Business Media. ISBN 9783642213694. 29. ^ Kwon, Kyoung-Joo; Shim, Ki-Nam; Song, Eun-Mi; Choi, Ju-Young; Kim, Seong-Eun; Jung, Hye-Kyung; Jung, Sung-Ae (2013-02-07). "Clinicopathological characteristics and prognosis of signet ring cell carcinoma of the stomach". Gastric Cancer. 17 (1): 43–53. doi:10.1007/s10120-013-0234-1. ISSN 1436-3291. PMID 23389081. S2CID 8262409. ## External links[edit] Classification D * ICD-O: M8490/3 * MeSH: D018279 * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Signet ring cell carcinoma	c0206696	5,465	wikipedia	https://en.wikipedia.org/wiki/Signet_ring_cell_carcinoma	2021-01-18T18:59:09	{"mesh": ["D018279"], "umls": ["C0206696"], "wikidata": ["Q825923"]}
"AVCD" redirects here. For audio VCD, see Video CD. Atrioventricular septal defect Illustration of a atrioventricular septal defect SpecialtyMedical genetics Atrioventricular septal defect (AVSD) or atrioventricular canal defect (AVCD), also known as "common atrioventricular canal" (CAVC) or "endocardial cushion defect" (ECD), is characterized by a deficiency of the atrioventricular septum of the heart. It is caused by an abnormal or inadequate fusion of the superior and inferior endocardial cushions with the mid portion of the atrial septum and the muscular portion of the ventricular septum. ## Contents * 1 Symptoms * 1.1 Complications * 1.2 Associated conditions * 2 Pathophysiology * 2.1 Genetic Relationship * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 See also * 6 References * 7 External links ## Symptoms[edit] Symptoms include difficulty breathing (dyspnoea) and bluish discoloration on skin and lips (cyanosis). A newborn baby will show signs of heart failure such as edema, fatigue, wheezing, sweating and irregular heartbeat.[1] ### Complications[edit] When there are holes in the septum that divide the four chambers of the heart the oxygen-rich blood and oxygen-poor blood mix this creates more stress on the heart to pump blood to where oxygen is needed. As a result, you get enlargement of the heart, heart failure (being unable to adequately supply body with needed oxygen), pulmonary hypertension, and pneumonia.[1] The development of pulmonary hypertension is very serious. And this because the left ventricle is weakened due to its overuse. When this happens, the pressure backs up into the pulmonary veins and the lungs.[1] This type of damage is irreversible which is why immediate treatment is recommended after diagnosis.[2] ### Associated conditions[edit] Down syndrome is often associated with AVCD.[3] Other risk factors include: having a parent with a congenital heart defect, alcohol use while pregnant, uncontrolled diabetes treatment during pregnancy and some medications during pregnancy.[1] This type of congenital heart defect is associated with patients with Down syndrome (trisomy 21) or heterotaxy syndromes.[4] 45% of children with Down syndrome have congenital heart disease. Of these, 35–40% have AV septal defects.[5] Similarly, one-third of all children born with AVSDs also have Down syndrome.[6] A study also showed that there is also an increased risk of atrioventricular canal in patients who suffer from Noonan syndrome. The pattern seen in those patients with Noonan syndrome differ from those patients who have Down syndrome in that "partial" AVCD is more prevalent in those who suffer from NS, where as those who suffer from down syndrome show a prevalence of the "complete" form of AVCD.[7] ## Pathophysiology[edit] If there is a defect in the septum, it is possible for blood to travel from the left side of the heart to the right side of the heart, or the other way around. Since the right side of the heart contains venous blood with a low oxygen content, and the left side of the heart contains arterial blood with a high oxygen content, it is beneficial to prevent any communication between the two sides of the heart and prevent the blood from the two sides of the heart from mixing with each other. ### Genetic Relationship[edit] TBX2 is a T-box transcription factor and is usually expressed during various areas of embryogenesis. One notable expression is when it is shown in the development of the outflow system and atrioventricular canal of the developing heart. In a study, they used targeted mutagenesis in mice to delete Tbx2 locus in some specimen. The results showed that mice who were homozygous and heterozygous null (+/+ & +/-) for Tbx2 resulted in the development of a healthier heart, while those who were homozygous null (-/-) for Tbx2 died early because of the inability of the heart to supply the body. It showed that there was insufficient formation of the endocardial cushion. There was a clear abnormality not only in the atrioventricular canal but also in the left ventricle. This study supports the fact that Tbx2 expression is important in the development of proper chamber differentiation, and in turn cannot have a direct relation to the development of atrioventricular canal defect.[8] ## Diagnosis[edit] Ultrasound showing a complete atrioventricular septal defect AVSDs can be detected by cardiac auscultation; they cause atypical murmurs and loud heart tones. Confirmation of findings from cardiac auscultation can be obtained with a cardiac ultrasound (echocardiography \- less invasive) and cardiac catheterization (more invasive). Tentative diagnosis can also be made in utero via fetal echocardiogram. An AVSD diagnosis made before birth is a marker for Down syndrome, although other signs and further testing are required before any definitive confirmation of either can be made. ### Classification[edit] A variety of different classifications have been used, but the defects are usefully divided into "partial" and "complete" forms. * In the partial AVSD, there is a defect in the primum or inferior part of the atrial septum but no direct intraventricular communication (ostium primum defect). * In the complete AVSD (CAVSD), there is a large ventricular component beneath either or both the superior or inferior bridging leaflets of the AV valve. The defect involves the whole area of the junction of the upper and lower chambers of the heart, i.e. where the atria join the ventricles. There is a large hole between the lower portion of the atria and the upper or `inlet' portion of the ventricles and this is associated with a significant abnormality of the valves separating the atria from the ventricles. The valves in effect become a common atrio-ventricular valve, and the severity of the defect depends largely on the supporting attachments of the valve to the ventricles and whether the valve allows dominant flow from the right atrium to right ventricle and from left atrium to left ventricle ("unbalanced" flow). The overall problems are similar to those of VSD but are more complicated. There is an increased flow of blood to the lungs through both the ventricular and atrial components of the defect. In addition, the abnormal atrio-ventricular valve invariably leaks, so that when the ventricles contract, blood flows not only forwards to the body and the lungs, but also backwards into the atria. The back-pressure effect on the atria causes congestion of blood in the left atrium in particular, and this in turn causes congestion in the veins draining the lungs. The effect on the baby is to worsen the heart failure that is associated with an isolated VSD and to hasten the onset of pulmonary hypertension. It should be mentioned that CAVSD is found in approximately one-third of babies who have Down syndrome, but it also occurs as an isolated abnormality.[citation needed] ## Treatment[edit] Treatment is surgical and involves closure of the atrial and ventricular septal defects and restoration of a competent left AV valve as far as is possible. Open surgical procedures require a heart-lung machine and are done with a median sternotomy. Surgical mortality for uncomplicated ostium primum defects in experienced centers is 2%; for uncomplicated cases of complete atrioventricular canal defect, 4% or less. Certain complications such as tetralogy of Fallot or highly unbalanced flow across the common AV valve can increase risk significantly.[9][10] Infants born with AVSD are generally in sufficient health to not require immediate corrective surgery. If surgery is not required immediately after birth, the newborn will be closely monitored for the next several months, and the operation held-off until the first signs of lung distress or heart failure. This gives the infant time to grow, increasing the size of, and thereby the ease of operation on, the heart, as well as the ease of recovery. Infants will generally require surgery within three to six months, however, they may be able to go up to two years before the operation becomes necessary, depending on the severity of the defect.[11] ## See also[edit] * Atrial septal defect * Congenital heart disease * Heart * Heart sounds * Pulmonary hypertension * Ventricular septal defect ## References[edit] 1. ^ a b c d Mayo Clinic September 12, 2012"Atrioventricular Canal Defect" http://www.mayoclinic.com/health/atrioventricular-canal-defect/DS00745 2. ^ Calabrò R, Limongelli G (2006). "Complete atrioventricular canal". Orphanet J Rare Dis. 1: 8. doi:10.1186/1750-1172-1-8. PMC 1459121. PMID 16722604. 3. ^ Irving, Claire A.; Chaudhari, Milind P. (April 2012). "Cardiovascular abnormalities in Down's syndrome: spectrum, management and survival over 22 years". Archives of Disease in Childhood. 97 (4): 326–330. doi:10.1136/adc.2010.210534. ISSN 1468-2044. PMID 21835834. 4. ^ Report of the New England Regional Infant Cardiac Program" Pediatrics 1980;65(suppl):441–444. 5. ^ Al-Hay AA, et al. (2003). "Complete atrioventricular septal defect, Down syndrome and surgical outcome: Risk factors". Ann Thorac Surg. 75 (2): 412–421. doi:10.1016/s0003-4975(02)04026-2. PMID 12607648. 6. ^ Children's National Health System. (2019). Pediatric Atrioventricular Canal (AV canal or AVC). [online] Available at: https://childrensnational.org/choose-childrens/conditions-and-treatments/heart/atrioventricular-canal-av-canal-or-avc [Accessed 5 Feb. 2019]. 7. ^ Marino Bruno (1999). "Congenital Heart Diseases in Children with Noonan Syndrome: An expanded cardiac spectrum with high prevalence of Atrioventricular Canal". The Journal of Pediatrics. 135 (6): 703–706. doi:10.1016/S0022-3476(99)70088-0. PMID 10586172. 8. ^ Harrelson, Zachary "Tbx2 is Essential for Patterning the Atrioventricular Canal and for Morphogenesis of the Outflow Tract During Heart Development" 2004 October 15, The Company of Biologists http://dev.biologists.org/content/131/20/5041.full 9. ^ Kirklin J, Barratt-Boyes B, ed. Cardiac Surgery, New York: Wiley, 1986:463–497. 10. ^ Marx, GR, Fyler DC, "Endiocardial Cusion Defects", in Keane, JF, Lock, JE, Fyler DC ed. Nadas' Pediatric Cardiology 2ed., Philadelphia: Saunders-Elsevier, 2006:663-674.. 11. ^ Hay, WW, et al. 2007. Lange Current Pediatric Diagnosis and Treatment, 18th ed. New York: McGraw-Hill. ## External links[edit] Classification D * ICD-10: Q21.2 * ICD-9-CM: 745.6 * MeSH: D004694 * DiseasesDB: 31910 External resources * eMedicine: med/670 * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology 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Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Atrioventricular septal defect	c0014116	5,466	wikipedia	https://en.wikipedia.org/wiki/Atrioventricular_septal_defect	2021-01-18T19:10:55	{"gard": ["802"], "mesh": ["D004694"], "umls": ["C0014116"], "orphanet": ["98722"], "wikidata": ["Q390211"]}
A rare, genetic limb reduction defects syndrome characterized by bilateral radial aplasia/hypoplasia manifesting with absent/short forearms in association with anogenital abnormalities (e.g. hypospadias or imperforate anus). Additional features reported include hydrocephalus and absent preaxial digits. There have been no further descriptions in the literature since 1993. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Absent radius-anogenital anomalies syndrome	c1839410	5,467	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3016	2021-01-23T18:56:01	{"gard": ["4633"], "mesh": ["C535281"], "omim": ["312190"], "umls": ["C1839410"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Parathyroid neoplasm" – news · newspapers · books · scholar · JSTOR (March 2019) Parathyroid neoplasm SpecialtyOncology A parathyroid neoplasm is a tumor of the parathyroid gland. Types include: * Parathyroid adenoma * Parathyroid carcinoma ## References[edit] ## External links[edit] Classification D * ICD-10: C75.0, D35.1 * ICD-9-CM: 194.1, 227.1 * MeSH: D010282 * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B This article about a neoplasm is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Parathyroid neoplasm	c0030521	5,468	wikipedia	https://en.wikipedia.org/wiki/Parathyroid_neoplasm	2021-01-18T18:54:02	{"mesh": ["D010282"], "umls": ["C0030521"], "icd-9": ["227.1", "194.1"], "icd-10": ["C75.0", "D35.1"], "orphanet": ["100090"], "wikidata": ["Q7136148"]}
Tularemia is an infection caused by the bacterium Francisella tularensis. It is more common in rodents and rabbits but has been found in other animals including domestic cats, sheep, birds, and hamsters. Humans can become infected in several different ways: by handling infected animals, through tick or deer fly bites, by drinking contaminated water, or by inhaling contaminated dust or aerosols. Person-to-person transmission has not been reported. The type of tularemia and the particular signs and symptoms vary depending on how the bacteria enter the body. However, fever is seen in most cases. Though tularemia can be life-threatening, most infections can be treated with antibiotics. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tularemia	c0041351	5,469	gard	https://rarediseases.info.nih.gov/diseases/396/tularemia	2021-01-18T17:57:16	{"mesh": ["D014406"], "umls": ["C0041351"], "synonyms": ["Francisella tularensis infection", "Deerfly fever", "Rabbit fever", "Pahvant Valley plague", "Ohara disease", "Yatobyo (Japan)", "Lemming fever"]}
Implantation bleeding is the idea that a small amount of vaginal bleeding can occur in early pregnancy due to the fertilized egg attaching to the inside of the uterus.[1] However, there is no support for the notion that implantation produces vaginal bleeding.[2] Bleeding and spotting are common during the luteal phase of the menstrual cycle as well as during early pregnancy, and for reasons unrelated to implantation. ## References[edit] 1. ^ editor, Eyal Sheiner (2011). Bleeding during pregnancy a comprehensive guide. New York: Springer. p. 9. ISBN 9781441998101.CS1 maint: extra text: authors list (link) 2. ^ Weinberg, C. R.; Baird, D. D.; Wilcox, A. J.; Harville, E. W. (2003-09-01). "Vaginal bleeding in very early pregnancy". Human Reproduction. 18 (9): 1944–1947. doi:10.1093/humrep/deg379. ISSN 0268-1161. PMID 12923154. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Implantation bleeding	None	5,470	wikipedia	https://en.wikipedia.org/wiki/Implantation_bleeding	2021-01-18T19:00:25	{"wikidata": ["Q3724756"]}
Hsu et al. (1981) and Chan et al. (1984) described HLA-linked immune response (Ir) genes that control in vitro lymphoproliferative responses to challenge by certain synthetic polypeptide antigens (see 146950, 146960, 146810, 146820). Without prior in vivo immunization, human peripheral blood lymphocytes proliferate vigorously when cultured for 7 days in the presence of antigen. Presumably, this is a secondary response resulting from exposure of the subject to similar epitopes in nature. While responsiveness in most families segregated as a mendelian dominant trait, some mating between nonresponders produced responder offspring, suggesting that, as in the mouse, responsiveness requires 2 complementary loci. The complementary genes were in coupling when inheritance was 'dominant;' they were in repulsion when inheritance was 'recessive.' Chan et al. (1985) conducted further studies with the terpolymer composed of L-glutamic acid, L-lysine and L-phenylalanine. Again they concluded that 2 separate complementary loci in the MHC region are involved. Several models were proposed to account for seeming inconsistencies in the mapping data. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	IMMUNE RESPONSE TO SYNTHETIC POLYPEPTIDE--IRGLPHE 1	c3887956	5,471	omim	https://www.omim.org/entry/147080	2019-09-22T16:39:35	{"omim": ["147080"]}
A number sign (#) is used with this entry because susceptibility to Crohn disease can be conferred by variation in the ATG16L1 gene (610767) on chromosome 2q37. For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, see IBD1 (266600). Mapping Hampe et al. (2007) performed a genomewide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease and 368 controls, and followed up on all SNPs with a p value of 0.01 or less with an allele-based disease association test in 380 independent Crohn disease trios, 498 Crohn disease singleton cases, and 1,032 controls. By haplotype and regression analysis, the authors found that a nonsynonymous SNP (rs2241880; T300A, 610767.0001) in the ATG16L1 gene on chromosome 2q37.1 that was replicated in these samples (p = 4.0 x 10(-8)) and confirmed in a UK case-control sample (p = 0.0004), carried virtually all the disease risk exerted by the ATG16L1 locus. Hampe et al. (2007) also found a statistically significant interaction with respect to Crohn disease risk between rs2241880 and the established CARD15 (605956) susceptibility variants (p = 0.039). Together with the lack of association between rs2241880 and ulcerative colitis, these data suggested that the underlying biologic process may be specific to Crohn disease. In a genomewide association study of ileal Crohn disease and 2 independent replication studies, Rioux et al. (2007) identified a strong and significantly replicated association with rs2241880 in ATG16L1, previously reported by Hampe et al. (2007). Rioux et al. (2007) demonstrated that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggested that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study, using the Affymetrix GeneChip 500K Mapping Array Set undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. The strongest signal for Crohn disease in their scan was achieved at rs10210302 (p = 7.1 x 10(-14)), which maps to the ATG16L1 gene and was in strong linkage disequilibrium (r(2) = 0.97) with the nonsynonymous SNP rs2241880 identified by Hampe et al. (2007) as associated with Crohn disease in a German nonsynonymous SNP scan. Franke et al. (2008) investigated 50 previously reported IBD susceptibility loci in a German sample of 1,850 CD patients, 1,103 UC patients, and 1,817 controls, and replicated the association between CD and the ATG16L1 SNP rs2241880 (Bonferroni-corrected p = 2.74 x 10(-6)). In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) identified significant association with rs3828309 at 2q37 (combined p = 2.36 x 10(-32); case-control odds ratio, 1.28). In a case-control study involving 289 pediatric cases of Crohn disease and 290 controls, Amre et al. (2009) confirmed association of rs2241880 and CD. Children with the GG genotype (ala/ala) had a more than 3-fold elevated risk for disease compared to wildtype AA (thr/thr) homozygotes (p = 1.8 x 10(-6)). Association with rs2241880 was specific for ileal disease, with or without colonic involvement. Amre et al. (2009) noted that the variant is located in the WD-repeat domain, which is associated with protein-protein interactions, and suggested that the variant might play a key role in facilitating interactions with other proteins involved in autophagy. Molecular Genetics In studies in human epithelial cells, Kuballa et al. (2008) observed that the Crohn disease-associated ala300-containing variant of ATG16L1 (rs2241880) had markedly decreased efficiency of Salmonella autophagy compared to the wildtype thr300-containing variant, and suggested that the association of rs2241880 with increased risk of CD is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy. In a metaanalysis of 24 studies involving a total of 13,022 CD cases and 17,532 controls, Zhang et al. (2009) confirmed the association of rs2241880 with CD risk in Caucasians (p less than 0.01). Pathogenesis Murthy et al. (2014) showed that amino acids 296 to 299 of ATG16L1 constitute a caspase cleavage motif and that the T300A variant (610767.0001) (T316A in mice) significantly increases ATG16L1 sensitization to CASP3 (600636)-mediated processing. Murthy et al. (2014) observed that death receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knockin mice harboring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of Casp3 or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. Murthy et al. (2014) concluded that these findings demonstrated that CASP3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli, and impaired autophagy in a unified pathway that predisposes to Crohn disease. Animal Model Cadwell et al. (2008) generated and characterized mice that were hypomorphic for Atg16l1 protein expression and validated conclusions on the basis of studies in mice by analyzing intestinal tissues that they collected from Crohn disease patients carrying the Crohn disease risk allele of ATG16L1. Cadwell et al. (2008) showed that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein, ATG5 (604261), are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. Atg16L1- and Atg5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism, of acute phase reactants and of 2 adipocytokines, leptin (164160) and adiponectin (605441), known to directly influence intestinal injury responses. Importantly, Crohn disease patients homozygous for the ATG16L1 Crohn disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Cadwell et al. (2008) concluded that ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells. In mice, Bel et al. (2017) showed that during bacterial infection with the Salmonella enterica serovar Typhimurium, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced endoplasmic reticulum (ER) stress, requiring extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in autophagy gene Atg16L1 that confers increased risk for Crohn disease in humans. Bel et al. (2017) concluded that their findings identified a role for secretory autophagy in intestinal defense and helped elucidate why Crohn disease is associated with genetic mutations that affect both the ER stress response and autophagy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 10	c1970207	5,472	omim	https://www.omim.org/entry/611081	2019-09-22T16:03:40	{"mesh": ["C567021"], "omim": ["611081"]}
Retinal vasculitis Retinal artery (at center) SpecialtyNeurology Retinal vasculitis is inflammation of the vascular branches of the retinal artery, caused either by primary ocular disease processes, or as a specific presentation of any systemic form of vasculitis such as Behçet's disease, sarcoidosis, multiple sclerosis, or any form of systemic necrotizing vasculitis such as temporal arteritis, polyarteritis nodosa, and granulomatosis with polyangiitis, or due to lupus erythematosus, or rheumatoid arthritis.[1][2] Eales disease, pars planitis, birdshot retinochoroidopathy (autoimmune bilateral posterior uveitis), and Fuchs heterochromic iridocyclitis (FHI) can also cause retinal vasculitis.[1] Infectious pathogens such as Mycobacterium tuberculosis, visceral larva migrans (Toxocara canis & Toxocara cati) can also cause retinal vasculitis.[1] ## Contents * 1 Symptoms * 1.1 Diseases associated with retinal vasculitis * 2 Diagnosis * 2.1 Findings * 3 Treatment * 4 Sources * 5 External links ## Symptoms[edit] Retinal vasculitis presents as painless, decrease of visual acuity (blurry vision), visual floaters, scotomas (dark spot in vision), decreased ability to distinguish colors, and metamorphopsia (distortion of images such as linear images).[1] ### Diseases associated with retinal vasculitis[edit] * Behçet's disease * Common Variable Immune Deficiency[3] * Eales disease * Granulomatosis with polyangiitis * Idiopathic Retinal Vasculitis Aneurysms and Neuroretinitis * Lupus erythematosus * Multiple sclerosis * Polyarteritis nodosa * Q fever * Rheumatoid arthritis * Sarcoidosis * Temporal arteritis ## Diagnosis[edit] Retinal vasculitis is very rare as the only presenting symptom. Often there is sufficient systemic evidence to help the physician decide between any one of the aforementioned possible systemic diseases. For those patients who present with only vasculitis of the retinal vessels, great investigative effort (Chest X-ray, blood test, urinary analysis, vascular biopsy, ophthalmology assessment, etc.) should be undertaken to ensure that a systemic disease is not the hidden culprit.[citation needed] ### Findings[edit] Ophthalmic examination may reveal neovascularization (creation of new vessels in the retina), retinal vessel narrowing, retinal vessel cuffing, retinal hemorrhage, or possible vitritis (inflammation of the vitreous body) or choroiditis (inflammation of the choroid).[1] ## Treatment[edit] This section is empty. You can help by adding to it. (December 2017) ## Sources[edit] 1. ^ a b c d e Lynn K. Gordon, M.D., Ph.D. (January 2003). "Retinal Vasculitis". American Uveitis Society. Archived from the original on July 31, 2010. Retrieved December 10, 2010.CS1 maint: multiple names: authors list (link) 2. ^ Bolster, Marcy B.; Collier, Virginia U.; Bass, Anne R.; Brasington, Richard D.; Brown, Alan N.; Jonas, Beth; Staudt, Leslie S. (2009). Medical Knowledge Self-Assessment Program (MKSAP-15): Rheumatology. ACP (American College of Physicians). pp. 71–3. ISBN 978-1-934465-30-1. 3. ^ J. C. van Meurs, S. Lightman, P. W. T. De Waard et al., “Retinal vasculitis occurring with common variable immunodeficiency syndrome,” American Journal of Ophthalmology, vol. 129, no. 2, pp. 269–270, 2000. ## External links[edit] Classification D * ICD-10-CM: H35.06 * ICD-9-CM: 362.18 * MeSH: D031300 * SNOMED CT: 77628002 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Retinal vasculitis	c0152026	5,473	wikipedia	https://en.wikipedia.org/wiki/Retinal_vasculitis	2021-01-18T18:40:17	{"mesh": ["D031300"], "umls": ["C0152026"], "wikidata": ["Q7316771"]}
A number sign (#) is used with this entry because of evidence that Joubert syndrome-5 (JBTS5) is caused by homozygous or compound heterozygous mutation in the gene encoding the centrosomal protein CEP290 (610142) on chromosome 12q21. For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. Clinical Features Joubert syndrome (JBTS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities (Valente et al., 2006). Neuroradiologically, Joubert syndrome is characterized by a peculiar malformation of the midbrain-hindbrain junction known as the 'molar tooth sign' (MTS) consisting of cerebellar vermis hypoplasia or aplasia, thick and maloriented superior cerebellar peduncles, and abnormally deep interpeduncular fossa. A number of distinct syndromes sharing the MTS have been described, presenting wide phenotypic variability both within and among families (Gleeson et al., 2004). Valente et al. (2006) described the JBTS5 phenotype as characterized mainly by the neurologic and neuroradiologic features of Joubert syndrome associated with severe retinal and renal involvement, but noted that the clinical spectrum was broad, including incomplete phenotypes such as cerebelloretinal and cerebellorenal syndromes. The full-blown JBTS5 phenotype largely overlaps that of Senior-Loken syndrome (SLSN; see 266900), which is characterized by retinitis pigmentosa plus juvenile nephronophthisis and is attributable to mutations in genes associated with nephronophthisis and encoding ciliary proteins. In a comprehensive study of 279 patients from 232 unrelated families with Joubert syndrome in whom a genetic basis was determined by molecular analysis of 27 candidate genes, Bachmann-Gagescu et al. (2015) found a significant association between mutations in the CEP290 gene and retinal dystrophy (odds ratio (OR) of 22.9) and cystic kidney disease (OR of 3.3). None of 55 individuals with CEP290 mutations had seizures, suggesting a negative association with that feature. Mapping In Joubert syndrome, nephronophthisis (NPHP) is combined with retinal degeneration, cerebellar vermis aplasia, and mental retardation. Identification of 5 genes mutated in NPHP implicated primary cilia, basal bodies, and mechanisms of plantar cell polarity in the pathogenesis of renal cystic disease. In a worldwide cohort including 90 individuals with JBTS, recessive mutations in known NPHP-associated genes were found in only 1% of JBTS cases (Utsch et al., 2006). To identify further causative genes for NPHP, Sayer et al. (2006) performed a whole-genome search for linkage by homozygosity mapping in 25 consanguineous kindreds with NPHP, SLSN, or JBTS, ascertained worldwide, each of which had 2 affected individuals and was negative for mutations in known NPHP genes. Three kindreds showed an overlap of nonparametric lod score (NPL) peaks on 12q indicating potential homozygosity by descent. Refinement of the linkage narrowed the region to 12q21.32-q21.33. Valente et al. (2006) identified the JBTS5 locus on 12q21.31-q21.33 in linkage analysis from consanguineous families with Joubert syndrome-related disorders (JSRDs), which showed the neurologic features of Joubert syndrome associated with multiorgan involvement (mainly retinal dystrophy and nephronophthisis). Identification of causative mutations in the CEP290 gene in families with JBTS5 localized the phenotype to 12q21.32 (Sayer et al., 2006; Valente et al., 2006). Molecular Genetics Upon mutation analysis within the NPHP6 genetic interval, Sayer et al. (2006) identified an identical homozygous nonsense mutation, 5668G-T (G1890X), located in the CEP290 gene (610142.0001), which had been described as a component of the centrosomal proteome (Andersen et al., 2003), in 2 kindreds. Further mutation screening in 96 unrelated individuals with JBTS by direct sequencing identified this mutation in a third family. Altogether Sayer et al. (2006) identified 8 distinct mutations in CEP290 in 7 JBTS families. In 5 families with JBTS, Valente et al. (2006) found 5 mutations in the CEP290 gene, including 3 nonsense mutations resulting in premature protein truncation, one 1-bp deletion generating a frameshift and a premature stop codon, and 1 missense mutation (W7C; 610142.0003). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Congenital amaurosis \- Tapetoretinal degeneration \- Nystagmus \- Retinal coloboma \- Oculomotor apraxia RESPIRATORY \- Neonatal breathing dysregulation \- Hyperpnea, episodic \- Tachypnea, episodic \- Central apnea GENITOURINARY Kidneys \- Cortical cysts \- Nephronophthisis \- Urine concentration defect \- End stage renal disease NEUROLOGIC Central Nervous System \- Hypotonia \- Mental retardation \- Cerebellar vermis aplasia/hypoplasia \- Ataxia \- 'Molar tooth sign' \- Thick, maloriented superior cerebellar peduncles \- Deep interpeduncular fossa MISCELLANEOUS \- Allelic to Senior-Loken syndrome 6 ( 610189 ) and Leber congenital amaurosis type X ( 610142 ) MOLECULAR BASIS \- Caused by mutation in the 290-kD centrosomal protein gene (CEP290, 610142.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	JOUBERT SYNDROME 5	c1855675	5,474	omim	https://www.omim.org/entry/610188	2019-09-22T16:04:59	{"doid": ["0111000"], "mesh": ["C537430"], "omim": ["610188"], "orphanet": ["2318"], "genereviews": ["NBK1325"]}
Mulberry molar Other namesSyphilitic permanent first molar[1] Mulberry molars are a dental condition usually associated with congenital syphilis, characterized by multiple rounded rudimentary enamel cusps on the permanent first molars.[2] Mulberry molars are physically defective permanent molars. The deformity is caused by congenital syphilis. This type of abnormality is characterized by dwarfed molars with cusps covered with globular enamel growths. These teeth are functional but can be cosmetically fixed with crowns, bridges, or implants.[citation needed] Just above the gum line, the mulberry molar looks normal. A deformity becomes apparent towards the cusp or top grinding surface of the tooth. Here, the size of the mulberry molar is diminished in all aspects, creating a stumpy version of a conventional molar. The cause of the molar atrophy is thought to be enamel hypoplasia, or a deficiency in tooth enamel. The underlying dentin and pulp of the tooth is normal, but the enamel covering or molar sheath is thin and deformed, creating a smaller version of a typical tooth.[citation needed] The grinding surface of a mulberry molar is also corrupted. Normally, the grinding surface of a molar has a pit and is surrounded by a circular ridge at the top of the tooth, which is used for grinding. The cusp deformity of the mulberry molar is characterized by an extremely shallow or completely absent pit. Instead, the pit area is filled with globular structures bunched together all along the top surface of the cusp. This type of deformity is also thought to be caused by enamel hypoplasia. Mulberry molars are typically functional and do not need treatment. If the deformity is severe or the person is bothered by the teeth, there are several options. The teeth can be covered with a permanent cast crown, stainless steel crown, or the molars can be removed and an implant or bridge can be put in place of the mulberry molar.[citation needed] A mulberry molar is caused by congenital syphilis, which is passed from the mother to the child in the uterus through the placenta. Since this particular symptom of congenital syphilis manifests later in childhood with the eruption of the permanent molars, it is a late stage marker for the disease. Hutchinson's teeth, marked by dwarfed teeth and deformed cusps that are spaced abnormally far apart, are another dental deformity caused by congenital syphilis. Mulberry molars and Hutchinson's teeth will often occur together. Pregnant women with syphilis should tell their doctors about the condition and be treated for it during pregnancy, otherwise the baby should be screened for the disease after birth and treated with penicillin if necessary.[3] ## See also[edit] * Syphilis * List of cutaneous conditions ## References[edit] 1. ^ "Mulberry molar". NCBI. NIH. Retrieved 20 March 2019. 2. ^ Hillson, S; Grigson, C; Bond, S (1998). "Dental defects of congenital syphilis". Am J Phys Anthropol. 107 (1): 25–40. doi:10.1002/(SICI)1096-8644(199809)107:1<25::AID-AJPA3>3.0.CO;2-C. ISSN 0002-9483. PMID 9740299. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Mulberry molar	c0266024	5,475	wikipedia	https://en.wikipedia.org/wiki/Mulberry_molar	2021-01-18T18:50:07	{"umls": ["C0266024"], "wikidata": ["Q6933835"]}
## Clinical Features Fukushima et al. (1999) reported a family in which 13 members over 4 generations had a form of autosomal dominant nonsyndromic hearing loss, designated DFNA16, in which the phenotype included rapidly progressing and fluctuating hearing loss that appeared to respond to steroid therapy. Hearing-impaired persons stated that they had normal or nearly normal hearing until age 9 to 10 years. Mapping Fukushima et al. (1999) demonstrated that the DFNA16 locus maps to 2q23-q24.3 and is tightly linked to markers in the D2S2380-D2S335 interval. They noted that several voltage-gated sodium-channel genes map to the DFNA16 interval, making these cationic channels excellent DFNA16 candidate genes from both a positional and a functional point of view. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, sensorineural, fluctuating (predominantly affecting high frequencies) \- Tinnitus (in some patients) \- Vertigo, unrelated to hearing loss (in some patients) MISCELLANEOUS \- Age of onset between 6 to 10 years of age \- All hearing impaired females who had been pregnant reported acute hearing loss and tinnitus immediately after parturition \- Treatment with oral steroids can restore hearing during episodes of hearing loss and tinnitus \- One family has been described (last curated August 2015) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DEAFNESS, AUTOSOMAL DOMINANT 16	c1858916	5,476	omim	https://www.omim.org/entry/603964	2019-09-22T16:12:31	{"doid": ["0110547"], "mesh": ["C565832"], "omim": ["603964"], "orphanet": ["90635"], "synonyms": ["Autosomal dominant isolated neurosensory deafness type DFNA", "Autosomal dominant isolated neurosensory hearing loss type DFNA", "Autosomal dominant isolated sensorineural deafness type DFNA", "Autosomal dominant isolated sensorineural hearing loss type DFNA", "Autosomal dominant non-syndromic neurosensory deafness type DFNA", "Autosomal dominant non-syndromic neurosensory hearing loss type DFNA", "Autosomal dominant non-syndromic sensorineural hearing loss type DFNA"]}
## Summary ### Clinical characteristics. CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: * Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK * X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features. ### Diagnosis/testing. The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant on molecular genetic testing. Rarely, affected males have a mosaic pathogenic variant. ### Management. Treatment of manifestations: Treatment is symptomatic and includes standard management of developmental delay and intellectual disability issues; medication for seizures; nutritional support; use of physiotherapy; and treatment of abnormal vision or hearing loss. ### Genetic counseling. CASK disorders are inherited in an X-linked manner. Risk to the family members of a proband with a CASK disorder depends on the phenotype (i.e., MICPCH or XLID ± nystagmus) in the proband. * MICPCH. Most affected females and males represent simplex cases (i.e., the only affected family member) and have the disorder as the result of a de novo CASK pathogenic variant. Because heterozygous females manifest the phenotype, an asymptomatic mother is unlikely to be heterozygous for the CASK pathogenic variant. If a proband represents a simplex case, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of parental germline mosaicism. * XLID ± nystagmus. The father of a male with a CASK disorder will not have the disorder nor will he be hemizygous for the CASK pathogenic variant. If a male is the only affected family member, the mother may be a heterozygote or the affected male may have a de novo pathogenic variant. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If the mother of the proband has a CASK pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be asymptomatic but may have a range of manifestations. If the CASK pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. Once the CASK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a CASK disorder are possible. ## Diagnosis CASK disorders are associated with a wide phenotypic spectrum ranging from mild-to-severe intellectual disability with or without nystagmus to moderate-to-profound intellectual disability and progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH), often associated with seizures. CASK disorders are X-linked and more commonly reported in females than in males. MICPCH in females is the most common phenotype to date. ### Suggestive Findings CASK disorders should be considered in individuals with intellectual disability of any degree and any of the following additional findings: * Progressive microcephaly up to -10 SD * Pontine and cerebellar hypoplasia * Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities) * Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy) * Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy * Sensorineural hearing loss * Short stature ### Establishing the Diagnosis The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant (see Table 1). Note: Rarely, affected males have a mosaic pathogenic variant. Because the phenotype of CASK disorders is often indistinguishable from many other inherited disorders with intellectual disability, microcephaly, and/or pontine and cerebellar hypoplasia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. Note: Single-gene testing (sequence analysis of CASK, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. * A multigene panel for intellectual disability or brain malformation or specialized for pontocerebellar hypoplasia that includes CASK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include exome array or chromosomal microarray analysis to detect exon and whole-gene deletions or duplications). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Note: (1) In a few males, CASK rearrangements in the hemizygous state as well as CASK rearrangements and a deletion-insertion variant in the mosaic state have been reported [Saitsu et al 2012, Moog et al 2015, Hayashi et al 2017]. (2) Karyotype analysis may be appropriate when sequence analysis and deletion/duplication analysis do not identify a pathogenic variant and the suspicion of a CASK disorder is high. Two females with a balanced Xp inversion disrupting CASK have been observed [Najm et al 2008; K Kutsche, unpublished]. ### Table 1. Molecular Genetic Testing Used in CASK Disorders View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method CASKSequence analysis 3, 4~70% 5, 6 Gene-targeted deletion/duplication analysis 7~30% 5, 6, 7 CMA 8~28% 5, 8 KaryotypeRare 9 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\. Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017] 6\. Percentages are based on female probands. Surviving male probands are more likely to have a variant detected by sequence analysis (see Genotype-Phenotype Correlations.) 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Moog et al [2011], Burglen et al [2012], Hayashi et al [2012], Hayashi et al [2017]) may not be detected by these methods. 8\. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CASK) that cannot be detected by sequence analysis. Most reported deletions/duplications in CASK are large enough to be detected by CMA. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xp11.4 region. CMA designs in current clinical use target the Xp11.4 region. 9\. Two females with a balanced Xp inversion disrupting CASK have been observed [Najm et al 2008; K Kutsche, unpublished]. ## Clinical Characteristics ### Clinical Description CASK disorders are more commonly reported in females and include a spectrum of phenotypes that differs in females and males: * Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype. * In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [Moog et al 2015]. To date, 130 individuals (45 males and 85 females) have been identified with a pathogenic variant in CASK [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012, Moog et al 2015, Dunn et al 2017, Hayashi et al 2017, Muthusamy et al 2017, Cristofoli et al 2018, Rama Devi et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports. #### Females A total of 85 females with MICPCH have been reported to date, the eldest of whom is age 25 years. The following information about the natural history is based on the recent reviews of Moog et al [2011], Burglen et al [2012], Hayashi et al [2012], and Takanashi et al [2012] unless otherwise noted. Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH) Head circumference. At birth the occipital frontal circumference (OFC) is in the normal or low-normal range in approximately two thirds of affected females; the others show microcephaly (OFC < -2 SD). Microcephaly invariably becomes severe (OFC -3.5 to -10 SD) during the first year, and usually during the first four months of life. Developmental delay / intellectual disability (DD/ID). Affected females acquire head control and make eye contact in the range of two to 24 months. Most affected females are able to sit independently between seven and 36 months; only 20%-25% attain the ability to walk (between 18 and 72 months). Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate ID. The behavioral phenotype may include sleep disturbances, hand stereotypies, and self biting. Neurologic features include (axial) hypotonia, hypertonia of the extremities (possibly progressing to spasticity), and dystonia or other movement disorders. Seizures of various types are observed in about 40%; onset is between birth and age ten years. The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [Moog et al 2011]. MRI findings * Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012] (Figure 1). Pons and cerebellum have been reported to have a normal appearance in two females with progressive microcephaly, ID, and a pathogenic variant in CASK [Cristofoli et al 2018]. * Cerebellar hemispheres can be affected asymmetrically. * Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging. * Normal- or low normal-sized corpus callosum with low cerebrum/corpus callosum ratio [Takanashi et al 2010] * Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [Moog et al 2011] #### Figure 1. MRI of the brain of a girl age 2.5 years with MICPCH and a heterozygous CASK pathogenic variant a. Sagittal image showing mild pontocerebellar hypoplasia with sparing of pontine bulging. The corpus callosum is normal. Other findings * Birth length is normal. Short stature is common by age four years [Moog et al 2011, Takanashi et al 2012]. * Scoliosis is frequently observed. * Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [LaConte et al 2019]. * Approximately 28% of affected females have sensorineural hearing loss [Moog et al 2011, Burglen et al 2012, Takanashi et al 2012]. * Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently. * Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears. Mortality in affected females has not been reported. X-Linked Intellectual Disability (XLID) ± Nystagmus Clinical findings in the majority of heterozygotes (typically identified as relatives of more severely affected males): * Normal intelligence; mild-to-severe ID in some females only * Normal-to-mild ocular findings including congenital nystagmus and strabismus * No additional neurologic signs besides mild tremor or absence seizures * MRI finding: normal or mainly unknown #### Males A total of 45 males from birth to age 59 years with a pathogenic CASK variant have been described [Moog et al 2015, Dunn et al 2017, Hayashi et al 2017, Muthusamy et al 2017, Rama Devi et al 2019]. The phenotype in males represents a clinical continuum from the severe to the mild end of the spectrum and can be classified into three phenotypic groups [Moog et al 2015]. MICPCH with Severe Epileptic Encephalopathy Head circumference. At birth, the OFC was (low) normal in half of the individuals. The other half had primary microcephaly (OFC <-2 SD). Mild-to-severe postnatal microcephaly evolved rapidly during the first months (OFC -2.7 to -9 SD). DD/ID. All affected males had severe-to-profound DD or no development at all. Neurologic features include early and intractable seizures (Ohtahara syndrome [Saitsu et al 2012], West syndrome [Takanashi et al 2012], myoclonic epilepsy [Nakamura et al 2014]), burst suppression and spasms [Moog et al 2015], and hyperkinesia [Rama Devi et al 2019]. MRI findings * Typically severe diffuse pontocerebellar hypoplasia * Simplified gyri, cortical atrophy, and hypomyelination may be also observed. Other findings * Multiple (minor) anomalies have been reported [Burglen et al 2012, Saitsu et al 2012, Moog et al 2015]. * Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [Nakamura et al 2014, Moog et al 2015]. Mortality. Males with this phenotype may have perinatal or early lethality. One affected male died at age two months [Rama Devi et al 2019], one at seven months, and another at 21 months [Moog et al 2015]. MICPCH with Severe Developmental Disorder MICPCH in combination with a severe developmental disorder but without severe epilepsy has been reported in six males. The phenotype of male individuals in this group is comparable to MICPCH in females [Moog et al 2015, Hayashi et al 2017]: * Head circumference. Postnatal microcephaly * DD/ID. Severe * Neurologic features. Mild ataxia reported in one male, dystonia/dyskinesia in another male. No seizures. * MRI findings. Variable degree of diffuse pontocerebellar hypoplasia * Other findings. Nystagmus * Mortality. One affected male died at age two weeks. X-Linked Intellectual Disability (XLID) ± Nystagmus Mild-to-severe XLID with or without nystagmus and/or other anomalies have been reported in a total of 29 males [Moog et al 2015, Dunn et al 2017, Hayashi et al 2017]. * DD / mild-to-severe ID * Seizures/epilepsy * Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc Brain MRI has been reported in a minority of individuals only and did not show pontocerebellar hypoplasia. Other findings include microcephaly, hypotonia, autism spectrum disorder, behavioral problems, tremor and unsteady gait, sensorineural hearing loss, feeding difficulties, constipation, short stature, cryptorchidism, and gastrointestinal and gastroesophageal complications. ### Genotype-Phenotype Correlations In females, microcephaly with pontine and cerebellar hypoplasia (MICPCH) is typically associated with heterozygous CASK pathogenic loss-of-function variants [Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Takanashi et al 2012, Hayashi et al 2017]. The X-linked intellectual disability (XLID) with or without nystagmus phenotype in females is typically associated with CASK hypomorphic pathogenic variants. In males, the three clinically distinguishable groups are associated with different classes of pathogenic CASK variants [Moog et al 2015]: * In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of CASK pathogenic variants are germline loss-of-function alterations. * In the group with MICPCH, males are somatic mosaics of a CASK loss-of-function variant or carry partly penetrant variants in the hemizygous state. * The largest group of males with XLID with or without nystagmus typically have CASK hypomorphic pathogenic variants, including missense and splice variants [Moog et al 2015]. ### Penetrance Penetrance for the MICPCH phenotype (associated with the heterozygous CASK pathogenic loss-of-function variants) appears to be complete in the female individuals reported to date. Penetrance of CASK pathogenic variants appears to be complete in males. In males with mosaic CASK pathogenic variants the level of somatic mosaicism may be one factor that determines clinical variability. In females heterozygous for a pathogenic hypomorphic CASK variant penetrance is incomplete with high clinical variability. ### Nomenclature An FG syndrome (FGS)-like phenotype has been suggested as a distinct CASK-related phenotype based on findings in affected males from two families [Piluso et al 2009, Dunn et al 2017]. However, with the exception of FGS1 caused by a recurrent MED12 pathogenic variant (see MED12-Related Disorders), FGS is not clearly defined and FGS4 is not discernible as phenotype. Thus, it seems more appropriate to subsume the phenotype described in these families under XLID with or without nystagmus. ### Prevalence The prevalence of CASK disorders is unknown. At least 130 individuals (45 males and 85 females) with a CASK pathogenic variant have been reported. ## Differential Diagnosis ### Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH) ### Table 2. Genes of Interest in the Differential Diagnosis of MICPCH View in own window Gene(s)DisorderMOIClinical FeaturesBrain MRI Findings SEPSECS TSEN15 TSEN2 TSEN34 VPS53 TSEN54PCH2AR * Generalized clonus ("jitteriness") w/lack of voluntary motor development & later development of chorea & spasticity, impaired swallowing, & (in some) epilepsy * Persons w/PCH2 usually live into childhood. In persons w/PCH2/PCH4: * Cerebellar hemispheres are more affected than the vermis, → "dragonfly" appearance in coronal images. 2 * Pontine hypoplasia is more severe than in females w/MICPCH. * Corpus callosum is often thin & hypoplastic. TSEN54PCH4ARPolyhydramnios, contractures, severe generalized clonus, & central respiratory failure usually → neonatal death ARX STXBP1 (>80 genes) 1Ohtahara syndromeXL ADEarly-infantile epileptic encephalopathy w/suppression burstMay or may not be assoc w/abnormalities on brain MRI AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked 1\. See Phenotypic Series, Early Infantile Epileptic Encephalopathy for genes associated with this phenotype in OMIM. 2\. In CASK disorders, a "butterfly" pattern is visible that results from diffuse hypoplasia of the hemispheres and vermis. ### X-Linked Intellectual Disability (XLID) ± Nystagmus XLID with nystagmus may be seen in the X-linked disorder Allan-Herndon-Dudley syndrome caused by hemizygous pathogenic variants in SLC16A2. These individuals show severe ID, microcephaly, neurologic features (spasticity, dystonia, and ataxia), scoliosis, large ears, and other dysmorphisms. Nystagmus is reported in some individuals. XLID without nystagmus has a broad differential diagnosis as a multitude of genes are known to cause nonsyndromic and syndromic XLID (see OMIM Phenotypic Series: Nonsyndromic XLID, and Syndromic XLID). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a CASK disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with CASK Disorders View in own window System/ConcernEvaluationComment NeurologicNeurologic evalTo incl brain MRI & EEG if not already done DevelopmentDevelopmental assessment * To incl motor, adaptive, cognitive, & speech/language eval * Eval for early intervention / special education Psychiatric/ BehavioralNeuropsychiatric evalFor individuals age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT/OT evalTo incl assessment of: * Gross motor & fine motor skills. * Scoliosis. * Mobility, activities of daily living, & need for adaptive devices. * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team eval * To incl eval of aspiration risk & nutritional status * Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. EyesOphthalmologic evalAssess for nystagmus, optic nerve hypoplasia, retinopathy, & strabismus. HearingAudiologic evalAssess for hearing loss. CardiovascularEchocardiogramAssess for rare but possible cardiac anomaly. GenitourinaryUltrasound of the kidneysAssess for rare but possible renal/urologic anomaly. Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling Family support/resourcesAssess: * Use of community or online resources such as Parent to Parent. * Need for social work involvement for parental support. * Need for home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with CASK Disorders View in own window Manifestation/ ConcernTreatmentConsiderations/Other DD/IDSee Developmental Delay / Intellectual Disability Management Issues. EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many AEDs may be effective; none is demonstrated effective specifically for this disorder. * Education of parents/caregivers 1 Poor weight gain / Failure to thriveFeeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia SpasticityOrthopedics / physical medicine & rehabilitation / PT/OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices, disability parking placard. Abnormal vision &/or strabismusStandard treatment(s) as recommended by ophthalmologistCommunity vision services through early intervention or school district HearingHearing aids may be helpful as per otolaryngologist.Community hearing services through early intervention or school district Family/ Community * Ensure appropriate social work involvement to connect families w/local resources, respite, & support. * Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. * Ongoing assessment of need for palliative care involvement &/or home nursing * Consider involvement in adaptive sports or Special Olympics. AED = antiepileptic drug; DD = developmental dealy; ID = intellectual disability; OT = occupational therapy; PT = physical therapy 1\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit (pdf). #### Developmental Disability / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * Individualized education plan (IEP) services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). * For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures. 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 should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it. #### 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 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 ### Table 5. Recommended Surveillance for Individuals with CASK Disorders View in own window System/ConcernEvaluationFrequency Feeding * Measurement of growth parameters * Eval of nutritional status & safety of oral intake At each visit NeurologicMonitor those w/seizures as clinically indicated.At each visit Assess for new manifestations incl seizures, changes in tone, movement disorders. DevelopmentMonitor developmental progress & educational needs.At each visit Psychiatric/ BehavioralBehavioral assessment for anxiety, attention, & aggressive or self-injurious behavior MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skillsAt each visit EyesOphthalmologic evalAnnually HearingAudiologic evalAnnually Miscellaneous/ OtherAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.At each visit OT = occupational therapy; PT = physical therapy ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CASK Disorders	None	5,477	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK169825/	2021-01-18T21:38:46	{"synonyms": []}
A lethal skeletal osteochondrodysplasia characterized by severe generalized osteosclerosis. ## Epidemiology The disease is very rare and only five cases (four males and one female) have been reported in the literature so far. ## Clinical description Pyknoachondrogenesis may be detected prenatally due to the extreme shortening of the limbs and hydrops fetalis, or is recognized at birth. The main clinical manifestations include a large head, palpebral edema, a flat nose, low-set ears, a short neck, a short and wide trunk, a prominent abdomen, and severe micromelic dwarfism. ## Etiology Etiology remains unknown. Familial occurrence of affected sibs of both sexes points to an autosomal recessive pattern of inheritance but parental consanguinity has not been reported. ## Diagnostic methods Diagnosis is based on clinical findings and typical radiographic features. X-rays show marked sclerosis of the facial bones and extremities, and poor ossification elsewhere. ## Differential diagnosis Achondrogenesis (see this term) is the main differential diagnosis. ## Antenatal diagnosis Prenatal diagnosis of pyknoachondrogenesis may be made by ultrasound. ## Prognosis Pyknoachondrogenesis has a lethal outcome, either prenatally or during the early neonatal period. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pyknoachondrogenesis	c1849523	5,478	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3003	2021-01-23T19:00:34	{"gard": ["4610"], "mesh": ["C536251"], "omim": ["265880"], "umls": ["C1849523"], "icd-10": ["Q78.8"], "synonyms": ["Camera syndrome"]}
## Summary ### Clinical characteristics. X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only. ### Diagnosis/testing. The diagnosis of X-OS is established in a male proband most often by clinical findings. Identification of a hemizygous pathogenic variant in MID1 in a male proband by molecular genetic testing establishes the diagnosis if clinical features are inconclusive. The diagnosis of X-OS can be established in a female with suggestive clinical features by identification of a heterozygous pathogenic variant in MID1 on molecular genetic testing. ### Management. Treatment of manifestations: Management of anomalies by a multidisciplinary team; surgical treatment of medically significant laryngotracheoesophageal malformations; tracheostomy as needed; standard surgical management of hypospadias, cleft lip/palate, imperforate anus, heart defects; speech therapy; neuropsychological and educational support. Prevention of secondary complications: Antireflux measurements to minimize risk of aspiration. Surveillance: Based on the type of malformations present; regular monitoring of hearing for those with cleft lip/palate. ### Genetic counseling. X-OS is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate carrier. If the mother of an affected male is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be carriers and will usually manifest hypertelorism. Mildly affected males who have children will pass the pathogenic variant to all of their daughters and none of their sons. Prenatal and preimplantation genetic testing is possible for pregnancies at risk if the pathogenic variant in the family has been identified. ## Diagnosis X-linked Opitz G/BBB syndrome (X-OS) is diagnosed most often on the basis of clinical findings. There is variable expressivity among affected individuals, even within the same family. The manifestations of X-OS are classified into major and minor findings based on frequency of occurrence. Formal diagnostic criteria for X-OS have not been established. ### Suggestive Findings The clinical diagnosis of X-OS should be suspected in a male with the following major and/or minor findings. Major (more frequent) findings * Hypertelorism and/or telecanthus (present in virtually all affected individuals) * All degrees of hypospadias that, in the most severe form, can be associated with renal malformations (85%-90%) * Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction (60%-70%) * A family history consistent with X-linked inheritance – although variable expressivity among affected individuals, even within the same family, should be taken into consideration Minor findings (found in ≤50% of individuals) * Intellectual disability and developmental delay * Cleft lip and/or palate * Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus) * Imperforate or ectopic anus * Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia ### Establishing the Diagnosis Male proband. The diagnosis of X-linked Opitz G/BBB syndrome (X-OS) is established in a male proband with the above clinical findings. Identification of a hemizygous pathogenic variant in MID1 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive (see Table 1). Female proband. The diagnosis of X-OS is established in a female proband with suggestive clinical features and identification of a heterozygous pathogenic variant in MID1 by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-OS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of X-OS has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of X-OS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of MID1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes MID1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of X-OS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in X-Linked Opitz G/BBB Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method MID1Sequence analysis 3, 4~25% 5 Gene-targeted deletion/duplication analysis 610 individuals 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. 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\. The detection of an MID1 pathogenic variant in an individual without a family history of X-OS is approximately 15%. The pathogenic variant detection rate in individuals with documented X-linked inheritance is >50%. [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004, So et al 2005, Fontanella et al 2008]. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008]. In addition, single-exon deletions and duplications have been reported [Winter et al 2003, Hüning et al 2013, Migliore et al 2013]. ## Clinical Characteristics ### Clinical Description Affected males. X-linked Opitz G/BBB syndrome (X-OS) is characterized by clinical abnormalities of primarily midline structures. These defects include facial anomalies, genitourinary abnormalities, laryngotracheoesophageal defects, and congenital heart defects. Developmental delay and intellectual disability are common. Wide clinical variability has been described; individuals with an MID1 pathogenic variant may manifest only some of the clinical features with different degrees of severity, even among members of the same family. ### Table 2. Incidence of Clinical Features in Males with X-OS with an Identified MID1 Pathogenic Variant View in own window Clinical Feature# of Males with Clinical Feature / Total # of Males Hypertelorism82/82 Hypospadias65/85 Laryngotracheoesophageal defects46/85 Intellectual disability and/or developmental delay28/85 Cleft lip//palate42/85 Congenital heart defects20/85 Anal defects18/85 Brain abnormalities18/35 1 Fontanella et al [2008], Li et al [2015] 1\. Includes males with X-OS who have undergone MRI examination Facial appearance and head anomalies. The facial appearance of affected males is characterized by hypertelorism, which can also be accompanied by telecanthus, a prominent forehead, widow's peak, broad nasal bridge, anteverted nares, low-set and malformed ears, microcephaly, large fontanelle, and/or prominent metopic suture. Unilateral or bilateral cleft lip and/or palate is present in approximately 50% of affected individuals. Other oral manifestations include high-arched palate, ankyloglossia, micrognathia, hypodontia, and neonatal teeth [Robin et al 1996, Shaw et al 2006, Fontanella et al 2008]. Urogenital abnormalities. Hypospadias of varying severity is present in approximately 90% of males with X-linked Opitz G/BBB syndrome and is often associated with other genital anomalies such as cryptorchidism and hypoplastic/bifid scrotum. Severe hypospadias can be associated with urinary tract dysfunction (e.g., vesicoureteral reflux, hydronephrosis) [Fontanella et al 2008, Zhang et al 2011]. Laryngotracheoesophageal (LTE) defects. LTE abnormalities may result in coughing and choking with feeding, recurrent pneumonia, and life-threatening aspiration. In their most severe form, LTE defects are manifest as laryngeal and tracheoesophageal clefts and in more mild form as tracheoesophageal fistulae or LTE dysmotility. The incidence of respiratory and/or gastroesophageal symptoms is probably underestimated because mildly affected individuals may only manifest functional swallowing difficulties that improve with age and eventually disappear during infancy [Pinson et al 2004]. Neurologic findings. More than one third of individuals with X-OS show developmental delay and intellectual disability; they frequently manifest delay in onset of walking, short attention span, learning difficulties, and speech problems. In some cases, these delays are secondary to surgical interventions. Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in 50% of individuals with an MID1 pathogenic variant who underwent MRI examination [Fontanella et al 2008]. Congenital heart disease. Approximately 20% of individuals with X-OS present with congenital heart anomalies (e.g., ventricular septal defect, atrial septal defect, coarctation of the aorta, persistent left superior vena cava, patent ductus arteriosus, patent foramen ovale) [Robin et al 1996, Fontanella et al 2008]. Anal abnormalities are present in approximately 20% of individuals with X-OS (e.g., imperforate anus, ectopic anus) [Robin et al 1996, De Falco et al 2003, Pinson et al 2004, Fontanella et al 2008]. Ophthalmologic features. Refractive error and strabismus have been reported. Heterozygous females usually have hypertelorism only, and rarely other manifestations (e.g., characteristic facial features [anteverted nares, short nose, short uvula, high arched palate, micrognathia], tracheoesophageal cleft or esophageal stenosis, anal malformations) [So et al 2005]. ### Genotype-Phenotype Correlations In general, no genotype-phenotype correlations have been observed. Pathogenic missense, nonsense, splice site, and frameshift variants, insertions, and deletions all result in highly variable phenotypes even within the same family [Pinson et al 2004]. Two possible exceptions are: * An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [Fontanella et al 2008]; * Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [Mnayer et al 2006]. ### Penetrance Usually the presence of an MID1 pathogenic variant is associated with clinical findings of X-OS; however, recently an instance of reduced penetrance has been reported [Ruiter et al 2010]. ### Nomenclature Opitz G/BBB syndrome was first reported as two separate entities, BBB syndrome [Opitz et al 1969b] and G syndrome [Opitz et al 1969a]. Subsequently, it has become apparent that the two syndromes identified in 1969 are in fact a single entity, now named Opitz G/BBB syndrome. Other names, no longer used, include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome. Of note, X-linked Opitz G/BBB syndrome (X-OS; OSX; type I) is distinct from autosomal dominant Opitz G/BBB syndrome (ADOS; type II). ### Prevalence The prevalence of X-linked Opitz G/BBB syndrome ranges from 1:50,000 to 1:100,000 males. ## Differential Diagnosis ### Table 3. Disorders to Consider in the Differential Diagnosis of X-OS View in own window Differential DisorderGene(s) / Genetic MechanismMOIClinical Features of the Differential Disorder Overlapping w/X-OSDistinguishing from X-OS AD Opitz G/BBB syndrome (ADOS; Opitz G/BBB syndrome, type II)SPECC1L 22q11.2 deletion 1AD * Hypertelorism * Swallowing difficulties * Hypospadias * DD * MOI * More complex phenotype in females w/ADOS FG syndrome 2MED12 FLNA CASKXL * Facial dysmorphism * Congenital heart defects * Hypospadias * DD/ID * Congenital hypotonia w/joint hyperlaxity evolving into spasticity * Chronic constipation * Characteristic personality Craniofrontonasal dysplasia (OMIM 304110)EFNB1XL * Facial dysmorphism * Cleft lip/palate * Hypospadias * DD * Hypoplasia or agenesis of corpus callosum * Skeletal, skin, nail, & hair defects * Chest defects * Short stature * Hypotonia Mowat-Wilson syndromeZEB2AD * Facial dysmorphism * Cardiovascular defects * Hypospadias * DD * Hypoplasia or agenesis of corpus callosum * Ocular & gastrointestinal abnormalities * Short stature * Microcephaly * Pectus excavatum * Hypotonia AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked 1\. AD Opitz G/BBB syndrome can be caused either by a heterozygous pathogenic variant in SPECC1L [OMIM 145410] or by deletion on the chromosome region 22q11.2. 2\. FG syndrome is genetically heterogeneous and includes several X-linked forms: FGS1, caused by pathogenic variants in MED12 (see MED12-Related Disorders); FGS2 (OMIM 300321), associated with pathogenic variants in FLNA (locus Xq28); FGS3 (linked to Xp22.3) (OMIM 300406); FGS4 (OMIM 300422), caused by pathogenic variants in CASK (locus Xp11.4); FGS5 (linked to Xq22.3) (OMIM 300581). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked Opitz G/BBB syndrome, the following evaluations by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and clinical geneticist) are recommended if they have not already been performed: * Past medical history and physical examination with attention to palate, heart, genitourinary system, and lower respiratory system * Assessment of hypospadias by a urologist, including ultrasound examination to evaluate for renal/urinary tract abnormalities in males with severe hypospadias * Laryngoscopy and chest x-ray in individuals who have choking with feeding, recurrent pneumonia, and/or aspiration * Developmental evaluation * Referral of individuals with cleft lip/palate to a craniofacial surgeon * Echocardiogram * Assessment of anal position and patency * Complete ophthalmology evaluation including assessment of visual acuity, refractive error, and ocular alignment for possible strabismus ### Treatment of Manifestations Management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and clinical geneticist) to help assure coordination of care is indicated. * Surgical intervention as needed for hypospadias * Surgical treatment of medically significant laryngotracheoesophageal (LTE) abnormalities. Often tracheostomy is necessary initially to assure an adequate airway. * Neuropsychological support. Many males with X-linked Opitz G/BBB syndrome require special educational programs. * Surgical management for cleft lip/palate and other craniofacial anomalies; therapy for speech problems secondary to the cleft lip and palate * Surgical repair as needed for heart defects * Surgical intervention for imperforate anus * Treatment as needed by an ophthalmologist ### Prevention of Secondary Complications Antireflux pharmacologic therapy minimizes the risk for aspiration until laryngeal competence is assured. ### Surveillance Regular follow up depending on the type of malformations present: * Urology follow up for those with significant hypospadias and/or renal defects * Gastroenterology, pulmonary, and/or surgical follow up for those with LTE defects * Craniofacial team follow up for those with cleft lip/palate, including regular monitoring of hearing * Cardiac follow up for those with cardiac defects * Gastroenterology and/or surgical follow up for those with anal defects ### 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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	X-Linked Opitz G/BBB Syndrome	c2936904	5,479	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1327/	2021-01-18T20:48:17	{"mesh": ["C567932"], "synonyms": ["Opitz Syndrome", "X-Linked; XLOS"]}
A number sign (#) is used with this entry because of evidence that exudative vitreoretinopathy-6 (EVR6) is caused by heterozygous mutation in the ZNF408 gene (616454) on chromosome 11p11. One such family has been reported. Homozygous mutation in the ZNF408 gene has been reported to cause retinitis pigmentosa (see RP72, 616469). For a general phenotypic description and discussion of genetic heterogeneity of exudative vitreoretinopathy, see EVR1 (133780). Clinical Features Van Nouhuys (1982) described a large 6-generation Dutch pedigree (family D) with exudative vitreoretinopathy (EVR) and provided detailed descriptions of 16 affected individuals. Visual acuity varied widely, with some patients reporting reduced vision from early childhood, whereas others had 20/20 vision on examination. Temporal stretching of retinal vessels was consistently observed, with temporal ectopia of the macula and/or optic disc in some patients. Terminal ramifications of retinal vessels at the temporal equator were present, with avascularity of the temporal fundus peripherally. Some patients exhibited vitreous membranes, and others had complete vitreous detachment, sometimes with tractional retinal detachment as well. Exudates were observed in 3 of the 16 patients. Collin et al. (2013) studied 2 patients from the large Dutch pedigree with EVR that was originally reported by van Nouhuys (1982) as family D. The first was a 47-year-old man (patient IV-15 of van Nouhuys (1982)) with a history of school-age myopia who was treated for retinal detachment at age 20 years. Examination revealed visual acuities of 20/100 and 20/125 in the right and left eyes, respectively, with minimal cortical cataract present in both eyes. On funduscopy, the temporal retinal vessels showed a stretched course, with some temporal ectopia of the macula. There were local areas of choroid and retinal pigment epithelium (RPE) atrophy in the posterior pole, with avascularity of the peripheral retina temporally. The second patient was a 26-year-old woman (daughter of patient V-12 of van Nouhuys (1982)) who was diagnosed with EVR at 3 years of age. Examination at age 15 years revealed visual acuity in the right eye of finger counting only, with poor fixation, and in the left eye of 20/100. Funduscopy of the right eye showed a prominent falciform retinal fold traversing the posterior pole inferotemporally from the optic nerve head, with marked chorioretinal atrophy and retinal pigmentation on both sides of the fold. The left eye showed a dragged disc and marked deformation of the retina at the posterior pole; there were retinal vessels with an abnormally stretched course to the inferotemporal area, and a whitish mass of fibrous tissue was noted as well as several retinal exudates central to the mass. Fluorescein angiography revealed a deformed retinal network bilaterally, with leakage of dye from dilated capillaries in the left posterior pole. Beginning at age 19, the patient underwent treatment for slowly extending retinal exudates and progressive posterior vitreous detachment and tractional retinal detachment. By age 26, visual acuity in her left eye had deteriorated to finger counting, with an attached retina; the retinal fold and low visual function of the right eye remained unchanged. Mapping In a large Dutch pedigree with EVR, originally described by van Nouhuys (1982) and in which mutations in the LRP5 (603506) and FZD4 (604579) genes had been excluded by Boonstra et al. (2009), Collin et al. (2013) performed SNP genotyping and linkage analysis. They obtained a maximum multipoint lod score of 2.7 at both a 13.6-Mb interval on chromosome 2q, between rs1403970 and rs1995496, and at a 41.7-Mb interval on chromosome 11q, between rs8929 and rs1986778. Reanalysis after the discovery of a second Dutch EVR family sharing a common ancestor with family D yielded a 2-point lod score of 3.05 at marker D11S1395 on chromosome 11q. Molecular Genetics In 2 distantly related affected individuals from a large Dutch pedigree with EVR mapping to chromosome 11q, originally described by van Nouhuys (1982) as family D, Collin et al. (2013) performed exome sequencing and identified heterozygosity for a missense mutation in the ZNF408 gene (H455Y; 616454.0001) on chromosome 11p11. The mutation, which was present in all affected individuals as well as 2 unaffected family members, was not found in 220 ethnically matched controls or 1,154 in-house ethnically matched exomes. Analysis of 9 additional Dutch families with EVR revealed the same H455Y mutation in 1 proband and his affected grand-nephew. Microsatellite and SNP analysis revealed a 9.9-Mb shared haplotype between the 2 families, and genealogic analysis revealed a common ancestor 5 generations previously. Analysis of ZNF408 in another 77 European and 55 Japanese EVR probands revealed heterozygosity for a different missense mutation (S126N; 616454.0002) in a Japanese man; the S126N mutation was also present in his father, who had an erosive vitreoretinopathy phenotype, but it was not found in 191 Japanese controls or in an in-house exome variant database. Functional analysis in COS-1 cells demonstrated that, like wildtype ZNF408, the S126N variant, which involved a moderately conserved residue, localized almost exclusively to the nucleus, whereas the H455Y mutant was present predominantly in the cytoplasm. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity, progressive \- Myopia \- Lens opacities (rare) \- Stretched-appearing retinal vessels, especially temporally \- Terminal ramifications of retinal vessels in temporal equatorial zone \- Avascularity of far peripheral retina, especially temporally \- Temporal ectopia of macula and/or optic disc (in some patients) \- Chorioretinal atrophy (in some patients) \- Pigmentary abnormalities (in some patients) \- Preretinal vitreous membrane \- Vitreous detachment, progressive \- Retinal detachment, tractional \- Retinal exudates, progressive (in some patients) \- Deformed retinal network on fluorescein angiography \- Leaky dilated capillaries on fluorescein angiography MISCELLANEOUS \- Based on report of 1 large Dutch pedigree (last curated July 2015) MOLECULAR BASIS \- Caused by mutation in the zinc finger protein 408 gene (ZNF408, 616454.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	EXUDATIVE VITREORETINOPATHY 6	c0339539	5,480	omim	https://www.omim.org/entry/616468	2019-09-22T15:48:45	{"mesh": ["C580083"], "omim": ["616468"], "orphanet": ["891"]}
This article is about the congenital disorder. For the neurological syndrome, see split hand syndrome. Ectrodactyly Ectrodactyly on the hand of a one-year-old child SpecialtyMedical genetics Ectrodactyly, split hand, cleft hand,[1] derived from the Greek ektroma (abortion) and daktylos (finger)[2] involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformation (SHFM).[3] The hands and feet of people with ectrodactyly (ectrodactyls) are often described as "claw-like" and may include only the thumb and one finger (usually either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet.[4] It is a substantial rare form of a congenital disorder in which the development of the hand is disturbed. It is a type I failure of formation – longitudinal arrest.[5] The central ray of the hand is affected and usually appears without proximal deficiencies of nerves, vessels, tendons, muscles and bones in contrast to the radial and ulnar deficiencies. The cleft hand appears as a V-shaped cleft situated in the centre of the hand.[6] The digits at the borders of the cleft might be syndactilyzed, and one or more digits can be absent. In most types, the thumb, ring finger and little finger are the less affected parts of the hand.[7] The incidence of cleft hand varies from 1 in 90,000 to 1 in 10,000 births depending on the used classification. Cleft hand can appear unilateral or bilateral,[6] and can appear isolated or associated with a syndrome. Split hand/foot malformation (SHFM) is characterized by underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. SHFM is a heterogeneous condition caused by abnormalities at one of multiple loci, including SHFM1 (SHFM1 at 7q21-q22), SHFM2 (Xq26), SHFM3 (FBXW4/DACTYLIN at 10q24), SHFM4 (TP63 at 3q27), and SHFM5 (DLX1 and DLX 2 at 2q31). SHFM3 is unique in that it is caused by submicroscopic tandem chromosome duplications of FBXW4/DACTYLIN. SHFM3 is considered 'isolated' ectrodactyly and does not show a mutation of the tp63 gene. ## Contents * 1 Presentation * 2 Genetics * 3 Pathophysiology * 3.1 Genetics * 3.2 Embryology * 4 Diagnosis * 4.1 Classification * 5 Treatment * 5.1 Indications * 5.2 Timing of surgical interventions * 5.3 Classification and treatment * 5.4 Snow-Littler * 5.5 Ueba * 5.6 Miura and Komada * 6 History * 6.1 Symbrachydactyly * 7 Notable cases * 8 Other animals * 8.1 Wood frog * 8.2 Salamanders * 8.3 Cats and dogs * 9 See also * 10 References * 11 External links ## Presentation[edit] Ectrodactyly can be caused by various changes to 7q. When 7q is altered by a deletion or a translocation ectrodactyly can sometimes be associated with hearing loss.[8] Ectrodactyly, or Split hand/split foot malformation (SHFM) type 1 is the only form of split hand/ malformation associated with sensorineural hearing loss.[8] ## Genetics[edit] Syndrome Ectrodactyly–ectodermal dysplasia–cleft syndrome Split-Hand-Foot Malformation Syndrome Silver–Russell syndrome Cornelia de Lange syndrome Acrorenal syndrome Focal dermal hypoplasia Ectrodactyly and cleft palate syndrome Ectrodactyly/mandibulofacial dysostosis Ectrodactyly and macular dystrophy A large number of human gene defects can cause ectrodactyly. The most common mode of inheritance is autosomal dominant with reduced penetrance, while autosomal recessive and X-linked forms occur more rarely.[9] Ectrodactyly can also be caused by a duplication on 10q24. Detailed studies of a number of mouse models for ectrodactyly have also revealed that a failure to maintain median apical ectodermal ridge (AER) signalling can be the main pathogenic mechanism in triggering this abnormality.[9] A number of factors make the identification of the genetic defects underlying human ectrodactyly a complicated process: the limited number of families linked to each split hand/foot malformation (SHFM) locus, the large number of morphogens involved in limb development, the complex interactions between these morphogens, the involvement of modifier genes, and the presumed involvement of multiple gene or long-range regulatory elements in some cases of ectrodactyly.[9] In the clinical setting these genetic characteristics can become problematic and making predictions of carrier status and severity of the disease impossible to predict.[10] In 2011, a novel mutation in DLX5 was found to be involved in SHFM.[11] Ectrodactyly is frequently seen with other congenital anomalies.[9] Syndromes in which ectrodactyly is associated with other abnormalities can occur when two or more genes are affected by a chromosomal rearrangement.[9] Disorders associated with ectrodactyly include Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, which is closely correlated to the ADULT syndrome and Limb-mammary (LMS) syndrome, Ectrodactyly-Cleft Palate (ECP) syndrome, Ectrodactyly-Ectodermal Dysplasia-Macular Dystrophy syndrome, Ectrodactyly-Fibular Aplasia/Hypoplasia (EFA) syndrome, and Ectrodactyly-Polydactyly. More than 50 syndromes and associations involving ectrodactyly are distinguished in the London Dysmorphology Database.[12] ## Pathophysiology[edit] The pathophysiology of cleft hand is thought to be a result of a wedge-shaped defect of the apical ectoderm of the limb bud (AER: apical ectodermal ridge).[6] Polydactyly, syndactyly and cleft hand can occur within the same hand, therefore some investigators suggest that these entities occur from the same mechanism.[6] This mechanism is not yet defined. ### Genetics[edit] The cause of cleft hand lies, for what is known, partly in genetics. The inheritance of cleft hand is autosomal dominant and has a variable penetrance of 70%.[6] Cleft hand can be a spontaneous mutation during pregnancy (de novo mutation). The exact chromosomal defect in isolated cleft hand is not yet defined. However, the genetic causes of cleft hand related to syndromes have more clarity.[13] The identified mutation for SHSF syndrome (split-hand/split-foot syndrome) a duplication on 10q24, and not a mutation of the tp63 gene as in families affected by EEC syndrome (ectrodactyly–ectodermal dysplasia–cleft syndrome).[13] The p63 gene plays a critical role in the development of the apical ectodermal ridge (AER), this was found in mutant mice with dactylaplasia.[6] ### Embryology[edit] Some studies[13][14][15] have postulated that polydactyly, syndactyly and cleft hand have the same teratogenic mechanism. In vivo tests showed that limb anomalies were found alone or in combination with cleft hand when they were given Myleran. These anomalies take place in humans around day 41 of gestation.[13] ## Diagnosis[edit] ### Classification[edit] There are several classifications for cleft hand, but the most used classification is described by Manske and Halikis[16] see table 3. This classification is based on the first web space. The first web space is the space between the thumb and the index. Table 3: Classification for cleft hand described by Manske and Halikis Type Description[17][18] Characteristics[18] I Normal web Thumb web space not narrowed IIA Mildly narrowed web Thumb web space mildly narrowed IIB Severely narrowed web Thumb web space severely narrowed III Syndactylized web Thumb and index rays syndactylized, web space obliterated IV Merged web Index ray suppressed, thumb web space is merged with the cleft V Absent web Thumb elements suppressed, ulnar rays remain, thumb web space no longer present ## Treatment[edit] The treatment of cleft hand is usually invasive and can differ each time because of the heterogeneity of the condition. The function of a cleft hand is mostly not restricted, yet improving the function is one of the goals when the thumb or first webspace is absent.[citation needed] The social and stigmatising aspects of a cleft hand require more attention. The hand is a part of the body which is usually shown during communication. When this hand is obviously different and deformed, stigmatisation or rejection can occur. Sometimes, in families with cleft hand with good function, operations for cosmetic aspects are considered marginal[6] and the families choose not to have surgery.[citation needed] ### Indications[edit] Surgical treatment of the cleft hand is based on several indications:[6] * Improving function * Absent thumb * Deforming syndactyly (mostly between digits of unequal length like index and thumb) * Transverse bones (this will progress the deformity; growth of these bones will widen the cleft) * Narrowed first webspace * The feet Aesthetical aspects * Reducing deformity ### Timing of surgical interventions[edit] The timing of surgical interventions is debatable. Parents have to decide about their child in a very vulnerable time of their parenthood. Indications for early treatment are progressive deformities, such as syndactyly between index and thumb or transverse bones between the digital rays.[6] Other surgical interventions are less urgent and can wait for 1 or 2 years.[citation needed] ### Classification and treatment[edit] When surgery is indicated, the choice of treatment is based on the classification. Table 4 shows the treatment of cleft hand divided into the classification of Manske and Halikis. Techniques described by Ueba, Miura and Komada and the procedure of Snow-Littler are guidelines; since clinical and anatomical presentation within the types differ, the actual treatment is based on the individual abnormality.[citation needed] Table 4: Treatment based on the classification of Manske and Halikis Type Treatment I/IIA Reconstruction of the transverse metacarpal ligament[19] IIB/III Transposition of the index metacarpal with reconstruction of the thumb webspace[19] IV Mobility and/or position of the thumb of ulnar digit to promote pinch and grasp[16] V There is no cleft or web space and the thumb is very deficient. This hand requires consideration of creating a radial digit[16] ### Snow-Littler[edit] The goal of this procedure is to create a wide first web space and to minimise the cleft in the hand. The index digit will be transferred to the ulnar side of the cleft. Simultaneously a correction of index malrotation and deviation is performed.[6] To minimise the cleft, it is necessary to fix together the metacarpals which used to border the cleft. Through repositioning flaps, the wound can be closed.[citation needed] ### Ueba[edit] Ueba described a less complicated surgery.[6] Transverse flaps are used to resurface the palm, the dorsal side of the transposed digit and the ulnar part of the first web space. A tendon graft is used to connect the common extensor tendons of the border digits of the cleft to prevent digital separation during extension. The closure is simpler, but has cosmetic disadvantage because of the switch between palmar and dorsal skin.[citation needed] ### Miura and Komada[edit] The release of the first webspace has the same principle as the Snow-Littler procedure. The difference is the closure of the first webspace; this is done by simple closure or closure with Z-plasties.[6] ## History[edit] Typical cleft hand Atypical cleft hand (symbrachydactyly) Typical hand was manifest in the complete or incomplete absence of the middle finger[20] Atypical hand had a more severe manifestation in which there was varying absence of the central index, middle and ring finger rays[20] “V”-shaped cleft[6] “U”-shaped cleft[6] One to four limbs involved[6] One limb involved (no feet)[6] Higher incidence[16] Lower incidence[16] Autosomal dominant[6] Sporadic[6] Suppression progresses in a radial direction so that in the monodactylous form the most ulnar finger is preserved[6] Suppression progresses in a more ulnar direction; therefore in the monodactylous form the thumb is usually the last remaining digit[6] Literature shows that cleft hand is described centuries ago. The first reference to what might be considered a cleft hand was by Ambroise Paré in 1575. Hartsink (1770) wrote the first report of true cleft hand. In 1896, the first operation of the cleft hand was performed by Doctor Charles N. Dowed of New York City.[16] However, the first certain description of what we know as a cleft hand as we know it today was described at the end of the 19th century.[16] ### Symbrachydactyly[edit] Historically, a U-type cleft hand was also known as atypical cleft hand. The classification in which typical and atypical cleft hand are described was mostly used for clinical aspects and is shown in table 1. However, nowadays, this “atypical cleft hand” is referred to as symbrachydactyly and is not a subtype of cleft hand.[citation needed] ## Notable cases[edit] * Bree Walker[21] Once a popular television anchor woman in Los Angeles, she has appeared in the television drama Nip/Tuck as an inspirational character who battles her disease and counsels another family who have children with ectrodactyly * Grady Stiles Sr. and Grady Stiles Jr.: known publicly as Lobster Boy and family, famous side show acts, featured on the AMC reality show, Freakshow. * The Vadoma tribe in northern Zimbabwe * Mikhail Tal, Soviet chess player, world champion * Lee Hee-ah, a Korean pianist with only two fingers on each hand. * Cédric Grégoire (better known as Lord Lokhraed) is the guitarist and lead vocalist of French black metal band Nocturnal Depression and has ectrodactyly on his fretting hand, which has only two fingers. * Black Scorpion, freak show performer. ## Other animals[edit] Ectrodactyly is not only a genetic characteristic in humans, but can also occur in frogs and toads,[22] mice,[23] salamanders,[24] cows,[9] chickens,[9] rabbits,[9] marmosets,[9] cats and dogs,[25] and even West Indian manatees.[9] The following examples are studies showing the natural occurrence of ectrodactyly in animals, without the disease being reproduced and tested in a laboratory.[citation needed] In all three examples we see how rare the actual occurrence of ectrodactyly is. ### Wood frog[edit] The Department of Biological Sciences at the University of Alberta in Edmonton, Alberta performed a study to estimate deformity levels in wood frogs in areas of relatively low disturbance.[22] After roughly 22,733 individuals were examined during field studies, it was found that only 49 wood frogs had the ectrodactyly deformity.[22] ### Salamanders[edit] In a study performed by the Department of Forestry and Natural Resources at Purdue University, approximately 2000 salamanders (687 adults and 1259 larvae) were captured from a large wetland complex and evaluated for malformations.[24] Among the 687 adults, 54 (7.9%) were malformed. Of these 54 adults, 46 (85%) had missing (ectrodactyly), extra (polyphalangy) or dwarfed digits (brachydactyly).[24] Among the 1259 larvae, 102 were malformed, with 94 (92%) of the malformations involving ectrodactyly, polyphalangy, and brachydactyly.[24] Results showed few differences in the frequency of malformations among life-history changes, suggesting that malformed larvae do not suffer substantially higher mortality than their adult conspecifics.[24] ### Cats and dogs[edit] Davis and Barry 1977 tested allele frequencies in domestic cats. Among the 265 cats observed, there were 101 males and 164 females. Only one cat was recorded to have the ectrodactyly abnormality,[26] illustrating this rare disease. According to M.P. Ferreira, a case of ectrodactyly was found in a two-month-old male mixed Terrier dog.[27] In another study, Carrig and co-workers also reported a series of 14 dogs[28] with this abnormality proving that although ectrodactyly is an uncommon occurrence for dogs, it is not entirely unheard of. ## See also[edit] * Oligodactyly * Sonic hedgehog, a main gene responsible for body symmetry during development. ## References[edit] 1. ^ Giele, Henk; Cassell, Oliver (2008). Plastic and Reconstructive Surgery. Oxford: Oxford University Press. p. 197. ISBN 978-0-19-263222-7. 2. ^ Durowaye, Mathew; Adegboye, Abdulrasheed; Mokuolu, Olugbenga Ayodeji; Adeboye, Muhammed; Yahaya-Kongoila, Sefiyah; Adaje, Adeline; Adesiyun, Omotayo; Ernest, Samuel Kolade (2011). "Familial Ectrodactyly Syndrome in a Nigerian Child: A Case Report". Oman Medical Journal. 26 (4): 275–8. doi:10.5001/omj.2011.67. PMC 3191709. PMID 22043435. 3. ^ Moerman, P.; Fryns, J.P. (1998). "Ectodermal dysplasia, Rapp-Hodgkin type in a mother and severe ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) in her child". American Journal of Medical Genetics Part A. 63 (3): 479–81. doi:10.1002/(SICI)1096-8628(19960614)63:3<479::AID-AJMG12>3.0.CO;2-J. PMID 8737656. 4. ^ Peterson-Falzone, Sally J.; Hardin-Jones, Mary A.; Karnell, Michael P.; McWilliams, Betty Jane (2001). Cleft Palate Speech. Mosby. ISBN 978-0-8151-3153-3. 5. ^ Congenital Hand Deformities at eMedicine 6. ^ a b c d e f g h i j k l m n o p q r s t Kay, Simon P.; McCombe, David (2005). "Central hand deficiencies". In Green, David P.; Hotchkiss, Robert N.; Pederson, William C.; et al. (eds.). Green's Operative Hand Surgery (5th ed.). Philadelphia: Elsevier/ Churchill Livingstone. pp. 1404–15. ISBN 978-0-443-06626-9. 7. ^ Upton, Joseph; Taghinia, Amir H. (2010). "Correction of the Typical Cleft Hand". The Journal of Hand Surgery. 35 (3): 480–5. doi:10.1016/j.jhsa.2009.12.021. PMID 20138711. 8. ^ a b Wieland, I.; Muschke, P; Jakubiczka, S; Volleth, M; Freigang, B; Wieacker, PF; et al. (2004). "Refinement of the deletion in 7q21.3 associated with split hand/foot malformation type 1 and Mondini dysplasia". Journal of Medical Genetics. 41 (5): e54. doi:10.1136/jmg.2003.010587. PMC 1735762. PMID 15121782. 9. ^ a b c d e f g h i j Pascal, H.G.; et al. (2003). "Pathogenesis of split-hand/split-foot malformation". Human Molecular Genetics. 12 (1): R51–R60. doi:10.1093/hmg/ddg090. PMID 12668597. 10. ^ Scherer, Stephen; Cheung, J; MacDonald, JR; Osborne, LR; Nakabayashi, K; Herbrick, JA; Carson, AR; Parker-Katiraee, L; et al. (2003). "Human Chromosome 7: DNA Sequence and Biology". Science. 300 (5620): 767–772. Bibcode:2003Sci...300..767S. doi:10.1126/science.1083423. PMC 2882961. PMID 12690205. 11. ^ Shamseldin, Hanan E; Faden Maha A; Alashram Walid; Alkuraya Fowzan S (Nov 2011). "Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation". Journal of Medical Genetics. 49 (1): 16–20. doi:10.1136/jmedgenet-2011-100556. PMID 22121204. S2CID 25692622. 12. ^ Winter, R.M.; Baraitser, M. (August 1987). "The London Dysmorphology Database". Journal of Medical Genetics. 24 (8): 509–510. doi:10.1136/jmg.24.8.509. PMC 1050214. PMID 3656376. 13. ^ a b c d Katarincic, Julia A. (2003). Cleft Hand. American Society for Surgery of the Hand.[page needed] 14. ^ Naruse, Takuji; Takahara, Masatoshi; Takagi, Michiaki; Ogino, Toshihiko (2007). "Early Morphological Changes Leading to Central Polydactyly, Syndactyly, and Central Deficiencies: An Experimental Study in Rats". The Journal of Hand Surgery. 32 (9): 1413–7. doi:10.1016/j.jhsa.2007.06.017. PMID 17996777. 15. ^ Naruse, Takuji; Takahara, Masatoshi; Takagi, Michiaki; Oberg, Kerby C.; Ogino, Toshihiko (2007). "Busulfan-induced central polydactyly, syndactyly and cleft hand or foot: A common mechanism of disruption leads to divergent phenotypes". Development, Growth & Differentiation. 49 (6): 533–41. doi:10.1111/j.1440-169X.2007.00949.x. PMID 17661743. 16. ^ a b c d e f g Barsky, Arthur J (1964). "Cleft hand: Classification, incidence and treatment: review of the literature and report of nineteen cases". The Journal of Bone and Joint Surgery. 46: 1707–20. doi:10.2106/00004623-196446080-00006. PMID 14239859.[permanent dead link] 17. ^ Falliner AA., Analysis of anatomic variations in cleft hands, J Hand Surg Am. 2004 Nov;29(6):994-1001 18. ^ a b Manske, Paul R.; Halikis, Mark N. (1995). "Surgical classification of central deficiency according to the thumb web". The Journal of Hand Surgery. 20 (4): 687–97. doi:10.1016/S0363-5023(05)80293-X. PMID 7594304. 19. ^ a b Manske, Paul R.; Goldfarb, Charles A. (2009). "Congenital Failure of Formation of the Upper Limb". Hand Clinics. 25 (2): 157–70. doi:10.1016/j.hcl.2008.10.005. PMID 19380058. 20. ^ a b Jones, Neil F; Kono, Michiyuki (2004). "Cleft hands with six metacarpals". The Journal of Hand Surgery. 29 (4): 720–6. doi:10.1016/j.jhsa.2004.04.002. PMID 15249100. 21. ^ "Medical Mystery: Ectrodactyly". ABC News. January 27, 2007. 22. ^ a b c Eaton, Brian R.; Eaves, Sara; Stevens, Cameron; Puchniak, Allison; Paszkowski, Cynthia A.; et al. (2004). "Deformity Levels in Wild Populations of the Wood Frog (Rana sylvatica) in Three Ecoregions of Western Canada". Journal of Herpetology. 38 (2): 283–287. doi:10.1670/95-03N. S2CID 86275852. 23. ^ Manson, Jeanne; Dourson, Michael L.; Smith, Carl C. (1977). "Effects of Cytosine Arabinoside on In vivo and In vitro Mouse limb Development". In Vitro. 13 (7): 434–442. doi:10.1007/BF02615104. PMID 885563. S2CID 10311465. 24. ^ a b c d e Williams, Rod N; Bos, David H; Gopurenko, David; DeWoody, J Andrew (2008). "Amphibian malformations and inbreeding". Biology Letters. 4 (5): 549–52. doi:10.1098/rsbl.2008.0233. PMC 2610075. PMID 18593670. 25. ^ Jezyk, P.F. (1985). Constitutional Disorders of the Skeleton in Dogs and Cats: Textbook of Small Animal Orthopedics. Ithaca, New York: International Veterinary Information Service. 26. ^ Davis, Brian; Davis, Barry (1977). "Allele frequencies in a cat population in Budapest". Journal of Heredity. 68 (1): 31–34. doi:10.1093/oxfordjournals.jhered.a108768. PMID 864231. 27. ^ Ferreira, M.P.; Alievi, M.M.; Beck, C.A.C.; Voll, J.; Muccillo, M.S.; Gomes, C. (2007). "Ectrodactilia em cão: relato de caso". Arquivo Brasileiro de Medicina Veterinária e Zootecnia. 59 (4): 910–3. doi:10.1590/S0102-09352007000400015. 28. ^ Carrig, ColinB.; Wortman, JeffreyA.; Morris, EarlL.; Blevins, WilliamE.; Root, CharlesR.; Hanlon, GriseldaF.; Suter, PeterF. (1981). "Ectrodactyly (Split-hand deformity) in the dog". Veterinary Radiology. 22 (3): 123–44. doi:10.1111/j.1740-8261.1981.tb01363.x. ## External links[edit] * Online Mendelian Inheritance in Man (OMIM): 183600 * Online Mendelian Inheritance in Man (OMIM): 183800 Classification D * ICD-10: Q71.6 * ICD-9-CM: 755.4 * OMIM: 225300 * MeSH: C574275 * DiseasesDB: 32141 Wikimedia Commons has media related to Ectrodactyly. * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Ectrodactyly	c0265554	5,481	wikipedia	https://en.wikipedia.org/wiki/Ectrodactyly	2021-01-18T18:30:47	{"mesh": ["C574275"], "umls": ["C0265554"], "icd-9": ["755.4"], "icd-10": ["Q71.671.6"], "orphanet": ["2440"], "wikidata": ["Q650026"]}
3q29 microduplication syndrome (also known as 3q29 duplication syndrome) is a condition that results from the copying (duplication) of a small piece of chromosome 3 in each cell. The duplication occurs on the long (q) arm of the chromosome at a position designated q29. The features associated with 3q29 microduplication syndrome vary widely. Some individuals with this chromosomal change have very mild or no related signs and symptoms, and the duplication is discovered because they undergo genetic testing only after a family member is diagnosed. Other people with a 3q29 microduplication have delayed development (particularly speech delay) and intellectual disability or learning difficulties. Although most affected individuals have no major birth defects, eye abnormalities, heart defects, and an unusually small head (microcephaly) can occur. 3q29 microduplication syndrome may increase the likelihood of being overweight or obese, although it is hard to determine whether these weight issues are caused by the duplication. ## Frequency 3q29 microduplication syndrome appears to be very rare. Fewer than 30 affected individuals have been described in the medical literature. ## Causes Most people with 3q29 microduplication syndrome have an extra copy of about 1.6 million DNA building blocks (base pairs), also written as 1.6 megabases (Mb), at position q29 on chromosome 3. However, the duplication can vary in size. It affects one of the two copies of chromosome 3 in each cell. The segment that gets duplicated is surrounded by short, repeated sequences of DNA that make it prone to rearrangement during cell division. The rearrangement can lead to missing or extra copies of DNA at 3q29. (A missing copy of this segment causes another condition called 3q29 microdeletion syndrome.) The chromosome segment most commonly duplicated in people with 3q29 microduplication syndrome contains about 20 genes. Some of these genes are thought to be involved in brain and eye development. However, it is unknown which specific genes, when abnormally copied, are related to the varied signs and symptoms of 3q29 microduplication syndrome. It is also unclear why some people with a duplication at 3q29 have no associated health problems. It is possible that genetic changes outside the 3q29 region can influence the features of this condition. ### Learn more about the chromosome associated with 3q29 microduplication syndrome * chromosome 3 ## Inheritance Pattern This condition has an autosomal dominant pattern of inheritance, which means the duplication occurs on one copy of chromosome 3 in each cell. In many cases, an affected person inherits the duplication from a parent. The parent may have no signs and symptoms related to the duplication, or the features may be mild. The remaining cases result from a new chromosomal change and occur in people with no history of the duplication in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	3q29 microduplication syndrome	c2749873	5,482	medlineplus	https://medlineplus.gov/genetics/condition/3q29-microduplication-syndrome/	2021-01-27T08:25:29	{"gard": ["10360"], "mesh": ["C567626"], "omim": ["611936"], "synonyms": []}
Pigmented spindle cell nevus Other namesPigmented spindle cell tumor of Reed,[1] pigmented variant of Spitz nevus[1] Micrograph of a pigmented spindle cell nevus (top of image). H&E stain. SpecialtyDermatology A pigmented spindle cell nevus is a skin condition characterized by a dark brown to black macule or papule, usually less than 6 mm.[1] It was characterized in 1975.[2][3] ## See also[edit] * Partial unilateral lentiginosis * List of cutaneous conditions * Spitz nevus ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. 1730–2. ISBN 1-4160-2999-0. 2. ^ James J. Nordlund (2006). The pigmentary system: physiology and pathophysiology. Wiley-Blackwell. pp. 1093–. ISBN 978-1-4051-2034-0. Retrieved 17 May 2011. 3. ^ Reed, RJ.; Ichinose, H.; Clark, WH.; Mihm, MC. (Jun 1975). "Common and uncommon melanocytic nevi and borderline melanomas". Semin Oncol. 2 (2): 119–47. PMID 1234372. ## External links[edit] Classification D * MeSH: D018331 * v * t * e Skin cancer of nevi and melanomas Melanoma * Mucosal melanoma * Superficial spreading melanoma * Nodular melanoma * lentigo * Lentigo maligna/Lentigo maligna melanoma * Acral lentiginous melanoma * Amelanotic melanoma * Desmoplastic melanoma * Melanoma with features of a Spitz nevus * Melanoma with small nevus-like cells * Polypoid melanoma * Nevoid melanoma * Melanocytic tumors of uncertain malignant potential Nevus/ melanocytic nevus * Nevus of Ito/Nevus of Ota * Spitz nevus * Pigmented spindle cell nevus * Halo nevus * Pseudomelanoma * Blue nevus * of Jadassohn–Tièche * Cellular * Epithelioid * Deep penetrating * Amelanotic * Malignant * Congenital melanocytic nevus (Giant * Medium-sized * Small-sized) * Balloon cell nevus * Dysplastic nevus/Dysplastic nevus syndrome * Acral nevus * Becker's nevus * Benign melanocytic nevus * Nevus spilus This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pigmented spindle cell nevus	c0474967	5,483	wikipedia	https://en.wikipedia.org/wiki/Pigmented_spindle_cell_nevus	2021-01-18T18:41:41	{"mesh": ["D018331"], "umls": ["C0474967"], "wikidata": ["Q7193412"]}
Myotonia fluctuans (MF) is a form of potassium-aggravated myotonia (PAM, see this term) which is cold insensitive, dramatically fluctuating and profoundly worsened by potassium ingestion. ## Epidemiology Prevalence is unknown. ## Clinical description Fluctuating myotonia develops during childhood or adolescence and involves the extraocular, bulbar and limb muscles. Eyelid myotonia is often the first sign of the disease. Episodes of stiffness vary in severity and frequency and may be separated by prolonged periods of normality. Myotonia is aggravated by potassium ingestion and appears with a delayed onset (10-30 min) after exercise (exercise-induced delayed-onset myotonia). Cold has no effect on myotonia. Paralysis is never observed. Episodic weakness is rare. ## Etiology Myotonia fluctuans is a sodium muscle channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. ## Genetic counseling Transmission is autosomal dominant. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Myotonia fluctuans	c0752355	5,484	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99734	2021-01-23T18:33:57	{"mesh": ["D020967"], "omim": ["608390"], "umls": ["C0752355"], "icd-10": ["G71.1"], "synonyms": ["Exercise-induced delayed-onset myotonia", "Fluctuating myotonia"]}
A number sign (#) is used with this entry because of evidence that a syndrome of infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID) is caused by heterozygous mutation in the glutaminase gene (GLS; 138280) on chromosome 2q32. One such patient has been reported. Description Aside from the clinical features of infantile cataract, skin abnormalities, and impaired intellectual development, CASGID is characterized by strikingly high intracerebral and urinary glutamate excess with almost undetectable glutamine. A gain-of-function mutation in the GLS gene was found (see MOLECULAR GENETICS). GLS loss of function is implicated in a form of neonatal epileptic encephalopathy (EIEE71; 618328) and a syndrome of global developmental delay and progressive ataxia (GDPAG; 618412). Clinical Features Rumping et al. (2019) reported a female diagnosed with bilateral cataract at age 3 months who was the product of an uncomplicated full-term gestation to nonconsanguineous Dutch parents. After lens extraction and replacement, eye contact remained absent. By the age of 8 months developmental delay was noted, and head circumference had fallen from 0 standard deviations (SD) to -2 SD. She developed recurrent dermatologic abnormalities on her extremities, cheeks, and ears without pruritus, characterized as erythematic subcutaneous nodules of approximately 1 cm. Histopathologic analysis of these lesions showed deep perivascular and periglandular lymphohistiocytic infiltrates and pronounced leukocytoclasia at the surface of the dermis, and focal vacuolar alterations, hyperkeratosis, and parakeratosis of the epidermis. Over time, the girl lost the ability to make meaningful sounds and to sit. She developed profound axial hypotonia leading to kyphoscoliosis. Upon arousal she exhibited uncontrolled motoric agitation and self-injurious behavior. At the age of 11 years, she was able to use gestures for communication, to understand verbal single component instructions, and to steer her own wheelchair. Extensive diagnostic evaluation revealed extremely low glutamine levels and high glutamate levels in both cortex and white matter, detected consistently with quantitative brain proton magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging. Cerebrospinal fluid and plasma levels of glutamate and glutamine were unaffected. Brain MRI at the age of 16 months showed delayed myelination. Analyses of stored urine samples similarly showed low concentrations of glutamine and high concentrations of glutamate. Molecular Genetics By trio-based whole-exome sequencing, Rumping et al. (2019) identified a heterozygous de novo missense variant in the GLS gene (S482C; 138280.0004) in a girl with infantile cataract, skin abnormalities, glutamate excess, and intellectual developmental impairment. Patient fibroblasts showed increased intracellular glutamate-to-glutamine ratio. Transfection of mutant protein into HEK293 cells strongly increased the glutamate-to-glutamine ratio, while introduction of wildtype GLS had no effect. Alignment of the GLS sequence in more than 1,000 genera revealed that ser482, near the catalytic site of GLS, is extremely highly evolutionarily conserved, along with residues directly involved in the catalytic process. Rumping et al. (2019) stated that the substitution by cys for ser482 changes the electrostatic environment of tyr466, one of the catalytic residues that protonates glutamine and thereby accelerates deamination into glutamate. This change is likely to enhance the propensity for proton donation and thereby to increase the speed of the reaction. Injection of zebrafish embryos at the 1-cell stage with S482C-GLS cDNA resulted in structural lens opacities in 34 (72%) of 47 embryos, with no opacities observed in control embryos. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Acquired microcephaly Eyes \- Infantile cataracts SKIN, NAILS, & HAIR Skin \- Erythematic subcutaneous nodules (approx. 1 cm on extremities, cheeks, and ears) Skin Histology \- Perivascular and periglandular lymphohistiocytic infiltrates of the dermis \- Pronounced leukocytoclasia at the surface of the dermis \- Focal vacuolar alterations of the epidermis \- Hyperkeratosis and parakeratosis of the epidermis NEUROLOGIC Central Nervous System \- Slowed development \- Axial hypotonia \- Motor agitation \- Delayed myelination Behavioral Psychiatric Manifestations \- Self-injurious behavior LABORATORY ABNORMALITIES \- Increased glutamate in urine, fibroblasts, and brain \- Decreased glutamine in urine, fibroblasts, and brain MISCELLANEOUS \- De novo mutation \- Based on report of one patient (last curated February 2019) \- No measurable differences of glutamate or glutamine from control in plasma or CSF MOLECULAR BASIS \- Caused by mutation in the glutaminase gene (GLS, 138280.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	INFANTILE CATARACT, SKIN ABNORMALITIES, GLUTAMATE EXCESS, AND IMPAIRED INTELLECTUAL DEVELOPMENT	None	5,485	omim	https://www.omim.org/entry/618339	2019-09-22T15:42:27	{"omim": ["618339"]}
A rare, genetic, primary immunodeficiency disorder characterized by an abnormal immune response to Epstein-Barr virus (EBV) infection, caused by hemizygous mutations in the X-linked XIAP gene, resulting in B cell lymphoproliferation and manifestating with various phenotypes which include EBV-driven hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, recurrent splenomegaly, hepatitis, colitis, and intestinal bowel disease with features of Crohn's disease. Additional manifestations include variable auto-inflammatory symptoms such as uveitis, arthritis, skin abscesses, erythema nodosum, and nephritis. Neurological involvement is rare and lymphoma is never observed. Laboratory findings include normal or increased activated T cells, low or normal iNKT cells, and normal or reduced memory B cells. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	X-linked lymphoproliferative disease due to XIAP deficiency	c1845076	5,486	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=538934	2021-01-23T19:12:11	{"mesh": ["C564469"], "omim": ["300635"], "synonyms": ["X-linked lymphoproliferative syndrome type 2", "XIAP deficiency syndrome", "XLP2"]}
A number sign (#) is used with this entry because of evidence that Schindler disease types I and III are caused by homozygous or compound heterozygous mutation in the alpha-N-acetylgalactosaminidase gene (NAGA; 104170) on chromosome 22q13. Description Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (609242), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (Desnick and Schindler, 2001). Clinical Features ### Schindler Disease, Type I Van Diggelen et al. (1987, 1988) reported 2 sons of a German couple with remote consanguinity who were affected with type I lysosomal alpha-N-acetylgalactosaminidase deficiency. Starting at age 9 months, the boys showed neurologic symptoms and developmental delay followed by rapid progressive psychomotor deterioration. By the ages of 2.5 and 4 years, they had 'largely lost their previously acquired motor and language skills.' Growth had been normal. Computerized tomographic scans were normal, and there was no organomegaly, obvious coarsening of the facies, or skeletal dysplasia. A uniquely abnormal pattern of urinary oligosaccharides was demonstrated by thin-layer chromatography. The levels of NAGA were very low in cultured fibroblasts, leukocytes and plasma, whereas these levels were normal in a healthy brother. Both parents had low normal or reduced enzyme activity. A major neutral oligosaccharide from the urine of 1 patient was identified as the blood group A determinant, a trisaccharide with terminal alpha-N-acetylgalactosamine. The concentration of this product in the urine of the older boy, who was a secretor and had blood group A, was 5 times normal. The younger boy, who had blood group O, did not excrete this trisaccharide. Schindler et al. (1988) reported that the affected German boys demonstrated severe psychomotor retardation, myoclonic seizures, decorticate posture, optic atrophy, blindness, marked long tract signs, and total loss of contact with the environment by ages 3 to 4 years. No visceral features of other lysosomal storage diseases were present. Ultrastructural examination of peripheral nerves was unremarkable, whereas the rectal mucosa contained dystrophic autonomic axons with 'tubulovesicular' material consistent with a diagnosis of neuroaxonal dystrophy. Wang et al. (1988) pointed out that the brothers reported by van Diggelen et al. (1987) had a clinical course and neuropathologic findings similar to those in Seitelberger disease, the infantile form of neuroaxonal dystrophy (256600). Characteristic 'spheroids' were observed histologically and ultrastructurally in terminal axons in gray matter. They concluded that the disorder, which they referred to as Schindler disease, was an autosomal recessive form of infantile axonal dystrophy. Schindler et al. (1989) also characterized the disorder as a neuroaxonal dystrophy. Wolfe et al. (1995) reported neuropathologic findings from the affected boys reported by van Diggelen et al. (1988). Widespread spheroid formation was observed in terminal and preterminal axons. Neocortical and peripheral autonomic axons contained tubulovesicular and lamelliform membranous arrays, prominent acicular clefts, and electron-dense axoplasmic matrix. Other alterations resembling those in various neuronopathic lysosomal storage diseases were not observed. The findings were remarkably similar to those seen in Seitelberger disease. Keulemans et al. (1996) reported a distant affected relative of the boys described by van Diggelen et al. (1987). He had normal development until age 7 months, when he developed convulsions. He died at 18 months of hypoxia during a prolonged convulsion causing apnea. During the last 3 months of his life, development had stopped. Keulemans et al. (1996) noted that the original brothers were alive at ages 11 and 12 years, but remained in a persistent vegetative state. Bakker et al. (2001) reported a 3-year-old boy, born of consanguineous Moroccan parents, with alpha-NAGA deficiency. He showed congenital bilateral cataracts and an abnormal oligosaccharide pattern in urine suggestive of alpha-NAGA deficiency. At the age of 12 months, he showed slightly delayed neuromotor development, which became more prominent in the next 2 years. NMR of the brain showed diffuse white matter abnormalities with a secondary, symmetrical demyelinization. Histopathologic studies were not performed. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. Both patients had blood group O. The parents had alpha-NAGA activity consistent with heterozygosity. Bakker et al. (2001) noted that factors in addition to alpha-NAGA activity must play a role in the phenotype, as the 2 brothers had vastly different phenotypes. Bakker et al. (2001) also commented that NAGA deficiency with neuroaxonal dystrophy had not been reported since 1987, and suggested that the original German boys reported by van Diggelen et al. (1988) may have had 2 disorders: alpha-NAGA deficiency and neuroaxonal dystrophy. Accidental occurrence of 2 independent monogenic diseases may occur in consanguineous families, as was the case for the German boys. ### Schindler Disease, Type III De Jong et al. (1994) reported 2 Dutch sibs with alpha-NAGA deficiency. The proband was an 11-month-old girl with generalized seizures and persistent mild oligosacchariduria. Enzymatic study of plasma, leukocytes, and fibroblasts revealed alpha-NAGA deficiency. Electron microscopy of lymphocytes showed no vacuolization, but incubation of cultured fibroblasts with Helix pomatia lectin showed intracellular N-acetylgalactosamine-containing storage material. A younger asymptomatic brother, who was part of a dizygotic twin pair, had the same enzyme deficiency. De Jong et al. (1994) concluded that these were mild cases of alpha-NAGA deficiency. In a follow-up of the girl reported by de Jong et al. (1994), Keulemans et al. (1996) noted that she had psychomotor retardation since about 1 year of age. The brother remained healthy at age 3 years. Bakker et al. (2001) reported that the brother of the affected girl reported by de Jong et al. (1994) remained without clinical signs and symptoms at age 8 years. Molecular Genetics In the 2 German boys with alpha-N-acetylgalactosaminidase deficiency reported by van Diggelen et al. (1987, 1988), Wang et al. (1990) identified a homozygous glu325-to-lys (E325K) mutation in the NAGA gene (104170.0001). Keulemans et al. (1996) identified a distant affected relative of the 2 boys who had the same homozygous mutation. In the Dutch girl with type III NAGA deficiency reported by de Jong et al. (1994), Keulemans et al. (1996) identified compound heterozygosity for 2 mutations in the NAGA gene (104170.0001 and 104170.0004). The same genotype was found in the clinically unaffected 3-year-old brother of the proband, and the authors suggested that the brother might be a preclinical case of NAGA deficiency; the brother's twin sister did not have the genotype. Bakker et al. (2001) identified the homozygous E325K mutation in a 3-year-old Moroccan boy with NAGA deficiency. The same genotype was found in his clinically unaffected 7-year-old brother. A third unaffected sib and both parents were heterozygous for the mutation. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms of the disorder. Genotype/Phenotype Correlations Keulemans et al. (1996) found that the 3 related German boys with type I NAGA deficiency retained residual NAGA activity in fibroblasts that was higher than NAGA activity in 2 patients with the less severe adult-onset Kanzaki disease. They also noted the absence of visceral lysosomal storage findings in the infantile cases compared to the presence of vacuolization in the milder adult patients. Keulemans et al. (1996) postulated that additional factors or genes must contribute to the phenotype, and even suggested that severe infantile patients may have 2 distinct disorders of NAGA deficiency and neuroaxonal dystrophy. Bakker et al. (2001) reviewed the 11 known patients with alpha-NAGA deficiency. The patients, who were from 7 families of German, Japanese, Dutch, Spanish, French/Italian/Albanian, and Moroccan descent, showed extreme clinical heterogeneity from no clinical symptoms to infantile neuroaxonal dystrophy. They reiterated the suggestion of Keulemans et al. (1996) that alpha-NAGA deficiency is not a single disease entity but that factors other than alpha-NAGA contribute to the phenotype variation. They further speculated that severe infantile patients have a double disease: neuroaxonal dystrophy in addition to alpha-NAGA deficiency, without causal relationship. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Cortical blindness \- Optic atrophy \- Nystagmus \- Strabismus SKELETAL \- Limb contractures by age 4-5 years \- Osteopenia MUSCLE, SOFT TISSUES \- Muscular atrophy, generalized NEUROLOGIC Central Nervous System \- Normal early development, up to 8 to 15 months of age \- Delayed development, after 8-15 months \- Loss of developmental milestones \- Rapid regression \- Myoclonus \- Seizures \- Mental retardation, severe \- Hypotonia \- Spasticity \- Hyperreflexia \- Decorticate posturing \- Unresponsive to stimuli \- No voluntary movement \- Atrophy of cerebellum, brainstem, cervical spinal cord \- Neuroaxonal dystrophy \- 'Spheroid' inclusions in axons LABORATORY ABNORMALITIES \- Lack of lysosomal inclusions in visceral organs \- Decreased alpha-N-acetylgalactosaminidase protein \- Decreased alpha-N-acetylgalactosaminidase activity (less than 2% of control) \- Increased urinary oligosaccharides \- Increased urinary O-linked sialopeptides MISCELLANEOUS \- Three main phenotypes \- Type I is infantile-onset, severe \- Type II is adult-onset (Kanzaki disease, 609242 ) \- Type III is intermediate form \- Type I onset at 8 to 15 months of age after normal development \- Type I has most severe manifestations by age 4-5 years MOLECULAR BASIS \- Caused by mutation in the alpha-N-acetylgalactosaminidase gene (NAGA, 104170.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	SCHINDLER DISEASE, TYPE I	c1836544	5,487	omim	https://www.omim.org/entry/609241	2019-09-22T16:06:31	{"mesh": ["C536631"], "omim": ["609241"], "orphanet": ["3137", "79279", "79281"], "synonyms": ["Alternative titles", "NEUROAXONAL DYSTROPHY, SCHINDLER TYPE", "ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, TYPE I", "NAGA DEFICIENCY, TYPE I"]}
## Description Aspirin (acetylsalicylic acid) is a classic nonsteroidal antiinflammatory agent that irreversibly inhibits type I cyclooxygenase (PTGS1, or COX1; 176805) in platelets, resulting in decreased production of thromboxane A2 (TXA2) and inhibition of platelet aggregation. Because of this feature, it is used therapeutically to prevent cardiothrombotic events. Individuals show a variable response to the drug, referred to as aspirin ineffectiveness or resistance, in which not all individuals or populations appear to receive the full prophylactic or therapeutic benefits (summary by Zhou et al., 2011). Halushka and Halushka (2002) discussed a possible basis for resistance to the cardioprotective effect of aspirin. Clinical Features Metaanalyses by the Antiplatelet Trialists' Collaboration (1994, 1994, 1994) documented the effects of aspirin on more than 100,000 aspirin-treated patients and controls, highlighting a 25% reduction of death, myocardial infarction, and stroke in high-risk vascular patients, a 48% reduction in vascular graft and arterial occlusion, a 67% reduction of pulmonary embolism, and a 23% reduction of deep venous thrombosis. However, aspirin's antiplatelet effects are not uniform in all patients. Clinical aspirin resistance includes patients who, despite being on therapeutic doses of aspirin, experience thrombotic or embolic vascular events (Helgason et al., 1994). Gum et al. (2001) stated that estimates of the frequency of aspirin resistance range from 8 to 45%. Gum et al. (2001) determined the prevalence and clinical predictors of aspirin resistance by prospectively studying 325 patients with stable cardiovascular disease who were receiving aspirin but no other antiplatelet agents. They compared the detection of aspirin resistance with optical platelet aggregation, a widely accepted method, with a more rapid method, the platelet function analyzer (PFA)-100, a whole blood test that measures platelet adhesion and aggregation ex vivo. By optical aggregation, 5.5% of the patients were aspirin resistant and 23.8% were aspirin semiresponders. By PFA-100, 9.5% of patients were aspirin resistant. Of the 18 patients who were aspirin resistant by aggregation, 4 were also aspirin resistant by PFA-100. Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women and less likely to be smokers compared with aspirin-sensitive patients. Gum et al. (2001) found no difference in aspirin sensitivity by race, diabetes, platelet count, renal disease, or liver disease. Eikelboom et al. (2002) studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population. They found that, in aspirin-treated patients, urinary concentrations of 11-dehydro-thromboxane B2 predicted the future risk of myocardial infarction or cardiovascular death. These findings raised the possibility that elevated urinary 11-dehydro-thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity. Halushka and Halushka (2002) discussed a possible basis for resistance to the cardioprotective effect of aspirin. Biochemical Features Vane (1971) and Smith and Willis (1971) elucidated the mechanism of aspirin's effect, the irreversible acetylation of platelet cyclooxygenase (PTGS1, or COX1; 176805). The predominant product of COX1 in platelets is thromboxane A2 (see 188070). Funk et al. (1991) showed that aspirin irreversibly acetylates ser529 of COX1. In the case of the anucleate platelet, the enzyme is rendered inactive for its lifetime. Zhou et al. (2011) determined that aspirin is hydrolyzed and rendered biologically inactive by type I platelet-activating factor (PAF), and that the reaction occurs intracellularly within erythrocytes. Hydrolase activity can be mediated by either of the 2 catalytic subunits, PAFAH1B2 (602508) or PAFAH1B3 (603074), but not by plasma PAF (PLA2G7; 601690). In vitro studies showed that exposing platelets to aspirin and erythrocytes decreased the ability of aspirin to inhibit thromboxane A2 synthesis and platelet aggregation, and aspirin preincubated with erythrocytes was almost completely ineffective as a platelet inhibitor. Analysis of 10 different healthy blood donors revealed that aspirin hydrolysis varied more than 2-fold, and this variation corresponded to the erythrocyte protein content of PAFAH1B2, as determined by immunoblot, but did not correspond to levels of PAFAH1B3. Zhou et al. (2011) concluded that intracellular type I PAF acetylhydrolase is the major aspirin hydrolase in human blood (erythrocytes), and that variation in this hydrolase activity may underlie the variation in therapeutic response among humans. History Acetylsalicylic acid was first developed commercially in 1897 by Felix Hoffman and was registered under the name aspirin (Jack, 1997). The first report of a possible antithrombotic effect of aspirin appeared in 1953 (Craven, 1953). Craven (1953) noticed that patients who chewed Aspergum tended to bleed more easily. He concluded that aspirin must thin the blood and, because thrombosis of the coronary arteries leads to myocardial infarction, patients who take aspirin might be less prone to coronary attacks. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ASPIRIN RESISTANCE	c1842372	5,488	omim	https://www.omim.org/entry/608223	2019-09-22T16:08:09	{"omim": ["608223"], "synonyms": ["Alternative titles", "ASPIRIN, RESISTANCE TO ANTITHROMBOTIC EFFECT OF", "ASPIRIN, RESISTANCE TO CARDIOPROTECTIVE EFFECT OF"]}
Cerebellar degeneration refers to the deterioration of neurons (nerve cells) in the cerebellum (the area of the brain that controls muscle coordination and balance). Conditions that cause cerebellar degeneration may also affect other areas of the central nervous system, such as the spinal cord, the cerebral cortex (the thin layer of cells covering the brain), and the brain stem. Signs and symptoms of cerebellar degeneration may include a wide-based, uncoordinated walk; a back and forth tremor in the trunk of the body; uncoordinated movements of the arms and legs; slow and slurred speech; and nystagmus. Cerebellar degeneration can be caused by a variety of factors including inherited gene changes (mutations), chronic alcohol abuse, and paraneoplastic disorders. Treatment for cerebellar degeneration varies depending on the underlying cause. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Cerebellar degeneration	c0262404	5,489	gard	https://rarediseases.info.nih.gov/diseases/6019/cerebellar-degeneration	2021-01-18T18:01:34	{"umls": ["C0262404"], "synonyms": []}
A number sign (#) is used with this entry because primary microcephaly-2 (MCPH2) with or without cortical malformations is caused by homozygous or compound heterozygous mutation in the WDR62 gene (613583) on chromosome 19q13. Description Microcephaly-2 with or without cortical malformations is an autosomal recessive neurodevelopmental disorder showing phenotypic variability. Classically, primary microcephaly is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations (SD) below the age- and sex-matched population mean, and mental retardation with no other associated malformations and with no apparent etiology (Hofman, 1984). Patients with WDR62 mutations have head circumferences ranging from low-normal to severe (-9.8 SD), and most patients with brain scans have shown various types of cortical malformations. All have delayed psychomotor development; seizures are variable (summary by Yu et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200). Clinical Features Roberts et al. (1999) reported 2 unrelated consanguineous Pakistani families with primary microcephaly (SD, -4 to -7 below normal) noted at birth, mild to moderate mental retardation, normal motor development, and no significant dysmorphic features. All parents were unaffected. Detailed neuroimaging was not performed. Darvish et al. (2010) reported a consanguineous Iranian family with primary microcephaly who showed linkage to the MPCH2 locus. The 3 affected individuals also showed intrauterine growth retardation and facial dysmorphism, including broad nasal bridge, long philtrum, micrognathia, and thick lower lip. Nicholas et al. (2010) reported 7 consanguineous families, 5 of Pakistani origin, with primary microcephaly, including the 2 families previously reported by Roberts et al. (1999). Affected children from 6 of the families had microcephaly apparent at birth or in the first months of life. Head circumferences ranged from -4 to -7 SD below normal. None had malformations or congenital anomalies, and none were dysmorphic, except for sloping forehead and disproportionate face and ears compared to the skull. None had seizures. All had mild to moderate nonprogressive mental retardation and delayed speech acquisition. All parents were unaffected. Brain imaging available from 1 affected child showed a simplified gyral pattern. The seventh child, a girl, had a more severe phenotype with severe mental retardation, head circumference of -5 SD, and simplified gyral pattern and thickened cortex on brain MRI. At age 10 years, she used gestures and pictures to communicate simple needs, and was incontinent and socially withdrawn. She had no other neurologic or dysmorphic features and no seizures. Bilguvar et al. (2010) described 10 patients, the product of consanguineous Turkish unions, manifesting with microcephaly, moderate to severe mental retardation, and cortical malformations including pachygyria with cortical thickening, microgyria, lissencephaly, hypoplasia of the corpus callosum, schizencephaly, and, in 1 instance, cerebellar hypoplasia. Some patients had seizures. Yu et al. (2010) reported 6 consanguineous families in which affected offspring had microcephaly, severe developmental delay, and variable seizures. Most had lack of speech development, and some had lack of motor development. Some had spastic quadriparesis. Brain MRI showed small brains, markedly simplified gyral patterns, and corpus callosal abnormalities, as well as a diversity of additional cortical malformations including polymicrogyria, schizencephaly, and subcortical heterotopia, sometimes with asymmetry in the same brain. The cerebellum and brainstem were relatively spared in all patients. Postmortem examination of an affected 27-week-old fetus showed a profoundly small brain and smooth hemispheric surface with poorly defined Sylvian fissures and few sulci. The cerebral cortex was severely abnormal with thin layers and heterotopia. The findings indicated impaired neurogenesis with defects in proliferation and neuronal migration. Bhat et al. (2011) reported 2 unrelated consanguineous Indian families with MCPH2 with cortical malformations. The patients ranged in age from 5 to 11 years, and head circumferences were between -4 and -9 SD. All had developmental delay with variable degrees of mental retardation. Brain MRI showed variable changes, including pachygyria, dysplastic cortex, widened sulci, polymicrogyria, microlissencephaly, and band heterotopia. Murdock et al. (2011) reported 2 brothers, born of unrelated parents of northern European descent, with variable severity of MCHP2 with polymicrogyria. The first sib, whose pregnancy was complicated by gestational diabetes, had a more severe phenotype, with extensive bilateral polymicrogyria, abnormal corpus callosum, global developmental delay, intractable seizures, and spastic quadriparesis. The second sib, with extensive polymicrogyria and gray matter heterotopia but no seizures, had age-appropriate cognition at age 7 years and only mild unilateral hemiparesis. Both patients had head circumferences less than the fifth percentile. Mapping Roberts et al. (1999) demonstrated genetic heterogeneity in primary microcephaly by identifying a second locus on chromosome 19q13.1-q13.2 in 2 multiaffected consanguineous families. The minimum critical region containing the MCPH2 locus was defined by the polymorphic markers D19S416 and D19S420, spanning a region of approximately 7.6 cM. By homozygosity mapping of 112 consanguineous Iranian families with primary microcephaly, Darvish et al. (2010) identified 3 families with primary microcephaly that showed linkage to the MPCH2 locus. Molecular Genetics In affected members of 2 consanguineous Pakistani families with primary microcephaly, previously reported by Roberts et al. (1999), Nicholas et al. (2010) identified 2 different homozygous mutations in the WDR62 gene (R438H; 613583.0006 and 4241dupT; 613583.0007, respectively). In 5 additional consanguineous families of Pakistani, Arab, and Caucasian ancestry with primary microcephaly, they identified 4 different homozygous WDR62 mutations (see, e.g., 613583.0008-613583.0009, 613583.0011). Bilguvar et al. (2010) reported 2 missense, 2 nonsense, and 2 frameshift mutations in the WDR62 gene (see, e.g., 613583.0001-613583.0005) in 10 patients with microcephaly, cortical malformations, and mental retardation. Yu et al. (2010) identified 6 different homozygous mutations in the WDR62 gene (see, e.g., 613583.0009-613583.0011) in affected members of 6 consanguineous families with microcephaly-2 with cortical malformations, including polymicrogyria, schizencephaly, and subcortical heterotopia. Bhat et al. (2011) identified 2 different homozygous truncating WDR62 mutations in 2 unrelated consanguineous Indian families with MCPH2 with cortical malformations, bringing the total number of pathogenic mutations in the gene to 17. Six of the 17 mutations are missense, and mutations occurred throughout the gene sequence. Bhat et al. (2011) emphasized the wide phenotypic spectrum of cortical malformations in mutation carriers. Murdock et al. (2011) reported 2 brothers, born of unrelated parents of northern European descent, with variable severity of MCHP2 with polymicrogyria. Exome sequencing identified compound heterozygosity for 2 truncating mutations in the WDR62 gene (613583.0012 and 613583.0013). Sajid Hussain et al. (2013) found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. ASPM (605481) was the most commonly mutated gene, consistent with MCPH5 (608716), followed by WDR62. Linkage to the WDR62 gene was found in 7 families, but WDR62 mutations were only found in 5 families. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (-4 to -7 SD) Face \- Low forehead \- Sloping forehead NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Poor speech development \- Poor motor development \- Seizures (variable) \- Hypertonia \- Hyperreflexia \- Spastic quadriparesis \- Hemiparesis \- Small brain \- Polymicrogyria \- Pachygyria \- Abnormal gyral pattern \- Simplified gyral pattern \- Lissencephaly \- Schizencephaly \- Thin corpus callosum \- Abnormal corpus callosum \- Heterotopia \- Abnormal neuronal migration \- Relative preservation of the cerebellum Behavioral Psychiatric Manifestations \- Impulsivity \- Aggression \- Hyperactivity \- Head banging PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements MISCELLANEOUS \- Variable phenotype, particularly with regard to cortical malformations \- Onset in utero MOLECULAR BASIS \- Caused by mutation in the WD repeat-containing protein 62 (WDR62, 613583.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MICROCEPHALY 2, PRIMARY, AUTOSOMAL RECESSIVE, WITH OR WITHOUT CORTICAL MALFORMATIONS	c3711387	5,490	omim	https://www.omim.org/entry/604317	2019-09-22T16:12:12	{"doid": ["0070293"], "mesh": ["C579935"], "omim": ["604317"], "orphanet": ["2512"]}
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, presenting with a more prominent muscle weakness in lower than upper limbs and frequent postural tremor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Autosomal dominant Charcot-Marie-Tooth disease type 2A1	c1861678	5,491	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99946	2021-01-23T17:30:24	{"mesh": ["C566138"], "omim": ["118210"], "umls": ["C1861678"], "icd-10": ["G60.0"], "synonyms": ["CMT2A1"]}
Kuskokwim syndrome is characterized by joint deformities called contractures that restrict the movement of affected joints. This condition has been found only in a population of Alaska Natives known as Yup'ik Eskimos, who live in and around a region of southwest Alaska known as the Kuskokwim River Delta. In Kuskokwim syndrome, contractures most commonly affect the knees, ankles, and elbows, although other joints, particularly of the lower body, can be affected. The contractures are usually present at birth and worsen during childhood. They tend to stabilize after childhood, and they remain throughout life. Some individuals with this condition have other bone abnormalities, most commonly affecting the spine, pelvis, and feet. Affected individuals can develop an inward curve of the lower back (lordosis), a spine that curves to the side (scoliosis), wedge-shaped spinal bones, or an abnormality of the collarbones (clavicles) described as clubbing. Affected individuals are typically shorter than their peers and they may have an abnormally large head (macrocephaly). ## Frequency Kuskokwim syndrome is extremely rare. It affects a small number of people from the Yup'ik Eskimo population in southwest Alaska. ## Causes Kuskokwim syndrome is caused by mutations in the FKBP10 gene, which provides instructions for making the FKBP10 protein (formerly known as FKBP65). This protein is important for the correct processing of complex molecules called collagens, which provide structure and strength to connective tissues that support the body's bones, joints, and organs. Collagen molecules are cross-linked to one another to form long, thin fibrils, which are found in the spaces around cells (the extracellular matrix). The formation of cross-links results in very strong collagen fibrils. The FKBP10 protein attaches to collagens and plays a role in their cross-linking. A mutation in the FKBP10 gene alters the FKBP10 protein, making it unstable and easily broken down. As a result, people with Kuskokwim syndrome have only about 5 percent of the normal amount of FKBP10 protein. This reduction in protein levels impairs collagen cross-linking and leads to a disorganized network of collagen molecules. It is unclear how these changes in the collagen matrix are involved in the development of joint contractures and other abnormalities in people with Kuskokwim syndrome. ### Learn more about the gene associated with Kuskokwim syndrome * FKBP10 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Kuskokwim syndrome	c1850168	5,492	medlineplus	https://medlineplus.gov/genetics/condition/kuskokwim-syndrome/	2021-01-27T08:25:06	{"gard": ["3150"], "mesh": ["C537406"], "omim": ["259450"], "synonyms": []}
Carnitine palmitoyltransferase II (CPT II) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). There are three main types of CPT II deficiency: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a myopathic form. The lethal neonatal form of CPT II deficiency becomes apparent soon after birth. Infants with this form of the disorder develop respiratory failure, seizures, liver failure, a weakened heart muscle (cardiomyopathy), and an irregular heart beat (arrhythmia). Affected individuals also have low blood sugar (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. In many cases, the brain and kidneys are also structurally abnormal. Infants with the lethal neonatal form of CPT II deficiency usually live for a few days to a few months. The severe infantile hepatocardiomuscular form of CPT II deficiency affects the liver, heart, and muscles. Signs and symptoms usually appear within the first year of life. This form involves recurring episodes of hypoketotic hypoglycemia, seizures, an enlarged liver (hepatomegaly), cardiomyopathy, and arrhythmia. Problems related to this form of CPT II deficiency can be triggered by periods of fasting or by illnesses such as viral infections. Individuals with the severe infantile hepatocardiomuscular form of CPT II deficiency are at risk for liver failure, nervous system damage, coma, and sudden death. The myopathic form is the least severe type of CPT II deficiency. This form is characterized by recurrent episodes of muscle pain (myalgia) and weakness and is associated with the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown. This protein can also damage the kidneys, in some cases leading to life-threatening kidney failure. Episodes of myalgia and rhabdomyolysis may be triggered by exercise, stress, exposure to extreme temperatures, infections, or fasting. The first episode usually occurs during childhood or adolescence. Most people with the myopathic form of CPT II deficiency have no signs or symptoms of the disorder between episodes. ## Frequency CPT II deficiency is a rare disorder. The lethal neonatal form has been described in at least 18 families, while the severe infantile hepatocardiomuscular form has been identified in approximately 30 families. The myopathic form occurs most frequently, with more than 300 reported cases. ## Causes Mutations in the CPT2 gene cause CPT II deficiency. This gene provides instructions for making an enzyme called carnitine palmitoyltransferase 2. This enzyme is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them into energy. Fatty acid oxidation takes place within mitochondria, which are the energy-producing centers in cells. A group of fats called long-chain fatty acids must be attached to a substance known as carnitine to enter mitochondria. Once these fatty acids are inside mitochondria, carnitine palmitoyltransferase 2 removes the carnitine and prepares them for fatty acid oxidation. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues. Mutations in the CPT2 gene reduce the activity of carnitine palmitoyltransferase 2. Without enough of this enzyme, carnitine is not removed from long-chain fatty acids. As a result, these fatty acids cannot be metabolized to produce energy. Reduced energy production can lead to some of the features of CPT II deficiency, such as hypoketotic hypoglycemia, myalgia, and weakness. Fatty acids and long-chain acylcarnitines (fatty acids still attached to carnitine) may also build up in cells and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of the disorder. ### Learn more about the gene associated with Carnitine palmitoyltransferase II deficiency * CPT2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Carnitine palmitoyltransferase II deficiency	c1833511	5,493	medlineplus	https://medlineplus.gov/genetics/condition/carnitine-palmitoyltransferase-ii-deficiency/	2021-01-27T08:25:10	{"gard": ["1121"], "mesh": ["C563462"], "omim": ["600649", "608836", "255110"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs (FDLAB) is caused by homozygous mutation in the ASPH gene (600582) on chromosome 8q12. Description Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (Patel et al., 2014). Clinical Features Shawaf et al. (1995) noted an association of craniofacial dysmorphism (downward slanting palpebral fissures, large beaked nose, triangular retracted chin, dental malocclusion), ectopia lentis, variable degree of angle closure secondary to iridocorneal adhesions, patchy areas of atrophy in both irides, and avascular elevations of the bulbar conjunctiva in 6 members of a consanguineous Lebanese family, including a man, his 2 daughters, 2 of his sibs, and his maternal aunt. All affected persons were of average height and had normal body proportions and normal joint mobility. Shawaf et al. (1995) proposed that this is a new syndrome. Haddad et al. (2001) reported the same constellation of features in 4 sisters of a presumably unrelated Lebanese-Druze family. That this syndrome is distinct was apparently corroborated by the identification of a third presumably unrelated family. Among 8 Druze-Lebanese sibs of consanguineous parents, 2 sisters were affected (Traboulsi, 2002). Mansour et al. (2013) reported a 16-year-old Lebanese female orphan who presented with loss of vision to 20/200 bilaterally. She had an elongated face with a prominent, broad, and beaked nose. Ocular examination revealed central superficial corneal opacification as well as central retrocorneal nodular thickening bilaterally. There was iridocorneal touch on slit-lamp view, with a diffusely flat anterior chamber. The pupil failed to dilate due to diffuse posterior synechiae. Conjunctival blebs were present superiorly and nasally in both eyes with a low intraocular pressure of 8 mm Hg. The patient had decreased axial lengths, measuring 19.41 and 20.12 mm on the right and left, respectively, by ultrasonography. Optical coherence tomography (OCT) demonstrated central retrocorneal fibrosis and near-apposition of the cornea to the iris, with angle closure. Patel et al. (2014) described a 19-year-old Saudi woman, born of consanguineous parents, who first noticed visual difficulties at 10 years of age. Her facial features were consistent with FDLAB and included a beaked nose, flat cheeks, and retrognathia. At 18 years of age, she underwent implantation of scleral-fixated intraocular lenses bilaterally due to anterior dislocation of the right lens and spherophakia on the left. Best-corrected visual acuity was 20/25 in both eyes. Slit-lamp examination showed stable intraocular implants, with filtering blebs and patchy iris atrophy bilaterally. She had no other health issues, and her 3 sibs were unaffected. Abarca Barriga et al. (2018) reported a boy, born to consanguineous Peruvian parents, with bilateral lens dislocation, developmental delay, and inguinal hernias. His height was within normal limits, but his weight at age 11 years was -2.71 SD and his body mass index was 12.7 (-3.74 SD). He had a long and slender body build, dolichocephaly, long and somewhat asymmetric face, mild strabismus, downslanting palpebral fissures, malar hypoplasia, high nasal ridge, high-arched palate, bifid uvula, irregularly placed teeth, and small chin. He also had pectus excavatum, cubiti valgi, long and thin fingers, and joint hypermobility. Echocardiogram was normal. Abarca Barriga et al. (2018) compared the findings in their patient with the 12 previously reported patients, and noted that multiple ocular abnormalities were seen, with ectopia lentis being seen in all 13 and conjunctival blebs in 7. Typical facial appearance included a long face, downslanting palpebral fissures, a convex nasal ridge, malar hypoplasia, crowded teeth/malocclusion, and retrognathia. Novel findings in their patient included bifid uvula, pectus excavatum, cubitus valgus, flat feet, and lax joints. Inheritance Shawaf et al. (1995) suggested that the syndrome they reported in a Lebanese family was most compatible with autosomal recessive inheritance with pseudodominance. Haddad et al. (2001) also suggested autosomal recessive inheritance of the disorder. Molecular Genetics In a Saudi woman with facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs, Patel et al. (2014) performed autozygosity mapping followed by whole-exome sequencing and identified homozygosity for a 5-bp deletion/3-bp insertion mutation in the ASPH gene (600582.0001). The mutation, which segregated with disease in the family, was not found in 425 in-house Saudi exomes, 100 Saudi controls by Sanger sequencing, or any publicly available variant databases. Sequencing of ASPH in 2 Lebanese patients, including the 16-year-old girl reported by Mansour et al. (2013) and 1 of the 4 affected Lebanese Druze sisters reported by Haddad et al. (2001), revealed that they were both homozygous for the same missense mutation (R735W; 600582.0002), which was not found in 208 Lebanese Druze control chromosomes. In a boy with FDLAB, who was born to consanguineous Peruvian parents, Abarca Barriga et al. (2018) identified homozygosity for a nonsense mutation in the ASPH gene (W57X; 600582.0003). The mutation was identified by whole-exome sequencing. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes Project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Craniofacial dysmorphism \- Retrognathia \- Triangular chin \- Elongated face \- Flat cheeks Eyes \- Ectopia lentis \- Spherophakia (in some patients) \- Avascular conjunctival cystic elevations (filtering blebs) \- Iridocorneal adhesions \- Flat anterior chamber \- Variable degree of angle closure \- Posterior synechiae, diffuse \- Patchy iris atrophy \- Microphthalmia, mild (in some patients) \- Low intraocular pressure (in some patients) \- Central retrocorneal fibrosis (in some patients) \- Downslanting palpebral fissures Nose \- Prominent nose \- Beaked nose \- Broad nose Teeth \- Malocclusion (in some patients) MISCELLANEOUS \- Variable dysmorphic features may be present MOLECULAR BASIS \- Caused by mutation in the aspartate beta-hydroxylase gene (ASPH, 600582.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS	c1832167	5,494	omim	https://www.omim.org/entry/601552	2019-09-22T16:14:34	{"mesh": ["C563293"], "omim": ["601552"], "orphanet": ["412022"], "synonyms": ["Alternative titles", "TRABOULSI SYNDROME", "SHAWAF-TRABOULSI SYNDROME", "ECTOPIA LENTIS, SPONTANEOUS FILTERING BLEBS, AND CRANIOFACIAL DYSMORPHISM"]}
Paroxysmal extreme pain disorder is a form of peripheral neuropathy characterized by skin redness and warmth (flushing) and attacks of severe pain in various parts of the body. Early in life, the pain is often concentrated in the lower part of the body and may be triggered by a bowel movement. As a person ages, the location of the pain may change, with attacks affecting the head and face. Triggers of these pain attacks include changes in temperature, emotional distress or eating spicy foods and drinking cold beverages. Paroxysmal extreme pain disorder is caused by mutations in the SCN9A gene. This condition is inherited in an autosomal dominant pattern. Treatment may include medications used to manage chronic neuropathic pain (anticonvulsants) such as the sodium channel blocker carbamazepine. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Paroxysmal extreme pain disorder	c1833661	5,495	gard	https://rarediseases.info.nih.gov/diseases/12854/paroxysmal-extreme-pain-disorder	2021-01-18T17:58:26	{"mesh": ["C563475"], "omim": ["167400"], "orphanet": ["46348"], "synonyms": ["Familial rectal syndrome", "PEPD", "PEXPD", "Submandibular, ocular, and rectal pain with flushing", "Familial rectal pain"]}
This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (December 2016) Béguez-Chédiak–Higashi syndrome Béguez-Chédiak–Higashi syndrome is inherited in an autosomal recessive manner SpecialtyEndocrinology Béguez-Chédiak–Higashi syndrome[1] (CHS) is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein,[2] which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, albinism, and peripheral neuropathy. In Béguez–Higashi syndrome, the lysosomal trafficking regulator (LYST) gene is mutated, leading to disruption of protein synthesis as well as the storage and secretory function of lysosomal granules in white blood cells.[3] This results in defective white blood cell function with enlarged vesicles. This syndrome also leads to neutropenia and phagocyte bactericidal dysfunction due to impaired chemotaxis.[4] Deficiency in serotonin and adenosine-phosphate-containing granules in platelets causes impaired platelet aggregation, leading to prolonged bleeding time. Thus, patients are susceptible to infections and often present with oculo-cutaneous albinism and coagulation defects.[3] Patients often present with early-onset aggressive periodontitis associated with advanced alveolar bone loss and tooth mobility due to neutropenia and defective neutrophil function. Recurrent oral ulcerations are also one of the common oral manifestations in patients with this disease.[5] Dental practitioners who notice child patients who present with recurrent unexplained gingivitis and periodontitis along with hypopigmentation of hair, skin and eyes should consider making a referral to medical practitioners to investigate for the possible diagnosis of Chédiak-Higashi syndrome.[5] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Clinical findings * 5 Treatment * 6 Eponym * 7 Other species * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] People with CHS have light skin and silvery hair (albinism) and frequently complain of solar sensitivity and photophobia. Other signs and symptoms vary considerably, but frequent infections and neuropathy are common. The infections involve mucous membranes, skin, and the respiratory tract. Affected children are susceptible to infection by Gram-positive and gram-negative bacteria and fungi, with Staphylococcus aureus being the most common infectious cause. Infections in CHS patients tend to be very serious and even life-threatening. Neuropathy often begins in the teenage years and becomes the most prominent problem. Few patients with this condition live to adulthood.[citation needed] Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the "accelerated phase", or the "lymphoma-like syndrome", in which defective white blood cells divide uncontrollably and invade many of the body's organs. The accelerated phase is associated with fever, episodes of abnormal bleeding, overwhelming infections, and organ failure. These medical problems are usually life-threatening in childhood.[citation needed] ## Causes[edit] Mutations in the CHS1 gene (also called LYST) located on the chromosome 1q42-q43 have been found to be connected with Chédiak–Higashi syndrome. This gene provides instructions for making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role in the transport (trafficking) of materials into lysosomes. Lysosomes act as recycling centers within cells. They use digestive enzymes to break down toxic substances, digest bacteria that invade the cell and recycle worn-out cell components. Although the lysosomal trafficking regulator protein is involved in the normal function of lysosomes, its exact role is unknown.[6] In melanocytic cells, LYST gene expression may be regulated by MITF.[7] Mutations in MITF are known to cause Waardenburg syndrome type 2 and Tietz syndrome, which result in depigmentation and deafness.[citation needed] ## Pathophysiology[edit] CHS is a disease causing impaired bacteriolysis due to failure of phagolysosome formation.[8] As a result of disordered intracellular trafficking there is impaired lysosome degranulation with phagosomes, so phagocytosed bacteria are not destroyed by the lysosome's enzymes.[citation needed] In addition, secretion of lytic secretory granules by cytotoxic T cells is affected.[citation needed] The disease is characterised by large lysosome vesicles in phagocytes (neutrophils), which thus have poor bactericidal function, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes, anemia, and hepatomegaly. Döhle bodies (remnants of endoplasmic reticulum) in the neutrophil are also seen.[citation needed] ## Diagnosis[edit] The diagnosis is confirmed by bone marrow smears that show "giant inclusion bodies" in the cells that develop into white blood cells (leukocyte precursor cells). CHS can be diagnosed prenatally by examining a sample of hair from a fetal scalp biopsy or testing leukocytes from a fetal blood sample.[9] Under light microscopy the hairs present evenly distributed, regular melanin granules, larger than those found in normal hairs. Under polarized light microscopy these hairs exhibit a bright and polychromatic refringence pattern.[10] ### Clinical findings[edit] There are several manifestations of Chédiak–Higashi syndrome as mentioned above; however, neutropenia seems to be the most common. The syndrome is associated with oculocutaneous albinism. Patients are prone to infections, especially with Staphylococcus aureus, as well as Streptococci.[citation needed] It is associated with periodontal disease of the deciduous dentition. Associated features include abnormalities in melanocytes (albinism), nerve defects, and bleeding disorders.[citation needed] ## Treatment[edit] There is no specific treatment for Chédiak–Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate. Antiviral drugs such as acyclovir have been tried during the terminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.[11] ## Eponym[edit] It is named for the Cuban physician and serologist of Lebanese descent Moisés Chédiak Ahuayda[12] (1903–1993) and the Japanese pediatrician Otokata Higashi (1883–1981).[13] It is often spelled without the accent as Chediak–Higashi syndrome. ## Other species[edit] It occurs in humans, cattle, blue Persian cats, Australian blue rats,[14] mice,[15] mink,[15] foxes,[15] and the only known captive white orca.[16] ## See also[edit] * Griscelli syndrome (also known as "Chédiak–Higashi like syndrome") ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Kaplan J, De Domenico I, Ward DM (January 2008). "Béguez-Chediak-Higashi syndrome". Current Opinion in Hematology. 15 (1): 22–9. doi:10.1097/MOH.0b013e3282f2bcce. PMID 18043242. S2CID 43243529. 3. ^ a b Ajitkumar, Anitha; Ramphul, Kamleshun (2020), "Chediak Higashi Syndrome", StatPearls, StatPearls Publishing, PMID 29939658, retrieved 2020-02-26 4. ^ Delcourt-Debruyne, E. M.; Boutigny, H. R.; Hildebrand, H. F. (May 2000). "Features of severe periodontal disease in a teenager with Chédiak-Higashi syndrome". Journal of Periodontology. 71 (5): 816–824. doi:10.1902/jop.2000.71.5.816. ISSN 0022-3492. PMID 10872965. 5. ^ a b Karabel, Müsemma; Kelekçi, Selvi; Şen, Velat; Karabel, Duran; Aliosmanoğlu, Çiğdem; Söker, Murat (September 2014). "A Rare Cause of Recurrent Oral Lesions: Chediak-Higashi Syndrome". Turkish Journal of Hematology. 31 (3): 313–314. doi:10.4274/tjh.2013.0282. ISSN 1300-7777. PMC 4287037. PMID 25330529. 6. ^ "Chediak–Higashi syndrome". Retrieved 2008-11-06. 7. ^ Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 8. ^ "Chédiak–Higashi syndrome". Merck Manuals. Retrieved 2008-03-01. 9. ^ "Chediak Higashi syndrome". Retrieved 2008-11-06. 10. ^ Falus A, Fenyo M, Eder K, Madarasi A (September 2011). "[Polarized light as an epigenetic factor in inhibition of inflammation; a genome-wide expression analysis in recurrent respiratory diseases of children]". Orv Hetil (in Hungarian). 152 (37): 1492–9. doi:10.1556/OH.2011.29162. PMID 21893480. 11. ^ Hughes, DA (February 1999). "Effects of dietary antioxidants on the immune function of middle-aged adults". The Proceedings of the Nutrition Society. 58 (1): 79–84. doi:10.1079/pns19990012. PMID 10343344. 12. ^ Serrano-Barrera, Orlando Rafael; Lastre González, Miriam; Pérez Martín, Oliver; Serrano-Barrera, Orlando Rafael; Lastre González, Miriam; Pérez Martín, Oliver (June 2019). "Contributions of Moises and Alejandro Chediak to Immunology, Hematology and Clinical Laboratory in Cuba". Revista Cubana de Hematología, Inmunología y Hemoterapia. 35 (2). ISSN 0864-0289. 13. ^ Saez-De-Ocariz M, Orozco-Covarrubias L, Duràn-McKinster C, Ruiz-Maldonado R (2008). "Silver hair syndromes: Chediak–Higashi syndrome (CHS) and Griscelli syndromes (GS)". In Ruggieri M, Pascual-Castroviejo I, Di Rocco C (eds.). Neurocutaneous Disorders: Phakomatoses and Hamartoneoplastic Syndromes. Springer. pp. 407–26. doi:10.1007/978-3-211-69500-5_19. ISBN 978-3-211-21396-4. 14. ^ Australian blue rats: a hypothesis 15. ^ a b c Australian blue rats: a hypothesis 16. ^ The Orca Ocean ## External links[edit] Classification D * ICD-10: E70.3 (E70.340 ILDS) * ICD-9-CM: 288.2 * OMIM: 214500 * MeSH: D002609 * DiseasesDB: 2351 External resources * MedlinePlus: 001312 * eMedicine: derm/704 * Patient UK: Chédiak–Higashi syndrome * GeneReviews: Chediak-Higashi Syndrome * Orphanet: 167 * v * t * e Diseases of monocytes and granulocytes Monocytes and macrophages ↑ -cytosis: * Monocytosis * Histiocytosis * Chronic granulomatous disease ↓ -penia: * Monocytopenia Granulocytes ↑ -cytosis: * granulocytosis * Neutrophilia * Eosinophilia/Hypereosinophilic syndrome * Basophilia * Bandemia ↓ -penia: * Granulocytopenia/agranulocytosis (Neutropenia/Severe congenital neutropenia/Cyclic neutropenia * Eosinopenia * Basopenia) Disorder of phagocytosis Chemotaxis and degranulation * Leukocyte adhesion deficiency * LAD1 * LAD2 * Chédiak–Higashi syndrome * Neutrophil-specific granule deficiency Respiratory burst * Chronic granulomatous disease * Neutrophil immunodeficiency syndrome * Myeloperoxidase deficiency * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation * v * t * e Inherited disorders of trafficking / vesicular transport proteins Vesicle formation Lysosome/Melanosome: * HPS1–HPS7 * Hermansky–Pudlak syndrome * LYST * Chédiak–Higashi syndrome COPII: * SEC23A * Cranio-lenticulo-sutural dysplasia * COG7 * CDOG IIE APC: * AP1S2 * X-linked intellectual disability * AP3B1 * Hermansky–Pudlak syndrome 2 * AP4M1 * CPSQ3 Rab * ARL6 * BBS3 * RAB27A * Griscelli syndrome 2 * CHM * Choroideremia * MLPH * Griscelli syndrome 3 Cytoskeleton Myosin: * MYO5A * Griscelli syndrome 1 Microtubule: * SPG4 * Hereditary spastic paraplegia 4 Kinesin: * KIF5A * Hereditary spastic paraplegia 10 Spectrin: * SPTBN2 * Spinocerebellar ataxia 5 Vesicle fusion Synaptic vesicle: * SNAP29 * CEDNIK syndrome * STX11 * Hemophagocytic lymphohistiocytosis 4 Caveolae: * CAV1 * Congenital generalized lipodystrophy 3 * CAV3 * Limb-girdle muscular dystrophy 2B, Long QT syndrome 9 Vacuolar protein sorting: * VPS33B * ARC syndrome * VPS13B * Cohen syndrome * DYSF * Distal muscular dystrophy See also vesicular transport proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Chédiak–Higashi syndrome	c0007965	5,496	wikipedia	https://en.wikipedia.org/wiki/Ch%C3%A9diak%E2%80%93Higashi_syndrome	2021-01-18T18:29:12	{"gard": ["6035"], "mesh": ["D002609"], "umls": ["C0007965"], "icd-9": ["288.2"], "orphanet": ["167"], "wikidata": ["Q934034"]}
Embryonal rhabdomyosarcoma SpecialtyOncology Embryonal rhabdomyosarcoma (ERMS) is a rare histological form of cancer of connective tissue wherein the mesenchymally-derived malignant cells resemble the primitive developing skeletal muscle of the embryo. It is the most common soft tissue sarcoma occurring in children.[1] ERMS is also known as Fusion-Negative rhabdomyosarcoma (FN-RMS), as tumors of this subtype are unified by their lack of a PAX3-FOXO1 fusion oncogene (or other PAX fusions seen in alveolar rhabdomyosarcoma).[2] ## Contents * 1 Classification * 2 Prognosis * 3 References * 4 External links ## Classification[edit] ERMS (or FN-RMS) is the more common of two major sub-types of rhabdomyosarcoma, the other being alveolar rhabdomyosarcoma (ARMS) also known as Fusion Positive RMS (FP-RMS). Commonly, FN-RMS is driven by a mutation in the RAS family of proto-oncogenes, creating a powerful signal which is now known to promoter tumor growth by preventing muscle lineage progression by blocking expression of the transcription factor MYOG.[3] Inhibition of this signaling pathway with trametinib has been recently shown to overcome this differentiation block and reduce tumor progression in animal models of FN-RMS.[3] FN-RMS has been informally classified as a "small round blue cell tumor"[1] because of the characteristic microscopic appearance of its cells after histological staining with hematoxylin and eosin. ## Prognosis[edit] The prognosis for rhabdomyosarcoma has improved greatly in recent decades, with over 70% of patients surviving for five years after diagnosis.[4] Nevertheless, some FN-RMS patients with a rare Leu122Arg mutation in MYOD1 gene have very poor outcome.[5] ## References[edit] 1. ^ a b Masola V, Maran C, Tassone E, Zin A, Rosolen A, Onisto M (2009). "Heparanase activity in alveolar and embryonal rhabdomyosarcoma: implications for tumor invasion". BMC Cancer. 9: 304. doi:10.1186/1471-2407-9-304. PMC 2743710. PMID 19715595. 2. ^ Shern, Jack F.; Chen, Li; Chmielecki, Juliann; Wei, Jun S.; Patidar, Rajesh; Rosenberg, Mara; Ambrogio, Lauren; Auclair, Daniel; Wang, Jianjun (Jan 2014). "Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors". Cancer Discovery. 4 (2): 216–231. doi:10.1158/2159-8290.CD-13-0639. ISSN 2159-8290. PMC 4462130. PMID 24436047. 3. ^ a b Yohe, Marielle E.; Gryder, Berkley E.; Shern, Jack F.; Song, Young K.; Chou, Hsien-Chao; Sindiri, Sivasish; Mendoza, Arnulfo; Patidar, Rajesh; Zhang, Xiaohu (2018-07-04). "MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma". Science Translational Medicine. 10 (448): eaan4470. doi:10.1126/scitranslmed.aan4470. ISSN 1946-6234. PMID 29973406. 4. ^ Breitfeld PP, Meyer WH (August 2005). "Rhabdomyosarcoma: new windows of opportunity". Oncologist. 10 (7): 518–27. doi:10.1634/theoncologist.10-7-518. PMID 16079319. 5. ^ Kohsaka, Shinji; Shukla, Neerav; Ameur, Nabahet; Ito, Tatsuo; Ng, Charlotte K Y; Wang, Lu; Lim, Diana; Marchetti, Angela; Viale, Agnes (2014-05-04). "A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations". Nature Genetics. 46 (6): 595–600. doi:10.1038/ng.2969. ISSN 1061-4036. PMC 4231202. PMID 24793135. ## External links[edit] Classification D * OMIM: 268210 180295 * MeSH: D018233 * DiseasesDB: 1557 * SNOMED CT: 404051002 External resources * Orphanet: 99757 * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Embryonal rhabdomyosarcoma	c0206656	5,497	wikipedia	https://en.wikipedia.org/wiki/Embryonal_rhabdomyosarcoma	2021-01-18T18:44:03	{"gard": ["4702"], "mesh": ["D018233"], "umls": ["C0206656"], "orphanet": ["99757"], "wikidata": ["Q5370233"]}
Pallister-Killian syndrome (PKS) is a rare multiple congenital anomaly/intellectual deficit syndrome caused by mosaic tissue-limited tetrasomy for chromosome 12p. ## Epidemiology Incidence is uncertain and is estimated around 1/25,000. ## Clinical description A number of cases are prenatally diagnosed because of abnormal ultrasonic findings, and abnormal presentation at birth is usual. Most common signs include facial dysmorphism, rhizomelic limb shortness, small hands and feet with nail hypoplasia. Craniofacial manifestations include a ``coarse'' face with flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, upslanting palpebral fissures, hypertelorism, flat and broad nasal bridge, short nose with upturned nares, large mouth with downturned corners and prominent upper lip. Macroglossia and pointed chin occur with age. Hypotonia is present at birth with contractures developing with age. A wide range of congenital malformations may be present, the most specific being diaphragmatic and anal defects. Heart defects, mainly ventricular septal defects, are present in 25% of cases. Severe intellectual deficit, pigmentary skin anomalies, deafness and seizures are frequent signs. ## Etiology Patients with PKS have mosaïcism for a supernumerary isochromosome 12p, resulting in four copies of the short arm of chromosome 12 instead of the normal two. The isochromosome is mostly of maternal origin. Selection against i(12p) cells is observed in vitro, and probably also occur in vivo. Karyotype is 47, XX or XY, i(12)(p10)/ 46,XX or XY. ## Diagnostic methods Clinical recognition is very important as the additional chromosome is usually absent from routine blood lymphocytes examination. Cytogenetic diagnosis requires skin biopsy and fibroblast chromosome examination. The isochromosome is usually present in 30-100% of fibroblast metaphases. In situ hybridization with chromosome 12-specific DNA probes can be used to confirm the chromosome identity. Interphase FISH on a buccal smear may allow a fast preliminary diagnosis. ## Differential diagnosis Differential diagnoses include trisomy 12p and Fryns syndrome (see these terms). Antenatal diagnosis may be possible through ultrasound examination revealing abnormal findings such as diaphragmatic hernia, polyhydramnios, hydrops fetalis, cardiac malformations, short limbs, and other, leading to amniocentesis and chromosomal diagnosis. ## Antenatal diagnosis Antenatal diagnosis is also possible after choriocentesis for maternal age. ## Genetic counseling All reported cases of this disorder have been sporadic. ## Management and treatment There is no specific therapy. Affected children may benefit from early intervention programs and special education. ## Prognosis Prognosis is usually poor. Death may occur perinatally, mainly due to diaphragmatic hernias, or during the first years of life in about a half of patients. Intellectual deficit is mostly profound and almost always accompanied with seizures. The manifestations (facial dysmorphism and malformations) progress with age. Some patients with a low level mosaïcism are less severely affected. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tetrasomy 12p	c0265449	5,498	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=884	2021-01-23T18:10:10	{"gard": ["8421"], "mesh": ["C538105"], "omim": ["601803"], "umls": ["C0265449"], "icd-10": ["Q99.8"], "synonyms": ["Isochromosome 12p mosaicism", "Isochromosome 12p syndrome", "Pallister-Killian syndrome"]}
Fryns syndrome Other namesDiaphragmatic hernia-abnormal face-distal limb anomalies syndrome Fryns syndrome is inherited in an autoosomal recessive manner. SpecialtyMedical genetics Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period.[1] Fryns (1987) reviewed the syndrome.[2] ## Contents * 1 Presentation * 2 Cytogenetics * 3 Diagnosis * 4 Epidemiology * 5 Cases * 6 References * 7 External links ## Presentation[edit] Usually associated with diaphragmatic hernia, pulmonary hypoplasia, imperforate anus, micropenis, bilateral cryptorchidism, cerebral ventricular dilation, camptodactyly, agenesis of sacrum, low-set ear.[citation needed] ## Cytogenetics[edit] In a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2.[3] They suggested that the gene for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15, chromosome 6, chromosome 8 and chromosome 22, respectively.[4][5][6] Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder.[citation needed] By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations.[7] They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400). ## Diagnosis[edit] Prenatal Diagnosis: * Aymé, et al. (1989) reported prenatal diagnosis of Fryns syndrome by sonography between 24 and 27 weeks.[8] * Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma.[9] The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisors; natal teeth had not been mentioned in other cases of Fryns syndrome. Differential Diagnosis: * McPherson et al. (1993) noted the phenotypic overlap between Fryns syndrome and the Pallister–Killian syndrome (601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.[10] * Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister–Killian syndrome, noting that differentiation is important to genetic counseling because Fryns syndrome is an autosomal recessive disorder and Pallister–Killian syndrome is usually a sporadic chromosomal aberration.[11] However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with 'coarse face,' acral hypoplasia, and internal anomalies, the initial diagnosis of Fryns syndrome had to be changed because mosaicism of isochromosome 12p was detected in fibroblast cultures or kidney tissue.[12] Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister–Killian syndrome by Veldman et al. (2002).[11] * Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines.[13] She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta, dilatation of the ureters, proximal thumbs, and broad clavicles.[13] ## Epidemiology[edit] In France, Aymé, et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live births and perinatal deaths).[8] ## Cases[edit] * Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities.[14] A sporadic case was reported by Goddeeris et al. (1980).[15] Fitch (1988) claimed that she and her colleagues were the first to describe this disorder.[16] In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies.[17] * Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period.[18] Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.[citation needed] * Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance.[19] They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case.[20] The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features. * Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality.[21] Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins.[22] * Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies.[23] Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Post-mortem examination showed Dandy–Walker malformation, ventricular septal defect, and renal cystic dysplasia. * Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25.[24] One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct. * Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome.[25] * Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome.[26] They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia.[27] One of these patients was alive at the age of 14 months, but was severely retarded. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period.[28][29] In the report of Hanssen et al. (1992), 2 older sibs had died in utero.[29] The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients. * Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect.[30] Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients. * Aymé, et al. (1989) described 8 cases of Fryns syndrome in France.[8] The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy–Walker anomaly and/or agenesis of the corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane. * Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia.[1] They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm. * In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate.[31] Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age. * Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases).[32] Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm associated with profound mental retardation. * Fryns and Moerman (1998) reported a second-trimester male fetus with Fryns syndrome and midline scalp defects.[33] The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures. * Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks' gestation affected by a multiple congenital disorder suggestive of Fryns syndrome.[34] In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities with bilateral cleft lip and palate and cardiovascular malformation. * Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis, central nervous system defects with left arrhinencephaly and cerebellar hypoplasia, midline cleft of the upper lip, alveolar ridge, and maxillary bone, and cleft nose with bilateral choanal atresia.[35] * Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of them.[36] They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia and cloudy cornea. * Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH.[7] ## References[edit] 1. ^ a b Alessandri L, Brayer C, Attali T, et al. (2005). "Fryns syndrome without diaphragmatic hernia. Report on a new case and review of the literature". Genet. Couns. 16 (4): 363–70. PMID 16440878. 2. ^ Fryns JP (May 1987). "Fryns syndrome: a variable MCA syndrome with diaphragmatic defects, coarse face, and distal limb hypoplasia". J. Med. Genet. 24 (5): 271–4. doi:10.1136/jmg.24.5.271. PMC 1050049. PMID 3585941. 3. ^ Clark RD, Fenner-Gonzales M (November 1989). "Apparent Fryns syndrome in a boy with a tandem duplication of 1q24-31.2". Am. J. Med. Genet. 34 (3): 422–6. doi:10.1002/ajmg.1320340319. PMID 2596530. 4. ^ de Jong G, Rossouw RA, Retief AE (July 1989). "Ring chromosome 15 in a patient with features of Fryns' syndrome". J. Med. Genet. 26 (7): 469–70. doi:10.1136/jmg.26.7.469. PMC 1015654. PMID 2746621. 5. ^ Krassikoff N, Sekhon GS (July 1990). "Terminal deletion of 6q and Fryns syndrome: a microdeletion/syndrome pair?". Am. J. Med. Genet. 36 (3): 363–4. doi:10.1002/ajmg.1320360327. PMID 2363440. 6. ^ Dean JC, Couzin DA, Gray ES, Lloyd DJ, Stephen GS (November 1991). "Apparent Fryns' syndrome and aneuploidy: evidence for a disturbance of the midline developmental field". Clin. Genet. 40 (5): 349–52. doi:10.1111/j.1399-0004.1991.tb03108.x. PMID 1756610. 7. ^ a b Slavotinek A, Lee SS, Davis R, et al. (September 2005). "Fryns syndrome phenotype caused by chromosome microdeletions at 15q26.2 and 8p23.1". J. Med. Genet. 42 (9): 730–6. doi:10.1136/jmg.2004.028787. PMC 1736126. PMID 16141010. 8. ^ a b c Aymé S, Julian C, Gambarelli D, et al. (March 1989). "Fryns syndrome: report on 8 new cases". Clin. Genet. 35 (3): 191–201. doi:10.1111/j.1399-0004.1989.tb02927.x. PMID 2650934. 9. ^ Manouvrier-Hanu S, Devisme L, Vaast P, Boute-Benejean O, Farriaux JP (1996). "Fryns syndrome and erupted teeth in a 24-weeks-old fetus". Genet. Couns. 7 (2): 131–4. PMID 8831132. 10. ^ McPherson EW, Ketterer DM, Salsburey DJ (August 1993). "Pallister–Killian and Fryns syndromes: nosology". Am. J. Med. Genet. 47 (2): 241–5. doi:10.1002/ajmg.1320470219. PMID 8213912. 11. ^ a b Veldman A, Schlösser R, Allendorf A, et al. (July 2002). "Bilateral congenital diaphragmatic hernia: Differentiation between Pallister–Killian and Fryns syndromes". Am. J. Med. Genet. 111 (1): 86–7. doi:10.1002/ajmg.10438. PMID 12124742. 12. ^ Rodríguez JI, Garcia I, Alvarez J, Delicado A, Palacios J (November 1994). "Lethal Pallister–Killian syndrome: phenotypic similarity with Fryns syndrome". Am. J. Med. Genet. 53 (2): 176–81. doi:10.1002/ajmg.1320530211. PMID 7856644. 13. ^ a b Slavotinek AM (February 2004). "Fryns syndrome: a review of the phenotype and diagnostic guidelines". Am. J. Med. Genet. A. 124A (4): 427–33. doi:10.1002/ajmg.a.20381. PMID 14735597. 14. ^ Fryns JP, Moerman F, Goddeeris P, Bossuyt C, Van den Berghe H (1979). "A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities". Hum. Genet. 50 (1): 65–70. doi:10.1007/BF00295591. PMID 381161. 15. ^ Goddeeris P, Fryns JP, van den Berghe H (March 1980). "Diaphragmatic defects, craniofacial dysmorphism, cleft palate and distal limb deformities. — a new lethal syndrome". J Genet Hum. 28 (1): 57–60. PMID 7400786. 16. ^ Fitch N (February 1988). "Fryns syndrome". J. Med. Genet. 25 (2): 135. doi:10.1136/jmg.25.2.135. PMC 1015459. PMID 3346889. 17. ^ Fitch N, Srolovitz H, Robitaille Y, Guttman F (October 1978). "Absent left hemidiaphragm, arhinencephaly, and cardiac malformations". J. Med. Genet. 15 (5): 399–401. doi:10.1136/jmg.15.5.399. PMC 1013741. PMID 739533. 18. ^ Lubinsky M, Severn C, Rapoport JM (March 1983). "Fryns syndrome: a new variable multiple congenital anomaly (MCA) syndrome". Am. J. Med. Genet. 14 (3): 461–6. doi:10.1002/ajmg.1320140309. PMID 6859098. 19. ^ Meinecke P, Fryns JP (December 1985). "The Fryns syndrome: diaphragmatic defects, craniofacial dysmorphism, and distal digital hypoplasia. Further evidence for autosomal recessive inheritance". Clin. Genet. 28 (6): 516–20. doi:10.1111/j.1399-0004.1985.tb00419.x. PMID 4075561. 20. ^ Young ID, Simpson K, Winter RM (February 1986). "A case of Fryns syndrome". J. Med. Genet. 23 (1): 82–4. doi:10.1136/jmg.23.1.82. PMC 1049547. PMID 3950939. 21. ^ Samueloff A, Navot D, Birkenfeld A, Schenker JG (January 1987). "Fryns syndrome: a predictable, lethal pattern of multiple congenital anomalies". Am. J. Obstet. Gynecol. 156 (1): 86–8. doi:10.1016/0002-9378(87)90210-9. PMID 3799773. 22. ^ Schwyzer U, Briner J, Schinzel A (January 1987). "Fryns syndrome in a girl born to consanguineous parents". Acta Paediatr Scand. 76 (1): 167–71. doi:10.1111/j.1651-2227.1987.tb10441.x. PMID 3564997. 23. ^ Moerman P, Fryns JP, Vandenberghe K, Devlieger H, Lauweryns JM (December 1988). "The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): report of two sibs with further delineation of this multiple congenital anomaly (MCA) syndrome". Am. J. Med. Genet. 31 (4): 805–14. doi:10.1002/ajmg.1320310413. PMID 3239572. 24. ^ Cunniff C, Jones KL, Saal HM, Stern HJ (April 1990). "Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia". Pediatrics. 85 (4): 499–504. PMID 2314962. 25. ^ Kershisnik MM, Craven CM, Jung AL, Carey JC, Knisely AS (June 1991). "Osteochondrodysplasia in Fryns syndrome". Am. J. Dis. Child. 145 (6): 656–60. doi:10.1001/archpedi.1991.02160060074024. PMID 1903587. 26. ^ Willems PJ, Keersmaekers GH, Dom KE, et al. (November 1991). "Fryns syndrome without diaphragmatic hernia?". Am. J. Med. Genet. 41 (2): 255–7. doi:10.1002/ajmg.1320410225. PMID 1785645. 27. ^ Bartsch O, Meinecke P, Kamin G (October 1995). "Fryns syndrome: two further cases without lateral diaphragmatic defects". Clin. Dysmorphol. 4 (4): 352–8. doi:10.1097/00019605-199510000-00012. PMID 8574427. 28. ^ Bamforth JS, Leonard CO, Chodirker BN, et al. (January 1989). "Congenital diaphragmatic hernia, coarse facies, and acral hypoplasia: Fryns syndrome". Am. J. Med. Genet. 32 (1): 93–9. doi:10.1002/ajmg.1320320120. PMID 2650550. 29. ^ a b Hanssen AM, Schrander-Stumpel CT, Thiry PA, Fryns JP (1992). "Fryns syndrome: another example of non-lethal outcome with severe mental handicap". Genet. Couns. 3 (4): 187–93. PMID 1472353. 30. ^ Vargas JE, Cox GF, Korf BR (September 2000). "Discordant phenotype in monozygotic twins with Fryns syndrome". Am. J. Med. Genet. 94 (1): 42–5. doi:10.1002/1096-8628(20000904)94:1<42::AID-AJMG9>3.0.CO;2-6. PMID 10982481. 31. ^ Riela AR, Thomas IT, Gonzalez AR, Ifft RD (March 1995). "Fryns syndrome: neurologic findings in a survivor". J. Child Neurol. 10 (2): 110–3. doi:10.1177/088307389501000208. PMID 7782599. 32. ^ Van Hove JL, Spiridigliozzi GA, Heinz R, McConkie-Rosell A, Iafolla AK, Kahler SG (November 1995). "Fryns syndrome survivors and neurologic outcome". Am. J. Med. Genet. 59 (3): 334–40. doi:10.1002/ajmg.1320590311. PMID 8599357. 33. ^ Fryns JP, Moerman P (1998). "Scalp defects in Fryns syndrome". Genet. Couns. 9 (2): 153–4. PMID 9664213. 34. ^ Ramsing M, Gillessen-Kaesbach G, Holzgreve W, Fritz B, Rehder H (December 2000). "Variability in the phenotypic expression of fryns syndrome: A report of two sibships". Am. J. Med. Genet. 95 (5): 415–24. doi:10.1002/1096-8628(20001218)95:5<415::AID-AJMG2>3.0.CO;2-J. PMID 11146459. 35. ^ Arnold SR, Debich-Spicer DD, Opitz JM, Gilbert-Barness E (January 2003). "Documentation of anomalies not previously described in Fryns syndrome". Am. J. Med. Genet. A. 116A (2): 179–82, discussion 183. doi:10.1002/ajmg.a.10763. PMID 12494439. 36. ^ Pierson DM, Taboada E, Butler MG (March 2004). "Eye abnormalities in Fryns syndrome". Am. J. Med. Genet. A. 125A (3): 273–7. doi:10.1002/ajmg.a.20520. PMC 6719310. PMID 14994236. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 229850 * MeSH: C538070 External resources * GeneReviews: Fryns syndrome * Orphanet: 2059 * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Fryns syndrome	c0220730	5,499	wikipedia	https://en.wikipedia.org/wiki/Fryns_syndrome	2021-01-18T18:55:28	{"gard": ["3699"], "mesh": ["C538070"], "umls": ["C0220730"], "icd-10": ["Q87.8"], "orphanet": ["2059"], "wikidata": ["Q3508635"]}

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