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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: "Contagious disease" – news · newspapers · books · scholar · JSTOR (September 2016) (Learn how and when to remove this template message) A contagious disease is a subset category of transmissible diseases, which are transmitted to other persons, either by physical contact with the person suffering the disease, or by casual contact with their secretions or objects touched by them or airborne route among other routes.[1] Contagiousness varies between diseases. Non-contagious infections, by contrast, usually require a special mode of transmission between persons or hosts. These include need for intermediate vector species (mosquitoes that carry malaria) or by non-casual transfer of bodily fluid (such as transfusions, needle sharing or sexual contact).[2] The boundary between contagious and non-contagious infectious diseases is not perfectly drawn, as illustrated classically by tuberculosis, which is clearly transmissible from person to person, but was not classically considered a contagious disease. In the present day, most sexually transmitted infections are considered contagious, but only some of them are subject to medical isolation. A disease may be known to be contagious but its causative factors remain undetermined. A contagion may be more infectious if the incubation period is long. ## Contents * 1 Historical meaning * 2 Effect on Public Health Response * 3 See also * 4 References ## Historical meaning[edit] Originally, the term referred to a contagion (a derivative of 'contact') or disease transmissible only by direct physical contact. In the modern-day, the term has sometimes been broadened to encompass any communicable or infectious disease. Often the word can only be understood in context, where it is used to emphasise very infectious, easily transmitted, or especially severe communicable disease. In 1849, John Snow first proposed that cholera was a contagious disease. See also: Diseases and epidemics of the 19th century ## Effect on Public Health Response[edit] This clinic uses negative room pressure to prevent disease transmission Most epidemics are caused by contagious diseases, with occasional exceptions, such as yellow fever. The spread of non-contagious communicable diseases is changed either very little or not at all by medical isolation of ill persons or medical quarantine for exposed persons. Thus, a "contagious disease" is sometimes defined in practical terms, as a disease for which isolation or quarantine are useful public health responses.[3][failed verification] Some locations are better suited for the research into the contagious pathogens due to the reduced risk of transmission afforded by a remote or isolated location. Negative room pressure is a technique in health care facilities based on aerobiological designs. ## See also[edit] * Germ theory of disease * Herd immunity ## References[edit] 1. ^ "Merriam-Webster dictionary definition of contagious disease". Retrieved 2009-11-27. 2. ^ Non-Contagious Diseases - Contact With www.transfusionguidelines.org, accessed 27 January 2020 3. ^ A primer from the CDC on quarantine and its uses against contagious disease spread Accessed Nov. 27, 2009. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Contagious disease	c0009450	1,200	wikipedia	https://en.wikipedia.org/wiki/Contagious_disease	2021-01-18T19:05:39	{"mesh": ["D003141"], "wikidata": ["Q2995419"]}
Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. In rare cases, there may be neurological impairment or involvement of other body systems. Osteopetrosis may be caused by mutations in at least 10 genes. Inheritance can be autosomal recessive, autosomal dominant, or X-linked recessive with the most severe forms being autosomal recessive. Management depends on the specific symptoms and severity and may include vitamin D supplements, various medications, and/or surgery. Adult osteopetrosis requires no treatment by itself, but complications may require intervention. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Osteopetrosis autosomal recessive 6	c1969093	1,201	gard	https://rarediseases.info.nih.gov/diseases/4156/osteopetrosis-autosomal-recessive-6	2021-01-18T17:58:31	{"mesh": ["C566931"], "omim": ["611497"], "umls": ["C1969093"], "synonyms": ["OPTB6", "Autosomal recessive osteopetrosis type 6", "Osteopetrosis autosomal recessive intermediate form"]}
The leg of this Pisaster ochraceus sea star in Oregon is disintegrating as a result of sea star wasting syndrome Sea star wasting disease or starfish wasting syndrome is a disease of starfish and several other echinoderms that appears sporadically, causing mass mortality of those affected.[1] There are around 40 different species of sea stars that have been affected by this disease. The disease seems to be associated with raised water temperatures in some places,[2][3] but not others.[4][5] It starts with the emergence of lesions, followed by body fragmentation and death.[6] In 2014 it was suggested that the disease is associated with a single-stranded DNA virus now known as the sea star-associated densovirus (SSaDV); however, sea star wasting disease is still not fully understood.[7][8] ## Contents * 1 Symptoms * 2 1972 plague * 3 1978 plague * 4 2013 - current plagues * 5 Locations * 6 Causes * 7 Treatment * 8 Species affected * 9 See also * 10 References ## Symptoms[edit] Typically the first symptom of sea star wasting disease is refusal to accept food followed by listlessness for weeks and then white lesions that appear on the surface of the starfish and spread rapidly, followed by decay of tissue surrounding the lesions. Next the animal becomes limp as the water vascular system fails and it is no longer able to maintain its internal hydrostatic balance. The sea star loses its grip on the substrate. The body structure begins to break down, signs of stretching appear between the arms which may twist and fall off, and the animal dies. The arms may continue to crawl around for a while after being shed. Progression of these events can be rapid, leading to death within a few days.[9][10] A deflated appearance can precede other morphological signs of the disease. All of these symptoms are also associated with ordinary attributes of unhealthy stars and can arise when an individual is stranded too high in the intertidal zone (for example) and simply desiccates. "True" wasting disease will be present in individuals that are found in suitable habitat, often in the midst of other individuals that might also be affected.[10] The final result is a disintegrated, white, mushy blob, which no longer seems to be a sea star.[11] ## 1972 plague[edit] The 1972 plague was the first notable case of Sea Star Wasting Disease.[12] Scientists noticed a rapidly declining population of common starfish (Asterias rubens) occurring off the east coast of the United States.[13] The symptoms were that the starfish became limp and lost limbs until finally melting into a white mucus like paste.[12][14] ## 1978 plague[edit] In 1978 large numbers of the predatory starfish Heliaster kubiniji succumbed to a wasting disease in the Gulf of California. At the time it was suspected that high water temperatures were a causal factor. This starfish became locally extinct in some parts of the gulf and some populations had still not recovered by the year 2000. Because this starfish is a top-level predator, its disappearance had profound effects on the ecosystem.[15] In the Channel Islands off the coast of California, ten species of sea star were recorded as being affected as well as three species of sea urchins, two brittle stars and a sea cucumber, all of which experienced large population declines.[16] ## 2013 - current plagues[edit] In July 2013, populations of sea stars declined rapidly on the east coast of the United States between New Jersey and Maine. There had been a great increase in sea star numbers three years earlier, though in 2013 they were dying off. No cause for the mysterious deaths was apparent.[17] On the Pacific coast, a meltdown of sea stars was first found in ochre stars and sunflower stars in Howe Sound, British Columbia. In late August, the disease had also been found stretching from Alaska to the border of Mexico.[18] At the beginning of September 2013, a mass die-off of sea stars was reported off the coast of British Columbia. The sea bed was littered with disintegrating sunflower stars (Pycnopodia helianthoides), their detached arms and discs. Another species also suffering mortalities was the morning sun star (Solaster dawsoni), but no cause for the deaths was apparent. If they were caused by infection or toxins, the two species might have affected each other because the diet of each includes sea stars.[19] In spring/summer 2013, reports of sea stars experiencing wasting symptoms came from Vancouver, B.C. and from southern and central California.[20] Observations of symptoms spread throughout California, Washington and southern Canada throughout 2013, but sea star wasting disease did not begin affecting sea stars in the intertidal zone in Oregon until spring 2014.[4] The relatively high resolution of understanding of the pattern of disease spread came from marine scientists working along the coast, but also from citizen scientists visiting the coast and uploading their observations, of where they saw sea stars both with and without disease symptoms, to an online sea star wasting observation log database.[21] Because scientists had been studying sea star populations before the outbreak of sea star wasting disease, there is a good understanding of how the disease affected population sizes and dynamics. A study of the ochre sea star (Pisaster ochraceus) populations from San Diego, California, to southern British Columbia, along with at two locations near Sitka, Alaska, found that population declines were proportionately greater for sea stars in the southern part of the coast than the north;[5] however, population numbers are usually higher at more northern locations, so the number of sea stars that died from wasting disease was often higher at more northern sites. In October 2013, in a marine laboratory seawater tank in California holding various species of sea stars, other species started displaying similar symptoms. The ochre star (Pisaster ochraceus) was the first affected. Most of these developed symptoms, lost arms and died over the course of a week or so. Later the rainbow star (Orthasterias koehleri) developed the disease and died, but the bat star (Patiria miniata) and leather star (Dermasterias imbricata), which were living in the same tank and had been scavenging on the corpses, showed no ill effects.[9] At Natural Bridges State Marine Reserve in California, the ochre star is normally a very common resident on the mussel beds, but by November 2013 it was reported to have completely disappeared.[9] There have been signs of some recovery of ochre sea star populations (Pisaster ochraceus), with higher numbers of juvenile sea stars in the intertidal than had been previously common, especially for northern sites along the Pacific coast.[5][4][22] However, the biomass and the function of ochre sea stars in their communities, such as being important predators of mussels, has remained lower than pre-disease levels.[4][22] ## Locations[edit] Currently, most cases are located on the west coast of North America, affecting sea stars from Baja California to the gulf of Alaska.[23] Map of Sea Star Wasting Syndrome Locations ## Causes[edit] As of November 2013, no identifiable cause for the disease had been found. Pathogenic bacteria did not seem to be present, and though the plague might be caused by a viral or fungal pathogen, no causal agent had been found. Each episode of plague might have a different cause.[14] Other possible causes of the condition that have been suggested include high sea temperatures, oxygen depletion and low salinity due to freshwater runoff. Research suggests that high water temperatures can be indeed linked to the disease, increasing its incidence and virulence. The disease also seems more prevalent in sheltered waters than in open seas with much wave movement. One result of global warming is higher sea temperatures. There is a wave of unusually warm water along the west coast of the United States, which is where all of the sea stars are dying off.[24] These may impact both on starfish and on echinoderm populations in general, and a ciliate protozoan parasite (Orchitophrya stellarum) of starfish, which eats sperm and effectively emasculates male starfish, thrives at higher temperatures.[25] However, temperature was not related to the initial outbreak of sea star wasting disease at many places along the coast.[5][4] Unlike with many other wildlife diseases, there was no link between the density of sea stars at a location before disease outbreak and the severity of population decline.[5] Thus, this outbreak has defied prediction using what is typically understood about disease spread. Research in 2014 showed that the cause of the disease is transmissible from one starfish to another and that the disease-causing agent is a microorganism in the virus-size range. The most likely candidate causal agent was found to be the sea star-associated densovirus (SSaDV), which was found to be in greater abundance in diseased starfish than in healthy ones.[7][26] However, evidence for this virus as the cause of sea star wasting disease is inconclusive. ## Treatment[edit] In 2014, Point Defiance Zoo and Aquarium lost more than half of its 369 sea stars, and by September 2015 they numbered fewer than 100. The aquarium treated its affected sea stars with antibiotics in 2014, which proved effective.[27] Although a mechanism is still unknown, evidence suggests that a single mutation in the elongation factor 1-alpha locus in Pisaster ochraceus may be associated with reduced mortality.[28] ## Species affected[edit] Most affected (high mortality rates): * Solaster dawsoni (morning sun star), * Pisaster brevispinus (giant pink star), * Pisaster ochraceus (ochre/purple star), * Pycnopodia helianthoides (sunflower star), * Evasterias troschelii (mottled star), Affected (some mortality): * Dermasterias imbricata (leather star), * Solaster stimpsoni (striped sun star), * Orthasterias koehleri (rainbow star), * Henricia spp. (blood star), * Leptasterias spp (six-armed star), * Patiria (Asterina) miniata (bat star), and * Pisaster giganteus (giant star) ## See also[edit] * Effects of global warming on oceans ## References[edit] 1. ^ Dawsoni, Solaster. "Sea Star Species Affected by Wasting Syndrome." Pacificrockyintertidal.org Seastarwasting.org (n.d.): n. pag. Ecology and Evolutionary Biology. Web. 2. ^ Eisenlord, Morgan E.; Groner, Maya L.; Yoshioka, Reyn M.; Elliott, Joel; Maynard, Jeffrey; Fradkin, Steven; Turner, Margaret; Pyne, Katie; Rivlin, Natalie (2016-03-05). "Ochre star mortality during the 2014 wasting disease epizootic: role of population size structure and temperature". Phil. Trans. R. Soc. B. 371 (1689): 20150212. doi:10.1098/rstb.2015.0212. ISSN 0962-8436. PMC 4760142. PMID 26880844. 3. ^ Bates, Amanda E.; Hilton, Brett J.; Harley, Christopher D. G. (2009-11-09). "Effects of temperature, season and locality on wasting disease in the keystone predatory sea star Pisaster ochraceus". Diseases of Aquatic Organisms. 86 (3): 245–251. doi:10.3354/dao02125. ISSN 0177-5103. PMID 20066959. 4. ^ a b c d e Menge, Bruce A.; Cerny-Chipman, Elizabeth B.; Johnson, Angela; Sullivan, Jenna; Gravem, Sarah; Chan, Francis (2016-05-04). "Sea Star Wasting Disease in the Keystone Predator Pisaster ochraceus in Oregon: Insights into Differential Population Impacts, Recovery, Predation Rate, and Temperature Effects from Long-Term Research". PLOS ONE. 11 (5): e0153994. doi:10.1371/journal.pone.0153994. ISSN 1932-6203. PMC 4856327. PMID 27144391. 5. ^ a b c d e Miner, C. Melissa; Burnaford, Jennifer L.; Ambrose, Richard F.; Antrim, Liam; Bohlmann, Heath; Blanchette, Carol A.; Engle, John M.; Fradkin, Steven C.; Gaddam, Rani (2018-03-20). "Large-scale impacts of sea star wasting disease (SSWD) on intertidal sea stars and implications for recovery". PLOS ONE. 13 (3): e0192870. doi:10.1371/journal.pone.0192870. ISSN 1932-6203. PMC 5860697. PMID 29558484. 6. ^ "Sea Star Wasting Syndrome". Pacific Rocky Intertidal Monitoring. Retrieved 2014-02-01. 7. ^ a b Hewson, Ian; et al. (2014). "Densovirus associated with sea-star wasting disease and mass mortality". Proceedings of the National Academy of Sciences of the United States of America. 111 (48): 17278–83. doi:10.1073/pnas.1416625111. PMC 4260605. PMID 25404293. 8. ^ "Sea Star Wasting Syndrome \| MARINe". eeb.ucsc.edu. Retrieved 2018-06-03. 9. ^ a b c Gong, Allison J. (2013-09-07). "A plague of stars". Notes from a California naturalist. Retrieved 2013-11-17. 10. ^ a b "Sea Star Wasting Syndrome". Pacific Rocky Intertidal Monitoring: Trends and Synthesis. Retrieved 2014-02-03. 11. ^ https://jackiehildering.files.wordpress.com/2013/12/c2a9-2013-jackie-hildering-210130.jpg 12. ^ a b Meyer, Anna. "Will the Sea Stars Ever Be Able to Recover? - Islands' Sounder." Islands' Sounder. N.p., 20 July 2015. Web. 08 Oct. 2015. 13. ^ Menge, Bruce A. (August 1979). "Coexistence between the seastars Asterias vulgaris and A. forbesi in a heterogeneous environment: A non-equilibrium explanation". Oecologia. 41 (3): 245–272. doi:10.1007/bf00377430. ISSN 0029-8549. PMID 28309763. 14. ^ a b Mah, Christopher (2013-09-10). "Starfish Wasting Disease!". Echinoblog. Retrieved 2013-11-17. 15. ^ Dungan, Michael L.; Miller, Thomas E.; Thomson, Donald A. (1982). "Catastrophic Decline of a Top Carnivore in the Gulf of California Rocky Intertidal Zone". Science. 216 (4549): 989–991. doi:10.1126/science.216.4549.989. PMID 17809070. 16. ^ Eckert, Ginny L.; Engle, John M.; Kushner, David J. (2000). "Sea star disease and population declines at the Channel Islands" (PDF). Proceedings of the Fifth California Islands Symposium. Minerals Management Service 99-0038: 390–393. 17. ^ Laine, Martin (2013-07-24). "Massive east coast starfish die-off reported". Digital Journal. Retrieved 2013-11-17. 18. ^ "Sea Star Wasting Syndrome Now Documented on NE Vancouver Island." http://themarinedetective.com/2013/12/21/sea-star-wasting-syndrome-now-documented-on-ne-vancouver-island/ 19. ^ Mah, Christopher (2013-09-03). "Mysterious Mass Sunflower Starfish (Pycnopodia) Die-off in British Columbia". Echinoblog. Retrieved 2013-11-17. 20. ^ "Pacific Rocky Intertidal Monitoring". data.piscoweb.org. Retrieved 2018-11-27. 21. ^ "MARINe Sea Star Logs". gordon.science.oregonstate.edu. Retrieved 2018-11-27. 22. ^ a b Moritsch, Monica M.; Raimondi, Peter T. (2018-03-23). "Reduction and recovery of keystone predation pressure after disease-related mass mortality". Ecology and Evolution. 8 (8): 3952–3964. doi:10.1002/ece3.3953. ISSN 2045-7758. PMC 5916292. PMID 29721271. 23. ^ "Pacific Rocky Intertidal Monitoring: Trends and Synthesis." Pacific Rocky Intertidal Monitoring. N.p., n.d. Web. 08 Oct. 2015. 24. ^ "'Warm Blob' of Water Causing Extreme Weather, Climate Scientists Say". The Weather Channel. Retrieved 2015-10-10. 25. ^ Mah, Christopher (2010-07-20). "Another Worry From Global Warming: Parasites that eat Starfish Sperm". Echinoblog. Retrieved 2013-11-17. 26. ^ Netburn, Deborah (November 26, 2014) "Scientists find likely culprit behind mysterious sea star deaths" Los Angeles Times 27. ^ Glenn, Stacia. "Point Defiance loses half its sea stars to a wasting disease." http://www.thenewstribune.com/news/local/article34291203.html 28. ^ Wares, J. P. and L. M. Schiebelhut, 2016. PeerJ 4:e1876 https://peerj.com/articles/1876/?td=wk [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Sea star wasting disease	None	1,202	wikipedia	https://en.wikipedia.org/wiki/Sea_star_wasting_disease	2021-01-18T18:36:22	{"wikidata": ["Q15241744"]}
A rare, genetic, paroxysmal dystonia disorder characterized by childhood to adolescent-onset of episodic paroxysmal choreoathetosis, triggered mainly by sudden movements, prolonged exercise, anxiety and emotional stress, in association with progressive spastic paraparesis (onest in adulthood), gait ataxia, mild to moderate cognitive impairment, and/or epileptic seizures. Episodes typically last from a few minutes to hours, have a variable frequency (daily to yearly), and are relieved by rest. Frequency of episodes tends to decrease with age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity	c1832855	1,203	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=53583	2021-01-23T18:41:07	{"mesh": ["C563401"], "omim": ["601042"], "umls": ["C1832855"], "icd-10": ["G24.8"], "synonyms": ["DYT9", "Episodic choreoathetosis/spasticity"]}
Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by the rapid accumulation of eosinophils in the lungs. Eosinophils are a type of white blood cell and are part of the immune system. IAEP can occur at any age but most commonly affects otherwise healthy individuals between 20 and 40 years of age. Signs and symptoms may include fever, cough, fatigue, difficulty breathing (dyspnea), muscle pain, and chest pain. IAEP can progress rapidly to acute respiratory failure. The term “idiopathic” means the exact cause for the overproduction of eosinophils is not known. Possible triggers of acute eosinophilic pneumonia include cigarette smoking, occupational exposure to dust and smoke, and certain medications. Diagnosis of IAEP generally involves a bronchoscopy and bronchoalveolar lavage (BAL). Treatment with corticosteroids is effective in most cases. Because IAEP often progresses rapidly, respiratory failure can occur; in these cases, mechanical ventilation is required. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Idiopathic acute eosinophilic pneumonia	c4518469	1,204	gard	https://rarediseases.info.nih.gov/diseases/519/idiopathic-acute-eosinophilic-pneumonia	2021-01-18T17:59:50	{"orphanet": ["724"], "synonyms": ["IAEP"]}
A number sign (#) is used with this entry because Leber congenital amaurosis-15 and juvenile retinitis pigmentosa are caused by homozygous or compound heterozygous mutation in the TULP1 gene (602280) on chromosome 6p21.3. Description Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997). Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132). For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000. Clinical Features Hanein et al. (2004) studied 179 unrelated patients fulfilling strict inclusion criteria for diagnosis of LCA, including congenital nystagmus, no or very poor ocular pursuit, oculodigital sign of Franceschetti (repetitive eye-rubbing in infancy, attesting to profoundly impaired vision), and no recordable ERGs since birth or the first months of life. Among these probands, 3 were found to have homozygous or compound heterozygous mutations in the TULP1 gene (see MOLECULAR GENETICS). Mataftsi et al. (2007) reported a large consanguineous Algerian family in which 7 individuals from 3 sibships were affected with Leber congenital amaurosis or early-onset retinal degeneration. Symptoms started at birth in 2 patients and during infancy in 5 patients, with age at diagnosis ranging from 3 years to 12 years of age. All patients had night blindness and nystagmus, but none had photophobia. Six patients had myopia, and 1 had mild hyperopia; visual acuity ranged from perception of light to 20/100. Visual fields were moderately to severely restricted in patients who were tested, and color vision was severe disturbed without a specific axis of confusion. The pupillary reflex was extremely sluggish in most of the patients. None presented signs of keratoconus. Funduscopic findings varied significantly across and within the sibships, primarily in an age-dependent manner: the youngest patient had no detectable maculopathy, 3 patients of intermediate age had an indistinct foveolar reflex, and the 3 oldest affected individuals had pronounced maculopathy. In addition, the optic disc appeared healthy in the younger patients, whereas moderate to waxy disc pallor was evident in the 3 oldest; the latter patients also displayed an annulus of peripapillary retinal pigment epithelium (RPE) atrophy in both eyes. Pigment retinopathy and retinal vessel attenuation were present in all but the youngest subject, with some patients having severely sclerosed arteries and multiple occluded or ghost vessels in the periphery. Fluorescein angiography confirmed the presence of peripapillary RPE atrophy and absence of macular edema. The proband was examined on 2 occasions 8 months apart, and during that interval his visual acuity declined from 20/100 to 20/250 in the better eye. Full-field ERGs in the proband showed completely extinguished rod- and cone-driven responses, and macular optical coherence tomography scans showed an abnormal lamination due to the underlying degenerative disease. The nerve fiber layer and inner plexiform layer seemed to be preserved, but the structures of the outer retina were nondetectable, and retinal thickness was significantly reduced. Mapping In a large consanguineous Algerian pedigree in which 7 individuals from 3 sibships were affected with Leber congenital amaurosis or early-onset retinal degeneration, Mataftsi et al. (2007) performed homozygosity mapping which excluded all the tested loci except TULP1 (602280) at chromosome 6p21.3. Molecular Genetics In 179 unrelated patients diagnosed with Leber congenital amaurosis (LCA), Hanein et al. (2004) analyzed 7 known LCA genes and identified homozygous or compound heterozygous mutations in the TULP1 gene in 3 probands (602280.0004 and 602280.0010-602280.0012, respectively). In 7 affected individuals from 3 sibships of a large consanguineous Algerian pedigree with Leber congenital amaurosis or early-onset retinal degeneration, Mataftsi et al. (2007) identified homozygosity for a 6-bp duplication in the TULP1 gene (602280.0013). The unaffected parents were heterozygous for the mutation, as were 15 other family members. Examination of the 17 asymptomatic carriers of the duplication revealed that 15 had an unremarkable fundus appearance, whereas 2 individuals, aged 64 years and 66 years, had drusen-like macular deposits; 1 also had age-related pigmentary macular changes. In 4 unrelated patients diagnosed with juvenile retinitis pigmentosa, 2 from Afghanistan, 1 from Turkey, and 1 from Mexico, den Hollander et al. (2007) identified homozygosity for mutations in the TULP1 gene (see, e.g., 602280.0009). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Poor vision at birth \- Vision loss, progressive, during childhood or adolescence \- Visual acuity ranging from perception of light to 20/100 \- Nystagmus, congenital \- Ocular pursuit poor or absent \- Oculodigital sign of Franceschetti \- Night blindness \- Myopia \- Hyperopia (in some patients) \- Visual fields moderately to severely restricted \- Color vision disturbed \- Pupillary reflex sluggish \- Fundus examination normal at birth \- Foveolar reflex indistinct \- Maculopathy, marked (in older patients) \- Optic disc pallor (in older patients) \- Peripapillary retinal pigment epithelium atrophy (in older patients) \- Pigment retinopathy (in all but youngest patients) \- Retinal vessel attenuation (in all but youngest patients) \- Electroretinograms unrecordable at birth or in infancy MOLECULAR BASIS \- Caused by mutation in the tubby-like protein 1 gene (TULP1, 602280.0004 ) ▲ 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	LEBER CONGENITAL AMAUROSIS 15	c0339527	1,205	omim	https://www.omim.org/entry/613843	2019-09-22T15:57:16	{"doid": ["0110189"], "mesh": ["D057130"], "omim": ["613843"], "orphanet": ["65"], "genereviews": ["NBK531510"]}
## Clinical Features Reid et al. (1998) reported 4 individuals from 2 generations of a family who had recurrent episodes of parotitis beginning in childhood and, in the only adult at the time of report, remitting at the age of 14 years. In this individual, however, the episodes recurred during each of 2 pregnancies. Parotid gland ultrasonography demonstrated areas of punctate calcification and abnormality of parotid gland texture. Reid et al. (1998) also reported 2 additional individuals from previous generations of the same family who had experienced recurrent episodes of salivary gland swelling in one case and unilateral facial pain in the other case. A right submandibular calculus was found in the individual who had had episodes of salivary gland swelling. Inheritance Reid et al. (1998) stated that the transmission pattern of parotitis in the pedigree they reported was consistent with autosomal dominant inheritance with incomplete penetrance and variable expression since the mother of one affected individual was clinically unaffected but was shown to have flecks of calcification in the parotid gland, consistent with previous parotitis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PAROTITIS, JUVENILE RECURRENT	c1863691	1,206	omim	https://www.omim.org/entry/603588	2019-09-22T16:12:50	{"mesh": ["C566359"], "omim": ["603588"]}
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: "Microcoria" – news · newspapers · books · scholar · JSTOR (December 2009) (Learn how and when to remove this template message) Microcoria SpecialtyOphthalmology Microcoria is a congenital disease in which the pupils of the subject are narrower than 2 mm in diameter. Microcoria is associated with juvenile-onset glaucoma. It is also associated with Pierson syndrome chararacterized by microcoria and congenital nephrotic syndrome. The defect is in the Laminin beta 2 gene on chromosome 3p21 which encodes a protein essential to the glomerular basement membrane.[1] It is also part of the known manifestations of a born infant to a mother suffering from uncontrolled hyperglycemia.[citation needed] Other symptoms include transposition of great vessels, respiratory distress secondary to surfactant defect, sacral agensis, jitteriness, irritability, and lethargy due to rebound fetal hypoglycemia. Congenital microcoria is an autosomal dominant trait. However, it can also occur sporadically. ## See also[edit] * Miosis ## References[edit] 1. ^ Zenker et al., 2004. Zenker M., Aigner T., Wendler O., et al: Human laminin beta 2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 2004; 13:2625-2632 This article about the eye 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	Microcoria	c1303009	1,207	wikipedia	https://en.wikipedia.org/wiki/Microcoria	2021-01-18T18:38:29	{"gard": ["3635"], "mesh": ["C537550"], "umls": ["C1303009"], "orphanet": ["566"], "wikidata": ["Q720101"]}
Protein–energy malnutrition Other namesProtein–calorie malnutrition, PEM, PCM SpecialtyEndocrinology Protein–energy malnutrition (PEM), sometimes called protein-energy undernutrition (PEU), is a form of malnutrition that is defined as a range of pathological conditions arising from coincident lack of dietary protein and/or energy (calories) in varying proportions. The condition has mild, moderate, and severe degrees. Disability-adjusted life year for protein–energy malnutrition per 100,000 inhabitants in 2004. no data less than 10 10–100 100–200 200–300 300–400 400–500 500–600 600–700 700–800 800–1000 1000–1350 more than 1350 Types include:[1] * Kwashiorkor (protein malnutrition predominant) * Marasmus (deficiency in calorie intake) * Marasmic kwashiorkor (marked protein deficiency and marked calorie insufficiency signs present, sometimes referred to as the most severe form of malnutrition) PEM is fairly common worldwide in both children and adults and accounts for 6 million deaths annually.[2] In the industrialized world, PEM is predominantly seen in hospitals, is associated with disease, or is often found in the elderly.[2] Note that PEM may be secondary to other conditions such as chronic renal disease[3] or cancer cachexia[4] in which protein energy wasting may occur. Protein–energy malnutrition affects children the most because they have less protein intake. The few rare cases found in the developed world are almost entirely found in small children as a result of fad diets, or ignorance of the nutritional needs of children, particularly in cases of milk allergy.[5] ## Contents * 1 Prenatal protein malnutrition * 2 Epidemiology * 3 Co-morbidity * 4 References * 5 Further reading * 6 External links ## Prenatal protein malnutrition[edit] See also: Prenatal nutrition Protein malnutrition is detrimental at any point in life, but protein malnutrition prenatally has been shown to have significant lifelong effects. During pregnancy, one should aim for a diet that consists of at least 20% protein for the health of the fetus[citation needed]. Diets that consist of less than 6% protein in utero have been linked with many deficits, including decreased brain weight, increased obesity, and impaired communication within the brain in some animals. Even diets of mild protein malnutrition (7.2%) have been shown to have lasting and significant effects in rats. The following are some studies in which prenatal protein deficiency has been shown to have unfavorable consequences. * Decreased brain size: Protein deficiency has been shown to affect the size and composition of brains in rhesus monkeys. Monkeys whose mother had eaten a diet with an adequate amount of protein were shown to have no deficit in brain size or composition, even when their body weight amounted to less than one-half of that of the controls, whereas monkeys whose mothers had eaten low-protein diets were shown to have smaller brains regardless of the diet given after birth.[6] * Impaired neocortical long-term potentiation: Mild protein deficiency (in which 7.2% of the diet consists of protein) in rats has been shown to impair entorhinal cortex plasticity (visuospatial memory), noradrenergic function in the neocortex, and neocortical long-term potentiation.[7] * Altered fat distribution: Protein undernutrition can have varying effects depending on the period of fetal life during which the malnutrition occurred. Although there were not significant differences in the food intake, there were increased amounts of perirenal fat in rats that were protein-deprived during early (gestation days 0–7) and mid (gestation days 8–14) pregnancy, and throughout pregnancy, whereas rats that were protein-deprived only late in gestation (gestation days 15–22) were shown to have increased gonadal fat.[8] * Increased obesity: Mice exposed to a low-protein diet prenatally weighed 40% less than the control group at birth (intrauterine growth retardation). When fed a high-fat diet after birth, the prenatally undernourished mice were shown to have increased body weight and adiposity (body fat), while those who were adequately nourished prenatally did not show an increase in body weight or adiposity when fed the same high-fat diet after birth.[9] * Decreased birth weight, and gestation duration: Supplementation of protein and energy can lead to increased duration of gestation and higher birth weight. When fed a supplement containing protein, energy, and micronutrients, pregnant women showed more successful results during birth, including high birth weights, longer gestations, and fewer pre-term births, than women who had consumed a supplement with micronutrients and low energy but no protein (although this finding may be due to the increase of energy in the supplements, not the increase of protein).[10] * Increased stress sensitivity: Male offspring of pregnant rats fed low-protein diets have been shown to exhibit blood pressure that is hyperresponsive to stress and salt.[11] * Decreased sperm quality: A low-protein diet during gestation in rats has been shown to affect the sperm quality of the male offspring in adulthood. The protein deficiency appeared to reduce sertoli cell number, sperm motility, and sperm count.[12] * Altered cardiac energy metabolism: Prenatal nutrition, specifically protein nutrition, may affect the regulation of cardiac energy metabolism through changes in specific genes.[13] * Increased passive stiffness: Intrauterine undernutrition was shown to increase passive stiffness in skeletal muscles in rats.[14] From these studies it is possible to conclude that prenatal protein nutrition is vital to the development of the fetus, especially the brain, the susceptibility to diseases in adulthood, and even gene expression. When pregnant females of various species were given low-protein diets, the offspring were shown to have many deficits. These findings highlight the great significance of adequate protein in the prenatal diet. ## Epidemiology[edit] Deaths from protein-energy malnutrition per million persons in 2012 0-0 1-3 4-6 7-13 14-22 23-38 39-65 66-182 183-313 314-923 Although protein energy malnutrition is more common in low-income countries, children from higher-income countries are also affected, including children from large urban areas in low socioeconomic neighborhoods. This may also occur in children with chronic diseases, and children who are institutionalized or hospitalized for a different diagnosis. Risk factors include a primary diagnosis of intellectual disability, cystic fibrosis, malignancy, cardiovascular disease, end stage renal disease, oncologic disease, genetic disease, neurological disease, multiple diagnoses, or prolonged hospitalization. In these conditions, the challenging nutritional management may get overlooked and underestimated, resulting in an impairment of the chances for recovery and the worsening of the situation.[15] PEM is fairly common worldwide in both children and adults and accounts for 6 million deaths annually.[2] In the industrialized world, PEM is predominantly seen in hospitals, is associated with disease, or is often found in the elderly.[2] ## Co-morbidity[edit] A large percentage of children that suffer from PEM also have other co-morbid conditions. The most common co-morbidities are diarrhea (72.2% of a sample of 66 subjects) and malaria (43.3%). However, a variety of other conditions have been observed with PEM, including sepsis, severe anaemia, bronchopneumonia, HIV, tuberculosis, scabies, chronic suppurative otitis media, rickets, and keratomalacia. These co-morbidities tax already malnourished children and may prolong hospital stays initially for PEM and may increase the likelihood of death.[16] The general explanation of increased infectious comorbidity in malnourished people is that (1) the immune system is what prevents such diseases from being more widespread in healthy, well-nourished people and (2) malnutrition stresses and diminishes immune function. In other words, malnutrition tends to cause (mild or moderate) immunodeficiency, eroding the barriers that normally keep infectious diseases at bay. For example, this reversal is well established regarding the variable natural history of tuberculosis in the pre–TB drug era. Epidemiologically, there are also associations between malnutrition and other health risks via the common underlying factor of poverty. For example, condoms can reduce spread of HIV, but impoverished people often may not have money to buy condoms or a nearby place to buy them. Also, once a poor person has any particular infection, they may not have access to optimal treatment of it, which allows it to get worse, present more chances of transmission, and so on. Even when a developing country nominally/officially has national health insurance with universal health care, the poorest quarter of its population may face a de facto reality of poor health care access. ## References[edit] 1. ^ Franco, V.; Hotta, JK; Jorge, SM; Dos Santos, JE (1999). "Plasma fatty acids in children with grade III protein–energy malnutrition in its different clinical forms: Marasmus, marasmic kwashiorkor, and kwashiorkor". Journal of Tropical Pediatrics. 45 (2): 71–5. doi:10.1093/tropej/45.2.71. PMID 10341499. 2. ^ a b c d "Dietary Reference Intake: The Essential Guide to Nutrient Requirements" published by the Institute of Medicine and available online at https://www.nap.edu/read/11537/chapter/14?term=protein-energy+malnutrition#151 3. ^ Muscaritoli, Maurizio; Molfino, Alessio; Bollea, Maria Rosa; Fanelli, Filippo Rossi (2009). "Malnutrition and wasting in renal disease". Current Opinion in Clinical Nutrition and Metabolic Care. 12 (4): 378–83. doi:10.1097/MCO.0b013e32832c7ae1. PMID 19474712. 4. ^ Bosaeus, Ingvar (2008). "Nutritional support in multimodal therapy for cancer cachexia". Supportive Care in Cancer. 16 (5): 447–51. doi:10.1007/s00520-007-0388-7. PMID 18196284. 5. ^ Liu, T; Howard, RM; Mancini, AJ; Weston, WL; Paller, AS; Drolet, BA; Esterly, NB; Levy, ML; et al. (2001). "Kwashiorkor in the United States: Fad diets, perceived and true milk allergy, and nutritional ignorance". Archives of Dermatology. 137 (5): 630–6. PMID 11346341. 6. ^ Portman OW, Neuringer M, Alexander M (November 1987). "Effects of maternal and long-term postnatal protein malnutrition on brain size and composition in rhesus monkeys". The Journal of Nutrition. 117 (11): 1844–51. doi:10.1093/jn/117.11.1844. PMID 3681475. 7. ^ Hernández A, Burgos H, Mondaca M, Barra R, Núñez H, Pérez H, Soto-Moyano R, Sierralta W, Fernández V, Olivares R, Valladares L (2008). "Effect of prenatal protein malnutrition on long-term potentiation and BDNF protein expression in the rat entorhinal cortex after neocortical and hippocampal tetanization". Neural Plasticity. 2008: 1–9. doi:10.1155/2008/646919. PMC 2442167. PMID 18604298. 8. ^ Bellinger L, Sculley DV, Langley-Evans SC (May 2006). "Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats". International Journal of Obesity. 30 (5): 729–38. doi:10.1038/sj.ijo.0803205. PMC 1865484. PMID 16404403. 9. ^ Sutton GM, Centanni AV, Butler AA (April 2010). "Protein malnutrition during pregnancy in C57BL/6J mice results in offspring with altered circadian physiology before obesity". Endocrinology. 151 (4): 1570–80. doi:10.1210/en.2009-1133. PMC 2850243. PMID 20160133. 10. ^ Rasmussen KM, Habicht JP (February 2010). "Maternal supplementation differentially affects the mother and newborn". The Journal of Nutrition. 140 (2): 402–6. doi:10.3945/jn.109.114488. PMID 20032480. 11. ^ Augustyniak RA, Singh K, Zeldes D, Singh M, Rossi NF (May 2010). "Maternal protein restriction leads to hyperresponsiveness to stress and salt-sensitive hypertension in male offspring". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 298 (5): R1375–82. doi:10.1152/ajpregu.00848.2009. PMC 2867525. PMID 20200128. 12. ^ Toledo FC, Perobelli JE, Pedrosa FP, Anselmo-Franci JA, Kempinas WD (2011). "In utero protein restriction causes growth delay and alters sperm parameters in adult male rats". Reproductive Biology and Endocrinology. 9: 94. doi:10.1186/1477-7827-9-94. PMC 3141647. PMID 21702915. 13. ^ Slater-Jefferies JL, Lillycrop KA, Townsend PA, Torrens C, Hoile SP, Hanson MA, Burdge GC (August 2011). "Feeding a protein-restricted diet during pregnancy induces altered epigenetic regulation of peroxisomal proliferator-activated receptor-α in the heart of the offspring". Journal of Developmental Origins of Health and Disease. 2 (4): 250–255. doi:10.1017/S2040174410000425. PMC 3191520. PMID 22003431. 14. ^ Toscano AE, Ferraz KM, Castro RM, Canon F (2010). "Passive stiffness of rat skeletal muscle undernourished during fetal development". Clinics (São Paulo, Brazil). 65 (12): 1363–9. doi:10.1590/s1807-59322010001200022. PMC 3020350. PMID 21340228. 15. ^ "Marasmus and Kwashiorkor". Medscape Reference. May 2009. 16. ^ Ubesie, Agozie C.; Ibeziako, Ngozi S.; Ndiokwelu, Chika I.; Uzoka, Chinyeaka M.; Nwafor, Chinelo A. (2012-01-01). "Under-five Protein Energy Malnutrition Admitted at the University of In Nigeria Teaching Hospital, Enugu: a 10 year retrospective review". Nutrition Journal. 11: 43. doi:10.1186/1475-2891-11-43. ISSN 1475-2891. PMC 3487930. PMID 22704641. ## Further reading[edit] * Bistrian, Bruce R.; McCowen, Karen C.; Chan, Samuel (1999). "Protein–energy malnutrition in dialysis patients". American Journal of Kidney Diseases. 33 (1): 172–5. doi:10.1016/S0272-6386(99)70278-7. PMID 9915286. * Protein–Energy Undernutrition at Merck Manual of Diagnosis and Therapy Professional Edition ## External links[edit] Classification D * ICD-10: E40-E44 * ICD-9-CM: 260-263 * MeSH: D011502 External resources * eMedicine: derm/797 * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Protein–energy malnutrition	c0033677	1,208	wikipedia	https://en.wikipedia.org/wiki/Protein%E2%80%93energy_malnutrition	2021-01-18T18:51:12	{"mesh": ["D011502"], "umls": ["C0033677"], "wikidata": ["Q4082071"]}
Morahan et al. (1996) mapped an insulin-dependent diabetes mellitus gene, designated IDDM13, to chromosome 2q34 on the basis of analysis of 98 affected sib pairs. The maximum lod score with D2S164 was 3.345. Using the MAP-MAKER/Sibs program, which allows multipoint linkage analysis to be performed on data collected from affected sib pairs, a peak maximum lod score was obtained in the region of the markers D2S137-D2S164. Morahan et al. (1996) noted that a predictor of IDDM is the presence of circulating islet antibodies (ICA) in first-degree relatives of affected probands; however, since not all ICA+ individuals progress to clinical disease, genes that control this phenotype (i.e., development of ICA) may act early in the process leading to diabetes mellitus. Morahan et al. (1996) performed additional multipoint linkage analyses including those sibs that had either ICA or IDDM. Results of these analyses showed that evidence for linkage increases at map positions near IDDM13, suggesting that IDDM13 controls an early event in islet cell autoimmunity. Morahan et al. (1996) postulated that identification of this gene may facilitate identification of a subset of at-risk individuals. Fox et al. (2000) found that the murine ortholog of the human IDDM13 gene (Idd13) was involved in the nonobese diabetic (NOD) mouse model along with Idd5 (600320) in the regulation of a T lymphocyte-dependent progression from a benign to a destructive stage of insulitis. This was the first demonstration of a role for individual non-MHC loci, IDD5 and IDD13, in a specific, critical step in diabetes pathogenesis, namely, T-cell recruitment to islet lesions driving destructive inflammation. The study also illustrated the importance of identifying intermediate phenotypes in complex disease pathogenesis as an approach to gene identification. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	DIABETES MELLITUS, INSULIN-DEPENDENT, 13	c1832474	1,209	omim	https://www.omim.org/entry/601318	2019-09-22T16:15:11	{"mesh": ["C563352"], "omim": ["601318"], "synonyms": ["Alternative titles", "INSULIN-DEPENDENT DIABETES MELLITUS 13"]}
A Pierre Robin syndrome associated with bone disease characterized by severe short-limbed dwarfism, joint dislocations, club feet along with distinctive facies and radiographic findings. ## Epidemiology Atelosteogenesis I (AOI) is a very rare infrequently described disorder. ## Clinical description Affected neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and if born alive have cardiorespiratory failure. Craniofacial dysmorphism describes a prominent forehead, hypertelorism, a depressed nasal bridge with a grooved tip, micrognathia and frequently a cleft palate. There is a continuum with overlapping clinical findings between atelosteogenesis I, atelosteogenesis III and boomerang dysplasia. ## Etiology Atelosteogenesis I results from heterozygous mutations in exons 2-5 and 27-33 of the gene encoding filamin B (FLNB) located to 3p14. ## Diagnostic methods Diagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings comprise severe platyspondyly, distally tapered; shortened, incomplete or absent humeri and femurs; shortened or bowed radii, ulnas, and tibias; hypoplastic pelvis and fibulas; and deficient ossification of the metacarpals, middle and proximal phalanges. ## Differential diagnosis Differential diagnosis comprises other skeletal dysplasias with severe short-limbed dwarfism such as campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome, and thanatophoric dysplasia. Other, differential diagnosis includes achondrogenesis, hypophosphatasia, and osteogenesis imperfecta. ## Antenatal diagnosis Prenatal ultrasound can detect bone dysplasia and other manifestation and plays an important role in early detection and diagnosis. Prenatal ultrasound findings for AOI may include severe limb shortening and deficient ossification of the long bones, shortened flaring or absent humeri and femurs from 18 weeks onwards. Other skeletal abnormalities as well as some facial dysmorphic features may be detectable. ## Genetic counseling All cases have been autosomal dominant and sporadic resulting from de novo mutations in FLNB. ## Management and treatment Palliative care is offered to newborns suffering from AOI. ## Prognosis Prognosis is poor. Death is often due to a combination of pulmonary hypoplasia and tracheobronchomalacia early in life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Atelosteogenesis type I	c0265283	1,210	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1190	2021-01-23T18:39:19	{"gard": ["9287"], "mesh": ["C535396"], "omim": ["108720"], "umls": ["C0265283"], "icd-10": ["Q78.8"], "synonyms": ["AO1", "AOI", "Atelosteogenesis type 1", "Giant cell chondrodysplasia", "Spondylo-humero-femoral dysplasia"]}
For a phenotypic description of gout and a discussion of genetic heterogeneity of serum uric acid concentration quantitative trait loci, see UAQTL1 (138900). Mapping Sulem et al. (2011) tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. Sulem et al. (2011) identified the C allele of a C/T variant on telomeric chromosome 1, chr1_142697422 (NCBI36), as associated with gout (OR = 1.92, p = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 standard deviation, p = 4.5 x 10(-16)). The disease effect was confined to males. Sulem et al. (2011) also identified association of a missense variant in ALDH16A1 (613358) with gout and serum uric acid levels (UAQTL5; 614746). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 6	c3553635	1,211	omim	https://www.omim.org/entry/614747	2019-09-22T15:54:19	{"omim": ["614747"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (January 2018) Allomnesia or memory illusion is a memory disorder, which involves distorted memories of a past situation. It is generally a physiological phenomenon, which is occasionally found in most subjects.[1] Pathologically, it can occur frequently in subjects with mood disorders such as depression or mania and in those suffering from schizophrenia, paranoia or other types of delirium. Treatment is done by identifying the cause of the disease and treating the same. ## References[edit] 1. ^ Focosi, Daniele. "Mental disorders". www.ufrgs.br. Retrieved 29 January 2018. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Allomnesia	None	1,212	wikipedia	https://en.wikipedia.org/wiki/Allomnesia	2021-01-18T18:35:16	{"icd-9": ["780.93"], "icd-10": ["R41.3"], "wikidata": ["Q3612627"]}
See Immune Response to Synthetic Polypeptide--IRPHEGAL (146810) and Chan et al. (1984). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	IMMUNE RESPONSE TO SYNTHETIC POLYPEPTIDE--IRGAT	c1840267	1,213	omim	https://www.omim.org/entry/146820	2019-09-22T16:39:37	{"omim": ["146820"]}
Congenital hyperinsulinism is a disease where there are abnormally high levels of insulin, a hormone produced by the beta cells of the pancreas that helps control blood sugar levels. Because of the high levels of insulin, people with this disease have frequent episodes of low blood sugar (hypoglycemia) that can even occur after eating. In babies and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma. The severity and onset of these episodes varies, even among members of the same family. In about 60% of the cases, the episodes start within the first month of life and are very severe and difficult to manage. In other cases, the disease starts in childhood or later, and the symptoms are mild. Early diagnosis and treatment is important to prevent neurologic damage from hypoglycemia. Congenital hyperinsulinism is caused by mutations in at least 11 different genes, including ABCC8 (responsible for about 45 % of the cases), KCNJ11, GLUD1, GCK, HK1, HADH, HNF4A, HNF1A, SLC16A1, UCP2, and PGM1. Inheritance may be autosomal recessive or autosomal dominant. Some cases are caused by loss of genetic material in a region of chromosome 11 (11p15) that comes from the mother (maternal chromosome). According to the extent of abnormal beta cells, the disease can be focal (when abnormal beta cells are limited to 1 or a few areas in the pancreas) and diffuse (where the abnormal beta cells are spread throughout the pancreas). The goal of treatment is to manage the hypoglycemia to prevent brain damage. Medications may include diazoxide, octreotide, and glucagon. Surgery to remove part of the pancreas might be required in severe cases. Genetic testing may help to guide the best treatment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Congenital hyperinsulinism	c3888018	1,214	gard	https://rarediseases.info.nih.gov/diseases/3947/congenital-hyperinsulinism	2021-01-18T18:01:09	{"mesh": ["D044903"], "orphanet": ["657"], "synonyms": ["Persistent hyperinsulinemic hypoglycemia of infancy", "PHHI", "Hyperinsulinemic hypoglycemia familial", "Hypoglycemia hyperinsulinemic of infancy", "Hyperinsulinism familial with pancreatic nesidioblastosis", "Nesidioblastosis of pancreas", "Hyperinsulinism congenital", "Hyperinsulinemic hypoglycemia due to focal adenomatous hyperplasia", "CHI", "Familial hyperinsulinism", "Congenital isolated hyperinsulinism"]}
For a phenotypic description and a discussion of genetic heterogeneity of malignant hyperthermia, see MHS1 (145600). Mapping In 3 unrelated families, Levitt et al. (1991) excluded linkage of the MHS phenotype to loci on 19q13.1, thus indicating genetic heterogeneity. Levitt et al. (1992) extended these studies to 16 MHS families. Four were found to be linked to chromosome 19; 5 were found to be closely linked to the anonymous marker NM23 (156490) on 17q11.2-q24 (maximum lod = 3.26 at theta = 0.0); and 2 families were clearly unlinked to either of these regions. In 5 additional families, there were insufficient data to determine their linkage status. Olckers et al. (1992) provided evidence for linkage of MHS to the SCN4A gene (603967), which encodes the adult sodium channel alpha subunit, in 3 informative families (cumulative lod score of 2.1 at theta = 0.0). In a large family with autosomal dominant HYPP (170500) and MHS, Moslehi et al. (1998) found evidence for linkage of both disorders to the SCN4A locus on chromosome 17q (maximum lod for HYPP = 6.79 at theta = 0.0; lod for MHS = 1.76 at theta = 0.0). In 3 families in which MHS did not show linkage to chromosome 19, Sudbrak et al. (1993) excluded linkage also to an 84-cM interval on 17q. At the same time, they excluded linkage to CACNL1A3, which is located on 1q, as well as to CACNLB1 (114207), CACNLG (114209), and SCN4A, which are located on 17q. Neuro \- Hyperthermia Inheritance \- Autosomal dominant form (unlinked to 19q13.1-q13.2) \- heterogeneous Metabolic \- Lactic acidosis Misc \- Precipitated by general anesthesia \- Hypertonicity of voluntary muscles \- Response to Dantrolene sodium Lab \- Elevated blood CPK, phosphate and potassium Muscle \- Myopathy \- Rhabdomyolysis may follow severe exercise in hot conditions, neuroleptic drugs, alcohol, or infections ▲ 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	MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 2	c0024591	1,215	omim	https://www.omim.org/entry/154275	2019-09-22T16:38:34	{"mesh": ["D008305"], "omim": ["154275"], "orphanet": ["423"], "synonyms": ["Alternative titles", "MHS2"], "genereviews": ["NBK1146"]}
A rare form of chronic cutaneous lupus erythematosus characterized by extreme photosensitivity with intermittent formation of erythematous, edematous, urticarial-like, smooth plaques on sun-exposed skin areas. The lesions heal without scarring. The course of the disease is benign, and development of systemic lupus erythematosus is infrequent. Most patients do not have lupus-related autoantibodies. Skin biopsy shows a perivascular and periadnexal lymphocytic infiltrate and increased dermal mucin deposition without involvement of the dermoepidermal junction. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Lupus erythematosus tumidus	c0406636	1,216	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90283	2021-01-23T17:37:24	{"gard": ["13003"], "umls": ["C0406636"], "icd-10": ["L93.2"], "synonyms": ["Intermittent cutaneous lupus"]}
## Description Ebstein anomaly is characterized by downward displacement of variable severity of the tricuspid valve into the right ventricle. The valve leaflets may be dysplastic, and a variable portion of the proximal part of the right ventricle is in continuity with the right atrium ('atrialized'), because of the abnormally positioned tricuspid valve. The severity of this defect includes a spectrum ranging from severe disturbance in fetal and neonatal life to virtually asymptomatic survival to adult life. Associated extracardiac anomalies in the setting of chromosomal or mendelian disorders occur in about 20% of patients with Ebstein anomaly. Nonsyndromic Ebstein anomaly can occur as a sporadic or a familial defect (summary by Digilio et al., 2011). Clinical Features Gouffault et al. (1960) found Ebstein malformation in 1 sib and a comparable deformity of the mitral valve in a sister. The same combination of Ebstein anomaly in 1 sib and comparable mitral anomaly in another was apparently present in the family reported by Yamauchi and Cayler (1964). Gueron et al. (1966) described a brother and sister with Ebstein anomaly, a congenital malformation of the heart that consists of downward placement of the tricuspid valve such that part of the right ventricle becomes incorporated into the pretricuspid chamber. Associated deformity of the tricuspid leaflets and defect of the atrial septum are frequent. Donegan et al. (1968) found Ebstein anomaly in a 6-year-old boy and his maternal uncle. The Ebstein anomaly predisposes to right bundle branch block, preexcitation, and an increased risk of sudden cardiac death. Atrial fibrillation occurs in about one-third of patients with Ebstein anomaly. Pierard et al. (1985) reported atrial standstill in father and son with Ebstein anomaly. McIntosh et al. (1992) diagnosed severe Ebstein anomaly prenatally in 2 sisters born of Sri Lankan parents who were first cousins once removed. Digilio et al. (2011) studied 44 consecutive patients with Ebstein anomaly presenting to 2 pediatric cardiology centers. In 12 (27%) of the 44 patients, Ebstein anomaly was part of a syndrome, and 7 of those patients were diagnosed with distinct disorders, including CHARGE syndrome (214800) in 2, and VACTERL association (see 192350), Noonan syndrome (163950), Kabuki syndrome (147920), Holt-Oram syndrome (142900), and Cornelia de Lange syndrome (see 122470) in 1 each. Of the 32 patients with nonsyndromic Ebstein anomaly, 10 (31%) had additional congenital heart defects (CHDs), including 7 atrial septal defects, 2 ventricular septal defects, 2 pulmonary stenoses, 1 dextrocardia, 1 aortic coarctation, and 1 patent ductus arteriosus; 1 of the patients with ASD also had a Wolff-Parkinson-White cardiac conduction anomaly (WPW; see 194200). The remaining 22 patients had Ebstein defect alone; 1 of these patients also had WPW. Familial recurrence of CHD was seen in 1 family, in which a mother with nonsyndromic Ebstein anomaly had a son with persistence of left ventricular noncompaction (see 604169). Cytogenetics In 2 unrelated patients with Ebstein anomaly and other malformations, de Lonlay-Debeney et al. (1998) described 2 distinct rearrangements of the long arm of chromosome 11. In a study of 44 consecutive patients with Ebstein anomaly, Digilio et al. (2011) performed standard chromosome analysis and array CGH in the 12 patients in whom the anomaly was part of a syndrome, and identified chromosomal anomalies in 3 of them: a 1p36 deletion (see 607872) in association with an Xpter-Xp22.3 duplication (see 300830), an 8p23.1 deletion, and a deletion of 18q21.3-qter (see 601808). Molecular Genetics In 28 patients with nonsyndromic Ebstein anomaly, Digilio et al. (2011) screened the candidate genes GATA4 (600576) and NKX2.5 (600584), but did not find any mutations. Animal Model Canine tricuspid valve malformation (CTVM) is morphologically similar to Ebstein anomaly. Andelfinger et al. (2003) noted that familial occurrence of CTVM had been described, although most cases appeared to be sporadic. They studied 3 purebred Labrador retriever kindreds enriched for CTVM. Pedigree analysis indicated that CTVM segregated as an autosomal dominant trait with reduced penetrance. Genomewide linkage analysis in 1 kindred identified a CTVM susceptibility locus on chromosome 9 with a maximum multipoint lod score of 3.33. The 2 additional kindreds showed a conserved disease haplotype, indicating a founder effect in apparently unrelated Labrador retriever kindreds. The critical region of canine chromosome 9 contained a syntenic group of genes that has its human counterpart on 17q12-q23. Andelfinger et al. (2003) pointed to several possible candidate genes on 17q: TBX2 (600747) on 17q23, which plays a pivotal role in chamber differentiation and atrioventricular canal formation; TOB1 (605523) on 17q21, which is an important transmitter in the ERBB2 (164870) cascade involved in cardiac muscle and valve formation; and FZD2 (600667) on 17q21.1, which is a receptor in the Wnt-dishevelled signal transduction cascade expressed during cardiac morphogenesis. Cardiac \- Ebstein anomaly \- Congenital heart defect \- Downward placement of tricuspid valve \- Partial atrially displaced right ventricle \- Deformed tricuspid leaflets \- Atrial septal defect \- Deformed mitral valve \- Right bundle branch block \- Preexcitation \- Increased risk of sudden cardiac death \- Atrial fibrillation \- Atrial standstill 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	EBSTEIN ANOMALY	c0013481	1,217	omim	https://www.omim.org/entry/224700	2019-09-22T16:28:28	{"doid": ["14289"], "mesh": ["D004437"], "omim": ["224700"], "icd-9": ["746.2"], "icd-10": ["Q22.5"], "orphanet": ["1880"]}
## Clinical Features Arias et al. (1976) described a seemingly new form of skeletal dysplasia among the Irapa Indians of Venezuela. Features included short spine from platyspondyly, short metacarpals and metatarsals, and striking changes in the proximal femoral and distal humeral epiphyses. Hernandez et al. (1980) described SEMDIT in 3 sibs from a Mexican mestizo family. Arias (1981) suggested SEMI as a simple designation. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, disproportionate short-trunked (identifiable at birth) CHEST Ribs Sternum Clavicles & Scapulae \- Widened costochondral junction \- Pectus carinatum SKELETAL \- Osteoarthritis \- Spondyloepimetaphyseal dysplasia Spine \- Platyspondyly \- Small sacrum \- Increased lumbar lordosis Pelvis \- Protruding iliac wings \- Coxa vara \- Wide femoral neck Limbs \- Short arms \- Limited forearm extension \- Metaphyseal dysplasia \- Severe epiphyseal hypoplasia \- Osteoarthritis \- Arthralgias \- Diaphyseal shortness \- Genu valgum Hands \- Short metacarpals \- Short, broad hands \- Capitate-hamate fusion Feet \- Short metatarsals \- Flat, broad feet \- Long second toes MISCELLANEOUS \- Waddling gait ▲ 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	SPONDYLOEPIMETAPHYSEAL DYSPLASIA, IRAPA TYPE	c0432213	1,218	omim	https://www.omim.org/entry/271650	2019-09-22T16:22:02	{"mesh": ["C562958"], "omim": ["271650"], "orphanet": ["93351"]}
Remnants of the pupillary membrane persist as strands and other irregular tissue in the region of the pupil. Cassady and Light (1957) described a family in which 11 persons in 4 generations showed remnants of the pupillary membrane. Four of these also had congenital cataract and 3 had increased corneal diameter. Possibly the Rieger syndrome (see 180500) should be considered. Eyes \- Persistent pupillary membrane remnants \- Congenital cataract \- Increased corneal diameter Inheritance \- Autosomal dominant \- ? same as Rieger syndrome ▲ 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	PUPILLARY MEMBRANE, PERSISTENCE OF	c0271130	1,219	omim	https://www.omim.org/entry/178900	2019-09-22T16:35:22	{"mesh": ["C562700"], "omim": ["178900"]}
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-30 (EIEE30) is caused by heterozygous mutation in the SIK1 gene (605705) on chromosome 21q22. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350. Clinical Features Hansen et al. (2015) reported 6 unrelated children with a severe neurodevelopmental disorder associated with early-onset refractory epilepsy. Seizure onset occurred shortly after birth or within the first months of life and included myoclonic, generalized tonic-clonic, and atonic seizures, as well as infantile spasms. All patients had severely delayed psychomotor development. Two patients died in infancy, and the 4 who survived showed severe cognitive impairment with poor or absent speech and autistic features. EEG showed variable abnormalities, such as burst suppression patterns, multifocal spikes, slowed background activity, and hypsarrhythmia. Brain imaging, when performed, was normal. Additional features included abnormal involuntary movements, poor spontaneous movement, poor visual and/or auditory responses, bruxism, poor feeding, and respiratory insufficiency. Molecular Genetics In 6 unrelated children with early infantile epileptic encephalopathy-30, Hansen et al. (2015) identified 6 different de novo heterozygous mutations, 3 missense and 3 truncating, in the SIK1 gene (see, e.g., 605705.0001-605705.0005). In vitro functional expression studies showed that all the mutant proteins identified, even the truncated ones, retained normal kinase activity. Studies in HEK293 cells showed that the missense mutant proteins had normal punctate nuclear localization, similar to wildtype, whereas the truncated proteins had a broader pattern of localization in the nucleus and cytoplasm as well as increased stability compared to wildtype. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Poor visual contact RESPIRATORY \- Respiratory difficulties ABDOMEN Gastrointestinal \- Feeding difficulties NEUROLOGIC Central Nervous System \- Encephalopathy \- Delayed psychomotor development, profound \- Lack of speech \- Few spontaneous movements \- Abnormal involuntary movements \- Seizures, refractory \- Myoclonic seizures \- Generalized tonic-clonic seizures \- Variable abnormalities seen on EEG \- Burst suppression pattern \- Background slowing \- Multifocal spikes \- Hypsarrhythmia Behavioral Psychiatric Manifestations \- Autistic features MISCELLANEOUS \- Onset at birth or in the first months of life \- Early death may occur \- Mutations occur de novo MOLECULAR BASIS \- Caused by mutation in the salt-inducible kinase 1 gene (SIK1, 605705.0001 ) ▲ 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	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 30	c0270855	1,220	omim	https://www.omim.org/entry/616341	2019-09-22T15:49:11	{"doid": ["0080465"], "mesh": ["C562695"], "omim": ["616341"], "orphanet": ["1935", "3451", "1934"]}
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is an inherited metabolic disorder that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). People with MCADD do not have enough of an enzyme needed to metabolize a group of fats called medium-chain fatty acids. Signs and symptoms usually begin by early childhood and may include vomiting, lack of energy, and low blood sugar (hypoglycemia). Symptoms can be triggered by periods of fasting or by illnesses. MCADD is caused by mutations in the ACADM gene and inheritance is autosomal recessive. Treatment includes strict avoidance of fasting and avoidance of medium chain triglycerides in the diet. If not treated, people with MCADD are at risk of serious complications including sudden death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Medium-chain acyl-coenzyme A dehydrogenase deficiency	c0220710	1,221	gard	https://rarediseases.info.nih.gov/diseases/540/medium-chain-acyl-coenzyme-a-dehydrogenase-deficiency	2021-01-18T17:59:12	{"mesh": ["C536038"], "omim": ["201450"], "umls": ["C0220710"], "orphanet": ["42"], "synonyms": ["MCAD deficiency", "Acyl-CoA dehydrogenase medium chain deficiency of", "MCADH deficiency", "ACADM deficiency", "MCADD", "Medium chain acyl CoA dehydrogenase deficiency", "Medium-chain acyl-CoA dehydrogenase deficiency"]}
## Summary The purpose of this overview is to increase the awareness of clinicians regarding the causes of Bardet-Biedl syndrome and related genetic counseling issues. The following are the goals of this overview: ### Goal 1. Describe the clinical characteristics of Bardet-Biedl syndrome. ### Goal 2. Review the genetic causes of Bardet-Biedl syndrome. ### Goal 3. Provide an evaluation strategy to identify the genetic cause of Bardet-Biedl syndrome in a proband (when possible). ### Goal 4. Review management of Bardet-Biedl syndrome. ### Goal 5. Inform genetic counseling of family members of an individual with Bardet-Biedl syndrome. ## Diagnosis ## Clinical Characteristics ## Differential Diagnosis ## Management [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bardet-Biedl Syndrome Overview	None	1,222	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1363/	2021-01-18T21:40:16	{"synonyms": []}
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: "Sesamoiditis" – news · newspapers · books · scholar · JSTOR (January 2015) (Learn how and when to remove this template message) Sesamoiditis Some human sesamoid bones SpecialtyOrthopedics Sesamoiditis is inflammation of the sesamoid bones. ## Contents * 1 Humans * 2 Horses * 3 Causes * 4 Notable cases * 5 References * 6 External links ## Humans[edit] Sesamoiditis occurs on the bottom of the foot, just behind the big toe. There are normally two sesamoid bones on each foot; sometimes sesamoids can be bipartite, which means they each comprise two separate pieces. The sesamoids are roughly the size of jelly beans. The sesamoid bones act as a fulcrum for the flexor tendons, the tendons which bend the big toe downward. Symptoms include inflammation and pain. Sometimes a sesamoid bone is fractured. This can be difficult to pick up on X-ray, so a bone scan or MRI is a better alternative.[1] Among those who are susceptible to the malady are dancers, catchers and pitchers in baseball, soccer players, and football players.[2][3] ## Horses[edit] Location of the sesamoid bones, behind the fetlock. In the horse it occurs at the horse's fetlock. The sesamoid bones lie behind the bones of the fetlock, at the back of the joint, and help to keep the tendons and ligaments that run between them correctly functioning. Usually periostitis (new bone growth) occurs along with sesamoiditis, and the suspensory ligament may also be affected. Sesamoiditis results in inflammation, pain, and eventually bone growth. ## Causes[edit] In humans, excessive forces caused by sudden bending upwards of the big toe, high heels, or a stumble can contribute to sesamoiditis. Once the sesamoid bone is injured it can be very difficult to cure, because every time you walk you put additional pressure on the sesamoid bone. Treatment in humans consists of anti-inflammatory medication, cortisone injections, strapping to immobilize the big toe, and orthotics with special accommodations to keep pressure off the affected bone. In horses, sesamoiditis is generally caused by excess stress on the fetlock joint. Conformation that promotes sesamoiditis include long pasterns, or horses with long toes and low heels. ## Notable cases[edit] * Josh Zeid, major league baseball pitcher[4] * Melvin Upton, major league baseball player [5] * JJ O'Donnell, football player for Gateshead FC[6] ## References[edit] 1. ^ Dines, Joshua M.; Altchek, David W.; Andrews, James; Elattrache, Neal S.; Wilk, Kevin E.; Yocum, Lewis A. (September 26, 2012). Sports Medicine of Baseball. ISBN 9781451153828. Retrieved October 16, 2014. 2. ^ Walker, Brad (2007). The Anatomy of Sports Injuries. ISBN 9781556436666. Retrieved October 16, 2014. 3. ^ Rich, Brent S.E; Pratte, Mitchell K. (October 25, 2010). Tarascon Sports Medicine Pocketbook. ISBN 9781449671907. Retrieved October 16, 2014. 4. ^ "Astros P Zeid needs season-ending foot surgery". ESPN.com. Associated Press. July 30, 2014. Retrieved July 31, 2014. 5. ^ "Upton to miss rest of spring training with inflammation in left foot". MLB.com. Retrieved February 27, 2015. 6. ^ Association, Press (May 19, 2015). "Sunderland's Danny Graham helps fund Gateshead player's foot surgery". theguardian.com. Retrieved May 20, 2015. ## External links[edit] Classification D * ICD-10: M86.8 * ICD-9-CM: 733.99 * v * t * e Soft tissue disorders Capsular joint Synoviopathy * Synovitis/Tenosynovitis * Calcific tendinitis * Stenosing tenosynovitis * Trigger finger * De Quervain syndrome * Transient synovitis * Ganglion cyst * osteochondromatosis * Synovial osteochondromatosis * Plica syndrome * villonodular synovitis * Giant-cell tumor of the tendon sheath Bursopathy * Bursitis * Olecranon * Prepatellar * Trochanteric * Subacromial * Achilles * Retrocalcaneal * Ischial * Iliopsoas * Synovial cyst * Baker's cyst * Calcific bursitis Noncapsular joint Symptoms * Ligamentous laxity * Hypermobility Enthesopathy/Enthesitis/Tendinopathy upper limb * Adhesive capsulitis of shoulder * Impingement syndrome * Rotator cuff tear * Golfer's elbow * Tennis elbow lower limb * Iliotibial band syndrome * Patellar tendinitis * Achilles tendinitis * Calcaneal spur * Metatarsalgia * Bone spur other/general: * Tendinitis/Tendinosis Nonjoint Fasciopathy * Fasciitis: Plantar * Nodular * Necrotizing * Eosinophilic Fibromatosis/contracture * Dupuytren's contracture * Plantar fibromatosis * Aggressive fibromatosis * Knuckle pads * v * t * e Inflammation Symptoms * Flushing (Rubor) * Fever (Calor) * Swelling (Tumor) * Pain (Dolor) * Malaise Mechanism Acute Plasma-derived mediators * Bradykinin * complement * C3 * C5a * MAC * coagulation * Factor XII * Plasmin * Thrombin Cell-derived mediators preformed: * Lysosome granules * biogenic amines * Histamine * Serotonin synthesized on demand: * cytokines * IFN-γ * IL-8 * TNF-α * IL-1 * eicosanoids * Leukotriene B4 * Prostaglandins * Nitric oxide * Kinins Chronic * Macrophage * Epithelioid cell * Giant cell * Granuloma Other * Acute-phase reaction * Vasodilation * Increased vascular permeability * Exudate * Leukocyte extravasation * Chemotaxis Tests * Full blood count * Leukocytosis * C-reactive protein * Erythrocyte sedimentation rate General * Lymphadenopathy * List of inflammed body part states * v * t * e Bone and joint disease Bone Inflammation endocrine: * Osteitis fibrosa cystica * Brown tumor infection: * Osteomyelitis * Sequestrum * Involucrum * Sesamoiditis * Brodie abscess * Periostitis * Vertebral osteomyelitis Metabolic * Bone density * Osteoporosis * Juvenile * Osteopenia * Osteomalacia * Paget's disease of bone * Hypophosphatasia Bone resorption * Osteolysis * Hajdu–Cheney syndrome * Ainhum * Gorham's disease Other * Ischaemia * Avascular necrosis * Osteonecrosis of the jaw * Complex regional pain syndrome * Hypertrophic pulmonary osteoarthropathy * Nonossifying fibroma * Pseudarthrosis * Stress fracture * Fibrous dysplasia * Monostotic * Polyostotic * Skeletal fluorosis * bone cyst * Aneurysmal bone cyst * Hyperostosis * Infantile cortical hyperostosis * Osteosclerosis * Melorheostosis * Pycnodysostosis Joint Chondritis * Relapsing polychondritis Other * Tietze's syndrome Combined Osteochondritis * Osteochondritis dissecans Child leg: * hip * Legg–Calvé–Perthes syndrome * tibia * Osgood–Schlatter disease * Blount's disease * foot * Köhler disease * Sever's disease spine * * Scheuermann's_disease arm: * wrist * Kienböck's disease * elbow * Panner disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Sesamoiditis	c0264076	1,223	wikipedia	https://en.wikipedia.org/wiki/Sesamoiditis	2021-01-18T18:54:12	{"icd-9": ["733.99"], "icd-10": ["M89.37"], "wikidata": ["Q4411017"]}
Noncompaction cardiomyopathy Other namesSpongiform cardiomyopathy Noncompaction cardiomyopathy is inherited in an autosomal dominant manner SpecialtyCardiology Non-compaction cardiomyopathy (NCC), is a rare congenital cardiomyopathy that affects both children and adults.[1] It results from the failure of myocardial development during embryogenesis.[2][3] During development, the majority of the heart muscle is a sponge-like meshwork of interwoven myocardial fibers. As normal development progresses, these trabeculated structures undergo significant compaction that transforms them from spongy to solid. This process is particularly apparent in the ventricles, and particularly so in the left ventricle. Noncompaction cardiomyopathy results when there is failure of this process of compaction. Because the consequence of non-compaction is particularly evident in the left ventricle, the condition is also called left ventricular noncompaction. Other hypotheses and models have been proposed, none of which is as widely accepted as the noncompaction model. Symptoms range greatly in severity. Most are a result of a poor pumping performance by the heart. The disease can be associated with other problems with the heart and the body. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Genetics * 3 Diagnosis * 3.1 Differential diagnosis * 4 Management * 4.1 Prognosis * 5 Epidemiology * 6 History * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Subjects' symptoms from non-compaction cardiomyopathy range widely. It is possible to be diagnosed with the condition, yet not to have any of the symptoms associated with heart disease.[2] Likewise it possible to have severe heart failure,[3] which even though the condition is present from birth, may only manifest itself later in life.[2] Differences in symptoms between adults and children are also prevalent with adults more likely to have heart failure and children from depression of systolic function.[2] Common symptoms associated with a reduced pumping performance of the heart include:[4] * Breathlessness * Fatigue * Swelling of the ankles * Limited physical capacity and exercise intolerance Two conditions though that are more prevalent in noncompaction cardiomyopathy are: tachyarrhythmia which can lead to sudden cardiac death and clotting of the blood in the heart. ### Complications[edit] The presence of NCC can also lead to other complications around the heart and elsewhere in the body. These are not necessarily common complications and no paper has yet commented on how frequently these complications occur with NCC as well. * Cardiac * Abnormalities of the origin of the left coronary artery * Pulmonary atresia * Stenosis * Right or Left ventricle obstruction * Hypoplastic left ventricle * Mitral regurgitation * Neuromuscular (Pertaining to both nerves and muscles) * Becker's muscular dystrophy * Mitochondrial myopathy * Polyneuropathy and metabolic myopathy * Genetic related * Emery–Dreifuss muscular dystrophy * Myotubular cardiomyopathy * Barth syndrome ## Genetics[edit] The American Heart Association's 2006 classification of cardiomyopathies considers noncompaction cardiomyopathy a genetic cardiomyopathy.[5] Mutations in LDB3 (also known as "Cypher/ZASP") have been described in patients with the condition.[6] There is recent information in which NCC has been seen in combination with 1q21.1 deletion Syndrome.[7] Furthermore mutations in Titin (TTN), RBM20 and also LMNA could be detected in a large cohort of LVNC patients.[8] Loss-of-function variants in the NONO gene have been associated with an X-linked form of noncompaction cardiomyopathy in males who also often present with developmental delays.[9] In addition, a small in-frame deletion was identified in the DES gene, encoding the intermediate filament protein desmin.[10] ## Diagnosis[edit] Trabeculation of the ventricles is normal, as are prominent, discrete muscular bundles greater than 2mm. In non-compaction there are excessively prominent trabeculations. Echocardiography is the reference standard for diagnosing NCC, although it can be well defined by computer tomography scan, positron emission tomography and magnetic resonance imaging.[11] Chin, et al., described echocardiographic method to distinguish non-compaction from normal trabeculation. They described a ratio of the distance from the trough and peak, of the trabeculations, to the epicardial surface.[12] Non-compaction is diagnosed when the trabeculations are more than twice the thickness of the underlying ventricular wall. * Two-dimensional apical four chamber and parasternal short axis images at the level of the ventricles show dilatation of both ventricles, multiple trabeculae and intertrabecular recesses in inferior, lateral, anterior walls, middle and apical portions of the septum and apex of the left ventricle. [1] * Transthoracic two-dimensional study with color and continuous wave Doppler shows left ventricular noncompaction associated with patent ductus arteriosus (PDA). [2] * Transthoracic two-dimensional echocardiogram in apical four chamber and parasternal short axis at the level of both ventricles demonstrate dilatation, deep trabeculae and intertrabecular recesses in the inferior, lateral, anterior walls, middle and apical portions of the septum and apex of the left ventricle. [3] * Two-dimensional parasternal and color Doppler images at the level of both ventricles that show the noncompacted:compacted wall ratio and how the color enters the intertrabecular recesses [4] ### Differential diagnosis[edit] In a study (2006)[citation needed] carried out on 53 patients with the condition in Mexico, 42 had been diagnosed with another form of heart disease and only in the most recent 11 cases that ventricular noncompation was diagnosed and this took several echocardiograms to confirm. The most common misdiagnoses were: * dilated cardiomyopathy: 30 Cases * congenital heart disease: 6 Cases * ischemic heart disease: 2 Cases * disease of the heart valves: 2 Cases * dilated phase hypertensive cardiomyopathy: 1 Case * restrictive cardiomyopathy: 1 Case The high number of misdiagnoses can be attributed to non-compaction cardiomyopathy being first reported in 1990; diagnosis is therefore often overlooked or delayed. Advances in medical imaging equipment have made it easier to diagnose the condition, particularly with the wider use of MRIs. ## Management[edit] One paper [13] has listed the various types of management of care that have been used for various types of NCC. These are similar to management programs for other types of cardiomyopathies which include the use of ACE inhibitors, beta blockers and aspirin therapy to relieve the pressure on the heart, surgical options such as the installation of pacemaker is also an option for those thought to be at a high risk of arrhythmia problems. In severe cases, where NCC has led to heart failure, with resulting surgical treatment including a heart valve operation, or a heart transplant. ### Prognosis[edit] Due to non-compaction cardiomyopathy being a relatively new disease, its impact on human life expectancy is not very well understood. In a 2005 study [3] that documented the long-term follow-up of 34 patients with NCC, 35% had died at the age of 42 +/- 40 months, with a further 12% having to undergo a heart transplant due to heart failure. However, this study was based upon symptomatic patients referred to a tertiary-care center, and so were suffering from more severe forms of NCC than might be found typically in the population. Sedaghat-Hamedani et al. also showed the clinical course of symptomatic LVNC can be severe.[8] In this study cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (DCM).[8] As NCC is a genetic disease, immediate family members are being tested as a precaution, which is turning up more supposedly healthy people with NCC who are asymptomatic. The long-term prognosis for these people is currently unknown. ## Epidemiology[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Noncompaction cardiomyopathy" – news · newspapers · books · scholar · JSTOR (May 2016) Due to its recent establishment as a diagnosis, and it being unclassified as a cardiomyopathy according to the WHO, it is not fully understood how common the condition is. Some reports suggest that it is in the order of 0.12 cases per 100,000. The low number of reported cases though is due to the lack of any large population studies into the disease and have been based primarily upon patients suffering from advanced heart failure. A similar situation occurred with hypertrophic cardiomyopathy, which was initially considered very rare; however is now thought to occur in one in every 500 people in the population. Again due to this condition being established as a diagnosis recently, there are ongoing discussions as to its nature, and to various points such as the ratio of compacted to non-compacted at different age stages. However it is universally understood that non-compaction cardiomyopathy will be characterized anatomically by deep trabeculations in the ventricular wall, which define recesses communicating with the main ventricular chamber. Major clinical correlates include systolic and diastolic dysfunction, associated at times with systemic embolic events.[14] ## History[edit] Non-compaction cardiomyopathy was first identified as an isolated condition in 1984 by Engberding and Benber.[15] They reported on a 33-year-old female presenting with exertional dyspnea and palpitations. Investigations concluded persistence of myocardial sinusoids (now termed non-compaction). Prior to this report, the condition was only reported in association with other cardiac anomalies, namely pulmonary or aortic atresia. Myocardial sinusoids is considered not an accurate term as endothelium lines the intertrabecular recesses. ## See also[edit] * Barth syndrome * Emery–Dreifuss muscular dystrophy * Myotubular myopathy ## References[edit] 1. ^ Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, et al. (November 2003). "Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy". Circulation. 108 (21): 2672–8. doi:10.1161/01.CIR.0000100664.10777.B8. PMID 14623814. 2. ^ a b c d Espinola-Zavaleta N, Soto ME, Castellanos LM, Játiva-Chávez S, Keirns C (September 2006). "Non-compacted cardiomyopathy: clinical-echocardiographic study". Cardiovasc Ultrasound. 4: 35. doi:10.1186/1476-7120-4-35. PMC 1592122. PMID 17002802. 3. ^ a b c Jenni R, Oechslin E (2005). "Non-compaction of the Left Ventricular Myocardium – From Clinical Observation to the Discovery of a New Disease". European Cardiology Review. 1 (1): 23. doi:10.15420/ECR.2005.23. ISSN 1758-3756. 4. ^ The Cardiomyopathy Association (2007-07-23). "LV Non-compaction" (website). Retrieved 2007-07-23. 5. ^ Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. (April 2006). "Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention". Circulation. 113 (14): 1807–16. doi:10.1161/CIRCULATIONAHA.106.174287. PMID 16567565. 6. ^ Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, et al. (December 2003). "Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction". J. Am. Coll. Cardiol. 42 (11): 2014–27. doi:10.1016/j.jacc.2003.10.021. PMID 14662268. 7. ^ A publication is expected by Leiden University Medical Centre 8. ^ a b c Sedaghat-Hamedani F, Haas J, Zhu F, Geier C, Kayvanpour E, Liss M, et al. (2017). "Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy". European Heart Journal. 38 (46): 3449–3460. doi:10.1093/eurheartj/ehx545. PMID 29029073. 9. ^ Scott, Daryl A; Hernandez-Garcia, Andres; Azamian, Mahshid S; Jordan, Valerie K; Kim, Bum Jun; Starkovich, Molly; Zhang, Jinglan; Wong, Lee-Jun; Darilek, Sandra A; Breman, Amy M; Yang, Yaping (November 2016). "Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO". Journal of Medical Genetics. 54 (1): 47–53. doi:10.1136/jmedgenet-2016-104039. ISSN 0022-2593. 10. ^ Marakhonov, Andrey V.; Brodehl, Andreas; Myasnikov, Roman P.; Sparber, Peter A.; Kiseleva, Anna V.; Kulikova, Olga V.; Meshkov, Alexey N.; Zharikova, Anastasia A.; Koretsky, Serguey N. (2019-03-25). "Non-compaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect". Human Mutation. 40 (6): 734–741. doi:10.1002/humu.23747. ISSN 1098-1004. PMID 30908796. 11. ^ Kalavakunta, Jagadeesh K.; Tokala, Hemasri; Gosavi, Aparna; Gupta, Vishal (2010-01-01). "Left ventricular noncompaction and myocardial fibrosis: a case report". International Archives of Medicine. 3: 20. doi:10.1186/1755-7682-3-20. ISSN 1755-7682. PMC 2945326. PMID 20843341. 12. ^ Chin TK, Perloff JK, Williams RG, et al. (Aug 1990). "Isolated noncompaction of left ventricular myocardium. A study of eight cases". Circulation. 82 (2): 507–13. doi:10.1161/01.cir.82.2.507. PMID 2372897. 13. ^ Lorenzo Botto, MD (September 2004). "Left Ventricular Non-compacted" (PDF). Retrieved 2007-06-13. 14. ^ Weiford BC, Subbarao VD, Mulhern KM (2004). "Noncompaction of the ventricular myocardium". Circulation. 109 (24): 2965–71. doi:10.1161/01.CIR.0000132478.60674.D0. PMID 15210614. 15. ^ Engberding R, Bender F (June 1984). "Identification of a rare congenital anomaly of the myocardium by two-dimensional echocardiography: persistence of isolated myocardial sinusoids". Am. J. Cardiol. 53 (11): 1733–4. doi:10.1016/0002-9149(84)90618-0. PMID 6731322. ## Further reading[edit] * "Non-compaction of Myocardium Cardiomyopathy". Yale University. Archived from the original on September 7, 2006. Retrieved June 13, 2007. * "Cardiomyopathy Caused by Isolated Noncompaction of the Left Ventricle in Adults". Medscape Cardiology. Retrieved June 13, 2007. * "Non-compacted Cardiomyopathy: Clinical-Echocardiographic Study". Medscape Cardiology. Retrieved June 13, 2007. * "Left Ventriuclar noncompaction" (PDF). Orphanet. Retrieved June 14, 2007. * "Left Ventricular Non-compaction". Baylor College of Medicine. Archived from the original on September 30, 2007. Retrieved June 15, 2007. * "Contemporary Definitions and Classification of the Cardiomyopathies". American Heart Association Scientific Statement. Retrieved June 15, 2007. * Towbin JA, Bowles NE (2002). "The failing heart". Nature. 415 (6868): 227–33. Bibcode:2002Natur.415..227T. doi:10.1038/415227a. PMID 11805847. S2CID 2895156. * Moreira FC, Miglioransa MH, Mautone MP, Müller KR, Lucchese F (2006). "Noncompaction of the left ventricle: a new cardiomyopathy is presented to the clinician". Sao Paulo Med J. 124 (1): 31–5. doi:10.1590/S1516-31802006000100007. PMID 16612460. * "Non-compaction of the Left Ventricular Myocardium - From Clinical Observation to the Discovery of a New Disease". Touch Cardiology. Archived from the original on September 29, 2007. Retrieved June 26, 2007. ## External links[edit] Classification D * OMIM: 601493 * MeSH: D056830 * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever * v * t * e 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Noncompaction cardiomyopathy	c1858725	1,224	wikipedia	https://en.wikipedia.org/wiki/Noncompaction_cardiomyopathy	2021-01-18T18:42:20	{"gard": ["10985"], "mesh": ["C565821", "D056830"], "umls": ["C1858725"], "icd-10": ["I42.8"], "orphanet": ["54260"], "wikidata": ["Q1725245"]}
Aase syndrome Other namesHydrocephalus-cleft palate-joint contractures syndrome, Aase-Smith syndrome Aase syndrome or Aase–Smith syndrome is a rare inherited disorder characterized by anemia with some joint and skeletal deformities. Aase syndrome is thought to be an autosomal dominant inherited disorder.[1] The genetic basis of the disease is not known. The anemia is caused by underdevelopment of the bone marrow, which is where blood cells are formed. It is named after the American paediatricians Jon Morton Aase and David Weyhe Smith, who characterized it in 1968.[2] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Prognosis * 7 References * 8 External links ## Signs and symptoms[edit] Among the presentation are:[citation needed] * Mildly slowed growth * Pale skin * Delayed closure of fontanelles (soft spots) * Narrow shoulders * Triple jointed thumbs, absent or small knuckles, decreased skin creases at finger joints * Inability to fully extend the joints from birth (congenital contractures) * Cleft palate * Deformed ears * Droopy eyelids ### Complications[edit] * Complications related to anemia include weakness, fatigue, and decreased oxygenation of the blood. * Decreased white blood cells alter the body's ability to fight infection. * If a heart defect exists, it may cause multiple complications (depending on the specific defect). * Severe cases have been associated with still birth or early death. ## Cause[edit] Some cases of Aase syndrome (45%) have been shown to be inherited, and are due to a change in one gene which makes ribosomal proteins. However, many cases are not inherited and occur without a known cause.[3] ## Diagnosis[edit] * A CBC (complete blood count) will show anemia and a decrease in the white blood cell count. * An echocardiogram may reveal heart defects (ventricular septal defect is most common). * X-rays will show skeletal abnormalities as described above. * A bone marrow biopsy may be performed. ## Prevention[edit] As with most genetic diseases there is no way to prevent the entire disease. With prompt recognition and treatment of infections in childhood, the complications of low white blood cell counts may be limited.[citation needed] ## Treatment[edit] Frequent blood transfusions are given in the first year of life to treat anemia. Prednisone may be given, although this should be avoided in infancy because of side effects on growth and brain development. A bone marrow transplant may be necessary if other treatment fails.[citation needed] ## Prognosis[edit] Anemia usually resolves over the years.[citation needed] ## References[edit] 1. ^ http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Aase%20Syndrome "Aase Syndrome" 2. ^ Aase JM, Smith DW (1968). "Dysmorphogenesis of joints, brain, and palate: a new dominantly inherited syndrome". J Pediatr. 73 (4): 606–9. doi:10.1016/S0022-3476(68)80278-1. PMID 5678002. 3. ^ "Aase syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-04-19. ## External links[edit] Classification D * OMIM: 147800 * MeSH: C535332 * DiseasesDB: 29332 External resources * MedlinePlus: 001662 * Orphanet: 916 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Aase syndrome	c0220686	1,225	wikipedia	https://en.wikipedia.org/wiki/Aase_syndrome	2021-01-18T18:45:28	{"gard": ["5642"], "mesh": ["C535332"], "umls": ["C0220686"], "orphanet": ["916"], "wikidata": ["Q303400"]}
A number sign (#) is used with this entry because of evidence that isolated microphthalmia-4 (MCOP4) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. For a phenotypic description and a discussion of genetic heterogeneity of isolated microphthalmia, see MCOP1 (251600). Molecular Genetics Asai-Coakwell et al. (2009) screened DNA samples from 489 patients with ocular anomalies (microphthalmia, clinical anophthalmia, and coloboma) and 81 patients with vertebral segmentation anomalies for mutations in the GDF6 gene (601147). They identified heterozygosity for 5 different missense mutations in 5 patients with isolated microphthalmia, respectively (see, e.g., 601147.0001 and 601147.0005-601147.0006); heterozygous mutations were also found in 3 patients with skeletal anomalies and in 1 patient with coloboma and preaxial polydactyly. Incomplete penetrance was demonstrated in the 2 microphthalmia cases in which parental DNA was available, with presence of the mutation in an unaffected father and an unaffected mother, respectively. None of the mutations were found in 366 controls. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	MICROPHTHALMIA, ISOLATED 4	c2751307	1,226	omim	https://www.omim.org/entry/613094	2019-09-22T15:59:41	{"doid": ["0060836"], "mesh": ["C567757"], "omim": ["613094", "251600"], "orphanet": ["2542"], "synonyms": ["Isolated anophthalmia-microphthalmia syndrome", "MAC spectrum", "Microphthalmia-anophthalmia-coloboma spectrum"], "genereviews": ["NBK1378"]}
Maroteaux et al. (1978) proposed this term for a type of oligosaccharidosis in which a glomerular nephropathy develops early and causes death at a young age. The clinical and radiologic features are dysmorphic facies, visceral storage disease, early and severe mental retardation, and skeletal abnormalities of a type often seen in this group of diseases. Foam cells are found in the bone marrow and, late in the illness, a cherry red spot is present on funduscopy. The condition is inherited as an autosomal recessive. The leukocytes are deficient in alpha-(2-6) neuraminidase, a defect found also in the sialidoses (256550) and in galactosialidosis (256540), which have clinical differences. Aylsworth et al. (1979) observed a case of nephrosialidosis. Congenital ascites, early-onset pericardial effusion, nephrosis, and greater overall severity of clinical features distinguished the disorder from other forms of neuraminidase deficiency. Roth et al. (1988) gave follow-up on a patient reported by Kelly and Graetz (1977) to have isolated acid neuraminidase deficiency with the phenotype of type 2 infantile sialidosis. An unusual feature was the abrupt onset and fulminant course of the nephrotic syndrome from which she died at the age of 9 years and 8 months. The kidneys showed epithelial cell damage most marked in the glomeruli and proximal tubules, with stored material in the form of polar sialyloligosaccharides of high molecular weight. Nephrosis was reported by Sperl et al. (1990) in a brother and sister with infantile sialic acid storage disease (269920). Nephrosis has also been described in the Hurler syndrome (607014) (Taylor et al., 1986) but this must be a rare complication of that particular lysosomal storage disease. It is by no means clear that nephrosialidosis is due to a mutation at a different locus from that represented by entry 256550. Skel \- Skeletal abnormalities GU \- Childhood glomerular nephropathy \- Nephrosis \- Renal failure Neuro \- Early and severe mental retardation Lab \- Leukocyte alpha-(2-6) neuraminidase defect \- Renal epithelial cell damage worst in glomeruli and proximal tubules, with high molecular weight sialyloligosaccharide storage Inheritance \- Autosomal recessive \- ? neuraminidase deficiency (256550) Cardiac \- Early-onset pericardial effusion HEENT \- Dysmorphic facies \- Fundus cherry red spot Misc \- Early death GI \- Visceral storage disease \- \- Congenital ascites Heme \- Bone marrow foam cells ▲ 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	NEPHROSIALIDOSIS	c0268228	1,227	omim	https://www.omim.org/entry/256150	2019-09-22T16:24:25	{"mesh": ["C537366"], "omim": ["256150"], "orphanet": ["87876"]}
Neonatal onset multisystem inflammatory disease (NOMID) is a disorder that causes persistent inflammation and tissue damage primarily affecting the nervous system, skin, and joints. Recurrent episodes of mild fever may also occur in this disorder. People with NOMID have a skin rash that is usually present from birth. The rash persists throughout life, although it changes in size and location. Affected individuals often have headaches, seizures, and vomiting resulting from chronic meningitis, which is inflammation of the tissue that covers and protects the brain and spinal cord (meninges). Intellectual disability may occur in some people with this disorder. Hearing and vision problems may result from nerve damage and inflammation in various tissues of the eyes. People with NOMID experience joint inflammation, swelling, and cartilage overgrowth, causing characteristic prominent knees and other skeletal abnormalities that worsen over time. Joint deformities called contractures may restrict the movement of certain joints. Other features of this disorder include short stature with shortening of the lower legs and forearms, and characteristic facial features such as a prominent forehead and protruding eyes. Abnormal deposits of a protein called amyloid (amyloidosis) may cause progressive kidney damage. ## Frequency NOMID is a very rare disorder; approximately 100 affected individuals have been reported worldwide. ## Causes Mutations in the NLRP3 gene (also known as CIAS1) cause NOMID. The NLRP3 gene provides instructions for making a protein called cryopyrin. Cryopyrin belongs to a family of proteins called nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins. These proteins are involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops (inhibits) the inflammatory response to prevent damage to its own cells and tissues. Cryopyrin is involved in the assembly of a molecular complex called an inflammasome, which helps trigger the inflammatory process. Researchers believe that NLRP3 mutations that cause NOMID result in a hyperactive cryopyrin protein and an inappropriate inflammatory response. Impairment of the body's mechanisms for controlling inflammation results in the episodes of fever and widespread inflammatory damage to the body's cells and tissues seen in NOMID. In about 50 percent of individuals diagnosed with NOMID, no mutations in the NLRP3 gene have been identified. The cause of NOMID in these individuals is unknown. ### Learn more about the gene associated with Neonatal onset multisystem inflammatory disease * NLRP3 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In almost all cases, NOMID results from new mutations. These cases occur in people with no history of the disorder in their family. A few cases have been reported in which an affected person has inherited the mutation from one affected parent. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neonatal onset multisystem inflammatory disease	c0409818	1,228	medlineplus	https://medlineplus.gov/genetics/condition/neonatal-onset-multisystem-inflammatory-disease/	2021-01-27T08:25:08	{"gard": ["1356"], "mesh": ["D056587"], "omim": ["607115"], "synonyms": []}
Jejunal atresia is a birth defect in a newborn characterized by partial or complete absence of the membrane connecting the small intestines to the abdominal wall (the mesentery). It causes a portion of the small intestines (the jejunum) to twist around an artery that supplies blood to the colon (the marginal artery). This leads to an intestinal blockage or "atresia." Common symptoms in the newborn include feeding difficulties, failure to thrive, vomiting bile (a yellowish-green fluid), abdominal swelling, and/or absence of bowel movements after birth. It typically occurs sporadically in people with no family history of the condition; however, more than one family member can rarely be affected, suggesting that there may be a genetic component in some cases. Jejunal atresia is typically treated with surgery. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Jejunal atresia	c0266175	1,229	gard	https://rarediseases.info.nih.gov/diseases/6799/jejunal-atresia	2021-01-18T17:59:41	{"mesh": ["D007409"], "omim": ["243600"], "synonyms": ["Apple peel syndrome", "Apple peel small bowel syndrome", "APSB", "Apple-peel intestinal atresia", "Familial apple peel jejunal atresia", "Atresia of small intestine", "Intestinal atresia type IIIb", "Jejunoileal atresia", "Small intestinal atresia"]}
Prolidase deficiency is an inherited disorder of peptide metabolism characterized by severe skin lesions, recurrent infections (involving mainly the skin and respiratory system), dysmorphic facial features, variable cognitive impairment, and splenomegaly. ## Epidemiology The exact prevalence is unknown but a prevalence estimate of 1/1,235,000 live births has been suggested. A higher carrier frequency of 1/21 has been reported in the Druze community. Approximately 90 patients from different ethnic groups have been reported in the literature to date, but due to underdiagnosis the exact number is probably higher. ## Clinical description Clinical manifestations and age of onset are quite variable. Prolidase deficiency can present in infancy with splenomegaly. Diarrhea, vomiting, and dehydration may also occur. Dysmorphic facial features include low anterior and posterior hairline, hypertelorism, proptosis, flat nasal bridge, thin vermilion of the upper lip and prognathism. Skin involvement usually appears during childhood (but can appear as early as 6 months and as late as 30 years of age) with severe, chronic, recalcitrant, and painful skin ulcers of the feet, lower legs and, less commonly, the hands. Telangiectasia of the face and hands may precede ulcers as well as erythematous, maculopapular lesions or purpuric lesions. Most patients have some degree of intellectual disability, ranging from mild to severe. Pulmonary (e.g. asthma-like chronic reactive airway disease), immunologic (susceptibility to infections with recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis) and hematologic (e.g. anemia, thrombocytopenia) manifestations have also been reported. Additional, less commonly reported manifestations include short stature, lymphedema, joint laxity, protuberant abdomen, hirsutism, dental dysplasia and keratitis. Some patients, however, remain asymptomatic. An association between prolidase deficiency and systemic lupus erythematosus (SLE; see this term) has been reported. ## Etiology Prolidase deficiency is due to a mutation in the PEPD gene (19q13.11), encoding Xaa-Pro dipeptidase, which plays an important role in the biosynthesis and degradation of collagen. Mutations in this gene lead to impaired collagen synthesis and wound healing. ## Diagnostic methods Diagnosis is based on clinical and laboratory findings. Urine amino acid analysis reveals massive imidodipeptiduria (10-30 mmol/day) in all cases. Patients also usually have elevated liver enzymes, mild anemia, mild thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia. Molecular genetic testing, identifying a mutation in the PEPD gene, confirms diagnosis. ## Differential diagnosis Differential diagnoses include Werner syndrome, beta-thalassemia, vasculitis (see these terms), autosomal dominant and recessive forms of hyper-IgE syndrome, sickle cell disease, pressure ulcers, and arterial and venous insufficiency. ## Antenatal diagnosis Prenatal diagnosis is possible in families with a known disease-causing mutation. ## Genetic counseling Prolidase deficiency is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of transmission to future offspring. ## Management and treatment Treatment is symptomatic. Care should be provided by a multidisciplinary team in order to monitor and treat skin, lung, and immunologic manifestations. Topical proline plus glycine ointment, steroids, methylprednisolone, blood transfusions, plasmapheresis, and topical growth hormone ointment have all been used to treat ulcers, with varying degrees of improvement reported. Antibiotic prophylaxis may be necessary in some cases. In patients with splenomegaly, contact sports should be avoided. ## Prognosis Prognosis varies but patients often have a decreased life-expectancy due to severe and sometimes fatal infections. Quality of life is also reduced due to infections and chronic pulmonary complications. When severe, ulcers can lead to amputation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Prolidase deficiency	c0268532	1,230	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=742	2021-01-23T17:21:11	{"gard": ["7473"], "mesh": ["D056732"], "omim": ["170100"], "umls": ["C0268532", "C1534653"], "icd-10": ["E72.8"], "synonyms": ["Hyperimidodipeptiduria"]}
## Summary ### Clinical characteristics. The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: * Charcot-Marie-Tooth disease type 2C * Scapuloperoneal spinal muscular atrophy * Congenital distal spinal muscular atrophy The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: * Familial digital arthropathy-brachydactyly * Autosomal dominant brachyolmia * Spondylometaphyseal dysplasia, Kozlowski type * Spondyloepiphyseal dysplasia, Maroteaux type * Parastremmatic dysplasia * Metatropic dysplasia The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. ### Diagnosis/testing. The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified on molecular genetic testing. ### Management. Treatment of manifestations: Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. SNHL is managed by specialists to determine the best management options. * For neuromuscular disorders, neuropathy and respiratory dysfunction are managed in a routine manner; individuals with laryngeal dysfunction require ENT evaluation that should include speech therapy, laryngoscopy, and, in some instances, surgery. * For skeletal dysplasias, physical therapy/exercise and heel-cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present. Surveillance: For neuromuscular disorders, annual neurologic examinations, physical therapy assessments, ENT monitoring of laryngeal function, dynamic breathing chest x-ray, and hearing assessment. For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment. Agents/circumstances to avoid: For neuromuscular disorders, obesity, as it makes walking more difficult; diabetes; medications that are toxic or potentially toxic to persons with a peripheral neuropathy. For skeletal dysplasias, extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints. Pregnancy management: Ideally a woman with TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery. ### Genetic counseling. TRPV4 disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an autosomal dominant TRPV4 disorder have an affected parent. However, since the most severe skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes likely have a de novo pathogenic variant and unaffected parents. Each child of an individual with an autosomal dominant TRPV4 disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced penetrance and variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have the same phenotype as the parent. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member. ## Diagnosis ### Suggestive Findings #### Neuromuscular Disorders An autosomal dominant TRPV4 neuromuscular disorder should be suspected in individuals with the following range of clinical findings (see Table 1). Charcot-Marie-Tooth disease type 2C (CMT2C) * A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop * Nerve conduction studies [Dyck et al 1994, Zimoń et al 2010] show: (1) reduced compound motor action potential (CMAP) amplitudes with normal velocities (>40-60 m/s), although occasionally they may be mildly abnormal (36-40 m/s); and (2) normal, decreased, or absent distal sensory nerve action potential (SNAP) amplitudes. * Electromyography shows predominantly chronic neurogenic changes. * Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy. * Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [Dyck et al 1994]. Laryngoscopy often shows paresis of one or both vocal folds. * Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010]. * Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [Chen et al 2010]. Chest radiograph and pulmonary function tests may demonstrate diaphragm weakness with decreased inspiratory and expiratory pressures [Dyck et al 1994, Donaghy & Kennett 1999]. * Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases * A family history consistent with autosomal dominant inheritance Scapuloperoneal spinal muscular atrophy (SPSMA) * Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [DeLong & Siddique 1992, Auer-Grumbach et al 2010, Deng et al 2010]. * Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [Deng et al 2010, Berciano et al 2011]. * Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in CMT2C), vocal cord paresis, and transient dysphonia [Berciano et al 2011] * SNHL (as in CMT2C) * Sensory deficits (rare) * Kyphoscoliosis Congenital distal spinal muscular atrophy (CDSMA) * Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal) * Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen. * MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [Astrea et al 2012]. ### Table 1. Neurologic Findings by TRPV4 Neuromuscular Phenotype View in own window FindingPhenotype CMT2CSPSMACDSMA Age at onsetBirth – adulthoodBirth – adulthoodPrenatal NeuropathyPeripheral, progressive (distal)Peripheral, progressive (distal > proximal)Paresis of legs at birth 1 Vocal cord paralysis+\+ (transient dysphonia)± SNHL++– Respiratory dysfunction 2++± Joint contractures––AMC (mainly involving feet, knees, & hips) OtherSee footnote 3.See footnote 4.See footnote 5. AMC = arthrogryposis multiplex congenita; CMT2C = Charcot-Marie-Tooth disease type 2C; CDSMA = congenital distal spinal muscular atrophy; SNHL= sensorineural hearing loss; SPSMA = scapuloperoneal spinal muscular atrophy 1\. More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis. 2\. Secondary to diaphragmatic and intercostal muscle involvement 3\. Cold sensitivity (i.e., worsening of hand weakness in the cold) 4\. Rounded shoulders, laterally displaced scapulae 5\. Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course #### Skeletal Dysplasias An autosomal dominant TRPV4 skeletal dysplasia should be suspected in individuals with the following skeletal findings: * Familial digital arthropathy-brachydactyly characterized by the following: * Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood * Progressive arthropathy of the other joints of the hands and feet with pain and deformity * No clinical overlap with other TRPV4 skeletal dysplasias * The other autosomal dominant TRPV4 skeletal dysplasias (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; spondyloepiphyseal dysplasia, Maroteaux type; parastremmatic dysplasia; and metatropic dysplasia) form a phenotypic continuum of overlapping disorders from mild to severe, each with: * Short stature * Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles * At least one additional distinctive feature (See Table 2.) ### Table 2. Radiographic and Clinical Features of Autosomal Dominant TRPV4 Skeletal Dysplasias View in own window FindingsPhenotype MildIntermediateSevere Familial digital arthropathy-brachydactylyAutosomal dominant brachyolmiaSpondylo-metaphyseal dysplasia, Kozlowski typeSpondylo-epiphyseal dysplasia, Maroteaux typeParastremmatic dysplasia 1Metatropic dysplasia Hands/ FeetNormal at birth; progressive swelling & arthropathy (see details)ClinodactylyBrachydactyly; hypoplastic carpal bones w/severe delay in ossificationBrachydactylyJoint contracturesBrachydactyly w/delayed carpal ossification SpineNormal± scoliosis, kyphosis; mild platyspondylyPlatyspondyly; overfaced pedicles 2Significant kyphoscoliosis; overfaced pedicles 2Platyspondyly; overfaced pedicles 2 Long bonesN/AMinimal metaphyseal changes; short femoral neck w/irregular proximal femoral metaphyses± mild metaphyseal changes; genu varumMild-to-moderate metaphyseal changes; genu varumSevere metaphyseal changes w/severe limb deformity; joint contractures; other 3Dumbbell-shaped long bones w/epiphyseal dysplasia & prominent joints; progressive joint contractures; other 4 PelvisNormalN/ASquare, short, flared iliac wings; flat, irregular acetabulae; coxa vara; ± supra-acetabular notchesChampagne-glass configuration of pelvic inletHalberd-shaped 5 pelvis; supra-acetabular notches OtherAverage height; early-childhood onsetMild short stature; limbs unaffected; good physical functionShort-trunk short-stature dwarfism; broad chest; early-childhood onset w/waddling gaitShort-trunk short-stature dwarfismSignificant short-trunk short-stature dwarfismMay be lethal prenatally or perinatally; at birth, short-limb short-stature dwarfism 6 1\. Rarest TRPV4-related skeletal dysplasia 2\. Overfaced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of TRPV4 skeletal dysplasias best viewed on AP x-ray of the spine; images in Nemec et al [2012]. 3\. Additional findings: hyperplastic femoral trochanters, severe genu valgum, bowing of long bones, legs twisted along the long axis 4\. Histologic findings: thin seal of bone at the chondroosseous junction, absent primary metaphyseal spongiosa, abnormal metaphyseal vascular invasion, arrest of endochondral ring structures with persistence of circumferential growth 5\. The term "Halberd-shaped pelvis" is derived from the shape of a Swedish battle ax. 6\. Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism. ### Establishing the Diagnosis The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TRPV4 identified by molecular genetic testing (see Table 3). Note: Identification of a heterozygous TRPV4 variant of uncertain significance does not establish or rule out a diagnosis of this disorder. Single-gene testing. Sequence analysis of TRPV4 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. (2) To date, a large TRPV4 deletion or duplication has not been reported in an individual with an autosomal dominant TRPV4 disorder. A multigene panel that includes TRPV4 and other genes of interest (see Differential Diagnosis) can be considered 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. ### Table 3. Molecular Genetic Testing Used in Autosomal Dominant TRPV4 Disorders View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method TRPV4Sequence analysis 3100% 4 Deletion/duplication analysis 5See footnote 6. 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis can detect 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\. Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017] 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\. The authors are unaware of a whole-gene or contiguous gene deletion of TRPV4 causing one of the recognized phenotypes. ## Clinical Characteristics ### Clinical Description The two groups of disorders and the phenotypes comprising autosomal dominant TRPV4 disorders (listed from mildest to most severe) are: * Neuromuscular disorders (see Table 1): * Charcot-Marie-Tooth disease type 2C * Scapuloperoneal spinal muscular atrophy * Congenital distal spinal muscular atrophy * Skeletal dysplasias (see Table 2): * Familial digital arthropathy-brachydactyly * Autosomal dominant brachyolmia * Spondylometaphyseal dysplasia, Kozlowski type * Spondyloepiphyseal dysplasia, Maroteaux type * Parastremmatic dysplasia * Metatropic dysplasia The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare cases overlap as well [Chen et al 2010, Unger et al 2011, Cho et al 2012]. Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010]. #### Neuromuscular Disorders The autosomal dominant TRPV4 neuromuscular disorders are peripheral neuropathies/neuronopathies in which motor nerves are more prominently affected than sensory nerves [Landouré et al 2010]. Clinical findings and age of onset can be extremely variable in TRPV4 neuromuscular disorders both between and within families [Dyck et al 1994, Donaghy & Kennett 1999, Zimoń et al 2010, Echaniz-Laguna et al 2014]. Affected individuals usually become symptomatic between early childhood and age 25 years; however, disease onset can range from birth, with breathing difficulties and delayed walking, to after the eighth decade [Zimoń et al 2010, Echaniz-Laguna et al 2014]. In some, the manifestations can be so mild as to go unrecognized by the affected individual and his/her physicians. Affected individuals typically demonstrate progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. However, the congenital phenotypes, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA), are characterized by long plateau periods without obvious deterioration [Vlam et al 2012]. Atrophy of the intrinsic hand muscles is common, but tendon reflexes may be intact in the arms. Proximal limb muscles may be involved, particularly in SPSMA. The pattern of muscle involvement in SPSMA includes progressive shoulder girdle atrophy and weakness leading to scapular winging (scapula alata) and involvement of the two muscle groups below the knee (peroneal distribution) [DeLong & Siddique 1992]. Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and is often observed in individuals with SPSMA and CDSMA [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Zimoń et al 2010, Echaniz-Laguna et al 2014]. The typical presenting symptoms are difficulty with phonation and breathing (inspiratory stridor and hoarseness) and distal leg weakness and atrophy. Individuals with severe features may have a decreased life span secondary to respiratory complications [Santoro et al 2002, McEntagart et al 2005]. #### Skeletal Dysplasias Familial digital arthropathy-brachydactyly is not evident at birth because the hands and feet and skeletal examination (including radiographs) are normal. In early childhood relative shortening of the middle and distal phalanges and swelling and decreased range of motion of the interphalangeal joints become apparent. Later, in the first decade and beyond, the other joints of the hands and feet become painful and deformed. No overlap is currently recognized with the manifestations of the other autosomal dominant TRPV4 skeletal dysplasias. The remaining autosomal dominant TRPV4 skeletal disorders are characterized by varying degrees of disproportionate short stature and progressive spinal deformity with scoliosis with or without kyphosis. Autosomal dominant brachyolmia is the mildest of the short stature TRPV4 skeletal conditions. Its name derives from the Greek roots brachy-, meaning "short," and -olmos, meaning "trunk" or "shoulder." Affected individuals have only mild short stature and the limbs are typically unaffected; thus, physical function is unaffected. Spondylometaphyseal dysplasia, Kozlowski type is characterized by short-trunk short stature, although the chest is broader than in some of the more severe autosomal dominant TRPV4 skeletal dysplasias. Birth length is average. Affected children usually come to medical attention in early childhood when poor growth with disproportionate stature and a waddling gait with genu varum become evident. Premature osteoarthritis of the joints is common. Spondyloepiphyseal dysplasia, Maroteaux type is characterized by short-trunk dwarfism and brachydactyly. Birth length is usually average. Poor growth with a short trunk and overall short stature become evident in childhood. Over time, genu valgum and kyphoscoliosis develop. Osteoporosis has been described. Parastremmatic dysplasia, probably the rarest of the autosomal dominant TRPV4 skeletal dysplasias, is characterized by severe limb deformities and joint malalignment, short stature, and kyphoscoliosis, which are present at birth and progressively worsen throughout life. Metatropic dysplasia (from the Greek metatropos, meaning "with change/changing pattern") was named after the striking reversal of body proportions between birth and childhood. At birth, the limbs are disproportionately short (due to the long bone metaphyseal abnormalities) compared to the trunk. In childhood, when the platyspondyly and scoliosis and/or kyphosis become more severe, the trunk becomes relatively short compared to the limbs. Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis that eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of autosomal dominant TRPV4 disorders [Unger et al 2011]. ### Genotype-Phenotype Correlations In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasia; overlap may occur, however, making genotype-phenotype correlations difficult (see Molecular Genetics) [Unger et al 2011, Sullivan & Earley 2013]. Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and skeletal dysplasias may cause a gain-of-channel function [Rock et al 2008, Krakow et al 2009, Nilius & Voets 2013, Sullivan et al 2015], whereas the pathogenic variants associated with familial digital arthropathy-brachydactyly (FDAB) may cause a loss-of-channel function. TRPV4 neuromuscular disorders. Several studies suggest that most TRPV4 pathogenic variants associated with a neuromuscular phenotype cluster on the highly positively charged convex surface of the ankyrin repeats domain and target arginine residues that are strictly conserved throughout 27 available TRPV4 orthologs [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Sullivan et al 2015]. These surface pathogenic variants are located in three consecutive finger loops of the protein, a distinct region of the TRPV4 ankyrin repeats. The most commonly reported and best validated pathogenic TRPV4 variants are the following: p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys, and p.Arg316His [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Klein et al 2011, Landouré et al 2012]. Variable phenotypes have been reported, even among members of the same family [Landouré et al 2010]. TRPV4 skeletal dysplasias. In total, more than 50 pathogenic variants in TRPV4 have been reported to cause brachyolmias. While the pathogenic variants are spread throughout the gene, two hot spots have been observed at residues Pro799 in exon 15 and Arg594 in exon 11 [Nishimura et al 2012], which localize to the channel pore region. The familial digital arthropathy-brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants p.Gly270Val, p.Arg271Pro, p.Phe273Leu) [Nilius & Voets 2013]. Overlap of TRPV4 neuromuscular disorders and skeletal dysplasias. Of note, the pathogenic variants p.Ala217Ser, p.Glu278Lys, p.Arg269Cys, p.Arg315Trp, p.Tyr591Cys, p.Arg594His, p.Val620Ile, p.Glu797Lys, and p.Pro799Arg have been associated with both neuromuscular disease and skeletal dysplasia [Zimoń et al 2010, Cho et al 2012, Faye et al 2019]. In addition, the pathogenic variant p.Ser542Tyr caused both CMT2C and short stature in one family [Chen et al 2010]. ### Penetrance Autosomal dominant TRPV4 neuromuscular disorders. Penetrance is reduced with the neuromuscular disease-associated pathogenic variants. Autosomal dominant TRPV4 skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant [Dai et al 2010]. ### Nomenclature Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C. Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2. ### Prevalence The prevalence of the autosomal dominant TRPV4 neuromuscular and skeletal dysplasias has not been well studied. Fawcett et al [2012] determined that 13 (<1%) of 422 individuals with a CMT2 (axonal CMT) phenotype were heterozygous for a TRPV4 pathogenic variant. Of note, the detection of a TRPV4 pathogenic variant increased to between 9% and 16% in those with a CMT2 phenotype with additional unusual features (e.g., vocal fold weakness, diaphragmatic paresis, skeletal dysplasia) [Fawcett et al 2012, Echaniz-Laguna et al 2014]. ## Differential Diagnosis ### Autosomal Dominant TRPV4 Neuromuscular Disorders Autosomal dominant TRPV4 neuromuscular disorders (Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy) resemble several other disorders (see Table 4): Note: See Charcot-Marie-Tooth Hereditary Neuropathy Overview for a general overview of CMT2. ### Table 4. Genes of Interest in the Differential Diagnosis of Autosomal Dominant TRPV4 Neuromuscular Disorders View in own window GeneMOIDisorder ATP7AXLdSMA (see ATP7A-Related Copper Transport Disorders) BICD2ADLower extremity-predominant SMA (SMA2A; SMA2B) (OMIM 615290) BSCL2ADdHMN5A (see BSCL2 Neurologic Disorders/Seipinopathy) DCTN1ADdHMN7B (OMIM 607641): motor neuropathy w/vocal cord paralysis DYNC1H1ADCMT2O (see CMT Overview); lower extremity-predominant SMA GARS1ADGARS1-associated axonal neuropathy (CMT2D; dSMA-V) HSPB1ADdHMN2B; CMT2F (see CMT Overview) HSPB3ADdHMN2C (OMIM 613376) HSPB8ADdHMN2A (OMIM 158590) IGHMBP2ARCMT2S (see CMT Overview); dSMA1 JAG1ADCMT2C 1: mild neuropathy w/severe vocal cord paralysis MYH14ADPeripheral neuropathy, myopathy, hoarseness, and hearing loss (OMIM 614369): hoarseness w/o vocal cord paralysis; reported in 1 family PLEKHG5ARIntermediate CMTC (see CMT Overview); dSMA4: variably assoc w/scapular winging & diaphragmatic weakness SETXADJuvenile ALS (dHMN) SLC5A7ADdHMN7A (OMIM 158580): motor neuropathy w/vocal cord paralysis Genes are listed in alphabetic order. AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; dHMN = distal hereditary motor neuropathy; dSMA = distal spinal muscular atrophy; MOI = mode of inheritance; SMA = spinal muscular atrophy; XL = X-linked 1\. Sullivan et al [2020] ### Autosomal Dominant TRPV4 Skeletal Dysplasias Autosomal dominant TRPV4 skeletal dysplasias have a broad phenotypic spectrum and, thus, many skeletal dysplasias to consider in the differential diagnosis. Mild (familial digital arthropathy-brachydactyly). The differential diagnosis includes reactive arthropathy, diabetic arthropathy, and other forms of brachydactyly [Amor et al 2002]. Intermediate (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; and spondyloepiphyseal dysplasia, Maroteaux type) and severe (parastremmatic dysplasia and metatropic dysplasia). See Table 5. ### Table 5. Genes of Interest in the Differential Diagnosis of Intermediate and Severe Autosomal Dominant TRPV4 Skeletal Dysplasias View in own window PhenotypeGeneMOIDisorder IntermediateCOL2A1AD (AR)Spondyloepiphyseal dysplasia congenita (see Type II Collagen Disorders Overview) GALNSARMorquio syndrome type A (MPS IVA) GLB1ARMorquio syndrome type B (MPS IVB) TRAPPC2XLX-linked spondyloepiphyseal dysplasia tarda SevereCOL2A1ADKniest dysplasia (see Type II Collagen Disorders Overview): platyspondyly & coronal cleft, shortened tubular bones & metaphyseal flaring, broad & short thorax COL11A1 COL11A2AR ADFibrochondrogenesis 1 & 2 (OMIM PS228520): rhizomelic limb shortening, broad dumbbell-shaped metaphyses, pear-shaped vertebral bodies, short & distally cupped ribs COL11A2AR ADOtospondylomegaepiphyseal dysplasia 1 (OMIM 184840, 215150) HSPG2ARDyssegmental dysplasia, Silverman-Handmaker type (OMIM 224410) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked 1\. Autosomal recessive otospondylomegaepiphyseal dysplasia may also be referred to as Weissenbacher Zweymuller syndrome. Brachyolmia types 1 and 2 (OMIM 271530 and 613678) can also be considered in the differential diagnosis of intermediate autosomal dominant TRPV4 skeletal dysplasias. The molecular basis of these disorders is unknown. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 neuromuscular disorder, the evaluations summarized in Table 6a (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 6a. Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder View in own window System/ConcernEvaluationComment NeurologicPhysical/neurologic examTo determine extent of weakness & atrophy, pes cavus, gait stability, & sensory loss EMG w/NCVAs needed to document status of neuropathy ENT consult w/laryngoscopyAs needed to document status of vocal folds RespiratoryPulmonary function testing & dynamic breathing chest x-rayAs needed to assess pulmonary & respiratory function AudiologicHearing assessmentSee Hereditary Hearing Loss and Deafness Overview for different types of hearing assessment. SkeletalSkeletal x-raysTo identify any assoc skeletal dysplasia Genetic counselingBy genetics professionals 1To inform individuals & families re nature, MOI, & implications of TRPV4 disorders 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; * Need for home nursing referral; * Need for referral to physiatry, PT, OT, & speech therapy. EMG = electromyography; NCV = nerve conduction velocity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy 1\. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 skeletal dysplasia, the evaluations summarized in Table 6b (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 6b. Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia View in own window System/ConcernEvaluationComment SkeletalSkeletal x-raysTo document involvement of long bones & spine, which can help determine individual needs & provide baseline for comparison w/future studies Flexion/extension cervical spine filmsTo determine if there is atlanto-axial instability secondary to odontoid hypoplasia RespiratoryPulmonary function testing &/or sleep studyIf thorax is particularly narrow &/or kyphoscoliosis is progressive AudiologyHearing assessmentSee Hereditary Hearing Loss and Deafness Overview for different types of hearing assessment. Genetic counselingBy genetics professionals 1To inform individuals & families re nature, MOI, & implications of TRPV4 disorders to facilitate medical & personal decision making Family support/ resourcesAssess: * Use of community or online resources such as Parent to Parent & Little People of America; * Need for social work involvement for parental support; * Need for home nursing referral; * Need for referral to physiatry, PT, & OT. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy 1\. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ### Treatment of Manifestations Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, ENT specialists, and physical and occupational therapists. ### Table 7a. Treatment of Manifestations in Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder View in own window Manifestation/ConcernTreatmentConsiderations/Other Neuropathy * Special shoes, incl those w/good ankle support * AFO to correct foot drop & aid walking * Orthopedic surgery to correct severe pes cavus deformity as needed * Forearm crutches, canes/walkers for gait stability, & wheelchairs * Exercise w/in person's capability (Many remain physically active.) Pain & depressionSymptomatic treatment Vocal cord involvement * Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy) * Speech therapy Respiratory dysfunctionRespiratory therapy/support (e.g., BiPAP) SNHLTreatment per hearing loss specialists to determine best habilitation optionsSee Hereditary Hearing Loss and Deafness Overview for discussion of management issues. AFO = ankle-foot orthosis; BiPAP = bilevel positive airway pressure; SNHL = sensorineural hearing loss ### Table 7b. Treatment of Manifestations in Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia View in own window Manifestation/ConcernTreatmentConsiderations/Other ContracturesPT/exerciseTo maintain as much function as possible Daily heel cord-stretching exercisesTo prevent Achilles tendon shortening KyphoscoliosisOrthopedic eval w/consideration of surgical intervention (e.g., spinal fusion)If kyphoscoliosis results in pain &/or compromised pulmonary function Odontoid hypoplasia / Cervical myelopathyOccipito-cervical or upper cervical decompression & fusion are required to stabilize upper cervical spine & relieve cervical cord compression when upper cervical spine instability is documented or when clinical findings of cervical myelopathy are present.It is preferred that intervention in children occur when signs of cervical compression are present by MRI, even in absence of symptoms to minimize neurologic injury & maximize function. Those undergoing surgical fusion typically do well; minor secondary complications can incl pin site infections, pressure sores, & long-term difficulty w/endotracheal intubation. If myelopathy is suspected: * Obtain cervical spine radiographs & MRI; * Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility. Upper cervical instability may result in deteriorating endurance & worsening gait. SNHLTreatment per hearing loss specialists to determine best habilitation optionsSee Hereditary Hearing Loss and Deafness Overview for discussion of management issues. Pain & depressionSymptomatic treatmentChronic pain management preceding or following orthopedic surgery is standard & often required. PT = physical therapy; SNHL = sensorineural hearing loss ### Surveillance ### Table 8a. Recommended Surveillance for Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder View in own window System/ConcernEvaluationFrequency NeuropathyNeurologic exam to determine extent of weakness & atrophy, & sensory lossAnnually PT exam to monitor feet to determine need for bracing, special shoes, &/or surgery Vocal cord involvementENT consult w/laryngoscopy Respiratory dysfunctionDynamic breathing chest x-ray SNHLHearing assessment PT = physical therapy; SNHL = sensorineural hearing loss ### Table 8b. Recommended Surveillance for Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia View in own window System/ConcernEvaluationFrequency MusculoskeletalAssessment for development of joint pain & scoliosisAnnually Cervical spinal films to assess for clinically significant odontoid hypoplasiaBefore: * A child reaches school age; * Surgical procedures involving general anesthesia. SNHLHearing assessmentAnnually SNHL = sensorineural hearing loss ### Agents/Circumstances to Avoid In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both For neuromuscular disorders. Preventive health care to avoid diabetes-related complications is recommended. Neurotoxic medications should be avoided. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. See also the Inherited Neuropathy Consortium website for additional information. For skeletal dysplasias * In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension. * Avoid activities and occupations that place undue stress on the spine and weight-bearing joints. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management There is no registry or data regarding the frequency or outcome of pregnancies in women with a TRPV4-related disorder; however, the following general information may be reasonable to consider. Ideally a woman with an autosomal dominant TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate her risks for pregnancy and delivery. Increased risk of ectopic pregnancy has been reported [Li et al 2019]. Autosomal dominant TRPV4 neuromuscular disorders. Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMTs. About 50% of women with CMT described increased weakness during pregnancy that usually resolved post partum [Rudnik-Schöneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] described the obstetric approach to women with mild and severe forms of CMT. Brock et al [2009] describe use of anesthesia during delivery in a single case study, indicating that regional management is the preferred and safer method, compared to general anesthesia. A German study reviewed 63 pregnancies in 33 women with CMT [Awater et al 2012] and found no increase in the frequency of cesarean section, forceps delivery, premature birth, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent. Autosomal dominant TRPV4 skeletal dysplasias. In autosomal dominant TRPV4 skeletal dysplasias, the degree of pulmonary compromise (from the short trunk and decreased lung capacity) may affect the ability to carry a pregnancy to term. Thus, it is unlikely that a woman with metatropic dysplasia could carry a pregnancy. Pregnant women with a TRPV4 skeletal dysplasia generally undergo cesarean section delivery because of the small size of the pelvis. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Mathis et al [2015] have reviewed the future of therapeutic options in CMT. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. ### Other Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal Dominant TRPV4 Disorders	None	1,231	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK201366/	2021-01-18T21:41:27	{"synonyms": []}
A rare, syndromic intellectual disability characterized by developmental delay, speech apraxia, autism with stereotypies, intellectual disability and unspecific dysmorphic facial features. Seizures or isolated EEG abnormalities may also be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Intellectual disability-autism-speech apraxia-craniofacial dysmorphism syndrome	c4540131	1,232	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=529965	2021-01-23T17:41:43	{"omim": ["617682"], "synonyms": ["Pilarowski-Bjornsson syndrome"]}
## Summary ### Clinical characteristics. Dysferlinopathy includes a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapuloperoneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy. ### Diagnosis/testing. Diagnosis depends on a combination of muscle biopsy and molecular genetic testing. Muscle biopsy western immunoblotting almost always indicates a primary dysferlinopathy. DYSF, which encodes the protein dysferlin, is the only gene in which pathogenic variants are known to cause dysferlinopathy. ### Management. Treatment of manifestations: Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support. Prevention of secondary complications: Stretching exercises to prevent contractures. Surveillance: Annual monitoring of muscle strength, joint range of motion, and respiratory function; and for evidence of cardiomyopathy for subtypes with cardiac involvement. Agents/circumstances to avoid: Weight control to avoid obesity; avoidance of steroid treatment. ### Genetic counseling. Dysferlinopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known. ## Diagnosis Dysferlinopathy caused by DYSF pathogenic variants includes a spectrum of muscle disease characterized mainly by two phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy is characterized by the following: * Mid- to late-childhood or early-adult onset; mean age at onset: 19.0 years [Aoki et al 2001] * Early and predominant involvement of the calf muscles * Slow progression * Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L [Aoki et al 2001] * Primarily myogenic pattern on EMG * Biopsy evidence of a chronic, active myopathy without rimmed vacuoles LGMD2B is characterized by the following: * Predominant weakness and atrophy of muscles of the pelvic and shoulder girdle * Onset in the proximal lower-limb musculature in the late teens or later * Massive elevation of serum CK concentration * Slow progression * Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan (in some individuals) ### Testing Muscle biopsy * Histology. Muscle biopsy shows evidence of a dystrophy with random variation in fiber size and evidence of degeneration and regeneration. Type one fibers may predominate. There is often evidence of inflammation, sometimes leading to a misdiagnosis of polymyositis [Gallardo et al 2001, Fanin & Angelini 2002, Serratrice et al 2002, Prelle et al 2003]. * Immunostaining. Antibodies to dysferlin identify a protein of approximately 230 kd and show that dysferlin is located in the muscle membrane [Anderson et al 1999, Matsuda et al 1999, Eymard et al 2000]. Most individuals with DYSF pathogenic variants show complete deficiency of the protein or sometimes patchy sarcolemmal and cytoplasmic staining on muscle biopsy. Many individuals with partial deficiency of dysferlin have been reported [Piccolo et al 2000, Matsuda et al 2001, Saito et al 2002]. * Immunoblot. Because of variable and nonspecific patterns, immunoblot is generally considered the more reliable method for testing. If possible, both immunostaining and immunoblotting should be performed [Tagawa et al 2003]. Dysferlin expression. In individuals with dysferlinopathy, dysferlin immunoreactivity in peripheral blood monocytes cannot be detected using a commercially available monoclonal antibody [Ho et al 2002, Ankala et al 2014]. #### Molecular Genetic Testing Gene. DYSF, which encodes the protein dysferlin, is the only gene in which pathogenic variants are known to cause dysferlinopathy. ### Table 1. Molecular Genetic Testing Used in Dysferlinopathy View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method DYSFTargeted analysis for pathogenic variants 2, 3, 495% Sequence analysis 5Unknown 1\. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. 2\. Note: Pathogenic variants included in a panel may vary by laboratory. 3\. Detects 1624delG pathogenic variant in Libyan Jews 4\. Detects 927delG pathogenic variant in Jews of the Caucasus [Leshinsky-Silver et al 2007] 5\. 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. 6\. Takahashi et al [2003b] ### Testing Strategy To confirm/establish the diagnosis in a proband. Because there are number of conditions that lead to muscle weakness with an elevated CK level, a reasonable approach is to test a muscle biopsy for dysferlin using western immunoblotting. Absence of dysferlin protein almost always indicates a primary dysferlinopathy; however, it is important to note that reduced levels of dysferlin may be secondary to other primary muscular dystrophies [Aoki et al 2001]. Further molecular genetic testing can then be pursued. One genetic testing strategy is molecular genetic testing of DYSF, the only gene in which pathogenic variants are known to cause dysferlinopathy. * For individuals of Libyan Jewish ancestry or Jews of the Caucasus, targeted analysis for pathogenic variants can be used for confirmation of the diagnosis and genetic counseling purposes. * For individuals of other ethnic backgrounds, sequence analysis of the entire coding region can be pursued. An alternative genetic testing strategy is use of a multigene panel that includes DYSF and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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. ## Clinical Characteristics ### Clinical Description Several different clinical presentations have been observed [Ueyama et al 2002] and can occur within families having the same pathogenic variants [Liu et al 1998, Weiler et al 1999, Illarioshkin et al 2000, Nakagawa et al 2001, Ueyama et al 2001]. The weakness and atrophy may be asymmetric with any of these presentations. Miyoshi myopathy. Young adults have muscle weakness and atrophy most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Early on, affected individuals are not able to stand on tiptoe, but retain the ability to stand on the heels. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles, at which time climbing stairs, standing, and walking become difficult. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. The weakness may eventually include the shoulder girdle muscles [Mahjneh et al 2001]. Limb-girdle muscular dystrophy syndrome. Early weakness and atrophy of the pelvic and shoulder girdle muscles begins in adolescence or young adulthood, with slow progression. Scapuloperoneal syndrome. Occasionally, affected individuals present with initial weakness of the shoulder girdle muscles combined with distal weakness of the legs. Distal myopathy with anterior tibial onset. Occasionally, leg weakness may involve the anterior compartment and cause foot drop [Illa et al 2001]. Elevated serum CK concentration only. Some individuals have only a marked elevation of serum CK concentration. This is usually considered a presymptomatic presentation of myopathy in an individual who eventually develops muscle weakness and atrophy. Sometimes the calf muscles are enlarged; this presentation may be confused with a dystrophinopathy (i.e., Duchenne or Becker muscular dystrophy). Congenital muscular dystrophy. Two sibs with hypotonia beginning between birth and age two months had delayed motor development and serum CK concentrations that were normal or slightly elevated before age three years [Paradas et al 2009]. Of 41 Japanese individuals with proven dysferlinopathy, 20 had Miyoshi myopathy and 21 had LGMD2B (Table 2) [Takahashi et al 2003b]. On occasion, both phenotypes can be observed in affected sibs [Liu et al 1998]. ### Table 2. Comparison of Miyoshi Myopathy and LGMD2B View in own window Miyoshi MyopathyLGMD2B Mean age at onset (range)21.8 ± 7.4 yrs (14-37 yrs)26.2 ± 9.2 yrs (14-41 yrs) Average age of using a cane (yrs after onset)35.5 yrs (16 yrs)39.3 yrs (13.6 yrs) Age at which wheelchair-bound (yrs after onset)42.8 yrs (22.8 yrs)45.1 yrs (21.4 yrs) Takahashi et al [2003b] ### Genotype-Phenotype Correlations One study reported that the 3370G>T pathogenic variant was associated with a milder form of Miyoshi myopathy and the 3510G>A pathogenic variant was associated with a more severe form [Takahashi et al 2003a, Takahashi et al 2013]. ### Nomenclature Dysferlinopathy was originally called LGMD2B because at the time that it was mapped to 2p13 it was the second form (2) of autosomal recessive (B) limb-girdle muscular dystrophy (LGMD) to be mapped. The gene for Miyoshi myopathy and the gene for LGMD2B were mapped to the same genetic interval at chromosome 2p13. Two groups independently identified a novel human skeletal muscle gene, DYSF, at this locus and documented that DYSF pathogenic variants cause both Miyoshi myopathy and LGMD2B. ### Prevalence The prevalence is not known. In the initial (1967) description of Miyoshi myopathy, 50 out of 72 families were from Japan. Tagawa et al [2003] examined a total of 107 unrelated Japanese individuals, including 53 with unclassified LGMD, 28 with Miyoshi myopathy, and 26 with other neuromuscular disorders. Expression of dysferlin protein was observed using immunohistochemistry (IHC) and mini-multiplex western blotting (MMW). They found a deficiency of dysferlin protein by using both IHC and MMW in 19% of individuals with LGMD and 75% of individuals with Miyoshi myopathy. In Libyan Jews, the prevalence is at least one per 1,300, with a carrier rate of approximately 10% [Argov et al 2000]. A founder variant (Arg1905Ter) has been reported in Spain [Vilchez et al 2005]. ## Differential Diagnosis Dysferlinopathy needs to be distinguished from other autosomal recessive limb-girdle muscular dystrophies. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. The limb-girdle muscular dystrophies typically show degeneration/regeneration of muscle (dystrophic biopsy), which is usually associated with elevated serum creatine kinase concentration. Biochemical testing (i.e., protein testing by immunostaining) performed on a muscle biopsy can establish the diagnosis of the LGMD subtypes sarcoglycanopathy (OMIM 608099 and 604286), calpainopathy, and dysferlinopathy. In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by molecular genetic studies of the corresponding gene. The caveolinopathies are a group of muscle diseases caused by pathogenic variants in CAV3, which encodes caveolin-3 (OMIM 601253), a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo. The caveolinopathies, which are inherited in an autosomal dominant manner, can be classified into five phenotypes: * Limb-girdle muscular dystrophy 1C (LGMD1C) characterized by onset usually in the first decade, mild-to-moderate proximal muscle weakness, calf hypertrophy, positive Gower sign, and variable muscle cramps after exercise; * Isolated hyperCKemia (i.e., elevated serum concentration of creatine kinase (CK) in the absence of signs of muscle disease) (HCK); * Rippling muscle disease (RMD), characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle); * Distal myopathy (DM), observed in one individual only; * Hypertrophic cardiomyopathy (HCM), without skeletal muscle manifestations. The differential diagnosis also includes the dystrophinopathies (Duchenne/Becker muscular dystrophy), polymyositis, and distal myopathies [Udd & Griggs 2001]. Other distal myopathies have been identified with clinical and genetic patterns as follows (see Table 3). ### Table 3. Distal Myopathies View in own window Disease NameMean Age at OnsetInitial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene (Locus) 1 Autosomal Dominant Welander distal myopathy (OMIM 604454)>40 yearsDistal upper limbs (finger & wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13) Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN Zaspopathy (Markesbery-Griggs late-onset distal myopathy) (OMIM 609452)>40Vacuolar & myofibrillar myopathyLDB3 Distal myotilinopathy (OMIM 609200)>40Posterior > anterior in legsSlightly increasedVacuolar & myofibrillar myopathyMYOT Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs & neck flexorsModerately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7 Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg & hands; dysphonia1-8 timesRimmed vacuoles(5q) Distal myopathy with pes cavus and areflexia15-50Anterior & posterior lower leg; dysphonia and dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13) New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22) Autosomal Recessive Nonaka early-adult-onset distal myopathy15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE Udd & Griggs [2001] 1\. Locus given only if the gene is not known ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the following evaluations are recommended: * Assessment of strength and function in the arms, hands, legs, and feet; especially calf muscle * If needed, measurement of serum CK concentration * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations No definitive treatments exist for the limb-girdle muscular dystrophies. Management should be tailored to each individual and each specific subtype. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995] and Bushby [1999]. * Physical therapy and stretching exercises to promote mobility and prevent contractures * Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility * Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis * Use of respiratory aids when indicated * Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders ### Prevention of Secondary Complications Stretching exercises to prevent contractures are indicated. ### Surveillance The following surveillance is appropriate: * Annual monitoring of muscle strength, joint range of motion, and respiratory function * Monitoring for evidence of cardiomyopathy in those subtypes with known occurrence of cardiac involvement ### Agents/Circumstances to Avoid Control weight to avoid obesity; avoid use of steroids [Walter et al 2013]. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation A double-blinded, placebo-controlled clinical trial of deflazacort in individuals with genetically confirmed dysferlinopathy has been completed [Walter et al 2013]. After six months of treatment, muscle strength did not improve; rather, there was a trend towards worsening muscle strength for affected individuals on deflazacort treatment. Muscle strength improved after the study drug was discontinued. Side effects included a broad spectrum typically seen in those taking steroids. Therefore, deflazacort treatment is not effective as a therapy for individuals with dysferlinopathies; additionally, the authors concluded that steroid treatment in general should be avoided in this condition [Walter et al 2013]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Dysferlinopathy	c2931687	1,233	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1303/	2021-01-18T21:29:54	{"mesh": ["C537995"], "synonyms": []}
## Description Otosclerosis is a hearing disorder that is associated with disordered bone remodeling in the otic capsule. The bone remodeling can result in conductive, mixed, or sensorineural hearing loss as a result of stapes footplate fixation or cochlear involvement (summary by Schrauwen et al., 2011). Clinical Features Schrauwen et al. (2011) studied a large Dutch family segregating autosomal dominant otosclerosis over 3 generations. Immobility of the stapes observed during surgery confirmed the diagnosis in 4 patients; 3 individuals who did not undergo surgery were considered affected because they met several criteria, including the presence of conductive or mixed hearing impairment, air-bone gap greater than 20 decibels averaged across 0.5 to 2 kHz, absent stapedial reflexes, and normal otoscopy. Four additional family members had hearing impairment abnormal for their age and sex, but did not meet the criteria for otosclerosis. Mapping In a large 3-generation Dutch family segregating autosomal dominant otosclerosis, in which linkage to known otosclerosis loci and the NOG gene (602991) had been excluded, Schrauwen et al. (2011) performed a genomewide screen with multipoint linkage analysis that revealed only 1 region with a lod score greater than 1, a 26.1-Mb interval at chromosome 1q41-q44. Analysis of 27 additional microsatellite markers confirmed the locus, and a maximum lod score of 3.3 was obtained by multipoint linkage analysis. Molecular Genetics ### Exclusion Studies In a large 3-generation Dutch family with autosomal dominant otosclerosis mapping to chromosome 1q41-q44, Schrauwen et al. (2011) screened the 26.1-Mb region for copy number variants based on the SNP microarray, but did not detect any aberration. In addition, 2 candidate genes in the region, TGFB2 (190220) and AGT (106150), were sequenced but no pathogenic variants were identified. Nomenclature Because the symbol OTSC9 was reserved by the HUGO Gene Nomenclature Committee on February 10, 2009 for an unpublished ninth locus for otosclerosis, the locus identified by Schrauwen et al. (2011) was designated OTSC10. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, conductive or mixed \- Absent stapedial reflexes or intraoperative stapes immobility \- Air-bone gap of greater than 20 dB across 0.5 to 2 kHz MISCELLANEOUS \- Based on report of 1 family (last curated January 2014) ▲ 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	OTOSCLEROSIS 10	c3888339	1,234	omim	https://www.omim.org/entry/615589	2019-09-22T15:51:33	{"omim": ["615589"]}
Form of dysgammaglobulinemia IgG deficiency Other namesSelective deficiency of immunoglobulin G Immunoglobulin G SpecialtyHematology IgG deficiency is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes. IgG deficiency is often found in children as transient hypogammaglobulinemia of infancy (THI), which may occur with or without additional decreases in IgA or IgM. IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4. It is possible to have either a global IgG deficiency, or a deficiency of one or more specific subclasses of IgG.[1][2] The main clinically relevant form of IgG deficiency is IgG2. IgG3 deficiency is not usually encountered without other concomitant immunoglobulin deficiencies, and IgG4 deficiency is very common but usually asymptomatic.[3] IgG1 is present in the bloodstream at a percentage of about 60-70%, IgG2-20-30%, IgG3 about 5-8 %, and IgG4 1-3 %. IgG subclass deficiencies affect only IgG subclasses (usually IgG2 or IgG3), with normal total IgG and IgM immunoglobulins and other components of the immune system being at normal levels. These deficiencies can affect only one subclass or involve an association of two subclasses, such as IgG2 and IgG4. IgG deficiencies are usually not diagnosed until the age of 10. Some of the IgG levels in the blood are undetectable and have a low percentage such as IgG4, which makes it hard to determine if a deficiency is actually present. IgG subclass deficiencies are sometimes correlated with bad responses to pneumoccal polysaccharides, especially IgG2 and or IgG4 deficiency. Some of these deficiencies are also involved with pancreatitis and have been linked to IgG4 levels. ## References[edit] 1. ^ Barton JC, Bertoli LF, Acton RT (June 2003). "HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama". BMC Med. Genet. 4: 3. doi:10.1186/1471-2350-4-3. PMC 166147. PMID 12803653. 2. ^ Dhooge IJ, van Kempen MJ, Sanders LA, Rijkers GT (June 2002). "Deficient IgA and IgG2 anti-pneumococcal antibody levels and response to vaccination in otitis prone children". Int. J. Pediatr. Otorhinolaryngol. 64 (2): 133–41. doi:10.1016/S0165-5876(02)00068-X. PMID 12049826. 3. ^ Driessen, G; van der Burg, M (June 2011). "Educational paper: primary antibody deficiencies". European Journal of Pediatrics. 170 (6): 693–702. doi:10.1007/s00431-011-1474-x. PMC 3098982. PMID 21544519. ## External links[edit] Classification D * ICD-10: D80.3 * ICD-9-CM: 279.03 * MeSH: D017099 External resources * eMedicine: med/1161 * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency This immunology 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	IgG deficiency	c0162539	1,235	wikipedia	https://en.wikipedia.org/wiki/IgG_deficiency	2021-01-18T18:46:20	{"gard": ["10371"], "mesh": ["D017099"], "umls": ["C0162539"], "wikidata": ["Q17094243"]}
A number sign (#) is used with this entry because of evidence that multiple epiphyseal dysplasia-3 (EDM3) is caused by heterozygous mutation in the COL9A3 gene (120270) on chromosome 20q13. Description Multiple epiphyseal dysplasia is characterized by early-onset short stature, waddling gait, and stiffness and/or pain in the knees and sometimes other joints (Muragaki et al., 1996). For a general phenotypic description and a discussion of genetic heterogeneity of multiple epiphyseal dysplasia, see EDM1 (132400). Clinical Features Individuals with multiple epiphyseal dysplasia (MED) typically present during childhood and adolescence with waddling gait and stiffness and/or pain in the knees. Few patients experience involvement of other joints such as the elbow, wrist, or ankle. Some patients are mildly short statured and/or have stubby hands. Often patients do not seek medical advice because of the mildness of their complaints. X-rays show flattened, irregular epiphyses, varus or valgus deformity of the knees, and gradually appearing osteoarthritis with or without loose bodies. Precocious osteoarthritis of the hips often requires early hip replacement. Typically there are no spine abnormalities (Muragaki et al., 1996). ### Clinical Variability Bonnemann et al. (2000) reported a family with autosomal dominant EDM affecting predominantly the knee joints and a mild proximal myopathy. The proband was a 10-year-old boy referred for evaluation of proximal muscle weakness and mildly elevated serum creatine kinase. He walked at 1 year of age but at age 3 was noted to have difficulty walking and climbing stairs. He always had difficulty rising from the floor and sometimes used a one-handed Gowers maneuver. He tired easily, never ran well, and complained of knee pain. He had significant weakness of neck flexion, mild weakness of shoulder abduction and elbow extension, and proximal lower limb weakness (hamstrings weaker than quadriceps). By x-ray, the epiphyseal changes characteristic of MED were most marked in the knee joints, followed by the ankle joints. Affected family members likewise showed MED predominantly affecting the knee joints and sparing the hips. The proband's mother had weak neck flexors and minimal weakness of the proximal extremities. Bonnemann et al. (2000) suggested that patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen. Mapping In a large family with EDM, Paassilta et al. (1999) found an inheritance pattern consistent with linkage to the COL9A3 gene on chromosome 20q13. Molecular Genetics In affected members of a large family with EDM3, Paassilta et al. (1999) identified a heterozygous mutation in the acceptor splice site of intron 2 of the COL9A3 gene (120270.0001). In a 3-generation Japanese family with MED, Nakashima et al. (2005) identified a heterozygous donor splice site mutation in intron 2 of the COL9A3 gene (120270.0004). Affected members had knee pain ('occasional' in females) but were of normal height and had no signs or symptoms of muscle weakness. Nakashima et al. (2005) commented that these cases were milder than those reported by Paassilta et al. (1999). In affected members of a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy, Bonnemann et al. (2000) detected a heterozygous splice acceptor mutation in intron 2 of the COL9A3 gene (120270.0002) that resulted in the skipping of exon 3. The authors suggested that the MED and mild myopathy was likely caused by a dominant-negative effect of this mutation. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature, mild SKELETAL Pelvis \- Hip arthrosis Limbs \- Osteoarthritis \- Small, irregular epiphyses \- Late ossifying epiphyses Hands \- Normal hands \- Short metacarpals MUSCLE, SOFT TISSUES \- Proximal muscle weakness ( 120270.0002 ) \- Mild variability in muscle fiber size LABORATORY ABNORMALITIES \- Mildly elevated creatine phosphokinase (CPK) ( 120270.0002 ) MISCELLANEOUS \- Genetic heterogeneity (see EDM1 132400 , EDM2 600204 , EDM4 226900 , EDM5 607078 ) \- Onset of symptoms in childhood with stiff, painful joints \- Joint replacement often necessary MOLECULAR BASIS \- Caused by mutation in the collagen IX, alpha-3 polypeptide gene (COL9A3, 120270.0001 ) ▲ 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	EPIPHYSEAL DYSPLASIA, MULTIPLE, 3	c1832998	1,236	omim	https://www.omim.org/entry/600969	2019-09-22T16:15:40	{"doid": ["0070304"], "mesh": ["C535503"], "omim": ["600969"], "orphanet": ["166002"], "synonyms": [], "genereviews": ["NBK1123"]}
A rare autoimmune bullous skin disease characterized by acquired, subepidermal tense bullae occurring on normal of inflamed skin and that is typically widespread (occurring in the flexor regions of the proximal arms and legs, in the armpits, groin and the abdomen) and often associated with pruritus. The evolution is typically chronic with spontaneous exacerbations and remission. ## Epidemiology Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. It has an estimated prevalence of 1/4,000 in Europe. The incidence is reported to be increasing but currently ranges between 2-22/1,000,000 worldwide. ## Clinical description BP predominantly affects the elderly with an average age of 80 years and is significantly associated with neurological disorders. Some cases have also been described in children and young adults. The disease is characterized clinically by tight, often large, bullae with a clear content, developing primarily on the edge of erythematous plaques. Intense itching is common. Some patients may have mucosal involvement (10-20% of cases). The rare infantile forms differ from the adult form by its palmo-plantar involvement, especially in children under 1 year of age, and its greater frequency of mucosal involvement. ## Etiology BP is immunologically characterized by the production of autoantibodies directed against two structural proteins found in the dermal-epidermal junction and ensuring dermal-epidermal cohesion: BP antigen 1 (BPAG1 or AgBP230), and BP antigen 2 (BPAG2, AgBP180 or collagen XVII). The binding between the autoantibodies and these proteins leads to the separation between the dermis and the epidermis and the formation of blisters. Some drugs are associated with the onset of BP (diuretics, antiarrhythmics, neuroleptics, gliptins, immunotherapies). ## Diagnostic methods The diagnosis is based on clinical features and skin biopsy showing typical light microscopy findings (subepidermal bullae containing eosinophils and/or neutrophils, associated with a dermal infiltrate of eosinophils and /or neutrophils, or a marginalization of eosinophils along the dermal-epidermal junction) and positive direct immunofluorescence microscopy findings (linear deposits of IgG and/or C3 along the dermal-epidermal junction). Blood samples are also needed in order to search for circulating IgG anti-basement membrane autoantibodies by indirect immunofluorescence microscopy studies and anti-BP180 IgG antibodies and anti-BP230 IgG antibodies by ELISA. ## Differential diagnosis The main differential diagnoses are some forms of acquired bullous epidermolysis and anti-P200 pemphigoid. BP with mucosal involvement may look like mucous membrane pemphigoid even if mucosal involvement is rarely predominant in BP. ## Management and treatment Systemic corticosteroids (CS) (prednisone: 0.5-1 mg/kg/day) is referred as the standard treatment in most countries. The European consensus for first line treatment is with super-potent topical corticosteroids to the whole-body surface sparing the face, or applied to lesions only where the disease is localized/limited, and is followed by a maintenance or tapering schedule as required. In patients with recalcitrant BP and in those with multiple relapses, immunosuppressive drugs (methotrexate, mycophenolate mofetil) are usually used. Doxycycline can be used, especially in patients with contraindications to immunosuppressive drugs or in poor general condition. Recently, new therapeutics have been tested in particular rituximab and omalizumab whose indications remain as yet unclear. ## Prognosis BP is a serious disease. In some cases, the prognosis for BP patients is poor. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bullous pemphigoid	c0030805	1,237	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=703	2021-01-23T18:27:37	{"gard": ["5972"], "mesh": ["D010391"], "umls": ["C0030805"], "icd-10": ["L12.0"]}
## Description Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). ### Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550). Clinical Features Mulcahy et al. (1970) described a high familial incidence. The disorder is rare in blacks. Burger (1972) found 23 families with 2 or more affected first-degree relatives and added 7 more containing a total of 20 affected first-degree relatives. The anatomic substrate was thought to be abnormally short intravesical ureter. Mother and at least 1 child were affected in 4 families. Fried et al. (1975) described 2 families, each with several affected children. In 1 family the mother had unilateral reflux. Investigating relatives is important because if the disorder is not treated, progressive renal damage may occur. Lewy and Belman (1975) observed vesicoureteral reflux in father and 3 sons. Van den Abbeele et al. (1987) studied 60 asymptomatic sibs of patients known to have vesicoureteral reflux, using radionuclide voiding cystography. Vesicoureteral reflux was detected in 27 of the 60 (45%). Reflux was unilateral in 15 and bilateral in 12. Van den Abbeele et al. (1987) stated that the gonadal dose with radionuclide cystography is low and recommended that this procedure should be used in screening all sibs of patients with known vesicoureteral reflux. Connolly et al. (1996) studied the natural history of vesicoureteral reflux as revealed by the clinical records and radionuclide cystograms of 76 girls and 32 boys of mean age 21 months with reflux detected in a sib screening program. Reflux resolved in 52.8% of cases at a mean follow-up of 18.5 months. Yearly resolution rates exceeded 28%. Predictors of the likelihood of resolution were not identified. By showing that spontaneous resolution is likely for children with this disorder, this study supported nonsurgical management with annual imaging evaluation. Population Genetics Lu et al. (2007) stated that VUR has an incidence of approximately 1 in 100 infants. Reflux nephropathy resulting from vesicoureteral reflux is said to account for as much as 15% of end-stage renal disease in children and young adults (Kincaid-Smith et al., 1984). In sibs and offspring of affected persons, the prevalence is as high as 50% (Van den Abbeele et al., 1987; Noe et al., 1992). Inheritance VUR may be multifactorial (Burger, 1972; Fried et al., 1975) rather than autosomal dominant. Chapman et al. (1985) applied complex segregation analysis to data from 88 families with at least 1 person with VUR. They concluded that a single major locus is the most important causal factor. The mutant allele was estimated to be dominant with a frequency of about 0.16%. As adults, about 45% of persons with the gene would have VUR and/or reflux nephropathy and 15% develop renal failure, compared to 0.05% and 0.001%, respectively, for persons without the gene. Whether this disorder is multifactorial or mendelian, the analysis points up the importance of studying asymptomatic relatives of persons with VUR. Peeden and Noe (1992) found 18 patients with vesicoureteral reflux among 48 children with urinary tract infections. All 24 sibs of these 18 index patients were studied for the presence of reflux which was found in 11 (46%). Kenda et al. (1991) had reported similar findings. Using data from a review of records in 2 medical centers, Wan et al. (1996) reported an overall reflux rate in 27% of 622 sibs, with a 33% rate in females. Twin sibs (zygosity unspecified) had the highest reflux rates (67%). Most sibs with reflux were younger than 7 years; less than 5% were older than 10 years, yet the older sibs comprised a significant proportion of those with RN. Nearly 14% of sibs had renal scarring, which did not correlate with reflux grade. The severity of sib reflux was usually low and was more common in the lesser grades (I, II, III). Robson et al. (1994, 1995) suggested that multicystic dysplasia of kidneys (143400), ureteropelvic junction obstruction, and VUR may have a common genetic cause. Devriendt et al. (1998) reviewed the evidence that VUR is an autosomal dominant condition with reduced penetrance. They suggested that since VUR can be seen in the contralateral side of individuals with syndromic or nonsyndromic multicystic renal dysplasia, ureterovesical junction obstruction, pelviureteral junction obstruction, ureteral duplication, renal hypoplasia, and renal aplasia, these different urologic malformations not only have a related pathogenesis, but may be caused by mutations in the same genes. Mapping Feather et al. (2000) performed a genomewide search in 7 European families with apparently dominant inheritance of VUR/RN. The most positive locus spanned 20 cM on 1p13 between 2 specific markers, giving a nonparametric lod score of 5.76 (P = 0.0002) and a parametric lod score of 3.16. Saturation with markers at 1-cM intervals increased the nonparametric lod score to 5.94 (P = 0.00009). There was evidence of genetic heterogeneity, and 12 additional loci were identified genomewide, with P less than 0.05. They found no positive results in areas that had previously been reported as renal malformation loci, including 6p (see 143400) and 10q, the site of the PAX2 gene (167409). Van Eerde et al. (2007) was unable to confirm linkage to the locus on chromosome 1p13 in 4 unrelated Dutch families with VUR. Further analysis excluded linkage to any loci or gene, indicating genetic heterogeneity. ### Associations Pending Confirmation By genomewide analysis of 104 primarily Irish families with primary VUR, Kelly et al. (2007) identified a candidate locus on chromosome 2q37.1-q37.3 (maximum nonparametric lod score of 4.10). Among French Canadian VUR patients, Yang et al. (2008) observed a significant association between primary VUR and a G691S polymorphism (rs1799939) in the RET gene (164762) on chromosome 10q11. The rare A allele was identified in 83 of 118 unrelated probands with VUR; 2 affected sibs were homozygous for the variant. The frequency of the A allele was 0.145 in controls and 0.360 in patients. Yang et al. (2008) hypothesized that the variant may result in local conformational changes and altered phosphorylation status of RET. As Skinner et al. (2008) observed an association between variants in the RET gene and renal adysplasia, VUR may be a manifestation of that disorder. Molecular Genetics Choi et al. (1998) studied 23 affected individuals from 8 families with primary familial VUR. Sanyanusin et al. (1995) demonstrated mutations in the PAX2 gene (167409.0001) in renal coloboma syndrome (120330), of which VUR is a part. By use of SSCP, Choi et al. (1998) found no mutations in exons 2 to 5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease. Choi et al. (1998) concluded that mutation in the PAX2 gene is not a major cause of primary familial reflux. GU \- Vesicoureteral reflux \- Progressive renal damage if untreated Radiology \- Detection by radionuclide voiding cystography Inheritance \- Autosomal dominant vs. multifactorial ▲ 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	VESICOURETERAL REFLUX 1	c4551858	1,238	omim	https://www.omim.org/entry/193000	2019-09-22T16:32:00	{"doid": ["9620"], "mesh": ["D014718"], "omim": ["193000"], "orphanet": ["289365"], "synonyms": ["VUR", "Alternative titles", "Familial VUR"]}
A rare subtype of kyphoscoliotic Ehlers-Danlos syndrome characterized by congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional common features are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Subtype-specific manifestations include congenital hearing impairment (sensorineural, conductive, or mixed), follicular hyperkeratosis, muscle atrophy, and bladder diverticula. Molecular testing is obligatory to confirm the diagnosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency	c3281160	1,239	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300179	2021-01-23T18:53:50	{"omim": ["614557"], "icd-10": ["Q79.6"], "synonyms": ["Ehlers-Danlos syndrome with kyphoscoliosis, myopathy, and deafness", "Ehlers-Danlos syndrome with kyphoscoliosis, myopathy, and hearing loss", "FKBP14-related EDS", "FKBP22-deficient EDS", "Kyphoscoliotic EDS due to FKBP22 deficiency", "kEDS-FKBP14"]}
A number sign (#) is used with this entry because hemoglobin H disease is caused by contiguous gene deletion of the hemoglobin alpha-1 (HBA1; 141800) and alpha-2 (HBA2; 141850) genes on one chromosome 16, and a defect, deletional or nondeletional, in either HBA1 or HBA2 on the other. Description Hemoglobin H disease is a subtype of alpha-thalassemia (see 604131) in which patients have compound heterozygosity for alpha(+)-thalassemia, caused by deletion of one alpha-globin gene, and for alpha(0)-thalassemia, caused by deletion in cis of 2 alpha-globin genes (summary by Lal et al., 2011). When 3 alpha-globin genes become inactive because of deletions with or without concomitant nondeletional mutations, the affected individual has only 1 functional alpha-globin gene. These people usually have moderate anemia and marked microcytosis and hypochromia. In affected adults, there is an excess of beta-globin chains within erythrocytes that will form beta-4 tetramers, also known as hemoglobin H (summary by Chui et al., 2003). Hb H disease is usually caused by the combination of alpha(0)-thalassemia with deletional alpha(+)-thalassemia, a combination referred to as 'deletional' Hb H disease. In a smaller proportion of patients, Hb H disease is caused by an alpha(0)-thalassemia plus an alpha(+)-thalassemia point mutation or small insertion/deletion. Such a situation is labeled 'nondeletional' Hb H disease. Patients with nondeletional Hb H disease are usually more anemic, more symptomatic, more prone to have significant hepatosplenomegaly, and more likely to require transfusions (summary by Lal et al., 2011). While most thalassemia-related hydrops fetalis is caused by the lack of all alpha-globin genes, there are reports of fetuses with Hb H disease that developed the hydrops fetalis syndrome; see 236750. Biochemical Features Hemoglobin H is observed as a 'fast' electrophoretic variant. Rigas et al. (1955), Jones et al. (1959), Kattamis and Lehmann (1970), Koler et al. (1971), and Lie-Injo et al. (1971) provided electrophoretic observations and genetic interpretations of hemoglobin H. Inheritance Necheles et al. (1966) provided evidence that Hb H disease results from mating of a parent with alpha-thalassemia and a parent with a silent H gene, and that double heterozygosity is necessary for Hb H disease. The findings of Na-Nakorn et al. (1969) led to roughly the same conclusion. Among the newborn offspring of persons with Hb H, they found some with 1 to 2% Hb Bart's and others with 5 to 6%. They suggested that these 2 types of children are heterozygous for 2 different alpha-thal genes, one of which is not detectable in the adult heterozygote. Clinical Features ### Deletional Hemoglobin H Disease Hb H disease is generally thought to be a mild disorder. However, there is marked phenotypic variability ranging from asymptomatic, to needing periodic transfusions, to severe anemia with hemolysis and hepatosplenomegaly, to fatal hydrops fetalis in utero. Patients with identical alpha-globin genotypes can have different phenotypes, suggesting that there are other genetic and/or environmental factors that can affect phenotypic expression of Hb H disease (summary by Chui et al., 2003). Lal et al. (2011) studied 60 patients with deletional Hb H disease identified by newborn screening. Although originally assumed to be an Asian-only phenotype, among these patients 15% had 1 or both parents with African American ancestry. Growth was normal in patients with deletional Hb H during the first decade. Height-for-age percentiles for deletional Hb H patients were below the mean but above -1 Z score for children through the age of 12 years. Most children with deletional Hb H did not require blood transfusion; only 1 was required in a child under age 20 years, a 2-year-old boy with severe pneumonia who required mechanical ventilation. In patients over 20 years of age, 2 adults required transfusion: one was a 26-year-old woman with hemoglobin level of 7.6 g/dl who required transfusion during a febrile illness, and the other was a 30-year-old female who was undergoing surgery. No patients with deletional Hb H required splenectomy, and serum ferritin levels did not increase significantly between birth and 18 years. Iron overload did not generally manifest in patients with deletional Hb H prior to the third decade. ### Nondeletional Hemoglobin H Disease In contrast to beta-thalassemia, nondeletional alpha(+)-thalassemia mutations are relatively uncommon. The alpha-2 globin gene (HBA2; 141850) accounts for 2 to 3 times more alpha-globin mRNA and alpha-globin chain production than the alpha-1 gene. Therefore, point mutations of the alpha-2-globin gene generally cause more severe anemia than the same mutations involving the alpha-1-globin gene. Patients with nondeletional Hb H disease usually are more anemic, more symptomatic, more prone to have significant hepatosplenomegaly, and more likely to require transfusions (summary by Chui et al., 2003). The form of nondeletional hemoglobin H disease termed Hb H Constant Spring arises from a deletion removing both alpha-globin genes on one chromosome 16 and the alpha(+)-thalassemia mutation hemoglobin Constant Spring (X142Q; 141850.0001) on the other chromosome 16. This hemoglobinopathy is found predominantly in persons of Southeast Asian ancestry. Lal et al. (2011) studied 23 patients with Hb H Constant Spring. Patients with Hb H Constant Spring exhibited growth deficits beginning in infancy. Anemia was more severe in patients with Hb H Constant Spring at all ages, and acute worsening of anemia with infections requiring urgent blood transfusions was observed in patients with Hb H Constant Spring but not in those with deletional Hb H. The probability of receiving at least 1 transfusion by the age of 20 years was 3% for patients with deletional Hb H and 80% for those with Hb H Constant Spring (p less than 0.001). Among patients with Hb H Constant Spring, transfusions occurred in 13% of infants and 50% of children under the age of 6 years; splenectomy was associated with a significant improvement in hemoglobin levels (P = 0.01) and a reduction in the number of transfusions. Patients with Hb H Constant Spring were of Chinese, Laotian, and Cambodian ethnicity. Patients with Hb H Constant Spring had a very high risk of severe anemia leading to urgent blood transfusions. Transfusions were precipitated by infections in 37 events (82%) with the majority of events (60%) diagnosed as viral illness owing to an unknown source or organism. Five of 23 patients with Hb H Constant Spring underwent splenectomy between the ages of 3.9 and 13.0 years because of the need for frequent blood transfusion. The average baseline hemoglobin level before splenectomy was 6.8 (range, 6.4 to 7.4), which increased to 9.7 (range, 7.0 to 11.3) after splenectomy (P = 0.01). Splenectomy reduced or eliminated acute hemolytic episodes requiring urgent transfusion in 4 of the 5 patients. Hepatic iron was higher in patients with Hb H Constant Spring, and these patients had an increased number of annual clinic visits and increased number of annual hospital admissions by a factor of 3.9 as compared with patients with deletional hemoglobin H. Lal et al. (2011) stated that Hb H Constant Spring should be recognized as a distinct thalassemia syndrome with a high risk of life-threatening anemia during febrile illness. Hill et al. (1987) described a unique nondeletion form of Hb H disease in Papua New Guinea: all 4 alpha genes were intact. Population Genetics Hb H disease is found in many parts of the world, including Southeast Asian, Middle Eastern, and Mediterranean populations. It is particularly prevalent in Southeast Asia and in southern China, because of the high carrier frequencies of the --(SEA) deletion and to a lesser extent the --(FIL) deletion there. Of a Thailand population of 62 million people, it was estimated that 7,000 infants with Hb H disease were born annually, and that there were 420,000 patients with Hb H disease in that country (summary by Chui et al., 2003). Pressley et al. (1980) showed that the form of hemoglobin H that is extraordinarily frequent in the population of the eastern Saudi Arabian oasis is the result of a different aberration of the alpha-globin haplotype than is Hb H in other populations. Zeinali et al. (2011) remarked that while unpublished data from a study of Hb H disease in Iran were consistent with the observations of Lal et al. (2011) regarding deletional Hb H disease, those results showed more diversity in the genotype and clinical presentation of nondeletional Hb H disease. Zeinali et al. (2011) concluded that their data and those of others consistent with it from the Mediterranean and the Middle East will be useful for clinicians treating patients from those regions in other countries. Vichinsky and Lal (2011) replied that in general the data of Zeinali et al. (2011) provided support for their observations that deletional Hb H disease is relatively benign and nondeletional Hb H is moderately severe. However, many other genetic variables affect phenotype, including involvement of the alpha-2 globin gene. Environmental factors are a major determination of severity. In their study, minor febrile illnesses triggered severe anemia in patients with hemoglobin Constant Spring, and splenectomy reduced or eliminated these hemolytic events. The estimated number of worldwide annual births of patients with Hb H disease is 9,568 and with Hb Bart's hydrops is 5,183 (Modell and Darlison, 2008 and Weatherall, 2010). Molecular Genetics Hemoglobin H disease results from the inactivation of 3 of the 4 alpha-globin genes on both chromosomes 16. There are more than 20 known natural deletions that remove both alpha-globin genes on the same chromosome 16 (in cis) or the complete zeta-alpha-globin gene cluster, and they are known as the alpha-0-thalassemia mutations. In addition, there are rare deletions that silence alpha-globin gene expression by removing the HS-regulatory sequences upstream of the zeta-alpha-globin gene cluster (summary by Chui et al., 2003). The southeast Asian deletion of alpha-0-thalassemia, termed --(SEA), is approximately 19.3 kb and removes both alpha-globin genes in cis but spares the embryonic zeta-globin gene. This mutation is the most common cause for Hb H disease and hydrops fetalis syndrome in that part of the world. In addition, the --(FIL), --(MED), and -(alpha20.5) deletions are relatively common in the Philippines and in the Mediterranean region, respectively (summary by Chui et al., 2003). Chui et al. (2003) reviewed the genotypes of 319 patients with Hb H disease from California, Hong Kong, and Ontario reported during the foregoing 2 years. Of those patients, 266 (83%) had deletional Hb H disease. The most common genotype was --(SEA)/-(alpha3.7), found in 175 patients (55%), followed by --(SEA)/-(alpha4.2) in 37 patients (12%), and --(FIL)/-(alpha3.7) in 36 patients (11%). Fifty-three patients (17%) had nondeletional Hb H disease. The most prevalent genotype among this subgroup was --(SEA)/Constant Spring, found in 31 patients (10%). Among the 638 chromosomes from these 319 patients, --(SEA) was found in 263 (41%), -(alpha3.7) in 224 (35%), -(alpha4.2) in 42 (7%), --(FIL) in 38 (6%), and Constant Spring in 32 chromosomes (5%). The 14 remaining mutations were found in 39 chromosomes (6%). In the Mediterranean region, the most common deletion removing both alpha-globin genes in cis is the --(MED) deletion. Among 78 Cypriot patients with Hb H disease, 79% had the --(MED) deletion and 17% had the -(alpha20.5) deletion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	HEMOGLOBIN H DISEASE	c1260396	1,240	omim	https://www.omim.org/entry/613978	2019-09-22T15:56:53	{"doid": ["0110031"], "omim": ["613978"], "orphanet": ["93616"], "synonyms": ["Alternative titles", "ALPHA-THALASSEMIA, HEMOGLOBIN H TYPE", "HEMOGLOBIN H DISEASE, DELETIONAL"]}
A rare group of inherited congenital malformation disorders characterized by craniosynostosis and fusion or webbing of the fingers or toes, often with other associated manifestations. ## Epidemiology The exact prevalence and birth incidence of ACS syndromes are not known. Overall incidence of all forms of craniosynostosis is reported to be 1/2,000 to 1/2,500 live births, but only small minorities of these cases are syndromic and the ACS syndromes are only one of many that have craniosynostosis as a finding. ## Clinical description Acrocephalosyndactyly includes a number of syndromes with similar and sometimes overlapping clinical manifestations. All include single-suture or multisutural craniosynostosis with distinctive facial features, variable intellectual and developmental deficits, and variable forms of hand or foot abnormalities. The group includes Apert, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, and Carpenter syndromes (see these terms). ## Etiology Mutations in the following genes have been found in ACS: FGFR1 (8p12), FGFR2 (10q25.3-q26), FGFR3 (4p16.3), and TWIST1 (7p21). ## Genetic counseling The pattern of inheritance in acrocephalosyndactyly syndromes is autosomal dominant but de novo gene mutations are very common, especially with more severe sub types. Genetic counseling is recommended. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acrocephalosyndactyly	c1510455	1,241	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=946	2021-01-23T18:46:03	{"mesh": ["D000168"], "umls": ["C1510455"], "icd-10": ["Q87.0"], "synonyms": ["ACS", "Acrocephalosyndactylia"]}
Amnion nodosum are nodules found on the amnion, and is frequently present in oligohydramnios.[1] The nodules are composed of squamous cell aggregates derived from the vernix caseosa on the fetal skin. Amnion nodosum is caused by the unexpected abrasion of amnion with depositions of the fetal surface cells and acellular debris on the eroded areas(due to moderate or severe oligohydramnios, the amnion can get "touch" with the fetal skin). Amnion nodosum and oligohydramnios are associated with pulmonary hypoplasia and renal agenesis. Amnion nodosum is granules on amnion whereas whitish nodules on the cord suggest a candidial infection.[citation needed] ## References[edit] 1. ^ Adeniran AJ, Stanek J (2007). "Amnion nodosum revisited: clinicopathologic and placental correlations". Arch Pathol Lab Med. 131 (12): 1829–33. doi:10.1043/1543-2165(2007)131[1829:ANRCAP]2.0.CO;2 (inactive 2021-01-14). PMID 18081444.CS1 maint: DOI inactive as of January 2021 (link) * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline This article about a disorder arising in the perinatal period 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	Amnion nodosum	c0269802	1,242	wikipedia	https://en.wikipedia.org/wiki/Amnion_nodosum	2021-01-18T18:29:53	{"umls": ["C0269802"], "icd-9": ["658.8"], "wikidata": ["Q4747401"]}
Ring chromosome 13 is a chromosomal anomaly of chromosome 13 characterized by a widely variable phenotype (ranging from mild to severe) principally characterized by intrauterine growth retardation, developmental delay, short stature, moderate to severe intellectual deficit, microcephaly, facial dysmorphism (i.e. upslanting palpebral fissures, hypertelorism, abnormal ears, broad nasal bridge, high arched palate, micrognathia, small mouth, and thin lips), hands and feet anomalies, and genital abnormalities. Additional features reported include behavioral problems, hearing and speech disorders, congenital heart defects, cerebral malformations, and anal atresia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Ring chromosome 13 syndrome	c2931808	1,243	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96176	2021-01-23T17:10:27	{"gard": ["6069"], "mesh": ["C538303"], "umls": ["C2931808"], "icd-10": ["Q93.2"], "synonyms": ["Ring 13", "Ring chromosome 13"]}
A complex form of hereditary spastic paraplegia, characterized by an onset in childhood or adulthood of progressive spastic paraplegia (with spastic gait, spasticity, lower limb weakness, pes cavus and urinary urgency) associated with the additional manifestation of peripheral sensorimotor neuropathy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal dominant spastic paraplegia type 36	c2936879	1,244	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=320365	2021-01-23T17:03:28	{"mesh": ["C567930"], "omim": ["613096"], "umls": ["C2936879"], "icd-10": ["G11.4"], "synonyms": ["SPG36"]}
Mastocytosis occurs when too many mast cells accumulate in the skin and/or internal organs such as the liver, spleen, bone marrow, and small intestines. Mast cells are a type of white blood cell in the immune system. Mast cells are responsible for protecting the body from infection and releasing chemicals to create inflammatory responses. The signs and symptoms of mastocytosis vary based on which parts of the body are affected. There are two main forms of mastocytosis. Cutaneous mastocytosis only affects the skin and is more common in children. Systemic mastocytosis affects more than one part of the body and is more common in adults. Mastocytosis is usually caused by changes (known as variations or mutations) in the KIT gene. Most cases are caused by somatic mutations, meaning they only occur in certain parts of the body and are not inherited or passed on to the next generation. However, mastocystosis can rarely affect more than one person in a family. Mastocysotis may be suspected when a doctor sees a person has signs and symptoms of the disease. Diagnosis may be confirmed with a skin biopsy or bone marrow biopsy. Treatment of mastocytosis is based on the signs and symptoms present in each person and can include antihistamines, mast cell stabilizers, corticosteroids, and oral psoralen plus UV-A therapy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Mastocytosis	c0024899	1,245	gard	https://rarediseases.info.nih.gov/diseases/6987/mastocytosis	2021-01-18T17:59:14	{"mesh": ["D008415"], "omim": ["154800"], "orphanet": ["98292"], "synonyms": ["Mast cell disease"]}
Synesthesia that associates numbers or letters with colors How someone with grapheme–color synesthesia might perceive (not "see") certain letters and numbers Grapheme–color synaesthesia or colored grapheme synesthesia is a form of synesthesia in which an individual's perception of numerals and letters is associated with the experience of colors. Like all forms of synesthesia, grapheme–color synesthesia is involuntary, consistent and memorable.[1][failed verification] Grapheme–color synesthesia is one of the most common forms of synesthesia and, because of the extensive knowledge of the visual system, one of the most studied.[2] While it is extremely unlikely that any two synesthetes will report the same colors for all letters and numbers, studies of large numbers of synesthetes find that there are some commonalities across letters (e.g., "A" is likely to be red).[3][4] Early studies argued that grapheme–color synesthesia was not due to associative learning, such as from playing with colored refrigerator magnets.[5] However, one recent study has documented a case of synesthesia in which synesthetic associations could be traced back to colored refrigerator magnets.[6] Despite the existence of this individual case, the majority of synesthetic associations do not seem to be driven by learning of this sort.[4][7] Rather, it seems that more frequent letters are paired with more frequent colors, and some meaning-based rules, such as ‘b’ being blue, drive most synesthetic associations. There has been a lot more research as to why and how synesthesia occurs with more recent technology and as synesthesia has become more well known. It has been found that grapheme–color synesthetes have more grey matter in their brain. There is evidence of an increased grey matter volume in the left caudal intraparietal sulcus (IPS).[8] There was also found to be an increased grey matter volume in the right fusiform gyrus. These results are consistent with another study on the brain functioning of grapheme–color synesthetes. Grapheme–color synesthetes tend to have an increased thickness, volume and surface area of the fusiform gyrus.[2] Furthermore, the area of the brain where word, letter and color processing are located, V4a, is where the most significant difference in make-up was found. Though not certain, these differences are thought to be part of the reasoning for the presence of grapheme–color synesthesia. ## Contents * 1 Experiences and reports * 2 Further research * 3 References and notes * 4 External links ## Experiences and reports[edit] Synesthetes often report that they were unaware their experiences were unusual until they realized other people did not have them, while others report feeling as if they had been keeping a secret their entire lives. Many synesthetes can vividly remember when they first noticed their synesthetic experiences, or when they first learned that such experiences were unusual.[1] Writer and synesthete Patricia Lynne Duffy remembers one early experience: > "'One day,' I said to my father, 'I realized that to make an 'R' all I had to do was first write a 'P' and then draw a line down from its loop. And I was so surprised that I could turn a yellow letter into an orange letter just by adding a line.'"[9] As does filmmaker Stephanie Morgenstern: > "A few years ago, I mentioned to a friend that I remembered phone numbers by their colour. He said "So you're a synesthete!" I hadn't heard of synesthesia (which means something close to 'sense-fusion') – I only knew that numbers seemed naturally to have colours: five is blue, two is green, three is red… And music has colours too: the key of C# minor is a sharp, tangy yellow, F major is a warm brown..."[10] As reported by poet and screenwriter Stephen Bishop 3rd: > "For me, numbers were always colors, for example, six is blue. But colors aren't numbers; it's a one way synesthesia for me. As a youth I was just crazy about the number six and the color blue. Whenever possible I would use the number six in relation to blue. I did grow out of this to some degree and it's more of an intellectual curiosity now. In general I find my mind is highly associative, it's a creative tool that allows me to dream up complex stories with interesting juxtapositions and analogies."[citation needed] On the other hand, many synesthetes never realize that their experiences are in any way unusual or exceptional. For example, the Nobel prize winning physicist, Richard Feynman reports: > When I see equations, I see the letters in colors – I don't know why. As I'm talking, I see vague pictures of Bessel functions from Jahnke and Emde's book, with light-tan j's, slightly violet-bluish n's, and dark brown x's flying around. And I wonder what the hell it must look like to the students."[11] While synesthetes sometimes report seeing colors projected in space, they do not confuse their synesthetic colors with real colors in the external world. Rather, they report that they are simultaneously aware of the external color and also the internal, synesthetic color: > As C relates ... "It is difficult to explain...I see what you see. I know the numbers are in black...but as soon as I recognise the form of a 7 it has to be yellow."[12] Finally, synesthetes are quite precise in the color mappings that they experience, which can lead them to make quite detailed comparisons of their colors: > I came back from college on a semester break, and was sitting with my family around the dinner table, and – I don't know why I said it – but I said, "The number five is yellow." There was a pause, and my father said, "No, it's yellow-ochre." And my mother and my brother looked at us like, 'this is a new game, would you share the rules with us?'" > > And I was dumbfounded. So I thought, "Well." At that time in my life I was having trouble deciding whether the number two was green and the number six blue, or just the other way around. And I said to my father, "Is the number two green?" and he said, "Yes, definitely. It's green." And then he took a long look at my mother and my brother and became very quiet. > > Thirty years after that, he came to my loft in Manhattan and he said, "you know, the number four is red, and the number zero is white. And," he said, "the number nine is green." I said, "Well, I agree with you about the four and the zero, but nine is definitely not green!"[13] ## Further research[edit] Individuals with grapheme–color synesthesia rarely claim that their sensations are problematic or unwanted. In some cases, individuals report useful effects, such as aid in memory or spelling of difficult words. > I sometimes use my synaesthesia to help me remember difficult proper names. Here's a Thai chef who wrote a terrific vegetarian cookbook [these letters appear in a distinct pattern for Cassidy]: > > * Vatcharin Bhumichitr > > > > Unfortunately, this method can backfire too, because I confuse similarly colored names easily [the following names appear very similarly colored to Cassidy]: > > * Mike > * Dave > * Dan > * Rob > > > > > > This is especially problematic at parties. > > — Cassidy Curtis, "Letter-Color Synaesthesia"[14] These experiences have led to the development of technologies intended to improve the retention and memory of graphemes by individuals without synesthesia. Computers, for instance, could use "artificial synesthesia" to color words and numbers to improve usability.[15] A somewhat related example of "computer-aided synesthesia" is using letter coloring in a web browser to prevent IDN homograph attacks. (Someone with synesthesia can sometimes distinguish between barely different looking characters in a similar way.) ## References and notes[edit] 1. ^ a b Grossenbacher, P.G.; Lovelace, C.T. (2001). "Mechanism of synesthesia: Cognitive and physiological constraints". Trends in Cognitive Sciences. 5 (1): 36–41. doi:10.1016/S1364-6613(00)01571-0. PMID 11164734. S2CID 15092606. 2. ^ a b Jäncke, Lutz; Beeli, Gian; Eulig, Cornelia; Hänggi, Jürgen (March 2009). "The neuroanatomy of grapheme–color synesthesia". European Journal of Neuroscience. 29 (6): 1287–1293. doi:10.1111/j.1460-9568.2009.06673.x. PMID 19302164. 3. ^ Day, S.A. (2005), "Some Demographic and Socio-cultural Aspects of Synesthesia" in L. Robertson & N. Sagiv, ed., Synesthesia: Perspectives from Cognitive Neuroscience, Oxford: Oxford University Press, ISBN 0-19-516623-X, pp. 11–33 4. ^ a b Simner, J.; Ward, J.; Lanz, M.; Jansari, A.; Noonan, K.; Glover, L.; Oakley, D.A. (2005). "Non-random associations of graphemes to colours in synaesthetic and non-synaesthetic populations". Cognitive Neuropsychology. 22 (8): 1069–85. doi:10.1080/02643290500200122. PMID 21038290. S2CID 670571. 5. ^ Ramachandran, V.S.; Hubbard, E.M. (2001). "Synaesthesia — A window into perception, thought and language". Journal of Consciousness Studies. 8 (12): 3–34. 6. ^ Witthoft, N.; Winawer, N. (2006). "Synesthetic colors determined by having colored refrigerator magnets in childhood". Cortex. 42 (2): 175–183. doi:10.1016/S0010-9452(08)70342-3. PMID 16683491. S2CID 4484975. 7. ^ Rich, A.N.; Bradshaw, J.L.; Mattingley, J.B. (2005). "A systematic, large scale study of synaesthesia: Implications for the role of early experience in lexical-colour associations". Cognition. 98 (1): 53–84. doi:10.1016/j.cognition.2004.11.003. PMID 16297676. S2CID 2269596. 8. ^ Weiss, Peter H.; Fink, Gereon R. (January 2009). "Grapheme-colour synaesthetes show increased grey matter volumes of parietal and fusiform cortex". Brain. 132 (1): 65–70. doi:10.1093/brain/awn304. PMID 19028762. 9. ^ Duffy, Patricia. "Quote from Blue Cats and Chartreuse Kittens (W. H. Freeman; 2001)". Retrieved 2007-03-15. 10. ^ Raskin, Richard (March 2003). "An interview with Stephanie Morgenstern and Mark Ellis on Remembrance" (PDF). P.o.v., A Danish Journal of Film Studies (15): 170–184. 11. ^ Feynman, Richard (1988). What Do You Care What Other People Think?. Norton. p. 59. 12. ^ Dixon, M.J., Smilek, D., Wagar, B. & Merikle, P.M. (2004). Alphanumeric-Colour Synaesthesia: When 7 is Yellow and C is Red. in Gemma A. Calvert, Charles Spence and Barry E. Stein (Eds.) Handbook of Multisensory Processes. Cambridge, MA: MIT Press. ISBN 0-262-03321-6 13. ^ Steen, Carol. "Quote from Carol Steen Artist and founding member of the American Synesthesia Association in an interview at the Massachusetts Institute of Technology". Retrieved 2007-03-15. 14. ^ Curtis, Cassidy. "Letter-Color Synaesthesia". Retrieved 2006-12-22. 15. ^ Plouznikoff, N.; Plouznikoff, A.; Robert, J.-M. (2005). "Artificial Grapheme-Color Synesthesia for Wearable Task Support" (PDF). Ninth IEEE International Symposium on Wearable Computers. pp. 108–113. doi:10.1109/ISWC.2005.11. ISBN 0-7695-2419-2. S2CID 8221450. Archived from the original (PDF) on 2007-03-29. ## External links[edit] * Danis, Alex. "Grapheme → colour synesthesia". Numberphile. Brady Haran. Archived from the original on 2015-09-18. Retrieved 2013-04-06. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Grapheme–color synesthesia	None	1,246	wikipedia	https://en.wikipedia.org/wiki/Grapheme%E2%80%93color_synesthesia	2021-01-18T18:43:47	{"wikidata": ["Q287285"]}
Congenital respiratory-biliary fistula (RBF) is a rare developmental defect characterized by an anomalous connection of trachea or bronchus with left hepatic duct presenting with respiratory distress, recurrent respiratory infections and biliary expectoration or vomitus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Congenital respiratory-biliary fistula	None	1,247	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2040	2021-01-23T17:00:32	{"gard": ["1475"], "icd-10": ["Q32.4"]}
A number sign (#) is used with this entry because neurofibromatosis type II (NF2) is caused by heterozygous mutation in the gene encoding neurofibromin-2 (NF2; 607379), which is also called merlin, on chromosome 22q12. Description The central or type II form of neurofibromatosis (NF2) is an autosomal dominant multiple neoplasia syndrome characterized by tumors of the eighth cranial nerve (usually bilateral), meningiomas of the brain, and schwannomas of the dorsal roots of the spinal cord. The incidence of neurofibromatosis type II is 1 in 25,000 live births (Asthagiri et al., 2009). NF2 has few of the hallmarks of the peripheral or type I form of neurofibromatosis (NF1; 162200), also known as von Recklinghausen disease. Asthagiri et al. (2009) provided a detailed review of neurofibromatosis type II. Clinical Features Gardner and Frazier (1933) reported a family of 5 generations in which 38 members were deaf because of bilateral acoustic neuromas; of these, 15 later became blind. The average age at onset of deafness was 20 years. The average age at death of affected persons in the second generation was 72, in the third generation 63, in the fourth 42, and in the fifth 28. Follow-up of this family (Gardner and Turner, 1940; Young et al., 1970) revealed no evidence of the systemic manifestations of neurofibromatosis I (NF1; 162200), also known as von Recklinghausen disease. Other families with no evidence of the latter disease were reported by Worster-Drought et al. (1937), Feiling and Ward (1920), and Moyes (1968). Worster-Drought et al. (1937) pointed out that Wishart (1822) was the first to report a case of bilateral acoustic neuroma. Wishart's patient, Michael Blair, was 21 years old when he consulted Mr. Wishart, president of the Royal College of Surgeons of Edinburgh, because of bilateral deafness. He had a peculiarly shaped head from infancy, and blindness in the right eye was discovered at about 4 months after birth. He became completely blind and deaf toward the end of his life. Autopsy revealed tumors of the dura mater and brain and also a 'tumour of the size of a small nut, and very hard, being attached to each of them (auditory nerves), just where they enter the meatus auditorius internus.' Nager (1969) showed that in about 4% of cases acoustic neuroma is bilateral. In addition to their autosomal dominant inheritance and association with neurofibromatosis, bilateral tumors differ from unilateral ones in that they can reach a remarkably large size with extensive involvement of the temporal bone and the nerves therein. Fabricant et al. (1979) reported that more than 30 kindreds with 'central neurofibromatosis' had been described. Most patients with the central form (NF2) have no cafe-au-lait spots or peripheral neurofibromata, and no patients in one large series had 6 or more cafe-au-lait spots (Eldridge, 1981). Kanter et al. (1980), who reviewed 9 personally studied kindreds and 15 reported ones, with a total of 130 cases, showed an increase only in antigenic activity of nerve growth factor (NGF; 162030) in central neurofibromatosis and only in functional activity in peripheral neurofibromatosis. In a series reported by Mrazek et al. (1988), 1 of 41 acoustic neurinoma cases was bilateral. This was in a 10-year-old girl with von Recklinghausen neurofibromatosis, whose first tumor had been diagnosed at age 6. Mayfrank et al. (1990) studied 10 patients with NF2 and found that all were sporadic cases, each presumably the result of a new mutational event. From a survey of these patients and those in the literature, they concluded that sporadic cases are characterized by a high incidence of multiple meningiomas and spinal tumors in addition to bilateral acoustic neurinomas. Pulst et al. (1991) described a family with spinal neurofibromatosis without cafe-au-lait spots or other manifestations of either NF1 or NF2 such as cutaneous tumors, Lisch nodules, or acoustic tumors. Mutation at the NF1 locus was excluded with odds greater than 100,000:1. Markers with the NF2 locus were uninformative in this family. Evans et al. (1992, 1992) studied 150 patients. The mean age at onset was 21.57 years (n = 110) and no patient presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumors. In 100 patients studied personally by the authors, 44 presented with deafness, which was unilateral in 35. Deafness was accompanied by tinnitus in 10. Muscle weakness or wasting was the first symptom in 12%. In 3 of the 100 patients, there was a distal symmetrical sensorimotor neuropathy, confirmed by nerve conduction studies and electromyography. Although similar features may result from the multiple spinal and intracranial tumors that occur in this condition, a generalized and isolated neuropathy appears to be a relatively common feature of NF2. Cafe-au-lait spots occurred in 43 of the 100 patients but only 1 had as many as 6 spots. Cataract was detected in 34 of 90 patients. Cataracts were probably congenital in 4 patients in this study. Three types of skin tumors were recognized. The first and least common was similar to the intradermal papillary skin neurofibroma with violaceous coloring occurring in NF1. The second type comprised subcutaneous well-circumscribed, often spherical, tumors that appeared to be located on peripheral nerves; the thickened nerve could often be palpated at either end of the tumor, the skin being mobile and separate from the tumor. The third and most frequent type, first described by Martuza and Eldridge (1988), was represented by discrete well-circumscribed, slightly raised, roughened areas of skin often pigmented and accompanied by excess hair. Skin tumors of some kind were found in 68% of patients, type 1 being present in 20%, type 2 in 33%, and type 3 in 47%. They could find no evidence that either pregnancy or contraceptive pills has adverse effects on vestibular schwannomas or other manifestations. Evans et al. (1992) provided useful advice on the follow-up of persons identified as having NF2 and the management of persons at risk of developing NF2. Evans et al. (1992) divided their 120 cases of NF2 into 2 types: the Wishart (1822) type, with early onset, rapid course, and multiple other tumors in addition to bilateral vestibular schwannomas, and the Gardner type (1930, 1933, 1940), with late onset, more benign course, and usually only bilateral vestibular schwannomas. This classification had been suggested by Eldridge et al. (1991). Evans et al. (1992) found no evidence for the existence of a third type of generalized meningiomatosis that might be designated the Lee-Abbott type (Lee and Abbott, 1969). The age at onset of deafness and the age at diagnosis were almost identical in the 2 sexes. Birth incidence of NF2 was estimated to be 1 in 33,000-40,562. Evans et al. (1992) considered 49% of the 150 cases to represent new mutations. The mutation rate was estimated to be 6.5 x 10(-6). A maternal effect on severity was noted in that age of onset was 18.17 years in 36 maternally inherited cases and 24.5 years in 20 paternally inherited cases (p = 0.027). A preponderance of maternally inherited cases was also significant (p = 0.03). (A maternal effect on severity had been noted also for NF1.) Baser et al. (2001) studied 140 patients and found that maternal inheritance was not an independent correlate of NF2 disease severity. Parry et al. (1994) assessed possible heterogeneity in NF2 by evaluating 63 affected members of 32 families. In addition to skin and neurologic examinations, workup included audiometry, complete ophthalmologic examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms were related to vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Screening uncovered 5 affected but asymptomatic family members; vestibular schwannomas were demonstrated in 62 (98.4%). Other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). As a rule, clinical manifestations and clinical course were similar within families but differed among families. Parry et al. (1994) concluded that 2 subtypes but not 3 can be defined. Evans et al. (1999) studied the presentation of NF2 in childhood. A total of 334 cases of NF2 were identified from a comprehensive UK dataset, of which 61 (18%) had presented in childhood (0-15 years). Twenty-six of these children presented with symptoms of vestibular schwannoma, 19 with meningioma, 7 with a spinal tumor, and 5 with a cutaneous tumor. In addition, Evans et al. (1999) identified 22 children with a meningioma from the Manchester Children's Tumor Registry, a prospective database of children presenting with a tumor since 1954 within a defined population. At least 3 of these children subsequently developed classic NF2, and in none of them was there a family history suggestive of NF2. The authors concluded that NF2 should be considered in any child presenting with meningioma, vestibular schwannoma, or cutaneous symptoms such as neurofibroma or schwannoma, especially if they have fewer than 6 cafe-au-lait patches and therefore do not fulfill the diagnostic criteria for NF1. Gijtenbeek et al. (2001) reported a patient with NF2, confirmed by genetic analysis, who presented with an axonal mononeuropathy multiplex with progression of axonal loss over several years. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesized that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons. Egan et al. (2001) reported 4 cases of NF2 with a monocular elevator paresis. Two of the patients had third nerve tumors demonstrable on MRI, which had not been present on earlier films. The other 2 patients may have had tumors too small for radiographic detection. The authors suggested that the isolated paresis may result from compression of particular fascicles of the third nerve that subserve the superior rectus and inferior oblique muscles as they exit the midbrain, and noted that ocular mobility defects should be closely monitored in patients with NF2. To evaluate clinical and molecular predictors of the risk of mortality in persons with NF2, Baser et al. (2002) analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. The relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis and was 2.51-fold greater in people with meningiomas compared with those without meningiomas. The relative risk of mortality in patients treated at specialty centers was 0.34, compared with those treated at nonspecialty centers. The relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense, frameshift, or splice site mutations, and large deletions), but the confidence interval could not be quantified because there was only 1 death among people with missense mutations. ### Ocular Abnormalities Pearson-Webb et al. (1986) pointed out that Lisch nodules, which are iris hamartomas that are frequently found in NF1, are not found in NF2. They found, however, an apparently high frequency of presenile posterior subcapsular and nuclear cataracts which sometimes required surgery and/or predated the symptoms of bilateral acoustic neurofibromatosis. Landau et al. (1990) described combined pigment epithelial and retinal hamartoma (CEPRH) in NF2. Kaiser-Kupfer et al. (1989) found posterior capsular lens opacities in 20 NF2 patients in 11 families. Parry et al. (1991) extended these observations. In 26 persons who were first-degree relatives of an affected individual, they found posterior capsular cataracts in 21. Of 14 at-risk individuals, i.e., persons with mild changes of NF but not NF1, persons under age 40 with unilateral acoustic neuroma, a child with meningioma and/or schwannoma, and a person with multiple meningioma, they found posterior capsular lens opacities in 13. These patients probably represented new mutations. The presence of posterior capsular opacities in a relative of persons with NF2 was suggestive of NF2. Furthermore, NF2 should be considered in young persons without NF1 but with mild skin findings of NF or CNS tumors with posterior capsular opacities. Bouzas et al. (1993) found posterior subcapsular/capsular cataracts in 36 (80%) of 45 affected individuals in 29 families. In addition, the association of peripheral cortical lens opacities with NF2 was found to be statistically significant: such cataracts were found in 17 of the patients (37.8%) but in none of the unaffected family members (p less than 0.0001). In 3 patients, peripheral cortical opacities were present despite the absence of posterior subcapsular/capsular cataracts. Bouzas et al. (1993), reporting further on the NIH experience, reviewed visual impairment in 54 NF2 patients, 51 of whom had bilateral vestibular schwannomas. Causes of decreased vision were cataracts, damage in the optic pathways, macular hamartomas, and corneal opacities. Although lens opacities are an important marker for NF2, they usually do not interfere with vision; some progress, requiring cataract extraction. In 6 patients, decreased visual acuity was due to corneal opacifications secondary to either seventh or fifth cranial nerve damage, or both. Damage to the seventh cranial nerve caused lagophthalmos and decreased lacrimal secretion; damage to the fifth cranial nerve caused corneal hypesthesia. The nerves were damaged by the growth of vestibular tumors in 1 patient, but in most patients they were damaged during neurosurgical procedures. Ragge et al. (1995) concluded that the most common ocular abnormalities in NF2 are posterior subcapsular or capsular, cortical, or mixed lens opacities, found in 33 of 49 patients (67%), and retinal hamartomas found in 11 of 49 patients (22%). The types of cataract that were most suggestive of NF2 were plaque-like posterior subcapsular or capsular cataract and cortical cataract with onset under the age of 30 years. Baser et al. (2003) confirmed the high prevalence of cataracts in young NF2 patients. They suggested that the frequent occurrence of cataracts before the tumor manifestations of NF2 indicated the usefulness of this non-eighth nerve feature in the diagnosis of NF2 in children and adolescents. McLaughlin et al. (2007) identified 3 types of NF2-associated ocular manifestations: juvenile posterior subcapsular cataract, epiretinal membrane, and intrascleral schwannoma. Their histopathologic analysis revealed that dysplastic lens cells accumulated just anterior to the posterior lens capsule in juvenile posterior subcapsular cataract, and that dysplastic Muller cells might be a major component of NF2-associated epiretinal membrane. McLaughlin et al. (2007) concluded that their findings suggested that a subset of glial cells with epithelial features (Schwann cells, ependymal cells, and Muller cells) might be particularly sensitive to loss of the NF2 gene. Diagnosis In a review of NF2, Martuza and Eldridge (1988) defined criteria for the diagnosis of both NF1 and NF2. An NIH Consensus Development Conference (1988) concluded that the criteria for NF2 are met if a person is found to have '(1) bilateral eighth nerve masses seen with appropriate imaging techniques (e.g., CT or MRI); or (2) a first-degree relative with NF2 and either unilateral eighth nerve mass, or two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.' Pastores et al. (1991) demonstrated that small (less than 8 mm) acoustic neuromas can be detected in asymptomatic individuals by the use of gadolinium-enhanced MRI. They demonstrated such neuromas in 2 asymptomatic children, aged 7 and 11 years, one of whom had normal audiometric and brainstem-evoked response testing. Using polymorphic DNA markers in a study of 13 NF2 kindreds, Ruttledge et al. (1993) concluded that it is possible to determine, with a high degree of certainty, the carrier status of about 85% of persons at risk. Risk prediction was possible in every case in which DNA was available from both parents. In 76% of informative individuals, it was possible to assign a decreased risk of being carriers. Thus, the use of probes for construction of chromosome 22 haplotypes for risk assessment should result in a greatly reduced number of individuals who will require periodic screening. Gutmann et al. (1997) provided guidelines for the diagnostic evaluation and multidisciplinary management of both NF1 and NF2. The criteria for definite NF2 were bilateral vestibular schwannomas; or family history of NF2 in 1 or more first-degree relative(s) plus (a) unilateral vestibular schwannomas at age less than 30 years, or (b) any two of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. The criteria for presumptive or probable NF2 was unilateral vestibular schwannomas at age less than 30 years, plus at least one of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract; or multiple meningiomas (two or more) plus (a) unilateral vestibular schwannomas at age less than 30 years, or (b) one of the following: glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Kluwe et al. (2000) studied 40 skin tumors (36 schwannomas and 4 neurofibromas) from 20 NF2 patients, 15 of whom had NF2 mutations previously identified in blood leukocytes. The detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%). Alterations in both NF2 alleles were found in 17 (43%) of the tumors. They concluded that loss of a functional NF2 gene product is a critical event in the generation of skin schwannomas and that mutation detection in skin tumors may be a useful diagnostic tool in patients with skin tumors where the clinical diagnosis of NF2 is ambiguous, or in unclear cases in which NF1 must be excluded. Baser et al. (2002) evaluated 4 previous sets of clinical diagnostic criteria for NF2 developed by groups of experts: the NIH Consensus Development Conference (1988), the Consensus Development Panel (1994) of the NIH, the Manchester Group criteria reported by Evans et al. (1992), and the National Neurofibromatosis Foundation (NNFF) criteria reported by Gutmann et al. (1997). Baser et al. (2002) concluded that none of the existing sets of criteria was adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas, particularly people with a negative family history of NF2. Baser et al. (2011) empirically developed and tested an improved set of diagnostic criteria that used understanding of the natural history and genetic characteristics of NF2 to increase sensitivity while maintaining very high specificity. They used data from the UK Neurofibromatosis 2 Registry and Kaplan-Meier curves to estimate frequencies of clinical features at various ages among patients with or without unequivocal NF2. On the basis of this analysis, Baser et al. (2011) developed the Baser criteria, a diagnostic system that incorporates genetic testing and gives more weight to the most characteristic features and to those that occur before 30 years of age. In an independent validation subset of patients with unequivocal NF2, the Baser criteria increased diagnostic sensitivity to 79% (9-15% greater than previous sets of criteria) while maintaining 100% specificity at the age of onset of the first characteristic sign of NF2. ### Mosaicism in NF2 Evans et al. (2007) showed that the chances of a de novo patient with NF2 being mosaic for the underlying mutation in the NF2 gene increased with age at presentation with vestibular schwannoma and was particularly high in patients with unilateral presentation of vestibular schwannoma, but who still had at least 2 further NF2-related tumors in order to fulfill the Manchester criteria. Evans and Wallace (2009) analyzed the mosaic risk in de novo patients with NF2 by age at the time of vestibular schwannoma diagnosis. They analyzed this risk in 4 age cohorts to derive figures for mosaicism and offspring risk both before and after lymphocyte DNA testing with sequencing and multiple ligation-dependent probe amplification. The study was based on actual genetic testing of lymphocyte DNA in 402 de novo patients and subsequent tumor testing in 51 patients with negative blood analysis. The risk of NF2 to an offspring of a patient presenting with bilateral vestibular schwannoma at less than 20 years of age was 29.3%, whereas the offspring risk for a patient presenting with asymmetric disease after 40 years of age was only 5.5%, as there is a 99% chance that they are mosaic. Clinical Management Stereotactic radiosurgery is the principal alternative to microsurgical resection for acoustic neuromas. The goals of radiosurgery are the long-term prevention of tumor growth, maintenance of neurologic function, and prevention of new neurologic deficits. Kondziolka et al. (1998) evaluated 162 consecutive patients who underwent radiosurgery for acoustic neuromas between 1987 and 1992, surveying the results between 5 and 10 years after the procedure. Resection had been performed previously in 42 patients; in 13 patients, the tumor represented a recurrence of disease after a previous total resection. The rate of tumor control (with no resection required) was 98%. Radiosurgery was believed to have been successful by all 30 patients who had undergone surgery previously and by 81 (95%) of the 85 who had not. Pitts and Jackler (1998) pointed out that when radiotherapy is considered for a benign, surgically curable tumor in a young patient, the risk of inducing a secondary tumor must be seriously weighed. The risk of intracranial arterial occlusion from external-beam irradiation must also be considered, although there had been no reports of accelerated atherosclerosis after radiosurgery. The anterior inferior cerebellar artery, which is the primary source of blood supply to the lateral pons and upper medulla, lies right next to the surface of acoustic neuromas. Mapping Seizinger et al. (1986) found loss of genes on chromosome 22 in acoustic neuromas; i.e., whereas normal tissue was heterozygous, tumor tissue was hemizygous (or homozygous) for the polymorphic markers SIS (190040), IGLC (147220), and the anonymous DNA locus D22S1. They were prompted to undertake the study by analogy to retinoblastoma and Wilms tumor and by the facts that meningioma occurs in association with familial acoustic neuroma and that cytologic change in chromosome 22 is frequent in meningioma (see 607174). Seizinger et al. (1987) found specific loss of alleles from chromosome 22 in 2 acoustic neuromas, 2 neurofibromas, and 1 meningioma from patients with bilateral acoustic neurofibromatosis. In each case, a partial deletion occurred with a breakpoint distal to the D22S9 locus in band 22q11. Wertelecki et al. (1988) confirmed localization of the causative gene on chromosome 22 (22q11.21-q13.1) by demonstration of linkage in family studies to markers on chromosome 22. Wertelecki et al. (1988) also presented the clinical data on 15 affected male and 8 affected female members of the 1 large kindred they studied for linkage data. Rouleau et al. (1990) identified markers on chromosome 22 bracketing the NF2 gene which are therefore useful for accurate presymptomatic and prenatal diagnosis, as well as for isolating the defective gene. Through linkage analysis on 12 families with NF2, Narod et al. (1992) confirmed the assignment of the NF2 gene to chromosome 22 and concluded that there is no evidence of genetic heterogeneity in NF2. They indicated that the presence of bilateral vestibular schwannomas, as they termed the acoustic neuromas, is sufficient for the diagnosis. Using 8 polymorphic loci on chromosome 22 to study tumor and constitutional DNAs isolated from 39 unrelated patients with sporadic or NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, Wolff et al. (1992) found 2 tumors with loss of heterozygosity (LOH) patterns consistent with the presence of chromosome 22 terminal deletions. By use of additional polymorphic markers, the terminal deletion breakpoint in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. In addition, they identified a sporadic acoustic neuroma with an LOH pattern consistent with mitotic recombination or deletion and reduplication. The findings lent further support to the recessive tumor suppressor model for the NF2 gene. Arai et al. (1992) described a patient with bilateral acoustic neurinomas and other tumors in the central nervous system and a constitutional translocation t(4;22)(q12;q12.2). Thus, 22q12.2 is a refined localization for the NF2 gene. The same karyotype that was seen in cultured peripheral lymphocytes was found in a paraspinal neurinoma. The patient's father was also a carrier of the translocation but he had no clinical symptoms of NF2, nor did other relatives. As explanation for the failure of expression in the father, Arai et al. (1992) suggested various possibilities including nonpenetrance, mosaicism, or genetic imprinting. They quoted Kanter et al. (1980) as demonstrating earlier onset of symptoms when NF2 is transmitted by the mother. Bovie et al. (2003) also reported a case of neurofibromatosis 2 in a patient with a balanced X;22 translocation. The patient presented with a large abdominal schwannoma and intellectual disability. A clinical diagnosis of NF2 was made when bilateral vestibular schwannomas were found on MRI. With demonstration of a de novo balanced reciprocal translocation between chromosome X and 22, the disorder in this patient was initially assumed to have been caused by the loss of NF2 at the translocation breakpoint. This was found, however, not to be the case; the breakpoint was 6 Mb centromeric to the NF2 gene and no mutations or deletions were found in the germline NF2 gene of the patient. The X-inactivation pattern in lymphocytes was 100% skewed to inactivate the normal X chromosome as predicted for X;autosome translocations whereas in tumor tissue there was aberrant X inactivation of the opposite derivative X chromosome. The mechanism of the disease in this case was thought to be that a proportion of Schwann cells had 1 NF2 allele acting as a functional null by virtue of NF2 being translocated to the X chromosome and aberrant X inactivation of the X;autosome. Molecular Genetics Rouleau et al. (1993) provided incontrovertible evidence that the NF2 gene (607379) is the site of the mutations causing neurofibromatosis II by demonstrating germline and somatic SCH mutations in NF2 patients and in NF2-related tumors. For description of the mutations identified in the NF2 gene and for a discussion of somatic mosaicism, see 607379. Wu et al. (1998) identified 15 patients from a series of 537 with unilateral vestibular schwannomas who also had 1 or more of the following: other tumors (10 of 15), features of NF2 (3 of 15), or a family history of neurogenic tumors (5 of 15). No germline NF2 mutations were detected, and in 7 of 9 cases where tumor material was available for analysis, a germline mutation in NF2 was excluded. Wu et al. (1998) concluded that most instances of unilateral vestibular schwannoma which do not fulfill criteria for NF2 represent chance occurrences. Baser et al. (2002) reported a patient with NF2 who developed malignant mesothelioma after a long occupational exposure to asbestos. Genetic analysis of the tumor tissue showed loss not only of chromosome 22 but also of chromosomes 14 and 15, and gain of chromosome 7. Baser et al. (2002) suggested that an individual with a constitutional mutation of an NF2 allele, as in NF2, is more susceptible to mesothelioma. Although mesothelioma is not a common feature in NF2, the authors cited the observation of Knudson (1995) that somatic mutations of a tumor suppressor gene, such as NF2, RB1 (614041), or p53 (191170), can be common in a tumor type that is not characteristic of the hereditary disorder, perhaps due to the proliferative timing of the cells involved. In a family with the mild or so-called Gardner type of neurofibromatosis type II, Watson et al. (1993) defined a submicroscopic deletion on chromosome 22q which involved the neurofilament heavy chain locus (NEFH; 162230) but did not extend as far as the Ewing sarcoma region (EWSR1; 133450) proximally or the leukemia inhibitory factor locus (LIF; 159540) distally. They estimated that the deletion was about 700 kb long. Mohyuddin et al. (2002) identified 45 patients aged 30 years or less at the onset of symptoms of unilateral vestibular schwannoma. Molecular genetic analysis of the NF2 gene was performed in all 45 patients and on 28 tumor samples. No pathogenic NF2 mutations were identified in any of the blood samples. NF2 point mutations were identified in 21 of 28 (75%) tumor samples and LOH in 21 of 28 (75%) tumor samples. Overlap, i.e., both mutational hits, were identified in 18 of 28 (65%) tumor samples. They observed 1 multilobular tumor in which 1 (presumably first hit) mutation was confirmed which was common to different foci of the tumor, while the second mutational event differed between foci. The molecular findings in this patient were consistent with somatic mosaicism for NF2 and a clinical diagnosis was confirmed with the presence of 2 meningiomas on a follow-up MRI scan. Tsilchorozidou et al. (2004) reported 5 NF2 patients with constitutional rearrangements of chromosome 22 and vestibular schwannomas, multiple intracranial meningiomas, and spinal tumors. The authors noted that an additional 10 NF2 patients with constitutional NF2 deletions had been discovered using NF2 FISH in their laboratory, and suggested that chromosome analysis with FISH might be a useful first screen prior to molecular testing in NF2 patients. Genotype/Phenotype Correlations Parry et al. (1996) identified mutations in the NF2 gene in 66% of 32 patients; 20 different mutations were found in 21 patients. They suggested that their results confirmed the association between nonsense and frameshift mutations and clinical manifestations compatible with severe disease. They stated that their data raised questions regarding the role of other factors, in addition to the intrinsic properties of individual mutations, that might influence the phenotype. Ruttledge et al. (1996) reported that when individuals harboring protein-truncating mutations are compared with patients having single codon alterations, a significant correlation (p less than 0.001) with clinical outcome is observed. They noted that 24 of 28 patients with mutations that cause premature termination of the NF2 protein presented with severe phenotypes. In contrast, all 16 cases from 3 families with mutations that affect only a single amino acid had mild NF2. Evans et al. (1998) reported 42 cases of NF2 from 38 families with truncating mutations. The average age of onset of symptoms was 19 years and age at diagnosis 22.4 years. Fifty-one cases from 16 families (15 with splice site mutations, 18 with missense mutations, and 18 with large deletions) had an average age of onset of 27.8 years and age at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to develop symptoms before 20 years of age (p less than 0.001) and to develop at least 2 symptomatic CNS tumors in addition to vestibular schwannoma before 30 years (p less than 0.001). There were significantly fewer multigenerational families with truncating mutations. Kehrer-Sawatzki et al. (1997) reported a patient with NF2 and a ring chromosome 22 (46,XX,r(22)/45,XX,-22). Severe manifestations included multiple meningiomas, spinal and peripheral neurinomas, and bilateral vestibular schwannomas. The patient was also severely mentally retarded, a feature not usually associated with NF2. The authors hypothesized that a mutation in the NF2 gene of the normal chromosome 22, in addition to the loss of the ring 22 in many cells during mitosis, could explain the presence of multiple tumors. Using a meningioma cell line lacking the ring chromosome, Kehrer-Sawatzki et al. (1997) searched for deletions, rearrangements, or other mutations of the NF2 gene on the normal chromosome 22; no such alterations were found. The authors concluded that the loss of the entire chromosome 22 and its multiple tumor suppressor genes may have led to the severe phenotype in this patient. In 406 patients from the population-based United Kingdom NF2 registry, Baser et al. (2004) evaluated genotype/phenotype correlations for various types of non-VIII nerve tumors using regression models with the additional covariates of current age and type of treatment center (specialty or nonspecialty). The models also permitted consideration of intrafamilial correlation. The authors found statistically significant genotype/phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. Baser et al. (2004) concluded that the type of constitution NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In 831 patients from 528 NF2 families, Baser et al. (2005) analyzed location of splice site mutations and severity of NF2, using age at onset of symptoms and number of intracranial meningiomas as indicators. They found that individuals with splice site mutations in exons 1 to 5 had more severe disease than those with splice site mutations in exons 11 to 15. Baser et al. (2005) confirmed the previously reported observation that missense mutations are usually associated with mild NF2. History Baser et al. (2004) noted that initial genotype/phenotype correlation studies of NF2 were limited by the generality of the definition of disease severity, which was often reported only as 'mild,' 'moderate,' or 'severe.' The mild and severe disease categories corresponded to the historical nomenclature of 'Gardner' (mild) and 'Wishart' (severe) subtypes, which were based on the clinical observation that the severity of NF2 tended to 'run true' within a family (Wishart, 1822; Gardner and Frazier, 1930). Another category, 'Lee-Abbott' (Lee and Abbott, 1969), which corresponds to very severe NF2, was not consistently adopted by subsequent studies. Cytogenetics Krone and Hogemann (1986) found monosomy 22 as a predominant numerical anomaly in cultured cells grown from peripheral neurofibromas in patients described simply as suffering 'from sporadic peripheral NF.' Duncan et al. (1987) observed a ring chromosome 22 in a man with an atypical form of neurofibromatosis. He lacked a family history of NF, cafe-au-lait spots, and axillary freckling. He had multiple neurofibromas and a plexiform neuroma. By in situ hybridization, Duncan et al. (1987) showed that both the normal chromosome 22 and the ring chromosome 22 carried this gene. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss \- Tinnitus Eyes \- Juvenile posterior subcapsular lenticular opacities \- Juvenile cortical cataract \- Epiretinal membranes \- Retinal hamartoma \- No Lisch nodules SKIN, NAILS, & HAIR Skin \- Occasional cafe-au-lait spots \- Occasional neurofibroma \- Schwannoma NEUROLOGIC Central Nervous System \- Headache \- Ataxia Peripheral Nervous System \- Peripheral neuropathy NEOPLASIA \- Meningioma \- Glioma \- Vestibular Schwannoma (over 90% of patients) \- Ependymoma \- Neurofibroma \- Astrocytoma MISCELLANEOUS \- Incidence of 1 in 25,000 livebirths \- Nearly 100% penetrance by 60 years of age \- Approximately half of the mutations are de novo MOLECULAR BASIS \- Caused by mutations in merlin (NF2, 101000.0001 ) ▲ 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	NEUROFIBROMATOSIS, TYPE II	c0027832	1,248	omim	https://www.omim.org/entry/101000	2019-09-22T16:45:31	{"doid": ["0111252"], "mesh": ["D016518"], "omim": ["101000"], "icd-9": ["237.72"], "icd-10": ["Q85.02"], "orphanet": ["637"], "synonyms": ["Alternative titles", "NEUROFIBROMATOSIS, CENTRAL TYPE", "ACOUSTIC SCHWANNOMAS, BILATERAL", "BILATERAL ACOUSTIC NEUROFIBROMATOSIS", "ACOUSTIC NEURINOMA, BILATERAL"], "genereviews": ["NBK1201"]}
A rare peeling skin syndrome characterized by superficial peeling of the skin predominantly affecting the dorsa of the hands and feet. ## Epidemiology Acral PSS is rare, with approximately 40 cases described in the literature to date. ## Clinical description The disease manifests shortly after birth or in early childhood with superficial peeling on the palmar, plantar and dorsal surfaces of the hands and feet, that leaves residual painless erythema. Manual skin removal is also possible. Seasonal variations are generally observed. Heat, humidity, exposure to water and friction or minor trauma can induce exfoliation. The lesions are not painful and heal without scarring. ## Etiology Some cases result from mutations in the TGM5 gene (15q15), encoding transglutaminase-5. TGM5 is widely expressed in the epidermis and is involved in protein cross-linking. It is thought to be required for structural integrity of the outermost epidermal layers. To date, no other causal genes have been identified but acral PSS could be a genetically heterogeneous disease. ## Diagnostic methods Clinical presentation is highly suggestive of the disease. Histological examination of skin lesion biopsies reveals tissue separation at the stratum granulosum-stratum corneum junction. Molecular analysis, if performed, may reveal a TGM5 mutation. ## Differential diagnosis Differential diagnosis includes epidermolysis bullosa simplex superficialis, keratolytic winter erythema, exfoliative ichthyosis (see these terms), keratolysis exfoliativa, fungal infection (dermatophytes), psoriasis and dyshidrosis. ## Antenatal diagnosis The disease is not severe enough to justify prenatal screening. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment There is no effective treatment. Emollients are often used to reduce skin peeling. Patients must avoid immersion in water and are recommended to use absorbing powders or aluminum antiperspirants. ## Prognosis Life expectancy is normal. No significant impairment in quality of life is reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acral peeling skin syndrome	c1853354	1,249	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=263534	2021-01-23T18:49:05	{"gard": ["12863"], "mesh": ["C536316"], "omim": ["609796"], "umls": ["C1853354"], "icd-10": ["Q80.8"], "synonyms": ["Acral PSS", "Acral deciduous skin", "Localized PSS", "Localized deciduous skin"]}
## Clinical Features Crome and Williams (1960) observed multilocular encephalomalacia in an infant who died at 1 month of age. A sib was living at age 6 years but may have had the same abnormality manifested by microcephaly, spastic diplegia, and mental retardation. It is not certain that this is a distinct entity. Head \- Microcephaly Neuro \- Mental retardation \- Spastic diplegia 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	ENCEPHALOMALACIA, MULTILOCULAR	c1856991	1,250	omim	https://www.omim.org/entry/225700	2019-09-22T16:28:21	{"mesh": ["C565597"], "omim": ["225700"]}
Citrullinemia type I is a rare autosomal recessive urea cycle defect characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting in the neonatal form (Acute neonatal citrullinemia type I, see this term) and by variable hyperammonemia in the later-onset form (Adult-onset citrullinemia type I, see this term). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Citrullinemia type I	c0751751	1,251	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247525	2021-01-23T17:43:33	{"mesh": ["D020159"], "omim": ["215700"], "umls": ["C0751751"], "icd-10": ["E72.2"], "synonyms": ["ASS deficiency", "Argininosuccinate synthase deficiency", "Argininosuccinate synthetase deficiency", "Argininosuccinic acid synthase deficiency", "Argininosuccinic acid synthetase deficiency", "CTLN1", "Citrullinemia type 1", "Classic citrullinemia"]}
Huang et al. (1999) described a brother and sister, in a sibship of 4, with multiple congenital anomalies, including Hirschsprung disease. The boy was born with bilateral complete cleft lip and palate, telecanthus, duplication of the great toes, and postaxial polydactyly of the right foot. Echocardiogram showed atrial septal defect, coarctation of the aorta, a large patent ductus arteriosus (see 607411), a cleft mitral valve, and a mildly hypoplastic aortic arch. At 1 day of age, he underwent colostomy and appendectomy because of a spontaneous perforation of the large bowel. Histologic studies showed aganglionosis of the entire colon and the appendix. Respiratory distress at 2 months of age necessitated direct laryngoscopy which showed a short epiglottis and short aryepiglottic folds. He showed mild developmental delay, particularly in expressive language usage. His karyotype was normal. His older sister also had duplication of the great toes, heart defects, airway anomalies, aganglionosis of the sigmoid colon, and mild developmental delay. The 2 other sibs were normal except for a bifid uvula and developmental delay in one. The parents were in good health and unrelated. Autosomal recessive inheritance was considered likely. Huang et al. (1999) reviewed 6 other reports of congenital anomalies associated with Hirschsprung disease. Also see Hirschsprung disease with polydactyly, renal agenesis, and deafness (235740), Hirschsprung disease with hypoplastic nails and dysmorphic facial features (235760), Hirschsprung disease with type D brachydactyly (306980), and Hirschsprung disease with ulnar polydactyly, polysyndactyly of big toes, and ventricular septal defect (235750). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	HIRSCHSPRUNG DISEASE WITH HEART DEFECTS, LARYNGEAL ANOMALIES, AND PREAXIAL POLYDACTYLY	c1858696	1,252	omim	https://www.omim.org/entry/604211	2019-09-22T16:12:27	{"mesh": ["C565817"], "omim": ["604211"]}
Leber congenital amaurosis is an eye disorder that primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning in infancy. The visual impairment tends to be stable, although it may worsen very slowly over time. Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all. Additionally, the clear front covering of the eye (the cornea) may be cone-shaped and abnormally thin, a condition known as keratoconus. A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of poking, pressing, and rubbing the eyes with a knuckle or finger. Researchers suspect that this behavior may contribute to deep-set eyes and keratoconus in affected children. In rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. However, researchers are uncertain whether these individuals actually have Leber congenital amaurosis or another syndrome with similar signs and symptoms. At least 13 types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities. ## Frequency Leber congenital amaurosis occurs in 2 to 3 per 100,000 newborns. It is one of the most common causes of blindness in children. ## Causes Leber congenital amaurosis can result from mutations in at least 14 genes, all of which are necessary for normal vision. These genes play a variety of roles in the development and function of the retina. For example, some of the genes associated with this disorder are necessary for the normal development of light-detecting cells called photoreceptors. Other genes are involved in phototransduction, the process by which light entering the eye is converted into electrical signals that are transmitted to the brain. Still other genes play a role in the function of cilia, which are microscopic finger-like projections that stick out from the surface of many types of cells. Cilia are necessary for the perception of several types of sensory input, including vision. Mutations in any of the genes associated with Leber congenital amaurosis disrupt the development and function of the retina, resulting in early vision loss. Mutations in the CEP290, CRB1, GUCY2D, and RPE65 genes are the most common causes of the disorder, while mutations in the other genes generally account for a smaller percentage of cases. In about 30 percent of all people with Leber congenital amaurosis, the cause of the disorder is unknown. ### Learn more about the genes associated with Leber congenital amaurosis * CEP290 * CRB1 * CRX * GUCY2D * RPE65 Additional Information from NCBI Gene: * AIPL1 * IMPDH1 * IQCB1 * LCA5 * LRAT * NMNAT1 * RD3 * RDH12 * RPGRIP1 * SPATA7 * TULP1 ## Inheritance Pattern Leber congenital amaurosis usually has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance 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. When Leber congenital amaurosis is caused by mutations in the CRX or IMPDH1 genes, the disorder has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. In most of these cases, an affected person inherits a gene mutation from one affected parent. Other cases result from new mutations and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Leber congenital amaurosis	c2931258	1,253	medlineplus	https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/	2021-01-27T08:25:08	{"gard": ["634"], "mesh": ["C536600"], "omim": ["204000", "611755", "610612", "612712", "613341", "204100", "604232", "604393", "604537", "608553"], "synonyms": []}
Not to be confused with Pneumococcal pneumonia. Pneumocystis pneumonia Other namesPneumocystis jirovecii pneumonia, pneumocystis carinii pneumonia Pneumocystis jirovecii cysts from bronchoalveolar lavage, stained with Toluidine blue O stain SpecialtyInfectious disease, Pulmonology CausesPneumocystis jirovecii Risk factorsWeakened immune system Differential diagnosisOther types of pneumonia Medicationsteroids, trimethoprim/sulfamethoxazole, pentamidine, trimetrexate, dapsone, atovaquone, primaquine, pafuramidine maleate and clindamycin. Pneumocystis pneumonia (PCP) is a form of pneumonia that is caused by the yeast-like fungus Pneumocystis jirovecii.[1] It is also known as PJP, for Pneumocystis jiroveci Pneumonia.[2] Pneumocystis specimens are commonly found in the lungs of healthy people although it is usually not a cause for disease.[3] However, they are a source of opportunistic infection and can cause lung infections in people with a weak immune system or other predisposing health conditions. PCP is seen in people with HIV/AIDS (who account for 30-40% of PCP cases), those using medications that suppress the immune system, and people with cancer, autoimmune or inflammatory conditions, and chronic lung disease.[4] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Pathophysiology * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 6.1 PCP and AIDS * 7 Nomenclature * 8 References * 9 External links ## Signs and symptoms[edit] Signs and symptoms may develop over several days or weeks[4] and may include: shortness of breath and/or difficulty breathing (of gradual onset), fever, dry/non-productive cough, weight loss, night sweats,[5] chills, and fatigue.[4] Uncommonly, the infection may progress to involve other visceral organs (such as the liver, spleen, and kidney).[5] * Cough \- typically dry/non-productive because sputum becomes too viscous to be coughed up. The dry cough distinguishes PCP from typical pneumonia.[5] ### Complications[edit] X-ray and CT of ground glass opacities and pneumothorax in Pneumocystis pneumonia.[6] Pneumothorax is a well-known complication of PCP.[7] Also, a condition similar to acute respiratory distress syndrome (ARDS) may occur in patients with severe Pneumocystis pneumonia, and such individuals may require intubation.[8] ## Pathophysiology[edit] The risk of PCP increases when CD4-positive T-cell levels are less than 200 cells/μL. In these immunosuppressed individuals, the manifestations of the infection are highly variable.[9] The disease attacks the interstitial, fibrous tissue of the lungs, with marked thickening of the alveolar septa and alveoli, leading to significant hypoxia, which can be fatal if not treated aggressively. In this situation, lactate dehydrogenase levels increase and gas exchange is compromised. Oxygen is less able to diffuse into the blood, leading to hypoxia, which along with high arterial carbon dioxide (CO 2) levels, stimulates hyperventilatory effort, thereby causing dyspnea (breathlessness).[citation needed] ## Diagnosis[edit] The diagnosis can be confirmed by the characteristic appearance of the chest X-ray and an arterial oxygen level (PaO2) that is strikingly lower than would be expected from symptoms. Gallium 67 scans are also useful in the diagnosis. They are abnormal in about 90% of cases and are often positive before the chest X-ray becomes abnormal. Chest X-ray typically shows widespread pulmonary infiltrates. CT scan may show pulmonary cysts (not to be confused with the cyst-forms of the pathogen). * Chest X-ray of increased opacification (whiteness) in the lower lungs. * These chest radiographs are of two patients. Both show ground glass opacities. The left X-ray shows a much more subtle ground-glass appearance while the right X-ray shows a much more gross ground-glass appearance mimicking pulmonary edema.[6] * X-ray of a cyst in pneumocystis pneumonia[6] * High-resolution computed tomography (HRCT) showing ground-glass attenuation with a geographic or mosaic distribution.[6] * HRCT of cysts of pneumocystis pneumonia. These are usually multiple and bilateral, but range in size, shape and distribution.[6] The diagnosis can be definitively confirmed by histological identification of the causative organism in sputum or bronchoalveolar lavage (lung rinse). Staining with toluidine blue, silver stain, periodic acid-Schiff stain, or an immunofluorescence assay shows the characteristic cysts.[10] The cysts resemble crushed ping-pong balls and are present in aggregates of two to eight (and not to be confused with Histoplasma or Cryptococcus, which typically do not form aggregates of spores or cells). A lung biopsy would show thickened alveolar septa with fluffy eosinophilic exudate in the alveoli. Both the thickened septa and the fluffy exudate contribute to dysfunctional diffusion capacity that is characteristic of this pneumonia. Pneumocystis infection can also be diagnosed by immunofluorescent or histochemical staining of the specimen, and more recently by molecular analysis of polymerase chain reaction products comparing DNA samples. Notably, simple molecular detection of P. jirovecii in lung fluids does not mean that a person has PCP or infection by HIV. The fungus appears to be present in healthy individuals in the general population.[11] ## Prevention[edit] In immunocompromised patients, prophylaxis with co-trimoxazole (trimethoprim/sulfamethoxazole),[12] atovaquone, or regular pentamidine inhalations may help prevent PCP. ## Treatment[edit] Antipneumocystic medication is used with concomitant steroids to avoid inflammation, which causes an exacerbation of symptoms about 4 days after treatment begins if steroids are not used. By far, the most commonly used medication is trimethoprim/sulfamethoxazole, but some patients are unable to tolerate this treatment due to allergies. Other medications that are used, alone or in combination, include pentamidine, trimetrexate, dapsone, atovaquone, primaquine, pafuramidine maleate (under investigation), and clindamycin. Treatment is usually for a period of about 21 days. Pentamidine is less often used, as its major limitation is the high frequency of side effects. These include acute pancreatic inflammation, kidney failure, liver toxicity, decreased white blood cell count, rash, fever, and low blood sugar.[citation needed] ## Epidemiology[edit] Pneumocystis jirovecii The disease PCP is relatively rare in people with normal immune systems, but common among people with weakened immune systems, such as premature or severely malnourished children, the elderly, and especially persons living with HIV/AIDS (in whom it is most commonly observed).[1][13] PCP can also develop in patients who are taking immunosuppressive medications. It can occur in patients who have undergone solid organ transplantation or bone marrow transplantation and after surgery.[14] Infections with Pneumocystis pneumonia are also common in infants with hyper IgM syndrome, an X-linked or autosomal recessive trait. The causative organism of PCP is distributed worldwide[15] and Pneumocystis pneumonia has been described in all continents except Antarctica.[15] More than 75% of children are seropositive by the age of 4, which suggests a high background exposure to the organism. A post mortem study conducted in Chile of 96 persons who died of unrelated causes (suicide, traffic accidents, and so forth) found that 65 (68%) of them had pneumocystis in their lungs, which suggests that asymptomatic pneumocystis infection is extremely common.[16] Up to 20% of adults may be asymptomatic carriers at any given time, and asymptomatic infection may persist for months before being cleared by an immune response.[4] P. jirovecii was originally described as a rare cause of pneumonia in neonates. It is commonly believed to be a commensal organism (dependent upon its human host for survival). The possibility of person-to-person transmission has recently gained credence, with supporting evidence coming from many different genotyping studies of P. jirovecii isolates from human lung tissue.[17][18] For example, in one outbreak of 12 cases among transplant patients in Leiden, it was suggested as likely, but not proven, that human-to-human spread may have occurred.[19] ### PCP and AIDS[edit] Since the start of the AIDS epidemic, PCP has been closely associated with AIDS. Because it only occurs in an immunocompromised host, it may be the first clue to a new AIDS diagnosis if the patient has no other reason to be immunocompromised (e.g. taking immunosuppressive drugs for organ transplant). An unusual rise in the number of PCP cases in North America, noticed when physicians began requesting large quantities of the rarely used antibiotic pentamidine, was the first clue to the existence of AIDS in the early 1980s.[20][21] Prior to the development of more effective treatments, PCP was a common and rapid cause of death in persons living with AIDS. Much of the incidence of PCP has been reduced by instituting a standard practice of using oral co-trimoxazole (Bactrim / Septra) to prevent the disease in people with CD4 counts less than 200/μL. In populations who do not have access to preventive treatment, PCP continues to be a major cause of death in AIDS.[citation needed] ## Nomenclature[edit] Both Pneumocystis pneumonia and pneumocystis pneumonia[22] are orthographically correct; one uses the genus name per se and the other uses the common noun based on it. (This is the same reason, for example, why "group A Streptococcus" and "group A streptococcus" are both valid.) Synonyms for PCP include pneumocystosis[22] (pneumocystis + -osis), pneumocystiasis[22] (pneumocystis + -iasis), and interstitial plasma cell pneumonia.[22] The older species name Pneumocystis carinii (which now applies only to the Pneumocystis species that is found in rats[23]) is still in common usage. As a result, Pneumocystis pneumonia (PCP) is also known as Pneumocystis jiroveci[i] pneumonia and (incorrectly) as Pneumocystis carinii pneumonia.[24][25][26] Regarding nomenclature, when the name of Pneumocystis pneumonia (PCP) changed from P. carinii pneumonia to P. jirovecii pneumonia, it was at first asked whether "PJP" should replace "PCP". However, because the short name "PCP" was already well established among physicians that managed patients with Pneumocystis infection, it was widely accepted that this name could continue to be used, as it could now stand for pneumocystis pneumonia.[27] ## References[edit] 1. ^ a b Aliouat-Denis, C-M.; et al. (2008). "Pneumocystis species, co-evolution and pathogenic power". Infection, Genetics and Evolution. 8 (5): 708–726. doi:10.1016/j.meegid.2008.05.001. PMID 18565802. 2. ^ Bennett, Nicholas John; Gilroy, Shelley A (2017-08-08). "Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia". Medscape. 3. ^ Ponce, Carolina A.; Gallo, Myriam; Bustamante, Rebeca; Vargas, Sergio L. (February 2010). "Pneumocystis Colonization Is Highly Prevalent in the Autopsied Lungs of the General Population". Clinical Infectious Diseases. 50 (3): 347–353. doi:10.1086/649868. ISSN 1058-4838. PMID 20047487. 4. ^ a b c d "Pneumocystis pneumonia \| Fungal Diseases \| CDC". www.cdc.gov. 2020-07-27. Retrieved 2020-08-10. 5. ^ a b c "Pneumocystis Pneumonia". NORD (National Organization for Rare Disorders). Retrieved 2020-08-10. 6. ^ a b c d e Khan, AliNawaz; Allen, CarolynM; AL-Jahdali, HamdanH; Irion, KlausL; Al Ghanem, Sarah; Gouda, Alaa (2010). "Imaging lung manifestations of HIV/AIDS". Annals of Thoracic Medicine. 5 (4): 201–16. doi:10.4103/1817-1737.69106. ISSN 1817-1737. PMC 2954374. PMID 20981180. Creative Commons Attribution License 7. ^ Kanne JP, Yandow DR, Meyer CA (June 2012). "Pneumocystis jiroveci pneumonia: high-resolution CT findings in patients with and without HIV infection". AJR Am J Roentgenol. 198 (6): W555–61. doi:10.2214/AJR.11.7329. PMID 22623570. S2CID 7041746. 8. ^ Nicholas John Bennett (2017-08-08). "What are possible complications of Pneumocystis jiroveci pneumonia (PJP)?". Medscape. 9. ^ Hughes WT (1996). "Pneumocystis Carinii". In Barron S; et al. (eds.). Barron's Medical Microbiology (4th ed.). University of Texas Medical Branch. ISBN 978-0-9631172-1-2. 10. ^ "Supplementary Information: Microscopic appearance of Pneumocystis jiroveci from bronchial washings". Archived from the original on 18 July 2009. Retrieved 5 June 2009. 11. ^ Medrano FJ, Montes-Cano M, Conde M, et al. (February 2005). "Pneumocystis jirovecii in general population". Emerging Infect. Dis. 11 (2): 245–50. doi:10.3201/eid1102.040487. PMC 3320436. PMID 15752442. 12. ^ Stern A, Green H, Paul M, Vidal L, Leibovici L (October 2014). "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients". Cochrane Database Syst Rev. 10 (CD005590): CD005590. doi:10.1002/14651858.CD005590.pub3. PMC 6457644. PMID 25269391. 13. ^ Ryan KJ, Ray CG, eds. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 978-0-8385-8529-0. 14. ^ Puzio J, Kucewicz E, Sioła M, et al. (2009). "[Atypical and opportunistic pulmonary infections after cardiac surgery.]". Anestezjologia Intensywna Terapia (in Polish). 41 (1): 41–5. PMID 19517677. 15. ^ a b Morris A, Lundgren JD, Masur H, et al. (October 2004). "Current epidemiology of Pneumocystis pneumonia". Emerging Infect. Dis. 10 (10): 1713–20. doi:10.3201/eid1010.030985. PMC 3323247. PMID 15504255. 16. ^ Ponce CA, Gallo M, Bustamante R, Vargas SL (2010). "Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population". Clin Infect Dis. 50 (3): 347–353. doi:10.1086/649868. PMID 20047487. 17. ^ Schmoldt S, Schuhegger R, Wendler T, et al. (March 2008). "Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation". J. Clin. Microbiol. 46 (3): 966–71. doi:10.1128/JCM.02016-07. PMC 2268360. PMID 18216217. 18. ^ Morris A, Beard CB, Huang L (January 2002). "Update on the epidemiology and transmission of Pneumocystis carinii". Microbes Infect. 4 (1): 95–103. doi:10.1016/S1286-4579(01)01514-3. PMID 11825780. 19. ^ de Boer M, Bruijnesteijn van Coppenraet L, Gaasbeek A, et al. (2007). "An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotypeamong renal transplant recipients: interhuman transmission or a common environmental source?". Clin Infect Dis. 44 (9): 1143–9. doi:10.1086/513198. PMID 17407029. 20. ^ Fannin S, Gottlieb MS, Weisman JD, et al. (1982). "A Cluster of Kaposi's Sarcoma and Pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Range Counties, California". MMWR Weekly. 31 (32): 305–7. 21. ^ Masur H, Michelis MA, Greene JB, et al. (10 December 1981). "An outbreak of community-acquired Pneumocystis carinii pneumonia". N Engl J Med. 305 (24): 1431–8. doi:10.1056/NEJM198112103052402. PMID 6975437. 22. ^ a b c d Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier. 23. ^ Stringer JR, Beard CB, Miller RF, Wakefield AE (September 2002). "A new name (Pneumocystis jiroveci) for Pneumocystis from humans". Emerging Infect. Dis. 8 (9): 891–6. doi:10.3201/eid0809.020096. PMC 2732539. PMID 12194762. 24. ^ Cushion MT (1998). "Ch. 34: Pneumocystis carinii". In Collier, L.; Balows, A.; Sussman, M. (eds.). Topley and Wilson's Microbiology and Microbial Infections (9th ed.). New York: Arnold and Oxford Press. pp. 645–683. 25. ^ Cushion MT (1998). "Taxonomy, genetic organization, and life cycle of Pneumocystis carinii". Semin. Respir. Infect. 13 (4): 304–312. PMID 9872627. 26. ^ Cushion MT (2004). "Pneumocystis: unraveling the cloak of obscurity". Trends Microbiol. 12 (5): 243–9. doi:10.1016/j.tim.2004.03.005. PMID 15120144. 27. ^ Stringer, James R.; Beard, Charles B.; Miller, Robert F.; Wakefield, Ann E. (Sep 2002). "A New Name for Pneumocystis from Humans and New Perspectives on the Host-Pathogen Relationship". Emerg Infect Dis. 8 (9): 891–896. doi:10.3201/eid0809.020096. PMC 2732539. PMID 12194762. ## External links[edit] Classification D * ICD-10: B59† J17.3* * ICD-9-CM: 136.3 * MeSH: D011020 * DiseasesDB: 10160 External resources * MedlinePlus: 000671 * eMedicine: med/1850 * v * t * e Fungal infection and mesomycetozoea Superficial and cutaneous (dermatomycosis): Tinea = skin; Piedra (exothrix/ endothrix) = hair Ascomycota Dermatophyte (Dermatophytosis) By location * Tinea barbae/tinea capitis * Kerion * Tinea corporis * Ringworm * Dermatophytids * Tinea cruris * Tinea manuum * Tinea pedis (athlete's foot) * Tinea unguium/onychomycosis * White superficial onychomycosis * Distal subungual onychomycosis * Proximal subungual onychomycosis * Tinea corporis gladiatorum * Tinea faciei * Tinea imbricata * Tinea incognito * Favus By organism * Epidermophyton floccosum * Microsporum canis * Microsporum audouinii * Trichophyton interdigitale/mentagrophytes * Trichophyton tonsurans * Trichophyton schoenleini * Trichophyton rubrum * Trichophyton verrucosum Other * Hortaea werneckii * Tinea nigra * Piedraia hortae * Black piedra Basidiomycota * Malassezia furfur * Tinea versicolor * Pityrosporum folliculitis * Trichosporon * White piedra Subcutaneous, systemic, and opportunistic Ascomycota Dimorphic (yeast+mold) Onygenales * Coccidioides immitis/Coccidioides posadasii * Coccidioidomycosis * Disseminated coccidioidomycosis * Primary cutaneous coccidioidomycosis. Primary pulmonary coccidioidomycosis * Histoplasma capsulatum * Histoplasmosis * Primary cutaneous histoplasmosis * Primary pulmonary histoplasmosis * Progressive disseminated histoplasmosis * Histoplasma duboisii * African histoplasmosis * Lacazia loboi * Lobomycosis * Paracoccidioides brasiliensis * Paracoccidioidomycosis Other * Blastomyces dermatitidis * Blastomycosis * North American blastomycosis * South American blastomycosis * Sporothrix schenckii * Sporotrichosis * Talaromyces marneffei * Talaromycosis Yeast-like * Candida albicans * Candidiasis * Oral * Esophageal * Vulvovaginal * Chronic mucocutaneous * Antibiotic candidiasis * Candidal intertrigo * Candidal onychomycosis * Candidal paronychia * Candidid * Diaper candidiasis * Congenital cutaneous candidiasis * Perianal candidiasis * Systemic candidiasis * Erosio interdigitalis blastomycetica * C. auris * C. glabrata * C. lusitaniae * C. tropicalis * Pneumocystis jirovecii * Pneumocystosis * Pneumocystis pneumonia Mold-like * Aspergillus * Aspergillosis * Aspergilloma * Allergic bronchopulmonary aspergillosis * Primary cutaneous aspergillosis * Exophiala jeanselmei * Eumycetoma * Fonsecaea pedrosoi/Fonsecaea compacta/Phialophora verrucosa * Chromoblastomycosis * Geotrichum candidum * Geotrichosis * Pseudallescheria boydii * Allescheriasis Basidiomycota * Cryptococcus neoformans * Cryptococcosis * Trichosporon spp * Trichosporonosis Zygomycota (Zygomycosis) Mucorales (Mucormycosis) * Rhizopus oryzae * Mucor indicus * Lichtheimia corymbifera * Syncephalastrum racemosum * Apophysomyces variabilis Entomophthorales (Entomophthoramycosis) * Basidiobolus ranarum * Basidiobolomycosis * Conidiobolus coronatus/Conidiobolus incongruus * Conidiobolomycosis Microsporidia (Microsporidiosis) * Enterocytozoon bieneusi/Encephalitozoon intestinalis Mesomycetozoea * Rhinosporidium seeberi * Rhinosporidiosis Ungrouped * Alternariosis * Fungal folliculitis * Fusarium * Fusariosis * Granuloma gluteale infantum * Hyalohyphomycosis * Otomycosis * Phaeohyphomycosis * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis Wikimedia Commons has media related to Pneumocystis pneumonia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pneumocystis pneumonia	c1535939	1,254	wikipedia	https://en.wikipedia.org/wiki/Pneumocystis_pneumonia	2021-01-18T18:43:20	{"mesh": ["D011020"], "wikidata": ["Q15401586"]}
Chromosome 6p duplication is a chromosome abnormality that occurs when there is an extra copy of genetic material on the short arm (p) of chromosome 6. The severity of the condition and the signs and symptoms depend on the size and location of the duplication and which genes are involved. Features that often occur in people with chromosome 6p duplication include developmental delay, intellectual disability, behavioral problems and distinctive facial features. This condition can occur sporadically or be inherited from a parent with the duplication (who is mildy affected) or carries a balanced translocation. Treatment is based on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Chromosome 6p duplication	c2931621	1,255	gard	https://rarediseases.info.nih.gov/diseases/5352/chromosome-6p-duplication	2021-01-18T18:01:20	{"mesh": ["C537811"], "umls": ["C2931621"], "synonyms": ["Duplication 6p", "Trisomy 6p", "6p duplication", "6p trisomy", "Partial trisomy 6p"]}
A rare, syndromic intellectual disability characterized by global developmental delay including severely delayed or absent speech, moderate to severe intellectual disability, behavioral issues, stereotypic behavior, febrile seizures and epilepsy, abnormal gait, vision defects, and characteristic facial features. Intrauterine growth restriction and feeding difficulties are frequently present. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion	None	1,256	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=268261	2021-01-23T19:09:55	{"icd-10": ["Q93.5"], "synonyms": ["21q22.13q22.2 microdeletion syndrome", "Del(21)(q22.13q22.2)", "Monosomy 21q22.13q22.2"]}
Prothrombin G20210A Other namesProthrombin thrombophilia,[1] factor II mutation, prothrombin mutation, rs1799963, factor II G20210A SymptomsBlood clots[1] Frequency2% (Caucasians)[1] Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism.[1] One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000.[1] Two copies increases the risk to up to 20 in 1,000 per year.[1] Most people never develop a blood clot in their lifetimes.[1] It is due to a specific gene mutation in which a guanine (G) is changed to an adenine (A) at position 20210 of the DNA of the prothrombin gene. Other blood clotting pathway mutations that increase the risk of clots include factor V Leiden. Prothrombin G20210A was identified in the 1990s.[2] About 2% of Caucasians carry the variant, while it is less common in other populations.[1] It is estimated to have originated in Caucasians about 20,000 years ago.[3][better source needed] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Terminology * 6 Notes * 7 References * 8 External links ## Signs and symptoms[edit] The variant causes elevated plasma prothrombin levels (hyperprothrombinemia),[4] possibly due to increased pre-mRNA stability.[5] Prothrombin is the precursor to thrombin, which plays a key role in causing blood to clot (blood coagulation). G20210A can thus contribute to a state of hypercoagulability, but not particularly with arterial thrombosis.[4] A 2006 meta-analysis showed only a 1.3-fold increased risk for coronary disease.[6] Deficiencies in the anticoagulants Protein C and Protein S further increase the risk five- to tenfold.[2] Behind non-O blood type[7] and factor V Leiden, prothrombin G20210A is one of the most common genetic risk factors for VTE.[4]Increased production of prothrombin heightens the risk of blood clotting. Moreover, individuals who carry the mutation can pass it on to their offspring.[8] The mutation increases the risk of developing deep vein thrombosis (DVT),[9] which can cause pain and swelling, and sometimes post-thrombotic syndrome, ulcers, or pulmonary embolism.[10] Most individuals do not require treatment but do need to be cautious during periods when the possibility of blood clotting are increased; for example, during pregnancy, after surgery, or during long flights. Occasionally, blood-thinning medication may be indicated to reduce the risk of clotting.[11] Heterozygous carriers who take combined birth control pills are at a 15-fold increased risk of VTE,[12] while carriers also heterozygous with factor V Leiden have an approximate 20-fold higher risk.[2] In a recommendation statement on VTE, genetic testing for G20210A in adults that developed unprovoked VTE[a] was disadvised, as was testing in asymptomatic family members related to G20210A carriers who developed VTE.[13] In those who develop VTE, the results of thrombophilia tests (wherein the variant can be detected) rarely play a role in the length of treatment.[14] ## Cause[edit] The classical blood coagulation pathway SNP: Prothrombin G20210A GeneF2 Chromosome11 External databases EnsemblHuman SNPView dbSNP1799963 HapMap1799963 SNPedia1799963 The polymorphism is located in a noncoding region of the prothrombin gene (3' untranslated region nucleotide 20210[b]), replacing guanine with adenine.[4][5] The position is at or near where the pre-mRNA will have the poly-A tail attached.[5] ## Diagnosis[edit] Diagnosis of the prothrombin G20210A mutation is straightforward because the mutation involves a single base change (point mutation) that can be detected by genetic testing, which is unaffected by intercurrent illness or anticoagulant use. Measurement of an elevated plasma prothrombin level cannot be used to screen for the prothrombin G20210A mutation, because there is too great of an overlap between the upper limit of normal and levels in affected patients.[16] ## Treatment[edit] Patients with the prothrombin mutation are treated similarly to those with other types of thrombophilia, with anticoagulation for at least three to six months. Continuing anticoagulation beyond three to six months depends on the circumstances surrounding thrombosis, for example, if the patient experiences a thromboembolic event that was unprovoked, continuing anticoagulation would be recommended. The choice of anticoagulant (warfarin versus a direct oral anticoagulant) is based on a number of different factors (the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions).[17] Patients with the prothrombin G20210A mutation who have not had a thromboembolic event are generally not treated with routine anticoagulation. However, counseling the patient is recommended in situations with increased thrombotic risk is recommended (pregnancy, surgery, and acute illness). Oral contraceptives should generally be avoided in women with the mutation as they increase the thrombotic risk.[18] ## Terminology[edit] Because prothrombin is also known as factor II, the mutation is also sometimes referred to as the factor II mutation or simply the prothrombin mutation; in either case, the names may appear with or without the accompanying G20210A location specifier (unhelpfully, since prothrombin mutations other than G20210A are known). ## Notes[edit] 1. ^ Provoked VTE is triggered by situations such as surgery, trauma, cancer, or immobility. 2. ^ Specifically, position 20210 refers to the nucleotide on the sense strand downstream from the DNA that codes for the start codon (ATG, positions 1 to 3).[15] ## References[edit] 1. ^ a b c d e f g h "Prothrombin thrombophilia". Genetics Home Reference. Retrieved 12 March 2018. 2. ^ a b c Rosendaal FR, Reitsma PH (July 2009). "Genetics of Venous Thrombosis". J. Thromb. Haemost. 7 Suppl 1: 301–304. doi:10.1111/j.1538-7836.2009.03394.x. PMID 19630821. S2CID 27104496. 3. ^ Kniffin, Cassandra L. & McKusick, Victor A. (2012-06-20). Coagulation factor II; F2: .0009 thrombosis, susceptibility to OMIM. Accessed January 23, 2012.[better source needed] 4. ^ a b c d Martinelli I, Bucciarelli P, Mannucci PM (2010). "Thrombotic risk factors: basic pathophysiology". Crit Care Med. 38 (2 Suppl): S3–9. doi:10.1097/CCM.0b013e3181c9cbd9. PMID 20083911. S2CID 34486553. 5. ^ a b c Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis". Blood. 88 (10): 3698–703. doi:10.1182/blood.V88.10.3698.bloodjournal88103698. PMID 8916933. 6. ^ Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R, et al. (2006). "Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls". Lancet. 367 (9511): 651–8. doi:10.1016/S0140-6736(06)68263-9. PMID 16503463. S2CID 22806065. 7. ^ Reitsma PH, Versteeg HH, Middeldorp S (2012). "Mechanistic view of risk factors for venous thromboembolism". Arterioscler Thromb Vasc Biol. 32 (3): 563–8. doi:10.1161/ATVBAHA.111.242818. PMID 22345594. S2CID 2624599. 8. ^ Varga, E. A. (2004). "Prothrombin 20210 mutation". Circulation. 110 (3): e15–8. doi:10.1161/01.CIR.0000135582.53444.87. PMID 15262854. 9. ^ Zakai, NA; McClure, LA (October 2011). "Racial differences in venous thromboembolism". Journal of Thrombosis and Haemostasis (Review). 9 (10): 1877–82. doi:10.1111/j.1538-7836.2011.04443.x. PMID 21797965. S2CID 41043925. 10. ^ Stubbs, M J; Mouyis, Maria; Thomas, Mari (February 2018). "Deep vein thrombosis". BMJ. 360: k351. doi:10.1136/bmj.k351. ISSN 0959-8138. PMID 29472180. S2CID 3454404. 11. ^ Phillippe, Haley M.; Hornsby, Lori B.; Treadway, Sarah; Armstrong, Emily M.; Bellone, Jessica M. (June 2014). "Inherited Thrombophilia". Journal of Pharmacy Practice. 27 (3): 227–233. doi:10.1177/0897190014530390. ISSN 0897-1900. PMID 24739277. S2CID 2538482. 12. ^ Rosendaal FR (2005). "Venous thrombosis: the role of genes, environment, and behavior". Hematology Am. Soc. Hematol. Educ. Program. 2005 (1): 1–12. doi:10.1182/asheducation-2005.1.1. PMID 16304352. 13. ^ Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2011). "Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members". Genetics in Medicine. 13 (1): 67–76. doi:10.1097/GIM.0b013e3181fbe46f (inactive 2021-01-14). PMID 21150787.CS1 maint: DOI inactive as of January 2021 (link)[dead link][dead link] 14. ^ Baglin T (2012). "Inherited and acquired risk factors for venous thromboembolism". Semin Respir Crit Care Med. 33 (2): 127–37. doi:10.1055/s-0032-1311791. PMID 22648484. 15. ^ Degen SJ, Davie EW (1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry. 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID 2825773. 16. ^ "UpToDate". 17. ^ Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149:315. 18. ^ Bauer, K.A.(2018). Prothrombin G20210A mutation. In T.W. Post, P. Rutgeerts, & S. Grover (Eds.), UptoDate. Available from https://www.uptodate.com/contents/prothrombin-g20210a-mutation?search=prothrombin%20gene%20mutation&source=search_result&selectedTitle=1~103&usage_type=default&display_rank=1#H3703116740 ## External links[edit] Classification D * OMIM: 176930#0009 * DiseasesDB: 32790 * Mannucci, P. M. & Franchini, M. (2015). "Classic thrombophilic gene variants". Thrombosis and Haemostasis. 114 (5): 885–889. doi:10.1160/th15-02-0141. PMID 26018405. Archived from the original (review) on 10 June 2016. Retrieved 21 May 2016. * v * t * e Genetics * Introduction * Outline * History * Index * Glossary Key components * Chromosome * DNA * RNA * Genome * Heredity * Nucleotide * Mutation * Genetic variation Fields * Classical * Conservation * Cytogenetics * Ecological * Immunogenetics * Molecular * Population * Quantitative Archaeogenetics of * the Americas * the British Isles * Europe * Italy * the Near East * South Asia Related topics * Behavioural genetics * Epigenetics * Geneticist * Genome editing * Genomics * Genetic code * Genetic engineering * Genetic diversity * Genetic monitoring * Genetic genealogy * Heredity * He Jiankui affair * Medical genetics * Molecular evolution * Plant genetics * Reverse genetics Lists * List of genetic codes * List of genetics research organizations * Category * Commons * WikiProject * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Prothrombin G20210A	c2584409	1,257	wikipedia	https://en.wikipedia.org/wiki/Prothrombin_G20210A	2021-01-18T18:35:24	{"umls": ["C2584409"], "wikidata": ["Q2113626"]}
Medical condition A flail limb (also flail arm or flail leg) is a medical term which refers to an extremity in which the primary nerve has been severed or ceased to function, resulting in complete lack of mobility and sensation. Although blood typically continues to flow through the limb, it is completely useless and potential for surgical repair is limited. The muscles soon wither away from atrophy, and the arm swings loosely at the side like a "dead weight." Flail limb can occur in cases of traumatic injury to the brachial plexus or in people with motor neuron diseases such as amyotrophic lateral sclerosis.[1][2] Amputation of the affected limb and replacement with a prosthesis in one option for treament. Amputation does not reduce pain experienced.[1][3] ## References[edit] 1. ^ a b Yeoman, P. M.; Seddon, H. J. (August 1961). "Brachial Plexus Injuries: Treatment of the Flail Arm". The Journal of Bone and Joint Surgery. British Volume. 43-B (3): 493–500. doi:10.1302/0301-620X.43B3.493. 2. ^ Althausen, Peter L.; Lee, Mark A.; Finkemeier, Christopher G. (November 2003). "Scapulothoracic Dissociation: Diagnosis and Treatment". Clinical Orthopaedics and Related Research. 416: 237–244. doi:10.1097/01.blo.0000093022.56370.fe. PMID 14646766. S2CID 24993921. 3. ^ Wilkinson, M. C. P.; Birch, R.; Bonney, G. (1 October 1993). "Brachial plexus injury: when to amputate?". Injury. 24 (9): 603–605. doi:10.1016/0020-1383(93)90123-N. PMID 8288380. ## See also[edit] * Progressive muscular atrophy This article about a medical condition affecting the nervous system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Flail limb	c0231446	1,258	wikipedia	https://en.wikipedia.org/wiki/Flail_limb	2021-01-18T18:32:04	{"umls": ["C0231446"], "wikidata": ["Q5457051"]}
Pressure of speech Other namesPressured speech SpecialtyPsychiatry Pressure of speech is a tendency to speak rapidly and frenziedly. Pressured speech is motivated by an urgency that may not be apparent to the listener. The speech produced is difficult to interrupt. Such speech may be too fast, erratic, irrelevant, or too tangential for the listener to understand. It is an example of cluttered speech, and is often associated with certain mental disorders, particularly mania and schizophrenia. It can be unrelenting, loud, and without pauses.[1] ## Contents * 1 Causes * 1.1 Stimulants * 2 Related conditions * 3 Stutter formation * 4 See also * 5 References * 6 External links ## Causes[edit] The pace of the speech indicates an underlying thought disorder known as "flight of ideas" wherein the flow of ideas and information through one's mind is so fast that it is difficult to follow their train of thought. This is also tied to an inability to focus on one topic or task.[2] People with schizophrenia, as well as anyone experiencing extreme anxiety, may also exhibit pressure of speech. Pressure of speech usually refers to the improperly verbalized speech which is a feature of hypomanic and manic illness.[3] Pressure of speech has commonly been observed in people diagnosed with attention deficit hyperactivity disorder. ### Stimulants[edit] Psychostimulants such as cocaine or amphetamines may cause speech resembling pressured speech in individuals with pre-existing psychopathology and produce hypomanic or manic symptoms in general, owing both to the substance's own qualities and the underlying nature of an individual's psyche. In many psychotic disorders, use of certain drugs amplifies certain expressions of symptoms, and stimulant-induced pressured speech is among them. ## Related conditions[edit] * Cluttering is a speech disorder that is related to pressure of speech in that the speech of a clutterer sounds improperly verbalized. However, cluttering is a distinct language disorder. Even though cluttering sounds almost identical to pressure of speech, it differs in that pressure of speech is rooted in anxiety, where cluttering is not. * Pressure of speech is an instance of tachylalia, or rapid speech. Pressure of speech is also variously related to agitolalia, agitophasia, tachyphasia, and verbomania. * Circumstantial speech is a communication disorder in which the focus of a conversation drifts, but often comes back to the point.[4] In circumstantiality, unnecessary details and irrelevant remarks cause a delay in getting to the point.[5] ## Stutter formation[edit] Pressured speech may also lead to the development of a stutter. The person's need or pressure to speak causes him or her to involuntarily stutter. Therefore, the person's need to express themselves is greater than their ability to vocalise their thoughts.[6] ## See also[edit] * Aphasia * Auditory processing disorder * Cluttered speech * Tachylalia * Logorrhea ## References[edit] 1. ^ Videbeck, Sheila (2010). Psychiatric-Mental Health Nursing (5th ed.). Lippincott Williams and Wilkins. ISBN 160547861X. 2. ^ Lesley Stevens; Ian Rodin (23 April 2001). Psychiatry: an illustrated colour text. Elsevier Health Sciences. pp. 24–. ISBN 978-0-443-05703-8. Retrieved 25 November 2010. 3. ^ Pressure of Speech - General Practice Notebook Archived 2005-02-05 at the Wayback Machine 4. ^ Problem-Based Psychiatry by Ben Green 2009 ISBN 1-84619-042-8 page 15 5. ^ "Dorlands.com". www.dorlands.com. Archived from the original on 2016-12-29. Retrieved 2017-03-05. 6. ^ Einer Boberg (1 January 1993). Neuropsychology of stuttering. University of Alberta. p. 226. ISBN 978-0-88864-239-4. Retrieved 13 December 2010. ## External links[edit] Classification D * ICD-10: R47.8 * ICD-9-CM: 784.5 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pressure of speech	c0233718	1,259	wikipedia	https://en.wikipedia.org/wiki/Pressure_of_speech	2021-01-18T18:29:17	{"umls": ["C0233718"], "wikidata": ["Q7241734"]}
A number sign (#) is used with this entry because Wolff-Parkinson-White syndrome can be caused by mutation in the gamma-2 regulatory subunit of AMP-activated protein kinase (PRKAG2; 602743). Mutation in the PRKAG2 gene can also cause a form of hypertrophic cardiomyopathy in which some patients exhibit WPW (CMH6; 600858). Clinical Features The features of this electrocardiographic syndrome are short PR interval and prolonged QRS, specifically with a slurred-up stroke of the R wave called a delta wave. The patients are prone to paroxysmal supraventricular tachycardia. The familial occurrence of the Wolff-Parkinson-White syndrome has been reported many times (Harnischfeger, 1959). In at least 2 reported families it has been associated with familial cardiomyopathy (Massumi, 1967). Schneider (1969) observed an affected mother and son. Chia et al. (1982) described a Chinese family in which the WPW syndrome was present in a 21-year-old male (who came to medical attention because of palpitations occasioned by paroxysmal atrial fibrillation) and in his father and 2 of his 5 brothers. One of the brothers died suddenly at age 19 years. Autopsy showed no gross cardiac abnormality but detailed examination of the conduction system was not done. A sister, aged 16 years, showed Lown-Ganong-Levine (LGL) preexcitation. Vidaillet et al. (1987) determined the prevalence of preexcitation in the first-degree relatives of 383 patients with electrophysiologically proved accessory atrioventricular pathways. In 13 of the 383 patients (3.4%), accessory pathways were documented in 1 or more first-degree relatives. Patients with familial preexcitation had a higher incidence of multiple accessory pathways and possibly an increased risk of sudden cardiac death. Vidaillet et al. (1987) suggested that an autosomal dominant factor is involved. The early study of Warner and McKusick (1958) was cited. Gollob et al. (2001) evaluated 2 families segregating autosomal dominant WPW syndrome in which the probands presented with syncope and characteristic electrocardiographic features. The clinical symptoms typically had their onset in late adolescence or the third decade of life. In addition to preexcitation, other forms of conduction disease were seen, including progression to high-grade sinoatrial or atrioventricular block requiring pacemaker implantation in 76% of affected members of both families older than 30 years of age. Cardiac hypertrophy was identified in 8 (26%) of 31 affected individuals who were evaluated. Anderson et al. (2001) emphasized the importance of careful definition of the phenotype in studies of presumed familial WPW syndrome. They quoted Vidaillet et al. (1987) as suggesting that in familial WPW syndrome structural changes are rare. On the other hand, Gollob et al. (2001) pointed to the report by Mehdirad et al. (1999) of typical accessory atrioventricular bundles in members of a family with a clinical syndrome identical to the one described by Gollob et al. (2001). Five to 10% of hypertrophic cardiomyopathy (see 192600) patients have ventricular preexcitation. An association between WPW and familial hypertrophic cardiomyopathy had been noted in earliest descriptions of the latter condition. Braunwald et al. (1960) proposed that abnormal ventricular activation might result in regional myocardial hypertrophy or that localized hypertrophy might disrupt normal cardiac electrical discontinuity at the atrial ventricular ring. Kimura et al. (1997) presented data indicating that the WPW syndrome can be associated with more than one type of CMH. They observed WPW in 3 individuals with the gly203-to-ser mutation in the cardiac troponin I gene (191044) and in 1 individual with a 2-bp deletion at codon 945 in the cardiac myosin-binding protein C gene (600958), which is the site of the mutation in familial hypertrophic cardiomyopathy 4 (CMH4; 115197). Kimura et al. (1997) noted that they had also found the 2-bp MYBPC3 deletion in 3 other CMH patients without WPW. Clinical Management Ventricular fibrillation can be the presenting arrhythmia in children with asymptomatic WPW syndrome. Pappone et al. (2004) concluded that deaths due to this arrhythmia are potentially preventable. In asymptomatic, high-risk children, prophylactic catheter ablation performed by an experienced operator reduced the risk of life-threatening arrhythmias. In 47 asymptomatic children with WPW syndrome ablation was performed in 20 and no ablation in 27. The characteristics of the 2 groups as to the presence of multiple accessory pathways (which has a worse prognosis) was essentially identical. At 40 months of follow-up, 19 of the 20 ablation patients were alive and free of arrhythmic events; 44% of the high risk patients who did not undergo prophylatic ablation had arrhythmic events, including cardiac arrest or sudden death, during the first 2 years of follow-up. Population Genetics The WPW syndrome is the second most common cause of paroxysmal supraventricular tachycardia in most parts of the world and is the most common cause in China, being responsible for more than 70% of cases (Wan et al., 1992). Mapping In a large family with 25 surviving individuals affected by WPW syndrome, familial hypertrophic cardiomyopathy or both, MacRae et al. (1995) found close linkage to DNA markers on 7q3. By haplotype analysis in 2 families segregating WPW in an autosomal dominant inheritance pattern, Gollob et al. (2001) demonstrated mapping of the disorder to 7q34-q36, the same region identified by MacRae et al. (1995). Molecular Genetics Gollob et al. (2001) noted that the PRKAG2 gene is located in the critical genomic region of the WPW syndrome locus identified by linkage on chromosome 7q34-q36. In affected members of 2 families with WPW syndrome, they identified an arg302-to-gln mutation in the PRKAG2 gene (602743.0001). An additional sequence variation at nucleotide 1912 in the 3-prime untranslated region of PRKAG2 was present in all affected members of family 2 but not family 1, indicating that the 2 families are unrelated. Gollob et al. (2001) reported a third, unrelated family in which affected members manifested ventricular preexcitation, atrial fibrillation, and conduction defects from childhood. Cardiac hypertrophy was absent. The molecular defect in this family was a novel PRKAG2 mutation (602743.0006). Cardiac \- Short PR interval and prolonged QRS, with slurred-up stroke of the R wave (delta wave) on EKG \- Paroxysmal supraventricular tachycardia \- Paroxysmal atrial fibrillation \- Familial cardiomyopathy \- Palpitations \- Preexcitation \- Higher incidence of multiple accessory pathways \- Possible increased risk of sudden cardiac death Inheritance \- ? Autosomal dominant factor ▲ 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	WOLFF-PARKINSON-WHITE SYNDROME	c0043202	1,260	omim	https://www.omim.org/entry/194200	2019-09-22T16:31:45	{"doid": ["384"], "mesh": ["D014927"], "omim": ["194200"], "icd-10": ["I45.6"], "synonyms": ["Alternative titles", "WPW SYNDROME"]}
A number sign (#) is used with this entry because of evidence that metatropic dysplasia is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.1. Description Metatropic dysplasia (MD) is characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. Radiologic features include severe platyspondyly, severe metaphyseal enlargement, and shortening of long bones (Genevieve et al., 2008). Clinical Features Maroteaux et al. (1966) described a chondrodystrophy that at birth is likely to be called achondroplasia ('hyperplastic type') because of the short limbs and later in life Morquio syndrome because of the relatively short spine and severe scoliosis. The designation for the condition was chosen to convey the change or reversal in body proportions. The manifestations are already present at birth, with generalized epimetaphyseal disturbance of ossification. Kyphoscoliosis is progressive and severe. Anisospondyly, halberd-shaped pelvis, and hyperplastic femoral trochanters are features. The coccyx is unusually long, resulting in a tail. The ends of the femurs and humeri are trumpeted. The 2 brothers reported by Michail et al. (1956) probably had this condition. Houston et al. (1972) suggested that 'hyperchondrogenesis' might be a good designation for this condition inasmuch as the histologic picture is characterized by exuberant cartilage formation in the trachea and bronchi, as well as in the growing ends of the bones. Some of the cases reported by Kaufmann (1892) and by MacCallum (1915) had metatropic dwarfism. Boden et al. (1987) had an opportunity to study bone from an infant with metatropic dysplasia who died at 7 months of respiratory failure. The major findings were (1) the absence of formation of normal primary spongiosa in the metaphysis; and (2) the presence of a thin seal of bone at the chondroosseous junction, with abnormal metaphyseal vascular invasion and arrest of endochondral ring structures with persistence of circumferential growth. The findings suggested an uncoupling of endochondral and perichondral growth and offered an explanation for the dumbbell-shaped morphologic changes in the metaphysis. Kannu et al. (2007) characterized the natural history of 11 patients (6 females and 5 males), ranging from 20 weeks' gestation to age 70 years, incorporating data collected over a 37-year period. The study included 1 father/daughter pair and 1 sib pair. The authors noted that complications such as upper respiratory obstruction secondary to laryngotracheal dysfunction need to be carefully monitored in infancy because this is a preventable cause of mortality. The progression of a thoracic kyphoscoliosis in the patients was often relentless and resistant to surgical treatment. Other causes of morbidity included cervical instability, hearing loss, and functional impairments resulting from degenerative joint deformity. Intellectual outcome in all surviving cases had been normal and final adult heights ranged from 107 to 135 cm. Genevieve et al. (2008) reported the clinical and radiologic features of 19 novel metatropic patients (5 lethal or terminated pregnancies, and 14 living patients) that had been collected over 40 years. They described new radiologic features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared-off calcaneal bones, severe hypoplasia of the anterior portion of the first cervical vertebrae, and erratic areas of microcalcifications in vertebral bodies and epiphyses. Krakow et al. (2009) described 2 patients with metatropic dysplasia. Both were identified in the newborn period with high forehead and flat nasal bridge. Both had congenital scoliosis, contractures, and prominent joints. One had respiratory compromise. Radiographic findings showed odontoid hypoplasia in 1 patient, clavicular pseudoarthrosis in 1 patient, anterior rib splaying in both, platyspondyly in both, dense wafer vertebrae in both, no evidence of overfaced vertebral pedicles, flared iliac wings in 1, halberd pelvis in 2, irregular proximal femoral growth plate in 1, dumbbell-shaped femora/humeri in both, and phalangeal cone epiphyses in both. Krakow et al. (2009) noted phenotypic overlap with spondylometaphyseal dysplasia, Kozlowski type (SMDK; 184252). Dai et al. (2010) provided a detailed radiographic review of 20 patients diagnosed with SMDK and 22 patients diagnosed with nonlethal metatropic dysplasia, noting that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femora ascertained distinction between MD and SMDK, respectively. Unexpected findings included the fact that although narrow thorax, prominent joints, and coccygeal tail are considered to be clinical hallmarks of MD, only prominent joints were consistently found in MD, and these features were also occasionally found in SMDK. Evolution of body proportion with age, another hallmark of MD, was not essential; several postpubertal MD patients showed short limbs, not short trunks. MD patients after infancy showed overfaced pedicles that were indistinguishable from those in SMDK patients. A small percentage of SMDK patients showed mild brachydactyly or mild epiphyseal dysplasia/premature degenerative joint disease, yet these cases were classified as SMDK based on the overall pattern of skeletal changes. Dai et al. (2010) concluded that accurate delineation of the total phenotypic spectrum in these disorders would require further accumulation of cases with radiographs taken at standard ages. Camacho et al. (2010) performed histologic studies of bone derived from 2 patients with lethal metatropic dysplasia. There was abnormally thick cartilage with nodular proliferation, short diaphyses, and abnormal bone formation, indicating disrupted endochondral ossification. There was also evidence of abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes. Camacho et al. (2010) suggested that the mechanism of disease may result from increased calcium in chondrocytes. Unger et al. (2011) reported 4 patients, including a pair of monozygotic twins, with a severe lethal form of metatropic dysplasia associated with fetal akinesia. Three of the 4 were found to have absent movements, severe contractures, and features of metatropic dysplasia on prenatal ultrasound, and the pregnancies were terminated. The fourth patient presented with multiple joint contractures and absent limb movements at birth, consistent with fetal akinesia. Features of severe metatropic dysplasia in these patients included short long bones, cartilaginous joint expansion, narrow thorax, flat vertebral bodies, and sacrococcygeal tail. The fourth patient had a normal neonatal neurologic examination, except for restricted movements, but electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Genetic analysis of the 4 patients identified 3 different heterozygous de novo missense mutations in the TRPV4 gene (605427.0027-605427.0029). Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and since electrophysiologic studies of 1 indicated a neuropathic process, these TRPV4 mutations may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia. Inheritance From personal observations and a review of the literature, Beck et al. (1983) suggested 3 types of metatropic dysplasia: (1) a nonlethal autosomal recessive form; (2) a nonlethal dominant form; and (3) a lethal form with death before or shortly after birth and with possible autosomal recessive inheritance. They illustrated the cases of brother and sister with type I, father and daughter with type II, and a stillborn fetus presumably with type III. Noteworthy is the father's age (45 years) in the last case. Genevieve et al. (2005) reported clinical and radiologic findings of one of the sporadic original cases reported by Maroteaux et al. (1966), followed from 15 days to 30 years of age. At birth the radiologic manifestations of dumbbell aspect of long bones, severe platyspondyly, and severe scoliosis were consistent with the nonlethal autosomal recessive form of metatropic dwarfism. However, over time there was striking modification of the skeletal anomalies with amelioration of the size of the long bones and significant improvement of the platyspondyly resulting in almost normal vertebral bodies at 15 years of age, corresponding to a description of the autosomal dominant form of metatropic dwarfism. Genevieve et al. (2005) suggested that a distinction between 3 different types of the disorder, especially in isolated cases, is questionable. Kannu et al. (2007) suggested that the clinical and radiologic findings show considerable overlap between the so-called mild, classic, and lethal forms of metatropic dysplasia and cannot reliably be separated. Furthermore, the radiologic and clinical findings in father/daughter and brother/sister cases were identical, suggesting a single mode of inheritance. In reported families, the ratio of affected to unaffected (close to 1:20) is not supportive of an autosomal recessive inheritance pattern. They therefore proposed that metatropic dysplasia represents a single gene dominant condition, and that the variable subtypes can be accounted for by variable expression and sib recurrence due to gonadal mosaicism. Genevieve et al. (2008) supported the hypothesis of gonadal mosaicism by the observation of recurrence in half-sibs from an unrelated Chinese family with 2 different fathers. Molecular Genetics In 2 sporadic cases of metatropic dysplasia, Krakow et al. (2009) identified heterozygosity for de novo missense mutations in the TRPV4 gene (605427.0006-605427.0007). Dai et al. (2010) analyzed the TRPV4 gene in 22 MD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MD proband. In the MD patients, the recurrent P799L mutation (605427.0007) was found in 9 patients, and 4 more patients had 3 different substitutions at pro799 (605427.0013-605427.0015), which the authors designated a 'hot codon' for metatropic dysplasia. The remaining 8 MD patients included 7 with novel missense mutations and 1 with a 3-bp deletion of a codon (F471del; 605427.0016), which Dai et al. (2010) stated was the first mutation other than a missense mutation to be reported in the TRPV4 gene. Camacho et al. (2010) reported 10 patients with varying severity of metatropic dysplasia, all of whom carried a heterozygous mutation in the TRPV4 gene (see, e.g., 605427.0006-605427.0007, 605427.0023-605427.0024). The findings confirmed that metatropic dysplasia is a dominant disorder. Five patients had a lethal form of the disorder with death in the neonatal period or infancy, whereas 5 had a nonlethal disorder classified as mild, moderately severe, or severe. There was no clear relationship between the severity of the disorder and type of mutation or domain affected, but Camacho et al. (2010) suggested that the degree of constitutive activation of the mutant channels likely correlates with disease severity. History Hall and Elcioglu (2004) attempted to classify the radiologic findings in 8 sporadic cases of lethal forms of metatropic dysplasia. INHERITANCE \- Autosomal dominant GROWTH Height \- Dwarfism, short limbed, recognizable at birth RESPIRATORY \- Respiratory failure Airways \- Exuberant cartilage formation in the trachea and bronchi CHEST External Features \- Narrow thorax Ribs Sternum Clavicles & Scapulae \- Short ribs with cupped ends SKELETAL \- Arthrogryposis multiplex (in some patients) \- Joint contractures (in some patients) Spine \- Relatively short spine \- Severe scoliosis \- Severe kyphosis \- Long coccyx \- Anisospondyly \- Coccygeal tail \- Platyspondyly \- Vertebral bodies broader than interpedicular distance Pelvis \- Halberd-shaped pelvis \- Hyperplastic femoral trochanters \- Supra-acetabular notches Limbs \- Flared femurs and humeri \- Dumbbell-shaped metaphyses \- Epiphyseal dysplasia \- Prominent joints \- A thin seal of bone at the chondroosseous junction \- Absent primary metaphyseal spongiosa \- Abnormal metaphyseal vascular invasion \- Arrest of endochondral ring structures with persistence of circumferential growth Hands \- Brachydactyly \- Delayed carpal age NEUROLOGIC Peripheral Nervous System \- Fetal akinesia (in some patients) \- Peripheral axonal neuropathy (in some patients) PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements (in some patients) MOLECULAR BASIS \- Caused by mutation in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4, 605427.0006 ) ▲ 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	METATROPIC DYSPLASIA	c0265281	1,261	omim	https://www.omim.org/entry/156530	2019-09-22T16:38:15	{"mesh": ["C537356"], "omim": ["156530"], "orphanet": ["2635"], "synonyms": ["Alternative titles", "METATROPIC DWARFISM"], "genereviews": ["NBK201366"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Hemotympanum" – news · newspapers · books · scholar · JSTOR (June 2020) (Learn how and when to remove this template message) Tympanic cavity Hemotympanum or hematotympanum, refers to the presence of blood in the tympanic cavity of the middle ear. Hemotympanum is often the result of basilar skull fracture.[1] Hemotympanum refers to the presence of blood in the middle ear, which is the area behind the eardrum. In most cases, the blood is trapped behind the eardrum, so no discharge is visible. Treating hemotympanum depends on the underlying cause. ## Contents * 1 Presentation * 2 Causes * 2.1 Skull fracture * 2.2 Nasal packing * 2.3 Bleeding disorders * 2.4 Anticoagulant medications * 2.5 Ear infections * 3 Treatment * 4 References ## Presentation[edit] The most common symptoms of hemotympanum are: * pain * sense of fullness in the ear * hearing loss ## Causes[edit] ### Skull fracture[edit] A basal skull fracture is a fracture in one of the bones at the base of the skull. This is almost always caused by impact trauma such as a hard fall or a car crash. If the temporal bone is affected, one of the following may co-occur: * Auricular cerebrospinal fluid discharge * Dizziness * Bruises around the eyes or behind the ears * Facial weakness * Difficulty seeing, smelling, or hearing ### Nasal packing[edit] Following nasal surgery or frequent nosebleeds, gauze or cotton may be inserted into the nose to stop the bleeding. This process is called therapeutic nasal packing. Nasal packing sometimes causes blood to back up into the middle ear, causing hemotympanum. Removing the packing may allow the blood to drain from the ear. Antibiotics can prevent an ear infection. ### Bleeding disorders[edit] Bleeding disorders, such as hemophilia or idiopathic thrombocytopenia purpura, can also cause hemotympanum. These disorders prevent proper blood clotting. In that circumstance, a mild head injury or a strong sneeze can cause hemotympanum. ### Anticoagulant medications[edit] Anticoagulants, often called blood thinners, are medications that keep blood from clotting too easily. In rare cases, anticoagulants can cause hemotympanum with no underlying cause or injury[citation needed]. Experiencing a head injury while taking anticoagulants, increases the likelihood of hemotympanum[citation needed]. ### Ear infections[edit] Frequent ear infections, ongoing inflammation and fluid buildup can increase the risk of hemotympanum.[citation needed] ## Treatment[edit] Skull fractures usually heal on their own[citation needed], but they can also cause several complications. Cerebrospinal fluid leaking out of the ear involves a higher risk of developing meningitis. Treatment may include corticosteroids, antibiotics, or surgery.[citation needed] ## References[edit] 1. ^ . It may also be secondary to fractures of the mandibular condyles. Blueprints Neurology, 2nd ed. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hemotympanum	c0019125	1,262	wikipedia	https://en.wikipedia.org/wiki/Hemotympanum	2021-01-18T19:04:06	{"umls": ["C0019125"], "wikidata": ["Q1642058"]}
Intellectual disability-developmental delay-contractures syndrome, formerly known as Wieacker-Wolff syndrome, is a severe X-linked recessive neurodevelopmental disorder characterized by severe contractures (arthrogryposis; see this term) and intellectual disability. ## Epidemiology Prevalence and incidence rates are not known. The syndrome has been reported in 5 families to date, with fewer than 30 affected individuals described. Affected patients are male, while carrier females are often asymptomatic. Cases have been reported from Germany, France, the Netherlands, Australia, and the United States. ## Clinical description The syndrome is characterized by an association of arthrogryposis multiplexa congenita and intellectual disability. Affected patients are born with severe contractures (arthrogryposis) and muscle weakness causing respiratory distress. Intellectual disability and delayed motor development are found in all patients. Facial weakness (ptosis) and bulbar weakness (feeding difficulty), characteristic dysmorphic facial features (possibly including long flat philtrum, low-set ears, high-arched palate, and carp-shaped mouth), and skeletal abnormalities (camptodactyly, hip dislocation, scoliosis, kyphosis, lordosis and pes equinovarus) have been reported. Other neurological signs may include spasticity and seizures. Heterozygous female carriers may also be affected, but to a lesser degree (intellectual disability, distal muscle weakness, camptodactyly, joint contractures, and pes equinovarus). ## Etiology Intellectual disability-developmental delay-contractures syndrome is caused by mutations in the ZC4H2 gene (Xq11.1) that is presumed to play a role in neuronal function during fetal growth. ## Genetic counseling The disorder follows an X-linked recessive pattern on inheritance. Simplex cases are also found. Genetic counseling should be provided to affected families. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Intellectual disability-developmental delay-contractures syndrome	c0796200	1,263	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3454	2021-01-23T18:11:00	{"gard": ["7890"], "mesh": ["C536703"], "omim": ["314580"], "umls": ["C0796200"], "icd-10": ["G71.8"], "synonyms": ["Foot contractures-muscle atrophy-oculomotor apraxia syndrome", "Wieacker-Wolff syndrome"]}
North American Indian childhood cirrhosis (NAIC) is a disease in humans that can affect Ojibway-Cree children in northwestern Quebec, Canada.[1] The disease is due to an autosomal recessive abnormality of the CIRH1A gene, which codes for cirhin.[2] NAIC is a ribosomopathy.[3][4] An R565W mutation of CIRH1A[2][5] leads to partial impairment of cirhin interaction with NOL11.[5] Initial transient neonatal jaundice advances over time to biliary cirrhosis with severe liver fibrosis.[1] Eventually, liver failure occurs, and requires liver transplantation.[1] ## References[edit] 1. ^ a b c Online Mendelian Inheritance in Man (OMIM): 604901 2. ^ a b Online Mendelian Inheritance in Man (OMIM): 607456 3. ^ McCann KL, Baserga SJ (2013). "Genetics. Mysterious ribosomopathies". Science. 341 (6148): 849–50. doi:10.1126/science.1244156. PMC 3893057. PMID 23970686.CS1 maint: uses authors parameter (link) 4. ^ Sondalle SB, Baserga SJ (2014). "Human diseases of the SSU processome". Biochim. Biophys. Acta. 1842 (6): 758–64. doi:10.1016/j.bbadis.2013.11.004. PMC 4058823. PMID 24240090.CS1 maint: uses authors parameter (link) 5. ^ a b Freed EF, Prieto JL, McCann KL, McStay B, Baserga SJ (2012). "NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing". PLoS Genet. 8 (8): e1002892. doi:10.1371/journal.pgen.1002892. PMC 3420923. PMID 22916032.CS1 maint: uses authors parameter (link) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	North American Indian childhood cirrhosis	c1858051	1,264	wikipedia	https://en.wikipedia.org/wiki/North_American_Indian_childhood_cirrhosis	2021-01-18T19:01:25	{"mesh": ["C565737"], "umls": ["C1858051"], "orphanet": ["168583"], "wikidata": ["Q25324164"]}
A very rare lysosomal storage disease that is clinically and pathologically heterogeneous and is characterized by deficient NAGA activity. ## Epidemiology Exact prevalence of NAGA deficiency is unknown but fewer than 20 cases have been reported to date in patients of German, Dutch, Spanish, Japanese, French and Moroccan origin. ## Clinical description Extreme clinical variability has been reported. Cases of NAGA deficiency have been divided into 3 clinical subtypes: NAGA deficiency type 1, type 2 and type 3 (see these terms). Type 1 is characterized by infantile-onset neuroaxonal dystrophy, type 2 is described in adult patients with angiokeratoma corporis diffusum and minimal involvement of the nervous system and type 3 is an intermediate clinical form with manifestations ranging from intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays or mild autism-like symptoms. ## Etiology All individuals with NAGA deficiency have mutations in the alpha-N-acetylgalactosaminidase gene (NAGA; 22q13.2) but not all develop neurological symptoms. A number of different NAGA mutations have been identified. There is however no direct genotype-phenotype correlation in view of the clinical heterogeneity of the reported cases. It has been suggested that other factors or genes contribute to the occurrence of neurological symptoms but there is no conclusive evidence to confirm this theory. ## Diagnostic methods The currently known cases were identified through reduced activity of the NAGA enzyme assessed by enzyme tests (assays) on white blood cells (leukocytes), blood plasma or cultured lymphoblasts or fibroblasts, or through urinalysis by thin layer chromatography for oligosaccharide and glycopeptide profiles that revealed increased levels of these complex compounds. Confirmation may be sought by mutation analysis of the NAGA gene. ## Differential diagnosis Differential diagnosis depends on the type of NAGA deficiency and may include infantile neuroaxonal dystrophy, associated with mutations in the PLA2G6 gene, pantothenate kinase-associated neurodegeneration, associated with mutations in the PANK2 gene and other lysosomal diseases, including Fabry disease, due to different lysosomal enzyme defects or unknown factors (see these terms). ## Antenatal diagnosis Prenatal diagnosis is theoretically possible by mutation analysis of the NAGA gene after amniocentesis or chorionic villus sampling but as the clinically different forms of the disease have been mapped to the same gene they cannot be determined prenatally. ## Genetic counseling NAGA deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should therefore be offered to affected families. ## Management and treatment Treatment of this disorder is symptomatic and supportive. It includes the maintenance of satisfactory nutrition and hydration, management of infectious diseases (possibly by antibiotic shielding), control of seizures by anti-epileptic drugs, reduction of spasticity or pain with medication, adequate positioning, physiotherapy to prevent joint contractures or pneumonia, and aspiration prophylaxis potentially including tube feeding. Recent studies identify NAGA deficiency as a typical protein folding disorder. As such, investigational studies are examining whether it is amenable to pharmacological chaperone approaches or enzyme replacement therapy. Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders. ## Prognosis Prognosis is variable depending on the type of NAGA deficiency, with type 1 having the worst and the other types having fairer outcomes. Evidence-based mortality rates or life expectancy figures are not available due to the very small number of patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Alpha-N-acetylgalactosaminidase deficiency	c1836544	1,265	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3137	2021-01-23T18:30:09	{"mesh": ["C536631"], "omim": ["609241", "609242"], "umls": ["C0342850", "C1836544"], "icd-10": ["E77.1"], "synonyms": ["NAGA deficiency", "Schindler disease"]}
A number sign (#) is used with this entry because of evidence that cranioectodermal dysplasia-4 (CED4) is caused by compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14. One such family has been reported. Description Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive heterogeneous ciliopathy that is primarily characterized by skeletal abnormalities, including craniosynostosis, narrow rib cage, short limbs, and brachydactyly, and ectodermal defects. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described (summary by Arts et al., 2011). For a discussion of genetic heterogeneity of cranioectodermal dysplasia, see CED1 (218330). Clinical Features Bredrup et al. (2011) described a 21-year-old Norwegian woman who was the second child of unrelated, healthy parents. At birth, she had developmental dysplasia of both hips and general hypotonia. At age 11 years, ophthalmoscopy revealed attenuated arteries and bone-spicule-shaped deposits in the periphery of the retina; electroretinogram (ERG) showed completely extinguished signals, indicative of tapetoretinal dystrophy. She had recurrent pneumonia and asthma, consistent with respiratory function tests that indicated reduced lung capacity. Short stature was treated with growth hormone therapy, after which her height attained the 10th centile. A renal ultrasound to investigate hypertension and a moderately increased serum creatinine revealed hyperechoic kidneys, and a biopsy showed nonspecific changes consistent with a nephronophthisis-like disease. The nephropathy progressed rapidly, and she underwent renal transplantation at 14 years of age. She also had idiopathic bone marrow hypoplasia. Her 16-year-old brother had developmental dysplasia of both hips and craniosynostosis of the sagittal suture. Routine ophthalmoscopy at 7 years of age revealed attenuated retinal vessels, and an ERG showed extinguished rod signals and severely reduced cone signals, consistent with a rod-cone dystrophy. Renal ultrasound showed hyperechoic kidneys, but there were no other signs of renal disease. Both sibs had multiple dental anomalies. A diagnosis of Sensenbrenner syndrome was made based on the combination of clinical findings in both sibs. Molecular Genetics In a sister and brother with clinical findings compatible with Sensenbrenner syndrome, from a Norwegian family in which haplotype analysis had excluded the 3 genes previously found to be mutated in Sensenbrenner syndrome, Bredrup et al. (2011) performed exome sequencing and identified variations in 7 candidate genes. Only 1 gene, WDR19 (608151), had variants that cosegregated with disease in the family: both affected sibs were compound heterozygous for a missense (L710S; 608151.0001) and a nonsense (R1103X; 608151.0002) mutation in WDR19. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 422 Norwegian controls. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Frontal bossing (in some patients) \- Full cheeks (in some patients) Ears \- Protruding ears (in some patients) Eyes \- Hypermetropia \- Retinitis pigmentosa with preserved central vision \- Nyctalopia, congenital (in some patients) Nose \- Smooth philtrum (in some patients) Mouth \- Thin lips (in some patients) Teeth \- Atypical cusps on maxillary first molars, mandibular first premolars, and canines \- Bony protrusion of hard palate (in some patients) \- Taurodontism of molars (in some patients) RESPIRATORY Airways \- Recurrent asthma (in some patients) Lung \- Recurrent pneumonia (in some patients) \- Reduced lung capacity CHEST External Features \- Short, narrow thorax \- Pectus excavatum Ribs Sternum Clavicles & Scapulae \- Short, thick ribs ABDOMEN Liver \- Palpable liver Spleen \- Palpable spleen GENITOURINARY Kidneys \- Nephronophthisis-like nephropathy \- Renal failure, endstage (in some patients) SKELETAL \- Joint hypermobility Skull \- Craniosynostosis, sagittal (in some patients) Pelvis \- Hip dysplasia, bilateral Hands \- Short and broad distal phalanges \- Short second and fifth phalanges \- Cutaneous syndactyly (in some patients) Feet \- Short, broad phalanges \- Small second through fifth toes (in some patients) \- Pes valgus SKIN, NAILS, & HAIR Skin \- Lax skin Nails \- Thick nails (in some patients) LABORATORY ABNORMALITIES \- Bone marrow hypoplasia (in some patients) MOLECULAR BASIS \- Caused by mutation in the WD repeat-containing protein-19 gene (WDR19, 608151.0001 ) ▲ 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	CRANIOECTODERMAL DYSPLASIA 4	c0432235	1,266	omim	https://www.omim.org/entry/614378	2019-09-22T15:55:28	{"doid": ["0080033"], "mesh": ["C562966"], "omim": ["614378"], "orphanet": ["1515"], "genereviews": ["NBK154653"]}
Large, right lower lobe pneumatocele is shown, compromising ventilation in a premature infant with RDS and superimposed RSV pneumonitis. A pneumatocele is a cavity in the lung parenchyma filled with air that may result from pulmonary trauma during mechanical ventilation.[1] Gas-filled, or air-filled lesions in bone are known as pneumocysts.[2] When a pneumocyst is found in a bone it is called an intraosseous pneumocyst, or a vertebral pneumocyst when found in a vertebra.[3] ## Contents * 1 Cause * 2 Diagnosis * 3 Management and treatment * 4 References * 5 Further reading ## Cause[edit] A pneumatocele results when a lung laceration, a cut or tear in the lung tissue, fills with air.[4] A rupture of a small airway creates the air-filled cavity.[1] Pulmonary lacerations that fill with blood are called pulmonary hematomas.[4] In some cases, both pneumatoceles and hematomas exist in the same injured lung.[5] A pneumatocele can become enlarged, for example when the patient is mechanically ventilated or has acute respiratory distress syndrome, in which case it may not go away for months.[5] Intraosseous pneumatocysts in the bone are rare and of unclear origin. They are benign and usually without symptoms.[3] They are also found around a sacroiliac joint, and there has been one reported case of an acetabular pneumocyst.[6] ## Diagnosis[edit] Diagnosis can be made using chest X-ray; the lesion shows up as a small, round area filled with air.[1] Computed tomography can give a more detailed understanding of the lesion.[1] Differential diagnoses – other conditions that could cause similar symptoms as pneumatocele include lung cancer, tuberculosis,[7] and a lung abscess[1] in the setting of hyper IgE syndrome (aka Job's syndrome) or on its own, often caused by Staphylococcus aureus infection during cystic fibrosis. ## Management and treatment[edit] Treatment typically is supportive and includes monitoring and observation.[1] ## References[edit] 1. ^ a b c d e f Atluri P, Karakousis GC, Porrett PM, Kaiser LR (2005). The Surgical Review: An Integrated Basic and Clinical Science Study Guide (Recall Series). Hagerstown, MD: Lippincott Williams & Wilkins. p. 376. ISBN 0-7817-5641-3. 2. ^ "pneumatocyst \| Definition of pneumatocyst in English by Oxford Dictionaries". Oxford Dictionaries \| English. Retrieved 4 June 2019. 3. ^ a b Al-Tarawneh, E; Al-Qudah, M; Hadidi, F; Jubouri, S; Hadidy, A (March 2014). "Incidental intraosseous pneumatocyst with gas-density-fluid level in an adolescent: a case report and review of the literature". Journal of Radiology Case Reports. 8 (3): 16–22. doi:10.3941/jrcr.v8i3.1540. PMC 4035364. PMID 24967024. 4. ^ a b White C, Stern EJ (1999). Chest Radiology Companion. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 80, 176. ISBN 0-397-51732-7. Retrieved 2008-04-30. 5. ^ a b Gavelli G, Canini R, Bertaccini P, Battista G, Bnà C, Fattori R (June 2002). "Traumatic injuries: imaging of thoracic injuries". European Radiology. 12 (6): 1273–1294. doi:10.1007/s00330-002-1439-6. PMID 12042932. 6. ^ Narváez, JA; Narváez, J; Rodríguez-Mijarro, M; Quintero, JC (1999). "Acetabular pneumatocyst containing air-fluid level". European Radiology. 9 (8): 1647–9. doi:10.1007/s003300050902. PMID 10525883. 7. ^ Puri, M. M.; Jain, A. K.; Kumar, Lokender; Sarin, R. (April 2014). "Total replacement of a lung by tuberculosis pneumatocele--an unusual post-tuberculosis sequel". The Indian Journal of Tuberculosis. 61 (2): 162–165. ISSN 0019-5707. PMID 25509941. ## Further reading[edit] Al-Tarawneh, Emad; AL-Qudah, Mohammad; Hadidi, Fadi (March 2014). "Incidental Intraosseous Pneumatocyst with gas-density-fluid level in an adolescent: a case report and review of the literature". Journal of Radiology Case Reports. 8 (3): 16–22. doi:10.3941/jrcr.v8i3.1540. PMC 4035364. PMID 24967024. * v * t * e Chest injury, excluding fractures Cardiac and circulatory system injuries * vascular: Traumatic aortic rupture * Thoracic aorta injury * heart: Myocardial contusion/Commotio cordis * Cardiac tamponade * Hemopericardium * Myocardial rupture Lung and lower respiratory tract injuries * Pneumothorax * Hemothorax * Hemopneumothorax * Pulmonary contusion * Pulmonary laceration * Tracheobronchial injury * Diaphragmatic rupture [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pneumatocele	c0333160	1,267	wikipedia	https://en.wikipedia.org/wiki/Pneumatocele	2021-01-18T19:01:47	{"umls": ["C0333160"], "icd-10": ["G93.88"], "wikidata": ["Q7205984"]}
Thousand cankers disease A walnut tree in Denver, Colorado affected by Thousand cankers disease. Common namesTCD Causal agentsGeosmithia morbida HostsWalnut trees (Juglans sp.) Vectorswalnut twig beetle (Pityophthorus juglandis) EPPO CodeGEOHMO Thousand cankers disease (TCD) is a recently recognized disease of certain walnuts (Juglans spp.). The disease results from the combined activity of the walnut twig beetle (Pityophthorus juglandis) and a canker producing fungus, Geosmithia morbida.[1] Until July 2010 the disease was only known to the western United States where over the past decade it has been involved in several large scale die-offs of walnut, particularly black walnut, Juglans nigra. However, in late July 2010 a well-established outbreak of the disease was found in the Knoxville, Tennessee area. This new finding is the first locating it within the native range of its susceptible host, black walnut. In 2013, an outbreak was found in the Veneto region of Italy, where the disease has been found on both black walnut and English walnut.[2] ## Contents * 1 Description * 2 History * 3 Management * 4 Pathogenesis * 5 Importance * 6 Origin * 7 References * 8 External links ## Description[edit] Adult walnut twig beetles carry spores of the Geosmithia morbida fungus, which grows profusely around the pupal chamber of the beetles. Following emergence from trees the beetles subsequently tunnel into branches and trunks of walnut for production of egg galleries or overwintering shelters. The fungus is introduced into the tree during this wounding where it subsequently germinates and grows. The fungal mycelium initially colonize tissue immediately surrounding the beetle galleries. However, in less than a month black, oval-shaped, inky cankers extend considerably beyond the galleries and may reach more than 3 cm in length in susceptible hosts (e.g., black walnut). In the beginning these cankers develop in phloem and tissues formed by the cork cambium. The affected area is very shallow and never show the ‘open-faced’, perennial, target-shape typical of many canker diseases of trees (e.g., Nectria canker). Instead, in TCD the bark remains firmly attached to the canker face making the necrotic areas very difficult to observe. Branch cankers usually are not visible until the outer bark is shaved to expose the beetle tunnels, although during late stages of the disease a dark amber stain may form on the bark surface in association with the cankers. Each time a beetle tunnels into a tree a canker is initiated. Cankers also may continue to expand and penetrate into the cambium of the tree. Each such injury destroys the phloem and robs the tree of its ability to store and move nutrients. As TCD progresses cankers coalesce to further girdle branches greatly restricting nutrient movement. As the tree declines, more bark beetles are attracted and more cankers are formed. Eventually the enormous number of beetle attacks and subsequent canker formation overwhelms and kills the tree. Thousand cankers is a progressive disease and its effects result from the culmination of a large number of relatively small cankers over a period of time. Just as a thousand cuts was once used as a form of human execution in Imperial China, black walnuts are subjected to death by thousands of branch and trunk cankers produced by infection from the Geosmithia fungus. In end stages of the disease external symptoms become visible. Leaf yellowing on the exterior of the crown is often the first symptom and may originally be restricted to a single branch. However, as the cumulative effects of the girdling progress increasingly large areas of the tree are affected. Sudden leaf wilting, ultimately involving large limbs, characterizes end stage thousand cankers disease. In susceptible hosts, trees are almost always killed within 2–3 years after external symptoms of leaf yellowing are first observed. The progress of thousand cankers will vary due to several factors, notably the susceptibility of the host. There appears to be a considerable range of TCD susceptibility among various Juglans species with Juglans nigra (black walnut) being particularly susceptible. Conversely, Arizona walnut (Juglans major) appears to be quite resistant to the disease, with bark beetle attacks largely limited to small diameter branches, the fungus growing to a very limited extent, and effects of the disease rarely, if ever, progressing to involve large areas of the tree. Similarly southern California walnut (Juglans californica) and little walnut (Juglans microcarpa) may show fairly high resistance. Northern California walnut (Juglans hindsii) and the commercial nut-producing Persian (English) walnut (Juglans regia) apparently show various degrees of intermediate TCD susceptibility. ## History[edit] Thousand cankers is a recently described disease and its involvement in tree mortality apparently is also recent. The first published note involving black walnut die-offs that likely can be attributed to TCD occurred in the Espanola Valley of northern New Mexico in 2001. Walnut twig beetles were associated with this unusual cluster of walnut mortality, but drought was originally thought to be the cause. A parallel situation occurred in eastern Colorado during the early 2000s where unexplained black walnut deaths were observed in several sites (Colorado Springs, Boulder, Westminster) and originally thought to be associated with drought. Walnut twig beetles were subsequently recovered in 2004, which constituted a new state record for the species. This appears to have been preceded by unusual black walnut mortality during the mid-1990s of undetermined cause that were noted in the vicinity of Logan, Utah. Collections of walnut twig beetles were made in 1996 in association with this outbreak. A 1988 collection of walnut twig beetle from the Provo area, collected incidentally when sweeping vegetation, appears to be a precedent first collection of this species in the state. New state records of walnut twig beetle have occurred in several other western states within the past 12 years including Oregon (1997), Idaho (2003) and Washington (2008). Most collections from these states were associated with walnut die-offs, although the beetle has also been incidentally collected in Lindgren funnel traps used for survey of other forest pests. Walnut twig beetle records in California date to 1959, when it was found in Los Angeles County; known range extensions for this species within the state have increased widely in recent years and it is now known to be widely distributed within the state. Although walnut twig beetles were repeatedly and regularly noted in association with unexplained walnut deaths since 2002 it was recognized that their activity alone appeared insufficient to produce all the effects that produce thousand cankers disease. It required discovery of the previously undescribed Geosmithia fungus - and an appreciation of its role in canker production - to complete an understanding of how the disease can develop. The initial description of the thousand cankers disease was constructed in early 2008 by researchers at Colorado State University and subsequently information was extended to alert researchers, arborists and others with interest in tree health care. This led to numerous new TCD records in the western US during 2008 and 2009. Initial description of thousand cankers disease in a refereed journal occurred in August 2009. Symposia dedicated to this new disease have been held at the Annual Meeting of the Entomological Society of America in December 2008 and at a Missouri Department of Agriculture sponsored meeting in St. Louis during November 3–4, 2009. ## Management[edit] Thousand cankers disease can be spread by moving infected black walnut wood. Trees intended for shipment should be inspected for dieback and cankers and galleries after harvest. G. morbidia or the walnut twig beetle (Pityophthorus juglandis) are not currently known to be moved with walnut seed.[3] There is currently no chemical therapy or prevention available for the disease making it difficult to control the spread of the disease from the west to the eastern United States. Wood from infected trees can still be used for commercial value, but safety measures such as removing the bark, phloem, and cambium should be followed to reduce the risk of spreading the disease with shipment.[4] Quarantines have been put in place in some states to reduce the potential movement of fungus or beetle from that region. On May 17, 2010, the Director of the Michigan Department of Agriculture issued a quarantine from affected states to protect Michigan’s black walnut ecology and production.[5] Contacting the appropriate entities about possible infections is important to stopping or slowing the spread of thousand cankers disease. ## Pathogenesis[edit] The genus Geosmithia (Ascomycota: Hypocreales) are generally saprophytic fungi affecting hardwoods. As of its identification in 2010, the species G. morbida is the first documented as a plant pathogen.[6] The walnut twig beetle (Pityophthorus juglandis) carries the mycelium and conidia of the fungus as it burrows into the tree. The beetle is currently only found in warmer climates, allowing for transmission of the fungus throughout the year. Generations of the beetle move to and from black walnut trees carrying the fungus as they create galleries, the adults typically moving horizontally, and the larvae moving vertically with the grain.[4] As they move through the wood, the beetles deposit the fungus, which is then introduced into the phloem; cankers then develop around the galleries, quickly girdling the tree.[4] The fungus has not been found to provide any value to the beetle. A study done by Montecchio and Faccoli in Italy in 2014 found that no fungal fruiting bodies were found around or on the cankers but in the galleries. Mycelium, and sometimes conidiophores and conidia were observed in the galleries as well.[7] No sexual stage of the fungus has currently been found. ## Importance[edit] Black walnut wood is valued for its use in cabinetry, furniture making, and other woodworking. In 2008, 700 trees in boulder Colorado were removed from what was thought to be a decline disease, but later discovered as Thousand Cankers Disease.[8] In 2009, the Missouri Department of Conservation issued a prediction of losses for the state due to the disease. They predicted the annual wood product loss after established infection would have a total value of $36,333,677, with a loss of 210 jobs. It was also predicted that the annual nut production loss would total $35,291,500, with 504 jobs lost in the industry and sector.[9] Although the integrity of the wood is not compromised, the rapid tree death greatly reduces the supply of black walnut wood.[4] The seed from black walnut is also valued for its ecological importance. G. morbida does not affect the seeds, but increased tree death would lead to decreased nut production, hindering both human industry, and creating a lost food source for wildlife.[4] With widespread loss of walnut trees spreading from the western united states, to Tennessee, there is increasing importance to protect walnuts in the eastern United States, or risk losing much of the walnut production in the United States. ## Origin[edit] The origin of thousand cankers disease remains a subject of some uncertainty and its resolution will require further studies likely based on genetic analyses. One proposal suggests that the disease is resulted from a host transfer of the walnut twig beetle and its Geosmithia associate from native, resistant Juglans (Arizona walnut and possibly southern California walnut) into susceptible species of walnut. Several data seem to support this hypothesis. The walnut twig beetle is a normal associate of Arizona walnut and was first described in 1929 from a collection near Silver City (Lone Mountain) in Grant County, New Mexico. Subsequent reviews of North American bark beetles through 1992 only note walnut twig beetles from areas within the range of Arizona walnut, excepting the two 1959 captures in Los Angeles County, where southern California walnut is native. Recent observations of walnut twig beetle activity in Arizona walnut trees indicate that the beetle in this host functions as a 'typical' twig beetle of the genus Pityophthorus, restricting breeding to overshaded or damaged branches and twigs. The appearance of extensive colonization of trees by walnut twig beetle have only been observed in black walnut, a species native to the eastern half of the US but planted widely in the western states over the past century. The Geosmithia fungus, although recently described, is consistently found where ever walnut twig beetles are recovered, including those associated with Arizona walnut. In Arizona walnut, laboratory inoculations indicate that it grows slowly, particularly compared to black walnut, and thousand cankers disease has not been observed to develop in native stands of this species that grow in Arizona and New Mexico. Optimum temperatures for development of the Geosmithia fungus are high, also suggesting a warm climate origin, a feature that is consistent with the native distribution of Arizona walnut. Genetic analysis of Geosmithia isolates from throughout the western United States is currently considered a high research priority. Preliminary observations indicate that there is considerable variability, indicating no genetic bottlenecks that might be expected from point introductions. Furthermore, genetically related strains may be found over wide geographic areas (e.g., California and Colorado). Alternatively it is suggested that thousand cankers may have developed from a recent introduction of the Geosmithia fungus or some change in its pathogenicity. Regardless there has been a broad range extension of the walnut twig beetle within the past 15 years so that it currently is known from all western states for which it has been surveyed (AZ, CA, CO, ID, OR, UT, WA). Whether this has occurred through natural dispersal events or by human transport of twig beetle infested walnut products (e.g., firewood, fresh cut logs, wood pieces used by woodworkers) is not known. The most recent finding of the beetle, in the Knoxville, Tennessee area, clearly is the result of human transport of walnut twig beetle-containing walnut wood, the original event probably occurring a decade or more ago. Walnut wood is extremely infectious (i.e., contains fungus bearing bark beetles) for at least 2–3 years after trees are cut. The beetles are capable of surviving on small pieces of wood, as long as some bark is attached, and some beetles can even survive normal wood chipping. New infestations from thousand cankers can become established with the movement of a single piece of wood. As the disease develops slowly, and external symptoms may not become visible for 10–20 years after the original establishment, it is possible that additional, undetected infestations are present in the eastern US. ## References[edit] 1. ^ Kolarik, M.; Freeland, E.; Utley, C.; Tisserat, N. (2011). "Geosmithia morbida sp. nov., a new phytopathogenic species living in symbiosis with the walnut twig beetle (Pityophthorus juglandis) on Juglans in USA". Mycologia. 103 (2): 325–332. doi:10.3852/10-124. PMID 20943528. S2CID 35496500. 2. ^ Montecchio, L.; Vettorazzo, M.; Faccoli, M. (2016). "Thousand cankers disease in Europe: an overview". EPPO Bulletin. 46 (2): 335–340. doi:10.1111/epp.12301. ISSN 0250-8052. 3. ^ "details". www.tsusinvasives.org. Retrieved December 15, 2017. 4. ^ a b c d e Centre, By Invasive Species. "Forest Invasives". forestinvasives.ca. Retrieved December 15, 2017. 5. ^ "Invasive Species - Thousand Cankers Disease". www.michigan.gov. Retrieved December 15, 2017. 6. ^ Kolarik, M (Winter 2017). "Geosmithia morbida sp. nov., a new phytopathogenic species living in symbiosis with the walnut twig beetle (Pityophthorus juglandis) on Juglans in USA". Mycologia. 103 (2): 325–32. doi:10.3852/10-124. PMID 20943528. S2CID 35496500. 7. ^ Montecchio, L.; Faccoli, M. (May 2014). "First Record of Thousand Cankers Disease and Walnut Twig Beetle on in Europe". Plant Disease. 98 (5): 696. doi:10.1094/PDIS-10-13-1027-PDN. PMID 30708556. 8. ^ Tisserat, Ned; Cranshaw, Whitney; Leatherman, David; Utley, Curtis; Alexander, Kathleen (2009). "Black Walnut Mortality in Colorado Caused by the Walnut Twig Beetle and Thousand Cankers Disease". Plant Health Progress. 10: 10. doi:10.1094/php-2009-0811-01-rs. 9. ^ Treiman; Tuttle. "Thousand Cankers Disease of Black Walnut: How Much Will It Hurt Missouri's Pocketbook?" (PDF). Missouri Agriculture- Notes for Forest Managers. 16. * Anonymous 2002. Forest Insect and Disease Conditions of the Southwestern Region, 2001. USDA-FS Southwestern Region, Forestry and Forest Health Publication R3-02-01. * Anonymous 2005. Forest Insect and Disease Conditions of the Rocky Mountain Region, 2004. USDA-FS Rocky Mountain Region, Renewable Resources and Forest Health Management Report R2-05-09. * Blackman, M. W. 1928. The genus Pityophthorus Eichh. in North America: A revisional study of the Pityphthori, with descriptions of two new genera and seventy-one new species. New York State College of Forestry Syracuse University Bulletin 1(3-6), Tech. Publ. 25: 183 pp. * Bright, D.E. and R.W. Stark. 1973. The Bark Beetles and Ambrosia Beetles of California (Scolytidae and Platypodidae). Bulletin of the California Insect Survey, Volume 16. 169 pp. * Furniss, R.L. and V.M Carolin. 1977. Western Forest Insects. USDA Forest Service Miscellaneous Publication No. 1339. 654 pp. * Tisserat, N., W. Cranshaw, D. Leatherman, C. Utley, and K. Alexander. 2009. Black walnut mortality in Colorado caused by the walnut twig beetle and Thousand Cankers disease. Plant Health Progress August 11, 2009. * Wood, S.L. 1982. The Bark and Ambrosia Beetles of North and Central America (Coleoptera: Scolytidae), a Taxonomic Monograph. Great Basin Naturalist Memoirs No. 6. 1359 pp. * Wood, S.L. and D.E. Bright. 1992. A Catalog of Scolytidae and Platypodidae (Coleoptera), Part 2.: Taxonomic Index Volume B. Great Basin Naturalist Memoirs No. 6. 1553 pp. ## External links[edit] * Species Profile - Thousand Cankers Black Walnut Disease (Geosmithia morbida), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Thousand Cankers Black Walnut 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	Thousand cankers disease	None	1,268	wikipedia	https://en.wikipedia.org/wiki/Thousand_cankers_disease	2021-01-18T18:55:43	{"wikidata": ["Q17119323"]}
Megacystis (fetal) SpecialtyUrology Fetal megacystis[1] is a rare disease that is identified by an abnormally large or distended bladder. ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Cause[edit] Megacystis is associated with Berdon syndrome (MMIH syndrome).[2] ## Diagnosis[edit] Ultrasound scan of a fetus with megacystis Fetal megacystis is diagnosed during pregnancy by ultrasound imaging procedures. Since it can be associated with genetic abnormalities, further ultrasounds and tests may be administered during pregnancy. It may also be diagnosed as megalocystis, and/or termed megabladder, which is the same condition. Megacystis is listed as a rare disease by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH), which means it affects fewer than 200,000 people within the U.S. ## Treatment[edit] Megacystis can often be treated pharmacologically or with biofeedback to improve bladder functioning, if the child survives past early infancy.[2] ## See also[edit] * Berdon syndrome ## References[edit] 1. ^ Taghavi, K.; Sharpe, C.; Stringer, M. D. (February 2017). "Fetal megacystis: A systematic review". Journal of Pediatric Urology. 13 (1): 7–15. doi:10.1016/j.jpurol.2016.09.003. ISSN 1873-4898. PMID 27889224. 2. ^ a b Petrikovsky, Boris M. (1999). Fetal Disorders: Diagnosis and Management. John Wiley & Sons. p. 143. ISBN 9780471191520. ## External links[edit] * Short article with links * Emedicine.com search on megacystis * Medical Dictionary definition * Signs of pregnancy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Megacystis (fetal)	c1855311	1,269	wikipedia	https://en.wikipedia.org/wiki/Megacystis_(fetal)	2021-01-18T18:35:42	{"mesh": ["C536139"], "umls": ["C1855311"], "wikidata": ["Q6808346"]}
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type VI (OI6) is caused by homozygous mutation in the SERPINF1 gene (172860) on chromosome 17p13.3. Description Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011). Clinical Features Glorieux et al. (2002) described a novel form of OI, which they designated OI type VI, in 8 patients (6 males). None of the patients, all of whom had earlier been diagnosed with OI type IV (166220) (Ward et al., 2000), had documented fractures at birth. Fractures were first documented between ages 4 and 18 months. Type VI OI patients sustained more frequent fractures than patients with OI type IV, which led to long bone deformity in 7 of the patients. Ligamentous laxity was present in 4 of the patients. Sclerae were white or faintly blue and teeth were normal. Radiologic findings included long bone deformity, coxa vara, and protrusio acetabuli. The vertebrae were wedge-shaped or biconcave. All patients had vertebral compression fractures. Wormian bones of the skull were absent. Lumbar spine bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Two brothers, born to consanguineous parents, were unusual in that they showed severe osteopenia, bulbous metaphyses, and severe limb deformity. Histology of iliac biopsy specimens revealed a distinctive 'fish-scale' pattern of the lamellae. Another distinctive feature was the presence of excessive osteoid. Glorieux et al. (2002) concluded that the hyperosteoidosis points toward a defect in mineralization. Levels of biochemical bone markers were generally within the reference range but serum alkaline phosphatase levels were elevated compared to the levels in patients with OI type IV. Becker et al. (2011) described 4 affected individuals from 3 unrelated consanguineous families with a severe form of OI, which the authors stated was compatible with OI type III in the Sillence classification (see 259420). No intrauterine fractures were reported, and birth length and weight were normal. Dentinogenesis imperfecta was not present, and the sclerae were grayish. All 4 individuals had fractures of long bones and severe vertebral compression fractures, with resulting deformities observed as early as the first year of life. Bone mineral density was severely reduced. All had short stature and were wheelchair bound. Clinical Management Land et al. (2007) described the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity. During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+53%, p = 0.06), but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment (p less than 0.05). Inheritance From their study, Glorieux et al. (2002) could not ascertain the mode of inheritance of OI type VI. The 3 boys (including 2 brothers) with the most severe phenotype were products of consanguineous parents, suggesting recessive inheritance. However, Glorieux et al. (2002) noted that for the 2 brothers, parental mosaicism with autosomal dominant inheritance was possible. Becker et al. (2011) confirmed autosomal recessive inheritance of OI type VI. Molecular Genetics Becker et al. (2011) applied next-generation sequencing and identification of homozygous regions to analyze the exome of a single male individual, the offspring of consanguineous parents, who had a severe form of OI. They identified a homozygous truncating mutation in the SERPINF1 gene (172860.0001), which was also found in his affected brother. Their parents and 2 unaffected sisters were heterozygous carriers. Becker et al. (2011) also identified homozygosity for different truncating SERPINF1 mutations in 2 unrelated Turkish patients with severe OI (172860.0002-172860.0003). Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. In affected members of 3 Saudi families with OI, Shaheen et al. (2012) identified homozygous mutations in the SERPINF1 gene (172860.0004-172860.0006). All of those affected had early childhood onset of fractures, and affected individuals in 2 families had blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy. ### PEDF Interaction with BRIL Farber et al. (2014) found that a missense mutation in the IFITM5 gene (S40L; 614757.0002) that resulted in OI (OI5; 610967) affected expression and secretion of PEDF. While IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein (the product of the IFITM5 gene) level was similar to controls, secretion of PEDF by patient fibroblasts was barely detectable, and analysis of patient osteoblasts confirmed minimal secretion of PEDF. The patient's phenotypic and bone histologic findings were most consistent with OI type VI. Farber et al. (2014) concluded that BRIL and PEDF have a relationship that connects the genes for OI types V and VI and their roles in bone mineralization. ### Exclusion Studies Glorieux et al. (2002) screened both type I collagen genes (COL1A1 and COL1A2) using cDNA and genomic DNA and detected no mutations in their patients. Nomenclature The form of OI caused by mutation in the SERPINF1 gene was originally designated OI type XII (OI12) in OMIM. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	OSTEOGENESIS IMPERFECTA, TYPE VI	c0268362	1,270	omim	https://www.omim.org/entry/613982	2019-09-22T15:56:57	{"doid": ["0110350"], "mesh": ["C536044"], "omim": ["613982"], "orphanet": ["216812", "216820", "666"]}
X-linked infantile nystagmus is a condition characterized by abnormal eye movements. Nystagmus is a term that refers to involuntary side-to-side movements of the eyes. In people with this condition, nystagmus is present at birth or develops within the first six months of life. The abnormal eye movements may worsen when an affected person is feeling anxious or tries to stare directly at an object. The severity of nystagmus varies, even among affected individuals within the same family. Sometimes, affected individuals will turn or tilt their head to compensate for the irregular eye movements. ## Frequency The incidence of all forms of infantile nystagmus is estimated to be 1 in 5,000 newborns; however, the precise incidence of X-linked infantile nystagmus is unknown. ## Causes Mutations in the FRMD7 gene cause X-linked infantile nystagmus. The FRMD7 gene provides instructions for making a protein whose exact function is unknown. This protein is found mostly in areas of the brain that control eye movement and in the light-sensitive tissue at the back of the eye (retina). Research suggests that FRMD7 gene mutations cause nystagmus by disrupting the development of certain nerve cells in the brain and retina. In some people with X-linked infantile nystagmus, no mutation in the FRMD7 gene has been found. The genetic cause of the disorder is unknown in these individuals. Researchers believe that mutations in at least one other gene, which has not been identified, can cause this disorder. ### Learn more about the gene associated with X-linked infantile nystagmus * FRMD7 ## Inheritance Pattern This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two copies of the X chromosome), one altered copy of the gene in each cell can cause the condition, although affected females may experience less severe symptoms than affected males. Approximately half of the females with only one altered copy of the FRMD7 gene in each cell have no symptoms of this 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	X-linked infantile nystagmus	c1839580	1,271	medlineplus	https://medlineplus.gov/genetics/condition/x-linked-infantile-nystagmus/	2021-01-27T08:25:15	{"gard": ["2969"], "mesh": ["C537853"], "omim": ["310700"], "synonyms": []}
Constitutional mismatch repair deficiency syndrome is a rare, inherited cancer-predisposing syndrome characterized by the development of a broad spectrum of malignancies during childhood, including mainly brain, hematological and gastrointestinal cancers, although embryonic and other tumors have also been occasionally reported. Non-neoplastic features, in particular manifestations reminiscent of neurofibromatosis type 1 (e.g., café-au-lait spots, freckling, neurofibromas), as well as premalignant and non-malignant lesions (such as adenomas/polpyps) are frequently present before malignancy development. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Constitutional mismatch repair deficiency syndrome	c0265325	1,272	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=252202	2021-01-23T17:30:31	{"mesh": ["C536928"], "omim": ["276300"], "synonyms": ["CMMR-D syndrome"]}
Nutcracker syndrome Other namesNutcracker phenomenon, renal vein entrapment syndrome, mesoaortic compression of the left renal vein The nutcracker syndrome results from compression of the left renal vein between the aorta and the superior mesenteric artery. The nutcracker syndrome (NCS) results most commonly from the compression of the left renal vein (LRV) between the abdominal aorta (AA) and superior mesenteric artery (SMA), although other variants exist.[1][2] The name derives from the fact that, in the sagittal plane and/or transverse plane, the SMA and AA (with some imagination) appear to be a nutcracker crushing a nut (the renal vein). Furthermore, the venous return from the left gonadal vein returning to the left renal vein is blocked, thus causing testicular pain (colloquially referred to as "nut pain"). There is a wide spectrum of clinical presentations and diagnostic criteria are not well defined, which frequently results in delayed or incorrect diagnosis.[1] This condition is not to be confused with superior mesenteric artery syndrome, which is the compression of the third portion of the duodenum by the SMA and the AA. ## Contents * 1 Signs and symptoms * 2 Etiology * 3 Diagnosis * 3.1 Doppler Ultrasound * 3.2 CT and MRI * 3.3 Venography * 3.4 Differential diagnosis * 4 Treatment * 4.1 Conservative management * 4.2 Surgical management * 4.2.1 Open and laparoscopic procedures * 4.2.2 Endovascular procedures * 5 Gallery * 6 References * 7 External links ## Signs and symptoms[edit] The signs and symptoms of NCS are all derived from the outflow obstruction of the left renal vein. The compression causes renal vein hypertension, leading to hematuria (which can lead to anemia)[3] and abdominal pain (classically left flank or pelvic pain).[4] The abdominal pain may improve or worsen depending on positioning.[4] Patients may also have orthostatic proteinuria, or the presence of protein in their urine depending on how they sit or stand.[5] Since the left gonadal vein drains via the left renal vein, it can also result in left testicular pain[6] in men or left lower quadrant pain in women, especially during intercourse and during menstruation.[7] Occasionally, the gonadal vein swelling may lead to ovarian vein syndrome in women. Nausea and vomiting can result due to compression of the splanchnic veins.[6] An unusual manifestation of NCS includes varicocele formation and varicose veins in the lower limbs.[8] Another clinical study has shown that nutcracker syndrome is a frequent finding in varicocele-affected patients and possibly, nutcracker syndrome should be routinely excluded as a possible cause of varicocele and pelvic congestion.[9] In women, the hypertension in the left gonadal vein can also cause increased pain during menses.[9] ## Etiology[edit] In normal anatomy, the LRV travels between the SMA and the AA.[7] Occasionally, the LRV travels behind the AA and in front of the spinal column. NCS is divided based on how the LRV travels, with anterior NCS being entrapment by the SMA and AA and posterior NCS being compression by the AA and spinal column.[7] NCS can also be due to other causes such as compression by pancreatic cancer, retroperitoneal tumors, and abdominal aortic aneurysms.[7] Although other subtypes exist, these causes are more uncommon in comparison to entrapment by the SMA and the AA.[7] Patients with NCS have a tendency to have a tall and lean stature, as this can lead to a narrower gap between the SMA and the AA for the LRV. [10] ## Diagnosis[edit] Nutcracker syndrome is diagnosed through imaging such as doppler ultrasound (DUS), computed tomography (CT), magnetic resonance imaging (MRI), and venography.[11] The selection of the imaging modality is a step-wise process. DUS is the initial choice after clinical suspicion based on symptoms. CT and MRI are used to follow up afterwards, and if further conrfirmation is necessary, venography is used to confirm.[11] ### Doppler Ultrasound[edit] Although its ability to detect renal vein compression is dependent on how a patient is positioned during imaging, DUS is recommended as an initial screening tool as it has a high sensitivity (69–90%) and specificity (89–100%). DUS measures the anteroposterior diameter, and a peak systolic velocity at least four times as fast as an uncompressed vein is indicative of NCS.[5] ### CT and MRI[edit] CT and MRI can be used afterward to confirm compression by the AA and SMA with comprehensive measurements of the abdominal vasculature. A "beak sign" can often be seen in CT scans due to the LRV compression. However, CT and MRI cannot demonstrate the flow within the compressed vein. These two modalities can be used to confirm other evidence for NCS such as back-up of blood flow into the ovarian veins.[10][5] ### Venography[edit] If further confirmation is necessary, venography is used as the gold standard test in diagnosing nutcracker syndrome. A renocaval pullback mean gradient of >3 mmHg is considered diagnostic. Although this method continues to be the gold standard, values in unaffected individuals may be vary considerably, leading to some measurements in NCS patients to be similar to those in normal individuals.[11] This may be partly due to compensatory mechanisms in the vasculature as a result of the increased blood pressure. The invasive nature of the procedure is another consideration in comparison to DUS and CT/MRI as imaging modalities.[7] ### Differential diagnosis[edit] * Pelvic congestion syndrome * Renal stones * Genitourinary malignancy * Loin pain hematuria syndrome[12] ## Treatment[edit] Treatment depends on the severity and symptoms. In addition to conservative measures, more invasive therapies include endovascular stenting,[4] renal vein re-implantation,[13] and gonadal vein embolization. The decision between conservative and surgical management is dependent on the severity of the symptoms.[11] Conservative management is used if the patient is a child and the hematuria is mild.[10] In contrast, more severe symptoms such as reduced renal function, flank pain, and anemia are managed with surgical interventions.[10] ### Conservative management[edit] Conservative management is advised in children as further growth may lead to an increase in tissue at the fork between the SMA and AA, providing room for the LRV to pass blood without obstruction.[11] Treatment in this case involves weight gain to build more adipose tissue, decreasing the compression. Venous blood may also be directed towards veins formed as a result of the higher blood pressure, which may contribute to symptomatic relief for individuals as they age.[11] 75% of adolescent patients have been found to have their symptoms resolved after two years. Medications that decrease blood pressure such as ACE inhibitors can also be used to reduce the proteinuria.[11] ### Surgical management[edit] #### Open and laparoscopic procedures[edit] There are several different procedures available to manage NCS include: * LRV transposition: The LRV is moved higher in the abdomen and re-implanted to the inferior vena cava (IVC) so that it is no longer being compressed.[5] * Gonadal vein transposition: The gonadal veins are connected to the (IVC) to reduce the amount of blood backed up in the pelvis.[5] * Renocaval bypass with saphenous vein: a segment of the great saphenous vein is used as a second connection between the LRV and the IVC to alleviate pressure build up.[5] * Renal autotransplantation: transfer of a kidney from its original location into the body to another location to prevent venous compression.[5] LRV transposition is the most common procedure done followed by renal autotransplantation and LRV bypass. [5]In all cases for open procedures, data is limited for long term follow-up. With respect to LRV transposition, most patients stated improvement of symptoms 70 months following the procedure.[5] Laparoscopic procedures involve laparoscopic spleno-renal venous bypass and laparoscopic LRV-IVC transposition.[11] They are uncommon in comparison to open procedures, but the outcomes of such procedures are similar to those of open procedures.[11] Although robotic surgery is possible, data on robotic procedures is limited concerning outcomes and cost-effectiveness.[11] #### Endovascular procedures[edit] Endovascular interventions involve the use of stents to improve blood flow in the area of LRV impingement.[11] Following catheterization, venography is done to visualize the vasculature and can provide confirmatory diagnosis of NCS prior to stenting.[11] Following stenting, 97% of patients have had improvement of symptoms by sixth months following the procedure, and long term follow-up showed no recurrence of symptoms after 66 months. Although less invasive, risks involved include incorrect placement of the stent as well as stent dislodging and migration to the right atrium.[11] Furthermore, patients must be on anticoagulation therapy after stenting for three months.[11] ## Gallery[edit] * Compression of the left renal vein (marked by the arrow) between the superior mesenteric artery (above) and the aorta (below) due to nutcracker syndrome. * Thrombosis in the left renal vein associated with dilation. * A nutcracker. The legs of this nutcracker, with some imagination, could represent the superior mesenteric artery and abdominal aorta in nutcracker syndrome. * Play media Summary video explaining signs and symptoms as well as etiology of nutcracker syndrome. ## References[edit] 1. ^ a b Kurklinsky AK, Rooke TW (June 2010). "Nutcracker phenomenon and nutcracker syndrome". Mayo Clinic Proceedings. 85 (6): 552–9. doi:10.4065/mcp.2009.0586. PMC 2878259. PMID 20511485. 2. ^ Sugimoto I, Takashi O, Ishibashi H, Takeuchi N, Nagata Y, Honda Y (2001). "Left Renal Vein Entrapment Syndrome (Nutcracker Syndrome) treated with Left Renal Vein Transposition". JNP J Vasc Surg. 10: 503–7. 3. ^ Oteki T, Nagase S, Hirayama A, Sugimoto H, Hirayama K, Hattori K, Koyama A (July 2004). "Nutcracker syndrome associated with severe anemia and mild proteinuria". Clinical Nephrology. 62 (1): 62–5. doi:10.5414/CNP62062. PMID 15267016. 4. ^ a b c Barnes RW, Fleisher HL, Redman JF, Smith JW, Harshfield DL, Ferris EJ (October 1988). "Mesoaortic compression of the left renal vein (the so-called nutcracker syndrome): repair by a new stenting procedure". Journal of Vascular Surgery. 8 (4): 415–21. doi:10.1067/mva.1988.avs0080415. PMID 3172376. 5. ^ a b c d e f g h i White JM, Comerota AJ (April 2017). "Venous Compression Syndromes". Vascular and Endovascular Surgery. 51 (3): 155–168. doi:10.1177/1538574417697208. PMID 28330436. S2CID 35732843. 6. ^ a b Hilgard P, Oberholzer K, Meyer zum Büschenfelde KH, Hohenfellner R, Gerken G (July 1998). "[The "nutcracker syndrome" of the renal vein (superior mesenteric artery syndrome) as the cause of gastrointestinal complaints]". Deutsche Medizinische Wochenschrift (in German). 123 (31–32): 936–40. doi:10.1055/s-2007-1024101. PMID 9721569. 7. ^ a b c d e f Gulleroglu K, Gulleroglu B, Baskin E (November 2014). "Nutcracker syndrome". World Journal of Nephrology. 3 (4): 277–81. doi:10.5527/wjn.v3.i4.277. PMC 4220361. PMID 25374822. 8. ^ Little AF, Lavoipierre AM (June 2002). "Unusual clinical manifestations of the Nutcracker Syndrome". Australasian Radiology. 46 (2): 197–200. doi:10.1046/j.1440-1673.2001.01037.x. PMID 12060163. 9. ^ a b Mohammadi A, Mohamadi A, Ghasemi-Rad M, Mladkova N, Masudi S (August 2010). "Varicocele and nutcracker syndrome: sonographic findings". Journal of Ultrasound in Medicine. 29 (8): 1153–60. doi:10.7863/jum.2010.29.8.1153. PMID 20660448. 10. ^ a b c d Orczyk K, Wysiadecki G, Majos A, Stefańczyk L, Topol M, Polguj M (2017). "What Each Clinical Anatomist Has to Know about Left Renal Vein Entrapment Syndrome (Nutcracker Syndrome): A Review of the Most Important Findings". BioMed Research International. 2017: 1746570. doi:10.1155/2017/1746570. PMC 5742442. PMID 29376066. 11. ^ a b c d e f g h i j k l m n Ananthan K, Onida S, Davies AH (June 2017). "Nutcracker Syndrome: An Update on Current Diagnostic Criteria and Management Guidelines". European Journal of Vascular and Endovascular Surgery. 53 (6): 886–894. doi:10.1016/j.ejvs.2017.02.015. PMID 28356209. 12. ^ Ahmed K, Sampath R, Khan MS (April 2006). "Current trends in the diagnosis and management of renal nutcracker syndrome: a review". European Journal of Vascular and Endovascular Surgery. 31 (4): 410–6. doi:10.1016/j.ejvs.2005.05.045. PMID 16431142. 13. ^ Rudloff U, Holmes RJ, Prem JT, Faust GR, Moldwin R, Siegel D (January 2006). "Mesoaortic compression of the left renal vein (nutcracker syndrome): case reports and review of the literature". Annals of Vascular Surgery. 20 (1): 120–9. doi:10.1007/s10016-005-5016-8. PMID 16374539. S2CID 45878200. ## External links[edit] Classification D * MeSH: D059228 * DiseasesDB: 32367 * Kimura K, Araki T (July 1996). "Images in clinical medicine. Nutcracker phenomenon". The New England Journal of Medicine. 335 (3): 171. doi:10.1056/NEJM199607183350305. PMID 8657215. * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension * 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	Nutcracker syndrome	c3178770	1,273	wikipedia	https://en.wikipedia.org/wiki/Nutcracker_syndrome	2021-01-18T18:32:30	{"gard": ["11971"], "mesh": ["D059228"], "umls": ["C3178770"], "orphanet": ["71273"], "wikidata": ["Q1504516"]}
A number sign (#) is used with this entry because of evidence that band heterotopia (BH) is caused by homozygous or compound heterozygous mutation in the EML1 gene (602033) on chromosome 14q32. Clinical Features Kielar et al. (2014) reported a French family in which 3 brothers had severe developmental delay with intellectual disability. Two of the boys had refractory epilepsy, whereas the third boy had no history of seizures by age 8 years. More variable features included hypotonia, mild spasticity, sleep disturbances, and behavioral problems. Kielar et al. (2014) also reported an unrelated boy, born of consanguineous Moroccan parents, with macrocephaly, congenital hydrocephalus, severe psychomotor delay, and seizures. A later pregnancy in the family was terminated because of hydrocephalus shown by ultrasound. All patients had enlarged head circumference (+2.5 SD). Brain imaging showed periventricular and ribbon-like subcortical heterotopia with polymicrogyria and agenesis of the corpus callosum. The heterotopia was most obvious in the frontal regions. Shaheen et al. (2017) reported a consanguineous Saudi family (family 22) in which 4 individuals had hydrocephalus. Two of the affected individuals were deceased. Detailed clinical information was only available for the proband, who was a 2-year-old girl with congenital hydrocephalus, profound global developmental delay, and intractable epilepsy. Brain imaging showed band heterotopia, extensive polymicrogyria, agenesis of the corpus callosum, dilated lateral ventricles, and compressed cerebellum with herniated cerebellar tonsils. Inheritance The transmission pattern of band heterotopia in the families reported by Kielar et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 4 patients from 2 unrelated families with band heterotopia, Kielar et al. (2014) identified compound heterozygous or homozygous mutations in the EML1 gene (602033.0001-602033.0003). The mutations in 1 family were found by direct sequencing of the EML1 gene, whereas the mutation in the other family was found by a combination of homozygosity mapping and exome sequencing. The mutations segregated with the disorder in both families. In a girl, born of consanguineous Saudi parents (family 22), with BH and congenital hydrocephalus, Shaheen et al. (2017) identified a homozygous nonsense mutation in the EML1 gene (R523X; 602033.0004). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. There were 3 additional similarly affected family members, 2 of whom were deceased, but DNA was not available from those patients. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a complete loss of function manifest as a severe phenotype. The patient was part of a genetic study of 27 consanguineous Saudi families with congenital hydrocephalus. Animal Model The spontaneous mouse mutant 'HeCo' has seizures and subtle learning deficits associated with heterotopic neurons in the brain white matter. Kielar et al. (2014) determined that the HeCo mutant resulted from truncation of the Eml1 gene. Examination of HeCo mice showed that by E17, both early- and late-born neurons formed the heterotopia, and radial glial cells were disorganized compared to controls. Postnatally, the late-born neurons failed to reach cortical layers and formed a column between the heterotopia and cortex, but the mutant neurons did not show migration abnormalities. In HeCo brains, the early-born neuronal progenitor cells showed altered distribution and were misplaced: they were present outside the ventricular zones and continued to proliferate longer than wildtype cells. In wildtype murine and ferret embryos, Eml1 was expressed in cortical neuronal progenitors of the ventricular zone and postmitotic neurons of the cortical plate. In neurons, punctate Eml1 appeared to be distributed throughout the cell, aligning with microtubules and spindles during cell division, and prominent in perinuclear regions and growth cones. The findings were consistent with a role for Eml1 in different types of neuronal progenitors, as well as in postmitotic neurons, during cortical development. Kielar et al. (2014) concluded that ectopic progenitors represent the primary defect leading to neuronal heterotopia. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Macrocephaly (+2.5 SD) NEUROLOGIC Central Nervous System \- Hydrocephalus, congenital \- Delayed psychomotor development, profound \- Intellectual disability, severe \- Spasticity \- Seizures \- Sleep disturbances \- Subcortical band heterotopia \- Polymicrogyria \- Agenesis of the corpus callosum \- Dilated ventricles Behavioral Psychiatric Manifestations \- Behavioral problems MISCELLANEOUS \- May result in early death MOLECULAR BASIS \- Caused by mutation in the echinoderm microtubule-associated protein-like 1 gene (EML1, 602033.0001 ) ▲ 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	BAND HETEROTOPIA	c1848201	1,274	omim	https://www.omim.org/entry/600348	2019-09-22T16:16:16	{"doid": ["0111169"], "mesh": ["D054221"], "omim": ["600348"], "orphanet": ["99796"]}
A rare urogenital tumor characterized by stromal and epithelial components forming cysts lined by hyperplastic epithelium in a cellular or sarcomatoid stroma. The tumors may be clinically benign or malignant and tend to recur after transurethral resection. Metastatic spread is to lungs, bone, and liver. Patients may present with obstructive voiding symptoms, dysuria, hematuria, urinary retention, or a palpable abdominal mass. The prostate is palpably enlarged but feels soft and spongy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Phyllodes tumor of the prostate	c1334615	1,275	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=498228	2021-01-23T17:08:32	{"mesh": ["C549759"], "synonyms": ["Cystic epithelial-stromal tumors of the prostate", "Cystosarcoma phyllodes of the prostate", "Phyllodes type of atypical prostatic hyperplasia"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant congenital deafness with onychodystrophy (DDOD) is caused by heterozygous mutation in the ATP6V1B2 gene (606939) on chromosome 8p21. Description The DDOD syndrome is characterized by autosomal dominant inheritance of congenital deafness and onychodystrophy. Conical, hypoplastic teeth is also a feature (Robinson et al., 1962). See also DOOR syndrome (220500), an autosomal recessive disorder, which includes congenital deafness, onychodystrophy, osteodystrophy, and mental retardation. Clinical Features Robinson et al. (1962) presented the pedigree of 17 persons in 3 generations with 5 affected. The propositus was a 15-year-old girl with fissured small dystrophic nails, coniform teeth with selective tooth agenesis, and syndactylism of the toes of the right foot with union of the first and second toes, and the third with the fourth toe. She had severe sensorineural hearing loss and had attended a school for the deaf. One brother was normal while another brother and a sister and their mother had similar nail and dental defects. All affected members had a high frequency hearing loss together with a 70 db low frequency loss in the propositus. The maternal grandmother of the propositus was thought to have a similar syndrome but was not available for study. The authors found elevation of electrolyte concentrations in sweat, suggesting this was a characteristic hidrotic form of ectodermal dysplasia with delayed primary and secondary dentition, misshapen and missing teeth, and dystrophic small nails. The hidrotic nature of the ectodermal dysplasia distinguishes this condition from that described under deafness with anhidrotic ectodermal dysplasia (125050). Goodman et al. (1969) observed a mother and son with sensorineural deafness and onychodystrophy. The mother's right thumb was triphalangic, and the left thumb was biphalangic with a rudimentary third phalanx that appeared to be fused with the middle phalanx. Moghadam and Statten (1972) observed triphalangeal thumbs with hypoplastic terminal phalanges, absent or hypoplastic fingernails, and deafness in mother and son of Filipino extraction. The authors noted that Feinmesser and Zelig (1961) reported 2 sisters with congenital deafness and onychodystrophy. However, the parents were consanguineous, suggesting autosomal recessive inheritance. Despite autosomal recessive inheritance, James et al. (2007) concluded that the family of Feinmesser and Zelig (1961) did not have DOOR syndrome since they lacked mental retardation. Kondoh et al. (1999) reported a girl, her mother, and her maternal grandfather with DDOD syndrome. The proband, an infant, had congenital hearing loss and hypoplastic nails or absence of nails. The mother was noted to have sensorineural deafness at age 1 year, had no toenails, hypoplastic fingernails, and coniform or small permanent teeth. The maternal grandfather had congenital deafness, conical teeth with oligodontia, and dystrophic nails. His mother was reportedly similarly affected. Kondoh et al. (1999) noted the similarities to the family reported by Robinson et al. (1962). White and Fahey (2011) suggested that the family reported by Robinson et al. (1962) may have had a distinct disorder with oligodontia as a feature. White and Fahey (2011) reported a 3-generation family in which 3 individuals had DDOD. The proband was a 28-year-old man with profound sensorineural hearing loss and abnormal hands and feet. He had mild brachydactyly of the hands, finger-like thumbs that were not triphalangeal, and small and dysplastic nails of the thumbs and fifth fingers; the fingertips of these digits were bulbous. The feet showed hypoplastic nails on both great toes and absent nails on the second to fifth toes. Hand radiographs showed a short distal phalanx of the fifth digits, and foot radiographs showed absence of the terminal phalanx of toes two through five and a pyramidal-shaped distal phalanx of the great toes. He had some mild facial features, including deep-set eyes with mild hypotelorism and midface hypoplasia. The remainder of the examination was normal with no abnormalities of skin, teeth, or hair. The patient's father reportedly had deafness and a similar appearance of the hands and feet. One of the proband's daughters, who died suddenly at age 2 months, had sensorineural deafness, absent nails on the thumbs and fifth fingers with bulbous fingertips, and hypoplastic or absent toenails. She also had cutis aplasia on the vertex of the scalp. Yuan et al. (2014) studied 3 unrelated Chinese probands who had been diagnosed with congenital deafness and onychodystrophy. All 3 were reported to display an identical phenotype, including severe congenital sensorineural hearing loss, absence of nails, and aplasia of the middle phalanx of the fifth finger. None had inner ear malformation or intellectual disability; successful language rehabilitation following unilateral cochlear implantation confirmed their normal mental development. The clinical information reported for these 3 patients was limited, and medical history was obtained by questionnaire. Menendez et al. (2017) studied a 12-year-old Guatemalan boy who at birth was noted to have bilateral digital anomalies of the hands and feet. Audiologic testing at age 1 year revealed profound bilateral sensorineural hearing impairment. Examination at age 12 years showed high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails on the second through fifth digits, and flat feet with absent toenails. He did not exhibit gingival hyperplasia, hypertrichosis, organomegaly, or joint hyperextensibility. His parents and 2 sibs were healthy. (Tekin (2017) noted that figure 2 in the article by Menendez et al. (2017) incorrectly indicates that the Guatemalan family was consanguineous.) Inheritance The transmission pattern of DDOD syndrome in the families reported by Robinson et al. (1962), Kondoh et al. (1999), and White and Fahey (2011) was consistent with autosomal dominant inheritance. Molecular Genetics By whole-exome sequencing in 2 unrelated Chinese pedigrees with congenital deafness, anonychia, and aplasia of the middle phalanx of the fifth finger, Yuan et al. (2014) identified heterozygosity for the same de novo nonsense mutation in the ATP6V1B2 gene (R506X; 606939.0001) in both probands. Sanger sequencing of ATP6V1B2 in a third Chinese DDOD family revealed a de novo R506X mutation in that proband as well. The mutation, which segregated with disease in all 3 families, was not found in 1,053 ethnically matched controls with normal hearing. By whole-exome sequencing in a 12-year-old Guatemalan boy with DDOD, Menendez et al. (2017) identified heterozygosity for the R506X mutation in ATP6V1B2. The mutation was not found in his unaffected parents or sibs; it appeared to have arisen de novo, although paternity testing was not performed. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, sensorineural Teeth \- Coniform teeth (in some patents) \- Selective tooth agenesis (in some patients) SKELETAL Hands \- Brachydactyly \- Finger-like thumbs \- Triphalangeal thumbs (in some patients) \- Short terminal phalanx of the fifth finger \- Aplasia of middle phalanx of fifth finger \- Bulbous swelling of the fingertips Feet \- Syndactyly of toes (in some patients) \- Hypoplasia or absence of the terminal phalanges SKIN, NAILS, & HAIR Nails \- Hypoplastic nails \- Absent nails \- Small nails \- Fissured nails \- Dystrophic nails MISCELLANEOUS \- Onset at birth \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the ATPase, H+ transporting, lysosomal, V1 subunit B, isoform 2 gene (ATP6B1B2, 606939.0001 ) ▲ 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	DEAFNESS, CONGENITAL, WITH ONYCHODYSTROPHY, AUTOSOMAL DOMINANT	c2675730	1,276	omim	https://www.omim.org/entry/124480	2019-09-22T16:42:34	{"mesh": ["C567274"], "omim": ["124480"], "orphanet": ["3231", "79499"], "synonyms": ["DDOD SYNDROME", "Alternative titles"]}
Keratosis follicularis spinulosa decalvans Other namesSiemens-1 syndrome Keratosis follicularis spinulosa decalvans is a rare X-linked disorder described by Siemens in 1926, a disease that begins in infancy with keratosis pilaris localized on the face, then evolves to more diffuse involvement.[1]:580,762[2]:649,714[3] An association with SAT1 has been suggested.[4] ## See also[edit] * Keratosis follicularis * Hermann Werner Siemens * Cicatricial alopecia * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 4. ^ Gimelli, G.; Giglio, S.; Zuffardi, O.; Alhonen, L.; Suppola, S.; Cusano, R.; Lo Nigro, C.; Gatti, R.; et al. (Sep 2002). "Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD)". Hum Genet. 111 (3): 235–41. doi:10.1007/s00439-002-0791-6. PMID 12215835. S2CID 23842885. ## External links[edit] Classification D * OMIM: 308800 * MeSH: C536159 This Genodermatoses 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	Keratosis follicularis spinulosa decalvans	c0343057	1,277	wikipedia	https://en.wikipedia.org/wiki/Keratosis_follicularis_spinulosa_decalvans	2021-01-18T18:29:38	{"gard": ["6829"], "mesh": ["C536159"], "umls": ["C0343057"], "orphanet": ["2340"], "wikidata": ["Q6393653"]}
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, craniofacial dysmorphism (such as ridged metopic sutures, long palpebral fissures, broad nasal bridge, hypoplastic alae nasi, low-set, prominent ears, prominent midline tongue groove, and downturned mouth), congenital heart defects, and variable skeletal abnormalities including hip dysplasia, vertebral anomalies, and scoliosis. Additional reported manifestations include high pain tolerance and genitourinary anomalies. Brain imaging may show a thin corpus callosum or white matter abnormalities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome	c4225274	1,278	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=453499	2021-01-23T18:08:23	{"omim": ["616580"], "synonyms": ["Au-Kline syndrome"]}
Capra-DeMarco syndrome is characterized by sagittal craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis. Other clinical findings include blepharophimosis, small low-set ears, hypoplastic philtrum, kidney malformation, and hypogenitalism. ## Epidemiology The syndrome was described in two brothers from a non consanguineous family. ## Etiology No causative mutation has been identified so far. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome	c3267187	1,279	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171839	2021-01-23T19:01:21	{"umls": ["C3267187"], "icd-10": ["Q87.8"], "synonyms": ["Berant syndrome", "Capra-DeMarco syndrome", "Familial scaphocephaly-radioulnar synostosis syndrome"]}
Hypocalcemic rickets is a group of genetic diseases characterized by hypocalcemia and rickets. It comprises hypocalcemic vitamin D dependent rickets (VDDR-I) and hypocalcemic vitamin D resistant rickets (HVDRR) (see these terms). ## Clinical description Characteristic clinical features include slow growth, bone pain and bone deformities. HVDRR is associated with resistance to vitamin D treatment. ## Etiology Hypocalcemic rickets is due to various mutations in genes involved in vitamin D metabolism and action. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hypocalcemic rickets	c4302195	1,280	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289103	2021-01-23T17:17:01	{}
## Description Human personality traits that can be reliably measured by rating scales show a considerable heritable component. One such instrument is the tridimensional personality questionnaire (TPQ), which was designed by Cloninger et al. (1993) to measure 4 distinct domains of temperament--novelty seeking, harm avoidance, reward dependence, and persistence--that are hypothesized to be based on distinct neurochemical and genetic substrates. Risk-taking is a characteristic of behaviors that occur under conditions of uncertainty and involves a tradeoff between beneficial versus detrimental outcomes, perceived or real. Risk-taking may or may not involve conscious evaluation of the probability and magnitude of possible outcomes (Anokhin et al., 2009). See also harm avoidance (607834) and pathologic gambling (606349), which may be related. Clinical Features Roe et al. (2009) noted that there are 2 main bodies of literature that measure risk attitudes: that of behavioral neuroscientists and geneticists who measure harm avoidance and novelty seeking, and that of economists who measure decisions among competing financial gambles or investment opportunities. In a study of 67 individuals, Roe et al. (2009) did not find a strong correlation between risk attitudes using measurements from the psychologic and economics literature, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. ### Risk-Taking Behavior Wang et al. (2009) presented evidence that propensity for risk-taking is influenced by variation in life history traits. A total of 448 mostly college-aged students, including 316 females and 132 males, provided information on risk-taking behavior, which was analyzed according to several life-history traits, including sex, age, parental status, reproductive goal setting, number of sibs, birth order, and subjective life expectancy. The domains examined included within- and between-group competition, mating and resource allocation, reproduction, and environmental challenge. Higher risk-taking was associated with male sex for all domains. Other associations with increased risk-taking propensity that varied by domain included younger age, lack of parental status, lower reproductive goals, being the last-born, and lower subjective life expectancy. The findings suggested that tendency for risk-taking is not necessarily a stable personality trait, but varies by life history traits and specific domains. Inheritance Developmental research has showed that the propensity for risk-taking is higher during adolescence compared to childhood and adulthood, and it has been suggested that this is due to the relative immaturity of neural connections involved in behavioral regulation and/or inhibition and decision making. Risk-taking in adolescence is associated with substance abuse, gambling, theft, aggression, and unprotected sex, and assessment of risk-taking can be used as an endophenotype for psychopathology in adolescence (review by Anokhin et al., 2009). Anokhin et al. (2009) evaluated 745 adolescent twin pairs, including 169 monozygotic (MZ) pairs and 203 dizygotic (DZ) pairs, using the Balloon Analogue Risk Task (BART) an experimental measure involving financial reward for risk taking. Risk-taking increased between 12 and 14 years of age overall, but also showed significant longitudinal stability for individuals. European Americans showed greater propensity for risk-taking compared to other ethnic groups, particularly African Americans. Genetic modeling showed that at age 12, heritability for risk-taking was modest but significant for both sexes (28% for males and 17% for females). However, at age 14, heritability increased to 55% in males and became nonsignificant in females. The findings indicated that there are age and sex differences in the heritability of risk-taking behavior, particularly during the years studied. In a study of 920 Swedish twin pairs, including 141 DZ twins and 319 MZ twins, most (80%) of whom were female, Cesarini et al. (2009) estimated that approximately 20% of individual variation in economic preferences for financial giving and risk-taking can be explained by genetic differences. The findings were consistent with larger studies of behavior genetics, which have concluded that there is a genetic influence on behaviors. Pathogenesis Cloninger et al. (1993) proposed that individual variations in the novelty seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ novelty seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered, and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered, and frugal. In a study of 20 abstinent alcohol-dependent men, a significant correlation was found between apomorphine-induced growth hormone release and the 'novelty seeking' score of the individual (Wiesbeck et al., 1995). This supported Cloninger's hypothesis by giving neuroendocrine evidence that this personality dimension is related to dopaminergic activity, albeit in the tuberoinfundibular dopaminergic system which is not directly associated with human personality traits. Molecular Genetics Cloninger et al. (1996) contrasted the difference between a trait such as novelty seeking and developmentally complex disorders like schizophrenia (see 181500) which have been found to be very elusive in the delineation of genetic factors. They suggested that it may be more fruitful to map genes contributing to temperament, which have a relatively simple genetic architecture and can be quantified easily and reliably by questionnaire. Later, susceptibility to complex disorders like schizophrenia and alcoholism (see 103780) can be evaluated in terms of risk from heritable personality traits and possible disease-specific factors. In this way, success in mapping genes for a normal personality trait may signal a fruitful way to map genes for psychopathology as well. Savitz and Ramesar (2004) reviewed the evidence that alleles of the SERT (182138) and DRD4 (126452) genes impact variations in personality. They argued for the existence of a genuine effect: a gene-personality relationship rendered periodically latent through genetic epistasis, gene-environment interactions, variation in genetic background, and the presence of other variables. ### DRD4 Gene In a group of 124 unrelated Israeli subjects, Ebstein et al. (1996) showed that higher than average novelty seeking test scores were significantly associated with a particular exonic polymorphism, the 7-repeat (7R) allele at the locus for the dopamine receptor D4 gene (DRD4; 126452). The association of high novelty seeking and the 7R allele was independent of ethnicity, sex, or age of the subjects. These results were corroborated by Benjamin et al. (1996) who investigated the relationship between DRD4 exon 3 sequence variants and personality test scores in a population of 315 mostly male sibs, other family members and individuals in the United States. The association between long alleles of exon 3 and personality traits related to novelty seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than a population stratification. Benjamin et al. (1996) pointed out that the possibility of a causal relationship between DRD4 and novelty seeking is supported by studies showing that the number of exon 3 repeats can affect the binding of ligands to the receptor; that DRD4 is expressed in limbic areas involved in cognition and emotion; that dopamine mediates exploratory behavior in experimental animals; that the rewarding effects of amphetamines and cocaine are related to dopamine release; and that novelty seeking is low in dopamine-deficient patients with Parkinson disease. Pogue-Geile et al. (1998) administered personality questionnaires measuring novelty-seeking and positive emotional experience to 306 male and female young adult twins (92 monozygotic pairs; 61 dizygotic pairs) from the general population, 281 of whom were genotyped for DRD4 exon 1 and 3 polymorphisms. They found no significant association between novelty-seeking or positive emotional experience and the DRD4 polymorphisms. The statistical power of their study reduced confidence in the generality of the positive findings in earlier studies. Kluger et al. (2002) conducted a metaanalysis of 20 studies, with a total of 3,907 individuals, involving the association between DRD4 polymorphisms and novelty seeking. Thirteen reports suggested that the presence of longer alleles is associated with higher novelty seeking scores and 7 reports suggested the opposite. Kluger et al. (2002) concluded that, on average, there was no association between DRD4 polymorphism and novelty seeking (average d = 0.06, 95% CI +/- 0.09). They found that there was true heterogeneity among the studies (i.e., unknown moderators exist), but that the strength of the association between DRD4 polymorphisms and novelty seeking in the presence of any moderator was likely to be weak. Kluger et al. (2002) also reported that a search for moderators had not yielded any reliable explanation for the variability among studies. Dreber et al. (2009) noted that risk preferences may be influenced by dopaminergic pathways in the brain, which play a role in regulating the anticipation of rewards as well as the motivation for obtaining rewards. In a study of financial risk taking of 94 young men assessed through a game with real monetary payoffs, Dreber et al. (2009) found an association between the 7R allele polymorphism in the DRD4 gene and increased risk-taking. The DRD4 7R allele was estimated to account for about 20% of the heritable variation in financial risk-taking. In vitro studies have suggested that the receptor encoded by the DRD4 7R allele is associated with decreased ligand binding and requires higher levels of dopamine to produce a response of similar magnitude compared to smaller-sized repeats (Asghari et al., 1995). The findings were consistent with evolutionary selection for this allele for behaviors associated with migration and male competition, which entail an element of risk. In the study of Dreber et al. (2009), no association was found between risk taking and the A1 allele of the DRD2 gene (126450). In a study of 65 individuals who performed a financial investment task, Kuhnen and Chiao (2009) found that carriers of the DRD4 7R allele polymorphism took 25% more risk in a financial investment risk game compared to individuals lacking the allele. The authors speculated that financial risk-taking may result from evolutionarily adaptive mechanisms that encourage novelty-seeking behavior (601696). ### SLC6A4 Gene In a study of 65 individuals who performed a financial investment task, Kuhnen and Chiao (2009) found an association between risk taking and variation in the SLC6A4 gene (182138), which regulates serotonin. Homozygous carriers of the short allele of the 5-HTTLPR SLC6A4 promoter polymorphism (182138.0001) took 28% less risk compared to those carrying the long allele. The short allele results in decreased transcriptional efficiency of SLC6A4 and has been associated with increased neuroticism and harm avoidance (see 607834). Misc \- Mediated by variability in dopamine transmission Neuro \- Novelty seeking personality trait \- Impulsive \- Exploratory \- Fickle \- Excitable \- Quick-tempered \- Extravagant 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	NOVELTY SEEKING PERSONALITY TRAIT	c1866430	1,281	omim	https://www.omim.org/entry/601696	2019-09-22T16:14:25	{"omim": ["601696"]}
Germ-cell tumor Micrograph of a seminoma, a common germ cell tumor. SpecialtyOncology Germ cell tumor (GCT) is a neoplasm derived from germ cells. Germ-cell tumors can be cancerous or benign. Germ cells normally occur inside the gonads (ovary[1] and testis). GCTs that originate outside the gonads may be birth defects resulting from errors during development of the embryo. ## Contents * 1 Cause * 2 Classification * 2.1 Germinomatous * 2.2 Nongerminomatous * 2.3 Mixed * 3 Location * 4 Treatment * 5 Prognosis * 6 See also * 7 References * 8 External links ## Cause[edit] Some investigators suggest that this distribution arises as a consequence of abnormal migration of germ cells during embryogenesis. Others hypothesize a widespread distribution of germ cells to multiple sites during normal embryogenesis, with these cells conveying genetic information or providing regulatory functions at somatic sites. Extragonadal GCTs were thought initially to be isolated metastases from an undetected primary tumor in a gonad, but many germ cell tumors are now known to be congenital and originate outside the gonads. The most notable of these is sacrococcygeal teratoma, the single most common tumor diagnosed in babies at birth. Of all anterior mediastinal tumors, 15–20% are GCTs of which about 50% are benign teratomas.[2] Ovarian teratomas may be associated with anti-NMDA receptor encephalitis.[3] ## Classification[edit] GCTs are classified by their histology,[4] regardless of location in the body. However, as more information about the genetics of these tumors become available, they may be classified based on specific gene mutations that characterize specific tumors.[5] They are broadly divided in two classes:[6] * The germinomatous or seminomatous germ-cell tumors (GGCT, SGCT) include only germinoma and its synonyms dysgerminoma and seminoma. * The nongerminomatous or nonseminomatous germ-cell tumors (NGGCT, NSGCT) include all other germ-cell tumors, pure and mixed. The two classes reflect an important clinical difference. Compared to germinomatous tumors, nongerminomatous tumors tend to grow faster, have an earlier mean age at time of diagnosis ( around 25 years versus 35 years, in the case of testicular cancers), and have a lower five-year survival rate. The survival rate for germinomatous tumors is higher in part because these tumors are very sensitive to radiation, and they also respond well to chemotherapy. The prognosis for nongerminomatous tumours has improved dramatically, however, due to the use of platinum-based chemotherapy regimens.[7] ### Germinomatous[edit] Tumor ICD-O Peak Age (yr) Benign or malignant Histology Tumor marker Germinoma (including dysgerminoma and seminoma) 40–50 Malignant Sheets of uniform polygonal cells with cleared cytoplasm; lymphocytes in the stroma About 10% have elevated hCG Dysgerminoma M9060/3 Seminoma M9061/3 Placental alkaline phosphate (PLAP)[8] ### Nongerminomatous[edit] Tumor ICD-O Peak Age (yr) Benign or malignant Histology Tumor marker Embryonal carcinoma 9070/3 20–30 Malignant Poorly differentiated, pleomorphic cells in cords, sheets, or papillary formation secrete hCG, AFP Endodermal sinus tumor, also known as yolk sac tumor (EST, YST) 9071/3 3 Malignant Poorly differentiated endothelium-like, cuboidal, or columnar cells 100% secrete AFP Choriocarcinoma 9100/3 20–30 Malignant Cytotrophoblast and syncytiotrophoblast without villus formation 100% secrete hCG Teratoma including mature teratoma, dermoid cyst, immature teratoma, teratoma with malignant transformation 9080/0-9080/3 0–3, 15–30 Mature teratoma, dermoid cyst usually benign (but follow-up required); others usually malignant Very variable, but "normal" tissues are common Pure tumors do not secrete hCG, AFP Polyembryoma 9072/3 15–25 ? ? ? Gonadoblastoma 9073/1 ? ? ? ? ### Mixed[edit] Tumor ICD-O Peak Age (yr) Benign or malignant Histology Tumor marker Mixed 15–30 Malignant Depends on elements present Depends on elements present Mixed germ cell tumors occur in many forms. Among these, a common form is teratoma with endodermal sinus tumor. Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma with embryonal carcinoma, or with choriocarcinoma, or with both.[9] This kind of mixed germ cell tumor may be known simply as a teratoma with elements of embryonal carcinoma or choriocarcinoma, or simply by ignoring the teratoma component and referring only to its malignant component: embryonal carcinoma and/or choriocarcinoma. They can present in the anterior mediastinum. ## Location[edit] Despite their name, GCTs occur both within and outside the ovary and testis. They are found in: * head * inside the cranium — pineal and suprasellar locations are most commonly reported * inside the mouth — a fairly common location for teratoma * neck * mediastinum — account for 1% to 5% of all germ cell neoplasms Main article: mediastinal germ cell tumor * pelvis, particularly sacrococcygeal teratoma In females, GCTs account for 30% of ovarian tumors, but only 1 to 3% of ovarian cancers in North America. In younger women, they are more common, thus in patients under the age of 21, 60% of ovarian tumors are of the germ-cell type, and up to one-third are malignant. In males, GCTs of the testis occur typically after puberty and are malignant (testicular cancer). In neonates, infants, and children younger than 4 years, most are sacrococcygeal teratomas. Males with Klinefelter syndrome have a 50 times greater risk of GSTs.[10] In these persons, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are gonadal in location.[medical citation needed] ## Treatment[edit] Women with benign GCTs such as mature teratomas (dermoid cysts) are cured by ovarian cystectomy or oophorectomy.[11] In general, all patients with malignant GCTs have the same staging surgery that is done for epithelial ovarian cancer.[12] If the patient is in her reproductive years, an alternative is unilateral salpingoophorectomy, while the uterus, the ovary, and the fallopian tube on the opposite side can be left behind. This is not an option when the cancer is in both ovaries. If the patient has finished having children, the surgery involves complete staging, including salpingoophorectomy on both sides, as well as hysterectomy.[11] Patients with germ-cell cancer often need to be treated with combination chemotherapy for at least three cycles, but female patients with early-stage disease may not require this treatment.[13] The chemotherapy regimen most commonly used in GCTs is called PEB (or BEP), and consists of bleomycin, etoposide, and a platinum-based antineoplastic (cisplatin).[11] Targeted treatments, such as immunotherapy, hormonal therapy and kinase inhibitors, are being evaluated for tumors that do not respond to chemotherapy.[14] ## Prognosis[edit] The 1997 International Germ Cell Consensus Classification[15] is a tool for estimating the risk of relapse after treatment of malignant germ-cell tumor. A small study of ovarian tumors in girls[16] reports a correlation between cystic and benign tumors, and conversely, solid and malignant tumors. Because the cystic extent of a tumor can be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate surgical plan to minimize risk of spillage of a malignant tumor. Access to appropriate treatment has a large effect on outcome. A 1993 study of outcomes in Scotland found that for 454 men with nonseminomatous (nongerminomatous) GCTs diagnosed between 1975 and 1989, five-year survival increased over time and with earlier diagnosis. Adjusting for these and other factors, survival was 60% higher for men treated in a cancer unit that treated the majority of these men, though the unit treated more men with the worst prognosis.[17] Choriocarcinoma of the testicles has the worst prognosis of all germ-cell cancers.[18] ## See also[edit] * Embryonic stem cells * Cancer research ## References[edit] 1. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 2. ^ "Clinical Image: Mediastinal Teratoma". Archived from the original on 2018-08-04. Retrieved 2011-12-22. 3. ^ Omata T, Kodama K, Watanabe Y, Iida Y, Furusawa Y, Takashima A, Takahashi Y, Sakuma H, Tanaka K, Fujii K, Shimojo N (May 2017). "Ovarian teratoma development after anti-NMDA receptor encephalitis treatment". Brain & Development. 39 (5): 448–451. doi:10.1016/j.braindev.2016.12.003. PMID 28040316. S2CID 8224022. 4. ^ Ulbright TM (February 2005). "Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues". Modern Pathology. 18 Suppl 2: S61-79. doi:10.1038/modpathol.3800310. PMID 15761467. 5. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 6. ^ Germinoma, Central Nervous System at eMedicine 7. ^ Robbins SL, Kumar V, Cotran RS (2003). Robbins Basic Pathology (7th ed.). Philadelphia: Saunders. p. 664. ISBN 0-7216-9274-5. 8. ^ Nielsen OS, Munro AJ, Duncan W, Sturgeon J, Gospodarowicz MK, Jewett MA, Malkin A, Thomas GM (1990). "Is placental alkaline phosphatase (PLAP) a useful marker for seminoma?". European Journal of Cancer. 26 (10): 1049–54. doi:10.1016/0277-5379(90)90049-y. PMID 2148879. 9. ^ Teratocarcinoma at the US National Library of Medicine Medical Subject Headings (MeSH) 10. ^ Bebb GG, Grannis FW, Paz IB, Slovak ML, Chilcote R (August 1998). "Mediastinal germ cell tumor in a child with precocious puberty and Klinefelter syndrome". The Annals of Thoracic Surgery. 66 (2): 547–8. doi:10.1016/S0003-4975(98)00504-9. PMID 9725401. 11. ^ a b c Treatment for germ cell tumors of the ovary at American Cancer Society. Last Medical Review: 12/05/2011. Last Revised: 01/11/2012 12. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 13. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 14. ^ Maoz, Asaf; Matsuo, Koji; Ciccone, Marcia A.; Matsuzaki, Shinya; Klar, Maximilian; Roman, Lynda D.; Sood, Anil K.; Gershenson, David M. (2020-05-29). "Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review". Cancers. 12 (6): 1398. doi:10.3390/cancers12061398. ISSN 2072-6694. PMC 7353025. PMID 32485873. 15. ^ International Germ Cell Cancer Collaborative Group (February 1997). "International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers". Journal of Clinical Oncology. 15 (2): 594–603. doi:10.1200/jco.1997.15.2.594. PMID 9053482. 16. ^ Stankovic ZB, Djukic MK, Savic D, Lukac BJ, Djuricic S, Sedlecki K, Zdravkovic D (October 2006). "Pre-operative differentiation of pediatric ovarian tumors: morphological scoring system and tumor markers". Journal of Pediatric Endocrinology & Metabolism. 19 (10): 1231–8. doi:10.1515/JPEM.2006.19.10.1231. PMID 17172084. S2CID 35087867. 17. ^ Harding MJ, Paul J, Gillis CR, Kaye SB (April 1993). "Management of malignant teratoma: does referral to a specialist unit matter?". Lancet. 341 (8851): 999–1002. doi:10.1016/0140-6736(93)91082-W. PMID 8096954. S2CID 29536953. 18. ^ Verville KM (2009). Testicular Cancer. Infobase Publishing. p. 76. ISBN 978-1-60413-166-6. ## External links[edit] Classification D * ICD-10: C56, C62, D27, D29.2 * ICD-9-CM: 183, 186, 220, 222.0 * ICD-O: 9060–9100 * MeSH: D009373 External resources * eMedicine: med/863 * humpath #2658 (Pathology images) * Childhood Extracranial Germ Cell Tumors * Extragonadal Germ Cell Tumors * Ovarian Germ Cell Tumors * Primary Germ Cell Tumors of the Thorax * Malignant Mediastinal Germ Cell Tumors * Packer RJ, Cohen BH, Cooney K, Coney K (2000). "Intracranial germ cell tumors". The Oncologist. 5 (4): 312–20. doi:10.1634/theoncologist.2000-0312. PMID 10964999. * Cancer.Net: Germ Cell Tumor * v * t * e Germ cell tumors Germinomatous * Germinoma * Seminoma * Dysgerminoma Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor/Yolk sac tumor * Teratoma: Fetus in fetu * Dermoid cyst * Struma ovarii * Strumal carcinoid * Trophoblastic neoplasm: Gestational trophoblastic disease * Hydatidiform mole * Choriocarcinoma * Placental site trophoblastic tumor * Polyembryoma * Gonadoblastoma * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma * v * t * e * Tumors of the male urogenital system Testicles Sex cord– gonadal stromal * Sertoli–Leydig cell tumour * Sertoli cell tumour * Leydig cell tumour Germ cell G * Seminoma * Spermatocytic tumor * Germ cell neoplasia in situ NG * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma * Choriocarcinoma * Embryoma Prostate * Adenocarcinoma * High-grade prostatic intraepithelial neoplasia * HGPIN * Small-cell carcinoma * Transitional cell carcinoma Penis * Carcinoma * Extramammary Paget's disease * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Hirsuties coronae glandis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Germ cell tumor	c0205851	1,282	wikipedia	https://en.wikipedia.org/wiki/Germ_cell_tumor	2021-01-18T18:49:27	{"mesh": ["D009373"], "umls": ["C0205851"], "icd-9": ["183", "220", "186", "222.0"], "icd-10": ["C62", "C56", "D27", "D29.2"], "orphanet": ["3399"], "wikidata": ["Q1737977"]}
Okamoto syndrome is characterised by congenital hydronephrosis, intellectual deficit, growth retardation, cleft palate, generalised hypotonia and a characteristic face. Cardiac anomalies have also been reported. To date, 6 cases have been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Okamoto syndrome	c1858043	1,283	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2729	2021-01-23T18:13:07	{"gard": ["4064"], "mesh": ["C565736"], "omim": ["604916"], "icd-10": ["Q87.8"]}
"Miner's lung" redirects here. For the book, see Miners' Lung (book). Pneumoconiosis Micrograph of asbestosis (with ferruginous bodies), a type of pneumoconiosis. H&E stain. SpecialtyPulmonology Pneumoconiosis is the general term for a class of interstitial lung diseases where inhalation of dust has caused interstitial fibrosis. Pneumoconiosis often causes restrictive impairment,[1] although diagnosable pneumoconiosis can occur without measurable impairment of lung function. Depending on extent and severity, it may cause death within months or years, or it may never produce symptoms. It is usually an occupational lung disease, typically from years of dust exposure during work in mining; textile milling; shipbuilding, ship repairing, and/or shipbreaking; sandblasting; industrial tasks; rock drilling (subways or building pilings);[2] or agriculture.[3][4] In 2013, it resulted in 260,000 deaths globally, up from 251,000 deaths in 1990.[5] Of these deaths, 46,000 were due to silicosis, 24,000 due to asbestosis and 25,000 due to coal workers pneumoconiosis.[5] ## Contents * 1 Types * 2 Pathogenesis * 3 Diagnosis * 4 Epidemiology * 5 Popular culture * 6 See also * 7 References * 8 Further reading * 9 External links ## Types[edit] Depending upon the type of dust, the disease is given different names: * Coalworker's pneumoconiosis (also known as miner's lung, black lung or anthracosis) – coal, carbon * Aluminosis – Aluminium * Asbestosis – asbestos * Silicosis (also known as "grinder's disease" or Potter's rot, or when related to silica inhaled from the ash of an erupting volcano, pneumonoultramicroscopicsilicovolcanoconiosis) – crystalline silica dust * Bauxite fibrosis – bauxite * Berylliosis – beryllium * Siderosis – iron * Byssinosis – cotton * Silicosiderosis – mixed dust containing silica and iron * Labrador lung (found in miners in Labrador, Canada) – mixed dust containing iron, silica and anthophyllite, a type of asbestos * Stannosis – tin oxide * Talcosis – talc ## Pathogenesis[edit] The reaction of the lung to mineral dusts depends on many variables, including size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10 μm are unlikely to reach distal airways, whereas particles smaller than 0.5 μm move into and out of alveoli, often without substantial deposition and injury. Particles that are 1 to 5 μm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable. Silica, asbestos, and beryllium are more reactive than coal dust, resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the particles become impacted at alveolar duct bifurcations, where macrophages accumulate and engulf the trapped particulates. The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of lung injury and fibrosis. Many particles activate the inflammasome and induce IL-1 production. The more reactive particles trigger the macrophages to release a number of products that mediate an inflammatory response and initiate fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/or to self-proteins that are modified by the particles. This then leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than with any other particle.[3] ## Diagnosis[edit] Positive indications on patient assessment: * Shortness of breath * Chest X-ray may show a characteristic patchy, subpleural, bibasilar interstitial infiltrates or small cystic radiolucencies called honeycombing. Pneumoconiosis in combination with multiple pulmonary rheumatoid nodules in rheumatoid arthritis patients is known as Caplan's syndrome.[6] ## Epidemiology[edit] In 2013 pneumoconiosis resulted in 260,001 deaths up from 251,000 deaths in 1990.[5] Of these deaths 46,000 were due to silicosis, 24,000 due to asbestosis and 25,000 due to coal workers pneumoconiosis.[5] ## Popular culture[edit] This section appears to contain trivial, minor, or unrelated references to popular culture. Please reorganize this content to explain the subject's impact on popular culture, providing citations to reliable, secondary sources, rather than simply listing appearances. Unsourced material may be challenged and removed. (January 2020) * In the 1939 movie Four Wives, actor Eddie Albert plays a doctor studying pneumoconiosis. * In the classic British film Brief Encounter (1945), derived from a Noël Coward play, housewife Laura (Celia Johnson) and physician Alec (Trevor Howard) begin an affair. She is desperately mesmerized in a train station lounge by his evocation of his passion for pneumoconiosis. * In the 1995 British film Brassed Off, the band leader (Pete Postlethwaite) in a small coal-mining town is hospitalized with pneumoconiosis. * A 2006 documentary film by Shane Roberts features interviews with miners suffering from the disease and footage shot inside the mine. * In the puzzle/shooter video game Portal 2, former CEO and founder of Aperture Science Laboratories, Cave Johnson, purportedly contracted and died of lunar pneumoconiosis after prolonged exposure to the moon rocks he was using in teleportation technology research. * In the 2001 film Zoolander, the "black lung" is referenced to after the male model protagonist spends one day working in a coal mine.[citation needed] * In the 2004 BBC miniseries North & South, Bessy Higgins dies from pneumoconiosis from working in the cotton mill in 19th-century England. ## See also[edit] * Aluminosis * Black Lung Benefits Act of 1972 * Chalicosis * Philip D'Arcy Hart * Popcorn workers' lung disease — diacetyl emissions and airborne dust from butter flavorings used in microwave popcorn production ## References[edit] 1. ^ American Thoracic Society (2004). "Diagnosis and Initial Management of Nonmalignant Diseases Related to Asbestos". American Journal of Respiratory and Critical Care Medicine. 170 (6): 691–715. doi:10.1164/rccm.200310-1436ST. PMID 15355871. 2. ^ Shih, Gerry (15 December 2019). "They built a Chinese boomtown. It left them dying of lung disease with nowhere to turn". New York Times. Retrieved 16 December 2019. 3. ^ a b Kumar, MBBS, MD, FRCPath, Vinay (2013). Robbins Basic Pathology 9th Edition. Philadelphia, Pennsylvania: Elsevier Saunders. pp. 474–475. ISBN 978-1-4377-1781-5.CS1 maint: multiple names: authors list (link) 4. ^ Schenker, Marc B.; Pinkerton, Kent E.; Mitchell, Diane; Vallyathan, Val; Elvine-Kreis, Brenda; Green, Francis H.Y. (2009). "Pneumoconiosis from Agricultural Dust Exposure among Young California Farmworkers". Environmental Health Perspectives. 117 (6): 988–994. doi:10.1289/ehp.0800144. PMC 2702418. PMID 19590695. 5. ^ a b c d GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. 6. ^ Andreoli, Thomas, ed. CECIL Essentials of Medicine. Saunders: Pennsylvania, 2004. p. 737. ## Further reading[edit] * Cochrane, A.L.; Blythe, M. (1989). One Man's Medicine, an autobiography of Professor Archie Cochrane. London: BMJ Books. ISBN 0727902776. (Paperback ed. (2009) Cardiff University ISBN 0954088433. ## External links[edit] Classification D * ICD-10: J60-J65 * ICD-9-CM: 500-505 * MeSH: D011009 * DiseasesDB: 31746 * "Pneumoconioses". NIOSH Safety and Health Topic. Center for Disease Control. * "Black Lung Benefits Act". U.S. Department of Labor. Archived from the original on 2010-05-27. Retrieved 2007-03-02. * Coal Workers' Pneumoconiosis at Merck Manual of Diagnosis and Therapy Professional Edition * Black Lung — United Mine Workers of America * "Black Lung" (PDF). U.S. Department of Labor Mine Safety and Health Administration. Archived from the original (PDF) on 2010-05-30. * A Conversation about Mining and Black Lung Disease * Flavorings-Related Lung Disease * The Institute of Occupational Medicine and its research into pneumocomiosis * Miller, B.G.; Kinnear, A.G. Pneumoconiosis in coalminers and exposure to dust of variable quartz content (PDF) (Technical report). Institute of Occupational Medicine. TM/88/17. * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis * v * t * e Occupational safety and health Occupational diseases and injuries * Acrodynia * Asbestosis * Asthma * Barotrauma * Berylliosis * Brucellosis * Byssinosis ("brown lung") * Chalicosis * Chimney sweeps' carcinoma * Chronic solvent-induced encephalopathy * Coalworker's pneumoconiosis ("black lung") * Concussions in sport * Decompression sickness * De Quervain syndrome * Erethism * Exposure to human nail dust * Farmer's lung * Fiddler's neck * Flock worker's lung * Glassblower's cataract * Golfer's elbow * Hearing loss * Hospital-acquired infection * Indium lung * Laboratory animal allergy * Lead poisoning * Mesothelioma * Metal fume fever * Mule spinners' cancer * Noise-induced hearing loss * Phossy jaw * Pneumoconiosis * Radium jaw * Repetitive strain injury * Silicosis * Silo-filler's disease * Sports injury * Surfer's ear * Tennis elbow * Tinnitus * Writer's cramp Occupational hygiene * Occupational hazard * Biological hazard * Chemical hazard * Physical hazard * Psychosocial hazard * Hierarchy of hazard controls * Prevention through design * Exposure assessment * Occupational exposure limit * Occupational epidemiology * Workplace health surveillance Professions * Environmental health * Industrial engineering * Occupational health nursing * Occupational health psychology * Occupational medicine * Occupational therapist * Safety engineering Agencies and organizations * Canadian Centre for Occupational Health and Safety * European Agency for Safety and Health at Work * UK Health and Safety Executive * International Labour Organization * US National Institute for Occupational Safety and Health * US Occupational Safety and Health Administration * National Institute for Safety and Health at Work (Spain) * World Health Organization Standards * Bangladesh Accord * ISO 45001 * Occupational Safety and Health Convention, 1981 * Worker Protection Standard (US) * Working Environment Convention, 1977 Safety * Checklist * Code of practice * Contingency plan * Diving safety * Emergency procedure * Emergency evacuation * Hazard * Hierarchy of hazard controls * Hazard elimination * Administrative controls * Engineering controls * Hazard substitution * Personal protective equipment * Job safety analysis * Lockout-tagout * Permit To Work * Operations manual * Redundancy (engineering) * Risk assessment * Safety culture * Standard operating procedure Legislation * Diving regulations * Occupational Safety and Health Act (United States) See also * Environment, health and safety * Environmental toxicology * Ergonomics * Health physics * Indoor air quality * International Chemical Safety Card * National Day of Mourning (Canadian observance) * Process safety management * Public health * Risk management * Safety data sheet * Toxic tort * Workers' compensation * Category * Occupational diseases * Journals * Organizations * Commons * Glossary Authority control * GND: 4077858-7 * NDL: 00562830 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pneumoconiosis	c0032273	1,284	wikipedia	https://en.wikipedia.org/wiki/Pneumoconiosis	2021-01-18T18:55:03	{"mesh": ["D011009"], "umls": ["C0032273"], "orphanet": ["182098"], "wikidata": ["Q651223"]}
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255). Mapping By analyzing a sample of 1,816 individuals from 79 pedigrees, Liu et al. (2004) found linkage evidence suggesting a quantitative trait locus underlying height on chromosome 9q22.32 (maximum multipoint lod score of 2.74 at marker D9S287). Liu et al. (2006) reported results of genomewide linkage analysis for stature in an extended sample of 3,726 Caucasians, including 1,816 individuals from previous linkage studies performed by the same group (Deng et al., 2002; Liu et al., 2004). The 3,726 subjects came from 434 pedigrees. A maximum lod score of 4.34 was obtained at 97 cM pter on 9q22. Two markers, GATA81C04M and ATA18A07M, flank the region. The authors noted that the ROR2 gene (602337) maps within the candidate region. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	STATURE QUANTITATIVE TRAIT LOCUS 8	c1864691	1,285	omim	https://www.omim.org/entry/610114	2019-09-22T16:05:12	{"omim": ["610114"]}
Charlie M syndrome is a rare bone developmental disorder which belongs to a group of oromandibular limb hypogenesis syndromes that includes hypoglossia-hypodactyly and glossopalatine ankylosis (see these terms). The major anomalies which occur commonly in this group are hypoplasia of the mandible, syndactyly and ectrodactyly, small mouth, cleft palate, hypodontia, and facial paralysis. Patients with Charlie M syndrome also present with hypertelorism, absent or conically crowned incisors, and variable degrees of hypodactyly of the hands and feet. There have been no further descriptions in the literature since 1976. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Charlie M syndrome	c4518555	1,286	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1406	2021-01-23T18:07:08	{"gard": ["1261"], "icd-10": ["Q87.0"]}
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: "Depigmentation" – news · newspapers · books · scholar · JSTOR (December 2006) (Learn how and when to remove this template message) Depigmentation is the lightening of the skin or loss of pigment. Depigmentation of the skin can be caused by a number of local and systemic conditions. The pigment loss can be partial (injury to the skin) or complete (caused by vitiligo). It can be temporary (from tinea versicolor) or permanent (from albinism).[1] Most commonly, depigmentation of the skin is linked to people born with vitiligo, which produces differing areas of light and dark skin. Monobenzone also causes skin depigmentation. Main article: Skin whitening Increasingly, people who are not afflicted with the vitiligo experiment with lower concentrations of monobenzone creams in the hope of lightening their skin tone evenly. An alternate method of lightening is to use the chemical mequinol over an extended period of time. Both monobenzone and mequinol produce dramatic skin whitening, but react very differently. Mequinol leaves the skin looking extremely pale. However, tanning is still possible. It is important to notice that the skin will not go back to its original color after the none treatment of mequinol. Mequinol should not be used by people that are allergic to any ingredient in mequinol, if you are pregnant, if you have eczema, irritated or inflamed skin, an increased number of white blood cells or if you are sensitive to sunlight or must be outside for prolonged periods of time.[2] Mequinol is used in Europe in concentrations ranging from 2-20% and is approved in many countries for the treatment of solar lentigines.[3] Monobenzone applied topically completely removes pigment in the long term and vigorous sun-safety must to be adhered to for life to avoid severe sun burn and melanomas. People using monobenzone without previously having vitiligo do so because standard products containing hydroquinone or other lightening agents are not effective for their skin and due to price and active ingredient strength. However, monobenzone is not recommended for skin conditions other than vitiligo. For stubborn pigmented lesions the Q-switched ruby laser, cryotherapy or TCA peels can be used to ensure the skin remains pigment-free. ## References[edit] 1. ^ "Depigmentation of Skin: Check Your Symptoms and Signs". 2. ^ "Mequinol/tretinoin: Indications, Side Effects, Warnings - Drugs.com". 3. ^ "Top 20 Skin Whitening Agents > Mequinol". www.skinwhiteningscience.com. * 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 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	Depigmentation	c0162835	1,287	wikipedia	https://en.wikipedia.org/wiki/Depigmentation	2021-01-18T18:40:52	{"mesh": ["D017496"], "wikidata": ["Q3705665"]}
Cylindroma SpecialtyOncology, dermatology A variant of eccrine spiradenoma which can be multiple on the scalp and can coalesce to form a 'Turban' tumour. In pathology, a cylindroma is a tumour with nests of cells that resemble a cylinder in cross section. Types include: * Dermal eccrine cylindroma, a benign tumour of the skin * Adenoid cystic carcinoma, a malignant tumour of the salivary gland ## See also[edit] * List of cutaneous neoplasms associated with systemic syndromes ## External links[edit] Classification D * ICD-10: D23 (ILDS D23.L33) * v * t * e Cancers of skin and associated structures Glands Sweat gland Eccrine * Papillary eccrine adenoma * Eccrine carcinoma * Eccrine nevus * Syringofibroadenoma * Spiradenoma Apocrine * Cylindroma * Dermal cylindroma * Syringocystadenoma papilliferum * Papillary hidradenoma * Hidrocystoma * Apocrine gland carcinoma * Apocrine nevus Eccrine/apocrine * Syringoma * Hidradenoma or Acrospiroma/Hidradenocarcinoma * Ceruminous adenoma Sebaceous gland * Nevus sebaceous * Muir–Torre syndrome * Sebaceous carcinoma * Sebaceous adenoma * Sebaceoma * Sebaceous nevus syndrome * Sebaceous hyperplasia * Mantleoma Hair * Pilomatricoma/Malignant pilomatricoma * Trichoepithelioma * Multiple familial trichoepithelioma * Solitary trichoepithelioma * Desmoplastic trichoepithelioma * Generalized trichoepithelioma * Trichodiscoma * Trichoblastoma * Fibrofolliculoma * Trichilemmoma * Trichilemmal carcinoma * Proliferating trichilemmal cyst * Giant solitary trichoepithelioma * Trichoadenoma * Trichofolliculoma * Dilated pore * Isthmicoma * Fibrofolliculoma * Perifollicular fibroma * Birt–Hogg–Dubé syndrome Hamartoma * Basaloid follicular hamartoma * Folliculosebaceous cystic hamartoma * Folliculosebaceous-apocrine hamartoma Nails * Neoplasms of the nailbed This Epidermal nevi, neoplasms, cysts article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Cylindroma	c1305968	1,288	wikipedia	https://en.wikipedia.org/wiki/Cylindroma	2021-01-18T18:51:49	{"gard": ["12346"], "mesh": ["C536611"], "umls": ["C1305968"], "icd-10": ["D23"], "wikidata": ["Q245711"]}
Spondyloepiphyseal dysplasia (SED) is a group of rare genetic conditions that affect bone growth in the spine, arms, and legs. Other features include problems with vision and hearing, clubfeet, cleft palate, arthritis, and difficulty with breathing as curvature of the spine progresses. There are two main types of SED, spondyloepiphyseal dysplasia congenita (which is present from bith) and spondyloepiphyseal dysplasia tarda (which develops later in childhood or adolescence). Spondyloepiphyseal dysplasia is caused by mutations in genes that are responsible for making proteins that are needed for the creation of bone and cartilage. Most cases are due to a new (de novo) mutation, although it can be passed down through families. Treatment is aimed at managing the symptoms and associated complications as they arise. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Spondyloepiphyseal dysplasia	c0038015	1,289	gard	https://rarediseases.info.nih.gov/diseases/7687/spondyloepiphyseal-dysplasia	2021-01-18T17:57:32	{"mesh": ["D010009"], "orphanet": ["253"], "synonyms": []}
## Description An X-linked recessive inhibitor (XS) of the Lutheran blood group system (111200) has been reported. For a discussion of Lutheran blood group phenotypes, see 247420. Clinical Features Norman et al. (1985, 1986) studied a family in which 5 males showed the Lu(a-b-) phenotype. The red cells of these persons had some characteristics of the dominant and some of the recessive trait. The inheritance pattern suggested X-linked recessive inheritance. They suggested that the common allele permitting normal Lutheran expression be called XS1 and the rare allele suppressing expression be called XS2. (This should be XS1 and XS2, for consistency with conventions for alleles as opposed to loci (Shows and the HGM nomenclature committee, 1979).) In 1 sibship, 1 of 2 brothers was Lu(a-b-) and the mother and 7 sisters were Lu(a-b+). In the next generation, all the girls were Lu(a-b+), 4 boys (sons of sisters) were Lu(a-b-), and 8 boys were Lu(a-b+). Close linkage with the Xg blood group (314700) was excluded. In the full report (Norman et al., 1986), 6 affected males in 4 sibships connected through presumed carrier females were diagrammed. The authors concluded that XS2 is not a common cause of the Lu(a-b-) phenotype because in only 8 of 39 families reported by Shaw et al. (1984) was the 'genetic origin' undetermined, and in only 2 of these were there male and no female Lu(a-b-) members. Mapping In the only known family segregating for the X-linked suppressor, Mulley et al. (1987, 1988) found a suggestion of linkage to markers near the centromere. They concluded that the probable location for XS is at Xp21.2-q21.1. In a study of 3 individuals with the McLeod red cell phenotype (300842), all of whom also expressed the Lutheran antigen, El Nemer et al. (2000) were able to exclude location of the XS locus from the Xp21.2-Xp21.1 region between DMD (300377) and RPGR (312610). Nomenclature McKusick, 1986 proposed LUXS as the designation for the X-linked Lutheran inhibitor. Lab \- Absent Lutheran blood group antigens \- Lu(a-b-) Inheritance \- X-linked recessive (Xp21.2-q21.1) \- heterogeneous, also by homozygosity of a silent Lutheran locus allele, or to In(Lu), an unlinked dominant suppressor ▲ 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	LUTHERAN SUPPRESSOR, X-LINKED	c3887995	1,290	omim	https://www.omim.org/entry/309050	2019-09-22T16:18:15	{"omim": ["309050"], "synonyms": ["Alternative titles", "LUXS"]}
A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, with an extra, well-formed, functional digit at the metacarpophalangeal/metatarsophalangeal or carpometacarpal/tarsometatarsal joint. The malformation can be an isolated finding or be associated with a large number of other anomalies. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Postaxial polydactyly type A	c3887487	1,291	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93334	2021-01-23T17:02:19	{"mesh": ["C562429"], "omim": ["174200", "263450", "602085", "607324", "608562", "615226", "618219", "618498"], "umls": ["C3887487"], "icd-10": ["Q69.0"]}
Stercoral perforation Play media Axial CT cine clip showing loculated fluid, free intraperitoneal fluid, extraluminal gas, and focal discontinuity of the wall of the sigmoid colon with stool in the defect consistent with stercoral perforation. The person was a heavy opioid user Stercoral perforation is the perforation or rupture of the intestine's walls by its internal contents, such as hardened feces or foreign objects. Hardened stools may form in prolonged constipation or other diseases which cause obstruction of transit, such as Chagas disease, Hirschprung's disease, toxic colitis, hypercalcelmia, and megacolon.[1] Symptoms can include abdominal distension, pain, and nausea.[1] Stercoral perforation is a rare and very dangerous, life-threatening situation, as well as a surgical emergency, because the spillage of contaminated intestinal contents into the abdominal cavity leads to peritonitis, a rapid bacteremia (bacterial infection of the blood), with many complications. ## See also[edit] * Gastrointestinal perforation * Stercoral ulcer, which can lead to stercoral perforation ## References[edit] 1. ^ a b Core Topics in General and Emergency Surgery (6 ed.). Elsevier. 2019. pp. 216–233. This article related to pathology 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	Stercoral perforation	None	1,292	wikipedia	https://en.wikipedia.org/wiki/Stercoral_perforation	2021-01-18T18:46:17	{"wikidata": ["Q7611182"]}
Eosinophilic fasciitis Other namesShulman syndrome[1] SpecialtyRheumatology Eosinophilic fasciitis (/ˌiːəˌsɪnəˈfɪlɪk ˌfæʃiˈaɪtɪs, ˌiːoʊ-, -ˌfæsi-/[2][3]), also known as "Shulman's syndrome",[4] is a form of fasciitis, the inflammatory diseases that affect the fascia, the connective tissues surrounding muscles, blood vessels and nerves. Unlike other diseases in that category, it is limited to the arms and legs, and usually resolves itself, although some cases require corticosteroids, and some cases are associated with aplastic anemia.[5] The presentation of eosinophilic fasciitis is similar to scleroderma or systemic sclerosis. However, unlike scleroderma, it affects the fascia, not the skin (dermis). The characteristic and severe effects of scleroderma and systemic sclerosis, such as Raynaud's syndrome, involvement of the extremities, prominent small blood vessels (telangiectasia), and visceral changes such as swallowing problems, are absent. It was first characterized in 1974,[6] and it is not yet known whether it is actually a distinct condition or just a different presentation. However, it remains used for diagnostic purposes.Several cases have been reported after strenuous exercise. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] As it is a rare disease, a clear set of symptoms is difficult to define. Usually, patients show severe pain and swelling is reported but clinical presentations vary. It can have an 'orange peel' like appearance.[7] Less common features are joint pain and carpal tunnel syndrome. ## Cause[edit] Most cases are idiopathic, but several triggers might related to the development of Eosinophilic fasciitis,[8] such as strenuous exercise,[6] initiation of hemodialysis,[9] infection with Borrelia burgdorferi,[10] some medications such as statins, phenytoin, ramipril, and subcutaneous heparin.[11] ## Diagnosis[edit] The key to diagnosis is skin changes combined with blood eosinophilia but the most accurate test is a skin, fascia and muscle biopsy.[citation needed] ## Treatment[edit] Common treatments include corticosteroids[12] such as prednisone, though other medications such as hydroxychloroquine[13] have also been used. The prognosis is usually good in the case of an early treatment if there is no visceral involvement.[7][14] ## Epidemiology[edit] Typical age of onset is around 40 to 50 years. It is not clear whether it is more common in women than men - patient numbers are small and some studies report a preponderance of men and others women.[15] It is also found in children. ## See also[edit] * Eosinophilia * List of cutaneous conditions ## References[edit] 1. ^ "Eosinophilic fasciitis: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 29 October 2019. 2. ^ "Eosinophilic". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 2016-01-21. "fasciitis". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 2016-01-21. 3. ^ "Eosinophilic". Merriam-Webster Dictionary. Retrieved 2016-01-21. "fasciitis". Merriam-Webster Dictionary. Retrieved 2016-01-21. 4. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.[page needed] 5. ^ Merck Manual, Professional Edition, Eosinophilic Fasciitis 6. ^ a b Shulman, L. E (1975). "Diffuse fasciitis with eosinophilia: A new syndrome?". Transactions of the Association of American Physicians. 88: 70–86. PMID 1224441. 7. ^ a b Bischoff, Lindsay; Chris T. Derk (January 2008). "Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature". International Journal of Dermatology. 47 (1): 29–35. doi:10.1111/j.1365-4632.2007.03544.x. PMID 18173597. S2CID 25791443. 8. ^ Pinal-Fernandez, I; Selva-O'Callaghan, A; Grau, J.M (2014). "Diagnosis and classification of eosinophilic fasciitis". Autoimmunity Reviews. 13 (4–5): 379–82. doi:10.1016/j.autrev.2014.01.019. PMID 24424187. 9. ^ Florell, Scott R; Egan, Conleth A; Gregory, Martin C; Zone, John J; Petersen, Marta J (2016). "Eosinophilic Fasciitis Occurring Four Weeks after the Onset of Dialysis in a Renal Failure Patient". Journal of Cutaneous Medicine and Surgery. 5 (1): 33–6. doi:10.1177/120347540100500108. PMID 11281432. S2CID 208066832. 10. ^ Mosconi, Sandro; Streit, Markus; Brönimann, Marcel; Braathen, Lasse R (2002). "Eosinophilic Fasciitis (Shulman Syndrome)". Dermatology. 205 (2): 204–6. doi:10.1159/000063916. PMID 12218249. S2CID 37435478. 11. ^ Long, Hai; Zhang, Guiying; Wang, Ling; Lu, Qianjin (2015). "Eosinophilic Skin Diseases: A Comprehensive Review". Clinical Reviews in Allergy & Immunology. 50 (2): 189–213. doi:10.1007/s12016-015-8485-8. PMID 25876839. S2CID 30806009. 12. ^ Antic M, Lautenschlager S, Itin PH (2006). "Eosinophilic fasciitis 30 years after - what do we really know? Report of 11 patients and review of the literature". Dermatology. 213 (2): 93–101. doi:10.1159/000093847. PMID 16902285. S2CID 29769383. 13. ^ Lakhanpal S, Ginsburg WW, Michet CJ, Doyle JA, Moore SB (1988). "Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases". Semin. Arthritis Rheum. 17 (4): 221–31. doi:10.1016/0049-0172(88)90008-X. PMID 3232080. 14. ^ Valadares, Diana; Joao Neves; Isabel Almeida; Carlos Lopes; Carlos Vasconcelos (February 2011). "Iron Lady: A Case of Eosinophilic Fasciitis". Journal of Medical Case Reports. 2: 34–36. doi:10.4021/jmc118w. 15. ^ Wojas-Pelc, Anna; Wielowieyska-Szybińska, Dorota; Lipko-Godlewska, Sylwia (2004). "Eozynofilowe zapalenie powięzi - aktualny stan wiedzy" [Eosinophilic fasciitis--current database]. Polski Merkuriusz Lekarski (in Polish). 16 (96): 585–8. PMID 15510903. ## Further reading[edit] * Lakhanpal, Sharad; Ginsburg, William W.; Michet, Clement J.; Doyle, John A.; Moore, S.Breanndan (1988). "Eosinophilic fasciitis: Clinical spectrum and therapeutic response in 52 cases". Seminars in Arthritis and Rheumatism. 17 (4): 221–231. doi:10.1016/0049-0172(88)90008-X. ISSN 0049-0172. PMID 3232080. * Barnes L, Rodnan GP, Medsger TA, Short D (August 1979). "Eosinophilic fasciitis. A pathologic study of twenty cases". The American Journal of Pathology. 96 (2): 493–518. PMC 2042453. PMID 474708. * Doyle JA, Ginsburg WW (September 1989). "Eosinophilic fasciitis". The Medical Clinics of North America. 73 (5): 1157–66. doi:10.1016/S0025-7125(16)30625-3. PMID 2671538. * Michet CJ, Doyle JA, Ginsburg WW (January 1981). "Eosinophilic fasciitis: report of 15 cases". Mayo Clinic Proceedings. 56 (1): 27–34. PMID 7453247. * Bennett, R M; Herron, A; Keogh, L (1977). "Eosinophilic fasciitis. Case report and review of the literature". Annals of the Rheumatic Diseases. 36 (4): 354–359. doi:10.1136/ard.36.4.354. ISSN 0003-4967. PMC 1006697. PMID 901033. * Falanga, Vincent; Medsger, Thomas A. (1987). "Frequency, levels, and significance of blood eosinophilia in systemic sclerosis, localized scleroderma, and eosinophilic fasciitis". Journal of the American Academy of Dermatology. 17 (4): 648–656. doi:10.1016/S0190-9622(87)70251-5. ISSN 0190-9622. PMID 3668010. * Varga J, Kähäri VM (November 1997). "Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders". Current Opinion in Rheumatology. 9 (6): 562–70. doi:10.1097/00002281-199711000-00013. PMID 9375286. * Kent, Lawrence T.; Cramer, Stewart F.; Moskowitz, Roland W. (1981). "Eosinophilic fasciitis". Arthritis & Rheumatism. 24 (5): 677–683. doi:10.1002/art.1780240508. ISSN 0004-3591. PMID 6972219. * Moulton SJ, Kransdorf MJ, Ginsburg WW, Abril A, Persellin S (March 2005). "Eosinophilic fasciitis: spectrum of MRI findings". AJR. American Journal of Roentgenology. 184 (3): 975–8. doi:10.2214/ajr.184.3.01840975. PMID 15728627. ## External links[edit] Classification D * ICD-10: M35.4 * ICD-9-CM: 728.89 * OMIM: 226350 * MeSH: C562487 * DiseasesDB: 29427 External resources * MedlinePlus: 000447 * eMedicine: med/686 * v * t * e Systemic connective tissue disorders General Systemic lupus erythematosus * Drug-induced SLE * Libman–Sacks endocarditis Inflammatory myopathy * Myositis * Dermatopolymyositis * Dermatomyositis/Juvenile dermatomyositis * Polymyositis* Inclusion body myositis Scleroderma * Systemic scleroderma * Progressive systemic sclerosis * CREST syndrome * Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune * Sjögren syndrome Other * Behçet's disease * Polymyalgia rheumatica * Eosinophilic fasciitis * Eosinophilia–myalgia syndrome * fibrillin * Marfan syndrome * Congenital contractural arachnodactyly * v * t * e Soft tissue disorders Capsular joint Synoviopathy * Synovitis/Tenosynovitis * Calcific tendinitis * Stenosing tenosynovitis * Trigger finger * De Quervain syndrome * Transient synovitis * Ganglion cyst * osteochondromatosis * Synovial osteochondromatosis * Plica syndrome * villonodular synovitis * Giant-cell tumor of the tendon sheath Bursopathy * Bursitis * Olecranon * Prepatellar * Trochanteric * Subacromial * Achilles * Retrocalcaneal * Ischial * Iliopsoas * Synovial cyst * Baker's cyst * Calcific bursitis Noncapsular joint Symptoms * Ligamentous laxity * Hypermobility Enthesopathy/Enthesitis/Tendinopathy upper limb * Adhesive capsulitis of shoulder * Impingement syndrome * Rotator cuff tear * Golfer's elbow * Tennis elbow lower limb * Iliotibial band syndrome * Patellar tendinitis * Achilles tendinitis * Calcaneal spur * Metatarsalgia * Bone spur other/general: * Tendinitis/Tendinosis Nonjoint Fasciopathy * Fasciitis: Plantar * Nodular * Necrotizing * Eosinophilic Fibromatosis/contracture * Dupuytren's contracture * Plantar fibromatosis * Aggressive fibromatosis * Knuckle pads [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Eosinophilic fasciitis	c0264005	1,293	wikipedia	https://en.wikipedia.org/wiki/Eosinophilic_fasciitis	2021-01-18T18:41:28	{"gard": ["6351"], "mesh": ["C562487"], "umls": ["C0264005"], "icd-9": ["728.89"], "icd-10": ["M35.4"], "orphanet": ["3165"], "wikidata": ["Q2325206"]}
Clay-shoveler fracture C7 spinous process. SpecialtyNeurosurgery Clay-shoveler's fracture is a stable fracture through the spinous process of a vertebra occurring at any of the lower cervical or upper thoracic vertebrae, classically at C6 or C7.[1] In Australia in the 1930s, men digging deep ditches tossed clay 10 to 15 feet above their heads using long handled shovels.[2] Instead of separating, the sticky clay would sometimes stick to the shovel; the worker would hear a pop and feel a sudden pain between the shoulder blades, unable to continue working. The mechanism of injury is believed to be secondary to muscle pull and reflex with force transmission through the supraspinous ligaments. The tremendous force pulls on the spinous process producing an avulsion fracture. The fracture is diagnosed by plain film examination. ## References[edit] 1. ^ Brant W, Helms C. "Fundamentals of Diagnostic Radiology" (Third Edition): 1110. Cite journal requires `\|journal=` (help) 2. ^ McKellar Hall RD (1940). "Clay-Shoveler's Fracture". J Bone Joint Surg Am. 22: 36–75. ## External links[edit] Classification D * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Clay-shoveler fracture	None	1,294	wikipedia	https://en.wikipedia.org/wiki/Clay-shoveler_fracture	2021-01-18T18:54:34	{"wikidata": ["Q5129816"]}
Main article: Myocardial infarction Myocardial infarction complications may occur immediately following a heart attack (in the acute phase), or may need time to develop (a chronic problem). After an infarction, an obvious complication is a second infarction, which may occur in the domain of another atherosclerotic coronary artery, or in the same zone if there are any live cells left in the infarct. Post-myocardial complications occur after a period of ischemia, these changes can be seen in gross tissue changes and microscopic changes.[1] Necrosis begins after 20 minutes of an infarction. Under 4 hours of ischemia, there are no gross or microscopic changes noted.[2] From 4-24 hours coagulative necrosis begins to be seen, which is characterized by the removal of dead cardiomyocytes through heterolysis and the nucleus through karyorrhexis, karyolysis, and pyknosis.[3] On gross examination, coagulative necrosis shows darkened discoloration of the infarcted tissue. The most common complication during this period is arrhythmias. Day 1-7 is marked by the inflammatory phase. Days 1-3 are marked by “acute inflammation”, in which neutrophils infiltrate the ischemic tissue. A major complication during this period is fibrinous pericarditis, particularly in transmural ventricular wall damage (an infarct that impacted all 3 layers of the heart, the epicardium, myocardium, and endocardium). This leads to inflammation, such as swelling, leading to rubbing of the heart on the pericardium. Day 4 through 7 are marked by “chronic inflammation”, on histology macrophages will be seen infiltrating the tissue. The role of these macrophages is the removal of necrotic myocytes. However, these cells are directly involved in the weakening of the tissue, leading to complications such as a ventricular free wall rupture, intraventricular septum rupture, or a papillary muscle rupture. At a gross anatomical level, this staged is marked by a yellow pallor. Weeks 1-3 are marked on histology by abundant capillaries, and fibroblast infiltration. Fibroblasts start replacing the lost cardiomyocytes with collagen type 1 and leads to the granulation of tissue. After several weeks fibrosis occurs and heavy collagen formation. Collagen is not as strong or compliant as the myocardium that it replaced, this instability could lead to a ventricular aneurysm, and the stasis of blood in an aneurysm can lead to a mural thrombus. A rarer complication that also occurs during this time is Dressler's syndrome and is thought to have autoimmune origins.[4] ## Contents * 1 Congestive heart failure * 2 Myocardial rupture * 3 Arrhythmia * 4 Pericarditis * 5 Cardiogenic shock * 6 References * 7 Further reading ## Congestive heart failure[edit] Main article: Congestive heart failure 3D still showing normal heart vs heart failure. A myocardial infarction may compromise the function of the heart as a pump for the circulation, a state called heart failure. There are different types of heart failure; left- or right-sided (or bilateral) heart failure may occur depending on the affected part of the heart, and it is a low-output type of failure. If one of the heart valves is affected, this may cause dysfunction, such as mitral regurgitation in the case of left-sided coronary occlusion that disrupts the blood supply of the papillary muscles. The incidence of heart failure is particularly high in patients with diabetes and requires special management strategies.[5] ## Myocardial rupture[edit] Main article: Myocardial rupture Myocardial rupture is most common three to seven days after myocardial infarction, commonly of small degree, but may occur one day to three weeks later. In the modern era of early revascularization and intensive pharmacotherapy as treatment for MI, the incidence of myocardial rupture is about 1% of all MIs.[6] This may occur in the free walls of the ventricles, the septum between them, the papillary muscles, or less commonly the atria. Rupture occurs because of increased pressure against the weakened walls of the heart chambers due to heart muscle that cannot pump blood out effectively. The weakness may also lead to ventricular aneurysm, a localized dilation or ballooning of the heart chamber. Risk factors for myocardial rupture include completion of infarction (no revascularization performed), female sex, advanced age, and a lack of a previous history of myocardial infarction.[6] In addition, the risk of rupture is higher in individuals who are revascularized with a thrombolytic agent than with PCI.[7][8] The shear stress between the infarcted segment and the surrounding normal myocardium (which may be hypercontractile in the post-infarction period) makes it a nidus for rupture.[9] Rupture is usually a catastrophic event that may result a life-threatening process known as cardiac tamponade, in which blood accumulates within the pericardium or heart sac, and compresses the heart to the point where it cannot pump effectively. Rupture of the intraventricular septum (the muscle separating the left and right ventricles) causes a ventricular septal defect with shunting of blood through the defect from the left side of the heart to the right side of the heart, which can lead to right ventricular failure as well as pulmonary overcirculation. Rupture of the papillary muscle may also lead to acute mitral regurgitation and subsequent pulmonary edema and possibly even cardiogenic shock.[10] ## Arrhythmia[edit] A 12 lead electrocardiogram showing ventricular tachycardia. Since the electrical characteristics of the infarcted tissue change (see pathophysiology section), arrhythmias are a frequent complication.[11] The re-entry phenomenon may cause rapid heart rates (ventricular tachycardia and even ventricular fibrillation), and ischemia in the electrical conduction system of the heart may cause a complete heart block (when the impulse from the sinoatrial node, the normal cardiac pacemaker, does not reach the heart chambers).[12][13] ## Pericarditis[edit] Main article: Pericarditis As a reaction to the damage of the heart muscle, inflammatory cells are attracted. The inflammation may reach out and affect the heart sac. This is called pericarditis. In Dressler's syndrome, this occurs several weeks after the initial event. If pericarditis were to persist, pericardial effusion may also occur which could in turn lead to cardiac tamponade if not properly treated.[2] ## Cardiogenic shock[edit] A complication that may occur in the acute setting soon after a myocardial infarction or in the weeks following is cardiogenic shock. Cardiogenic shock is defined as a hemodynamic state in which the heart cannot produce enough of a cardiac output to supply an adequate amount of oxygenated blood to the tissues of the body.[14] While the data on performing interventions on individuals with cardiogenic shock is sparse, trial data suggests a long-term mortality benefit in undergoing revascularization if the individual is less than 75 years old and if the onset of the acute myocardial infarction is less than 36 hours and the onset of cardiogenic shock is less than 18 hours.[15] If the patient with cardiogenic shock is not going to be revascularized, aggressive hemodynamic support is warranted, with insertion of an intra-aortic balloon pump if not contraindicated.[15] If diagnostic coronary angiography does not reveal a culprit blockage that is the cause of the cardiogenic shock, the prognosis is poor.[15] ## References[edit] 1. ^ Muscle Tissue. In: Mescher AL. eds. Junqueira’s Basic Histology: Text and Atlas, 15e New York, NY: McGraw-Hill 2. ^ a b Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth edition.). Philadelphia, PA: Elsevier/Saunders. 3. ^ Adigun, Rotimi; Bhimji, Steve S. (2018), "Necrosis, Cell (Liquefactive, Coagulative, Caseous, Fat, Fibrinoid, and Gangrenous)", StatPearls, StatPearls Publishing, PMID 28613685, retrieved 2018-11-03 4. ^ Leonard S. Lilly. Pathophysiology Of Heart Disease : a Collaborative Project of Medical Students and Faculty. Philadelphia :Lippincott Williams & Wilkins, 2003. 5. ^ Canto JG, Shlipak MG, Rogers WJ, Malmgren JA, Frederick PD, Lambrew CT, Ornato JP, Barron HV, Kiefe CI (2000). "Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain". JAMA. 283 (24): 3223–9. doi:10.1001/jama.283.24.3223. PMID 10866870. 6. ^ a b Yip HK, Wu CJ, Chang HW, Wang CP, Cheng CI, Chua S, Chen MC (2003). "Cardiac rupture complicating acute myocardial infarction in the direct percutaneous coronary intervention reperfusion era" (PDF). Chest. 124 (2): 565–71. doi:10.1378/chest.124.2.565. PMID 12907544. Archived from the original (PDF) on 2007-06-15. Retrieved 2010-10-06. 7. ^ Becker RC, Gore JM, Lambrew C, Weaver WD, Rubison RM, French WJ, Tiefenbrunn AJ, Bowlby LJ, Rogers WJ (1996). "A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction". J Am Coll Cardiol. 27 (6): 1321–6. doi:10.1016/0735-1097(96)00008-3. PMID 8626938. 8. ^ Moreno R, Lopez-Sendon J, Garcia E, Perez de Isla L, Lopez de Sa E, Ortega A, Moreno M, Rubio R, Soriano J, Abeytua M, Garcia-Fernandez MA (2002). "Primary angioplasty reduces the risk of left ventricular free wall rupture compared with thrombolysis in patients with acute myocardial infarction". J Am Coll Cardiol. 39 (4): 598–603. doi:10.1016/S0735-1097(01)01796-X. PMID 11849857. 9. ^ Shin P, Sakurai M, Minamino T, Onishi S, Kitamura H (1983). "Postinfarction cardiac rupture. A pathogenetic consideration in eight cases". Acta Pathol Jpn. 33 (5): 881–93. PMID 6650169. 10. ^ Rubin R, Strayer DS, Rubin E, eds. (2012). Rubin's pathology : clinicopathologic foundations of medicine (Sixth ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 519. ISBN 9781605479682. OCLC 664325098. 11. ^ Podrid, Philip J.; Peter R. Kowey (2001). Cardiac Arrhythmia: Mechanisms, Diagnosis, and Management. Lippincott Williams & Wilkins. ISBN 978-0-7817-2486-9. 12. ^ Sung, Ruey J.; Michael R. Lauer (2000). Fundamental Approaches to the Management of Cardiac Arrhythmias. Springer. ISBN 978-0-7923-6559-4. 13. ^ Josephson, Mark E. (2002). Clinical Cardiac Electrophysiology: Techniques and Interpretations. Lippincott Williams & Wilkins. ISBN 978-0-683-30693-4. 14. ^ Goldberg, Robert J.; Gore, Joel M.; Alpert, Joseph S.; Osganian, Voula; de Groot, Jacques; Bade, Jurgen; Chen, Zuoyao; Frid, David; Dalen, James E. (1991-10-17). "Cardiogenic Shock after Acute Myocardial Infarction". New England Journal of Medicine. 325 (16): 1117–1122. doi:10.1056/nejm199110173251601. ISSN 0028-4793. PMID 1891019. 15. ^ a b c Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH (1999). "Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock" (PDF). N Engl J Med. 341 (9): 625–34. doi:10.1056/NEJM199908263410901. PMID 10460813. ## Further reading[edit] * Rao, D. Sheshagiri; Barik, Ramachandra; Siva Prasad, Akula (1 September 2016). "Hemolysis induced by PMIVSD occluder". Indian Heart Journal. 68: S60–S63. doi:10.1016/j.ihj.2016.02.011. ISSN 0019-4832. PMC 5067760. PMID 27751330. * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Myocardial infarction complications	None	1,295	wikipedia	https://en.wikipedia.org/wiki/Myocardial_infarction_complications	2021-01-18T18:42:42	{"icd-10": ["I23"], "wikidata": ["Q6947903"]}
A number sign (#) is used with this entry because some evidence has suggested that susceptibility to idiopathic generalized epilepsy-11 (EIG11), juvenile myoclonic epilepsy-8 (EJM8), and juvenile absence epilepsy-2 (EJA2) may be conferred by variation in the chloride channel-2 gene (CLCN2; 600570) on chromosome 3q27. However, there has been some controversy over whether variation in the CLCN2 gene has a role in epilepsy (see MOLECULAR GENETICS). Description Both juvenile myoclonic epilepsy and juvenile absence epilepsy are subtypes of idiopathic generalized epilepsy (EIG). For a general phenotypic description and a discussion of genetic heterogeneity of these disorders, see EIG (600669), EJM (254770), and EJA (607631). Mapping Sander et al. (2000) used nonparametric multipoint linkage analysis to identify susceptibility loci among 130 IGE-multiplex families ascertained through a proband with childhood or juvenile absence epilepsy or juvenile myoclonic epilepsy, and 1 or more sibs affected by an IGE trait. They obtained evidence for a novel IGE susceptibility locus on chromosome 3q26 with a peak nonparametric linkage (NPL) score of 4.19 at D3S3725 (p = 0.000017). Molecular Genetics In 2 sibs with juvenile absence epilepsy found by Sander et al. (2000) to be linked to chromosome 3q26, Haug et al. (2003) identified a heterozygous mutation in the CLCN2 gene (G715E; 600570.0003). Another sib with generalized spike-wave discharges on EEG also carried the mutation. The father, who also carried the mutation, reportedly had unclassified seizures in childhood, but his severe alcoholism as an adult rendered his disease status uncertain. Functional studies of the mutant channel showed normal current amplitudes, but altered voltage-dependent gating, potentially leading to hyperexcitability. The family structure, diagnosis, and mutation status were confirmed by Kleefuss-Lie et al. (2009). The mutation was not observed in 4,700 German control individuals. In 3 of 46 unrelated families with IGE localized to 3q26 (including some of the families reported by Sander et al. (2000)), Haug et al. (2003) identified 3 mutations in the CLCN2 gene (600570.0001-600570.0003). In a reevaluation of 2 of the families, 1 with juvenile myoclonic epilepsy and 1 with childhood absence epilepsy Haug et al. (2003), Kleefuss-Lie et al. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper. Niemeyer et al. (2010) disagreed with the conclusion by Kleefuss-Lie et al. (2009) that some of the work by Haug et al. (2003) had merit. Based on lack of functional consequences of the variants reported by Haug et al. (2003) (600570.0001-600570.0003), Niemeyer et al. (2010) asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. In 2 sibs of Tunisian origin with juvenile myoclonic epilepsy, Saint-Martin et al. (2009) identified a heterozygous mutation in the CLCN2 gene (R235Q; 600570.0004). Another sib with JME was not available for genetic analysis. The mutation was not observed in 263 control individuals from North Africa or 183 French controls. Saint-Martin et al. (2009) identified a different heterozygous mutation in the CLCN2 gene (R577Q; 600570.0005) in 2 German sibs with idiopathic generalized epilepsy. The mutation was not observed in 203 German controls or 183 French controls. In both families, the unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression. Nomenclature 'ECA3' was previously used to designate the locus on 3q26 for childhood absence epilepsy; this had since been removed since the paper was retracted (Haug et al., 2003). INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Generalized tonic-clonic seizures (GTCS) on awakening \- GTCS during 'leisure' time (evening) \- Myoclonic seizures may occur \- Absence seizures may occur MISCELLANEOUS \- Variable age of onset (6 to 35 years) \- Precipitated by sleep deprivation MOLECULAR BASIS \- Caused by mutation in the chloride channel-2 gene (CLCN2, 600570.0001 ) ▲ 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	EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 11	c0270853	1,296	omim	https://www.omim.org/entry/607628	2019-09-22T16:08:59	{"doid": ["0111312"], "mesh": ["D020190"], "omim": ["607628"], "orphanet": ["307"]}
Type of congenital heart defect Not to be confused with Teratology. Tetralogy of Fallot Other namesFallot’s syndrome, Fallot’s tetrad, Steno-Fallot tetralogy[1] Diagram of a healthy heart and one with tetralogy of Fallot SpecialtyCardiac surgery, pediatrics SymptomsEpisodes of bluish color to the skin, difficulty breathing, heart murmur, finger clubbing[2] ComplicationsIrregular heart rate, pulmonary regurgitation[3] Usual onsetFrom birth[4] CausesUnknown[5] Risk factorsAlcohol, diabetes, >40, rubella during pregnancy[5] Diagnostic methodBased on symptoms, echocardiogram[6] Differential diagnosisTransposition of the great arteries, Eisenmenger syndrome, Ebstein anomaly[7] TreatmentOpen heart surgery[8] Frequency1 in 2,000 babies[4] Tetralogy of Fallot (TOF) is a type of heart defect present at birth.[4] Symptoms at birth may vary from none to severe.[9] Later, there are typically episodes of bluish color to the skin known as cyanosis.[2] When affected babies cry or have a bowel movement, they may develop a "tet spell" where they turn very blue, have difficulty breathing, become limp, and occasionally lose consciousness.[2] Other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding.[2] The cause is typically not known.[5] Risk factors include a mother who uses alcohol, has diabetes, is over the age of 40, or gets rubella during pregnancy.[5] It may also be associated with Down syndrome.[10] Classically there are four defects:[4] * pulmonary stenosis, narrowing of the exit from the right ventricle * a ventricular septal defect, a hole between the two ventricles * right ventricular hypertrophy, thickening of the right ventricular muscle * an overriding aorta, which allows blood from both ventricles to enter the aorta TOF is typically treated by open heart surgery in the first year of life.[8] The timing of surgery depends on the baby's symptoms and size.[8] The procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect.[8] In babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger.[8] With proper care, most people who are affected live to be adults.[4] Long-term problems may include an irregular heart rate and pulmonary regurgitation.[3] TOF occurs in about 1 in 2,000 newborns.[4] Males and females are affected equally.[4] It is the most common complex congenital heart defect, accounting for about 10 percent of cases.[11][12] It was initially described in 1671 by Niels Stensen.[1][13] A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named.[1][14] The first total surgical repair was carried out in 1954.[3] ## Contents * 1 Signs and symptoms * 1.1 Tet spells * 2 Cause * 3 Pathophysiology * 3.1 Four malformations * 3.2 Additional anomalies * 4 Diagnosis * 5 Treatment * 5.1 Tet spells * 5.2 Total surgical repair * 5.3 Palliative surgery * 6 Prognosis * 7 Epidemiology * 8 History * 9 Notable cases * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] Digital clubbing with cyanotic nail beds in an adult with tetralogy of Fallot Tetralogy of Fallot results in low oxygenation of blood. This is due to a mixing of oxygenated and deoxygenated blood in the left ventricle via the ventricular septal defect (VSD) and preferential flow of the mixed blood from both ventricles through the aorta because of the obstruction to flow through the pulmonary valve. The latter is known as a right-to-left shunt.[15] Infants with TOF -a cyanotic heart disease- have low blood oxygen saturation..[15] Blood oxygenation varies greatly from one patient to another depending on the severity of the anatomic defects.[9] Typical ranges vary from 60% to around 90%.[15] Depending on the degree of obstruction, symptoms vary from no cyanosis or mild cyanosis to profound cyanosis at birth.[9] If the baby is not cyanotic then it is sometimes referred to as a "pink tet".[16] Other symptoms include a heart murmur which may range from almost imperceptible to very loud, difficulty in feeding, failure to gain weight, retarded growth and physical development, labored breathing (dyspnea) on exertion, clubbing of the fingers and toes, and polycythemia.[2] The baby may turn blue with breast feeding or crying.[2] Those born with Tetralogy of Fallot are more likely to experience psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) in later life, potentially due to underlying genetic changes that predispose to both conditions.[17] ### Tet spells[edit] Infants and children with unrepaired tetralogy of Fallot may develop "tet spells".[15] These are acute hypoxia spells, characterized by shortness of breath, cyanosis, agitation, and loss of consciousness.[18]:200 This may be initiated by any event -such as anxiety, pain, dehydration, or fever-[19] leading to decreased oxygen saturation or that causes decreased systemic vascular resistance, which in turn leads to increased shunting through the ventricular septal defect.[15] Clinically, tet spells are characterized by a sudden, marked increase in cyanosis followed by syncope.[18]:200 Older children will often squat instinctively during a tet spell.[15] This increases systemic vascular resistance and allows for a temporary reversal of the shunt. It increases pressure on the left side of the heart, decreasing the right to left shunt thus decreasing the amount of deoxygenated blood entering the systemic circulation.[20][21] ## Cause[edit] Its cause is thought to be due to environmental or genetic factors or a combination. It is associated with chromosome 22 deletions and DiGeorge syndrome.[22]:62 Specific genetic associations include: JAG1,[23] NKX2-5,[24] ZFPM2,[25] VEGF,[26] NOTCH1, TBX1, and FLT4.[27] Embryology studies show that it is a result of anterior malalignment of the aorticopulmonary septum, resulting in the clinical combination of a VSD, pulmonary stenosis, and an overriding aorta.[18]:200 Right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract.[9] ## Pathophysiology[edit] Play media Video explanation The main anatomic defect in TOF is the anterior deviation of the pulmonary outflow septum.[9] This defect results in narrowing of the right ventricular outflow tract (RVOT), override of the aorta, and a ventricular septal defect (VSD).[28] ### Four malformations[edit] "Tetralogy" denotes four parts, here implying the syndrome's four anatomic defects.[2] This is not to be confused with the similarly named teratology, a field of medicine concerned with abnormal development and congenital malformations (including tetralogy of Fallot). Below are the four heart malformations that present together in tetralogy of Fallot: Heart with tetralogy of fallot A: Pulmonary stenosis; B: Overriding aorta; C: Ventricular septal defect (VSD); D: Right ventricular hypertrophy Normal heart Condition Description Pulmonary Infundibular Stenosis A narrowing of the right ventricular outflow tract. It can occur at the pulmonary valve (valvular stenosis) or just below the pulmonary valve (infundibular stenosis). Infundibular pulmonic stenosis is mostly caused by the overgrowth of the heart muscle wall (hypertrophy of the septoparietal trabeculae),[29] however, the events leading to the formation of the overriding aorta are also believed to be a cause. The pulmonic stenosis is the major cause of the malformations, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis.[30] The degree of stenosis varies between individuals with TOF and is the primary determinant of symptoms and severity. This malformation is infrequently described as sub-pulmonary stenosis or subpulmonary obstruction.[31] Overriding aorta An aortic valve with biventricular connection, that is, it is situated above the ventricular septal defect and connected to both the right and the left ventricle. The degree to which the aorta is attached to the right ventricle is referred to as its degree of "override." The aortic root can be displaced toward the front (anteriorly) or directly above the septal defect, but it is always abnormally located to the right of the root of the pulmonary artery. The degree of override is extremely variable, with 5-95% of the valve being connected to the right ventricle.[29] Ventricular septal defect (VSD) A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum (the outlet septum), and in the majority of cases is single and large. In some cases, thickening of the septum (septal hypertrophy) can narrow the margins of the defect.[29] Right ventricular hypertrophy The right ventricle is more muscular than normal, causing a characteristic boot-shaped (coeur-en-sabot) appearance as seen by chest X-ray. Due to the misarrangement of the external ventricular septum, the right ventricular wall increases in size to deal with the increased obstruction to the right outflow tract. This feature is now generally agreed to be a secondary anomaly, as the level of hypertrophy tends to increase with age.[32] Fallot's tetralogy specimen, from the UCT Pathology Learning Centre There is anatomic variation between the hearts of individuals with tetralogy of Fallot.[9] Primarily, the degree of right ventricular outflow tract obstruction varies between patients and generally determines clinical symptoms and disease progression.[9] Presumably, this arises from an unequal growth of the aorticopulmonary septum (aka pulmonary outflow septum).[18]:199 The aorta is too large, thus "overriding," and this "steals" from the pulmonary artery, which is therefore stenosed. This then prevents ventricular wall closure, therefore VSD, and this increases the pressures on the right side, and so the R ventricle becomes bigger to handle the work.[18]:199 ### Additional anomalies[edit] In addition, tetralogy of Fallot may present with other anatomical anomalies, including:[22]:66–8[33] 1. stenosis of the left pulmonary artery, in 40% 2. a bicuspid pulmonary valve, in 60% 3. right-sided aortic arch, in 25% 4. coronary artery anomalies, in 10% 5. a patent foramen ovale or atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot[34] 6. an atrioventricular septal defect 7. partially or totally anomalous pulmonary venous return Tetralogy of Fallot with pulmonary atresia (pseudotruncus arteriosus) is a severe variant[35] in which there is complete obstruction (atresia) of the right ventricular outflow tract, causing an absence of the pulmonary trunk during embryonic development.[22]:67–8 In these individuals, blood shunts completely from the right ventricle to the left where it is pumped only through the aorta. The lungs are perfused via extensive collaterals from the systemic arteries, and sometimes also via the ductus arteriosus.[22]:67–8 ## Diagnosis[edit] A CXR (Chest X-Ray) of a child with tetralogy of Fallot Congenital heart defects are now diagnosed with echocardiography, which is quick, involves no radiation, is very specific, and can be done prenatally.[36] Echocardiography establishes the presence of TOF by demonstrating a VSD, RVH, and aortic override. Many patients are diagnosed prenatally. Color Doppler (type of echocardiography) measures the degree of pulmonary stenosis. Additionally, close monitoring of the ductus arteriosus is done in the neonatal period to ensure that there is adequate blood flow through the pulmonary valve.[22][15]:171–72 In certain cases, coronary artery anatomy cannot be clearly viewed using echocardiogram. In this case, cardiac catheterization can be done.[18]:37, 201 Form a genetics perspective, it is important to screen for DiGeorge in all babies with TOF.[18]:37, 201 Before more sophisticated techniques became available, chest x-ray was the definitive method of diagnosis. The abnormal "coeur-en-sabot" (boot-like) appearance of a heart with tetralogy of Fallot is classically visible via chest x-ray, although most infants with tetralogy may not show this finding.[37] The boot like shape is due to the right ventricular hypertrophy present in TOF. Lung fields are often dark (absence of interstitial lung markings) due to decreased pulmonary blood flow.[15]:171–72 Electrocardiography shows right ventricular hypertrophy (RVH), along with right axis deviation.[22] RVH is noted on EKG as tall R-waves in lead V1 and deep S-waves in lead V5-V6.[38] ## Treatment[edit] ### Tet spells[edit] Tet spells may be treated with beta-blockers such as propranolol, but acute episodes require rapid intervention with morphine or intranasal fentanyl[39] to reduce ventilatory drive, a vasopressor such as phenylephrine, or norepinephrine to increase systemic vascular resistance, and IV fluids for volume expansion.[18]:18, 201 Oxygen (100%) may be effective in treating spells because it is a potent pulmonary vasodilator and systemic vasoconstrictor. This allows more blood flow to the lungs by decreasing shunting of deoxygenated blood from the right to left ventricle through the VSD. There are also simple procedures such as squatting and the knee chest position which increase systemic vascular resistance and decrease right-to-left shunting of deoxygenated blood into the systemic circulation.[18]:18, 201[40] If the spells are refractory to the above treatments, people are usually intubated and sedated. The treatment of last resort for tet spells is extracorporeal membrane oxygenation (ECMO) along with consideration of Blalock Taussig shunt (BT shunt).[18]:18, 201 ### Total surgical repair[edit] Total surgical repair of TOF is a curative surgery. Different techniques can be used in performing TOF repair. However, a transatrial, transpulmonary artery approach is used for most cases.[41]:153 The repair consists of two main steps: closure of the VSD with a patch and reconstruction of the right ventricular outflow tract.[42] This open-heart surgery is designed to relieve the right ventricular outflow tract stenosis by careful resection of muscle and to repair the VSD.[41]:154 Additional reparative or reconstructive surgery may be done on patients as required by their particular cardiac anatomy.[41]:153 Timing of surgery in asymptomatic patients is usually between the ages of 2 months to one year.[18]:201–2 However, in symptomatic patients showing worsening blood oxygen levels, severe tet-spells (cyanotic spells), or dependence on prostaglandins from early neonatal period (to keep the ductus arteriosus open) need to be planned fairly urgently[18]:201–2 Potential surgical repair complications include residual ventricular septal defect, residual outflow tract obstruction, complete atrioventricular block, arrhythmias, aneurysm of right ventricular outflow patch, and pulmonary valve insufficiency.[42]:59 Long term complications most commonly include pulmonary valve regurgitation, and arrhythmias.[43] Total repair of tetralogy of Fallot initially carried a high mortality risk, but this risk has gone down steadily over the years. Surgery is now often carried out in infants one year of age or younger with less than 5% perioperative mortality.[18]:205 Post surgery, most patients enjoy an active life free of symptoms.[18]:205 Currently, long term survival is close to 90%..[18]:167 Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.[44] ### Palliative surgery[edit] Initially surgery involved forming a side to end anastomosis between the subclavian artery and the pulmonary artery -i.e a systemic to pulmonary arterial shunt.[42]:57 This redirected a large portion of the partially oxygenated blood leaving the heart for the body into the lungs, increasing flow through the pulmonary circuit, and relieving symptoms. The first Blalock-Thomas-Taussig shunt surgery was performed on 15-month-old Eileen Saxon on November 29, 1944 with dramatic results.[45] The Potts shunt[46] and the Waterston-Cooley shunt[47][48] are other shunt procedures which were developed for the same purpose. These are no longer used. Currently, palliative surgery is not normally performed on infants with TOF except for extreme cases.[15]:173 For example, in symptomatic infants, a two-stage repair (initial systemic to arterial shunt placement followed by total surgical repair) may be done.[49] Potential complications include inadequate pulmonary blood flow, pulmonary artery distortion, inadequate growth of the pulmonary arteries, and acquired pulmonary atresia.[42]:59 ## Prognosis[edit] Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy due to the increased resistance caused by narrowing of the pulmonary trunk.[18]:199 This progresses to heart failure which begins in the right ventricle and often leads to left heart failure and dilated cardiomyopathy. Mortality rate depends on the severity of the tetralogy of Fallot. If left untreated, TOF carries a 35% mortality rate in the first year of life, and a 50% mortality rate in the first three years of life.[43] Patients with untreated TOF rarely progress to adulthood.[43] Patients who have undergone total surgical repair of tetralogy of Fallot have improved hemodynamics and often have good to excellent cardiac function after the operation with some to no exercise intolerance (New York Heart Association Class I-II).[50] Long-term outcome is usually excellent for most patients, however residual post-surgical defects -such as pulmonary regurgitation, pulmonary artery stenosis, residual VSD, right ventricular dysfunction, right ventricular outflow tract obstruction - may affect life expectancy and increase the need for reoperation.[18]:205 Within 30 years after correction, 50% of patients will require reoperation.[43] The most common cause of reoperation is a leaky pulmonary valve (pulmonary valve insufficiency).[43] This is usually corrected with a procedure called pulmonary valve replacement.[22]:136 ## Epidemiology[edit] Tetralogy of Fallot occurs approximately 400 times per million live births.[51] It accounts for 7 to 10% of all congenital heart abnormalities, making it the most common cyanotic heart defect.[44] Males and females are affected equally.[4] Genetically it is most commonly associated with Down's syndrome and DiGeorge syndrome.[5][22] ## History[edit] Tetralogy of Fallot was initially described in 1671 by Niels Stensen.[1][13] A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named.[1][14] In 1924, Maude Abbott coined the term "tetralogy of Fallot".[52] The first surgical repair was carried out in 1944 at Johns Hopkins.[53] The procedure was conducted by surgeon Alfred Blalock and cardiologist Helen B. Taussig, with Vivien Thomas also providing substantial contributions and listed as an assistant.[3] This first surgery was depicted in the film Something the Lord Made.[45] It was actually Helen Taussig who convinced Alfred Blalock that the shunt was going to work. 15-month-old Eileen Saxon was the first person to receive a Blalock-Thomas-Taussig shunt.[45] Furthermore, the Blalock-Thomas-Taussig procedure, initially the only surgical treatment available for tetralogy of Fallot, was palliative but not curative. The first total repair of tetralogy of Fallot was done by a team led by C. Walton Lillehei at the University of Minnesota in 1954 on an 11-year-old boy.[54] Total repair on infants has had success from 1981, with research indicating that it has a comparatively low mortality rate.[50] Today the adult TOF population continues to grow and is one of the most common congenital heart defect seen in adult outpatient clinics.[44] ## Notable cases[edit] * Shaun White,[55] American professional snowboarder and skateboarder * Beau Casson,[56] Australian cricketer * Dennis McEldowney,[57] New Zealand author and publisher * Max Page, Volkswagen's "Little Darth Vader" from the 2011 Super Bowl commercial[58] * Billy Kimmel, the son of talk show host Jimmy Kimmel; Billy's diagnosis led Kimmel to discuss access to health care on his show Jimmy Kimmel Live![59] ## See also[edit] * Trilogy of Fallot ## References[edit] 1. ^ a b c d e "Fallot's tetralogy". Whonamedit?. Archived from the original on 3 October 2016. 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Retrieved 2018-02-23. ## External links[edit] Wikimedia Commons has media related to Tetralogy of Fallot. * What Is Tetralogy of Fallot? at the National Institutes of Health * Understanding your child's heart: Tetralogy of Fallot by the British Heart Foundation Classification D * ICD-10: Q21.3 * ICD-9-CM: 745.2 * OMIM: 187500 * MeSH: D013771 * DiseasesDB: 4660 External resources * MedlinePlus: 001567 * eMedicine: emerg/575 * Patient UK: Tetralogy of Fallot * Orphanet: 3303 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Tetralogy of Fallot	c0039685	1,297	wikipedia	https://en.wikipedia.org/wiki/Tetralogy_of_Fallot	2021-01-18T18:54:21	{"gard": ["2245"], "mesh": ["D013771"], "umls": ["C0039685"], "orphanet": ["3303"], "wikidata": ["Q1126831"]}
"Hepatite" redirects here. For the mineral of that name, see Baryte. An inflammation of the liver. Hepatitis Alcoholic hepatitis as seen with a microscope, showing fatty changes (white circles), remnants of dead liver cells, and Mallory bodies (twisted-rope shaped inclusions within some liver cells). (H&E stain) SpecialtyInfectious disease, gastroenterology, hepatology SymptomsYellowish skin, poor appetite, abdominal pain[1][2] ComplicationsScarring of the liver, liver failure, liver cancer[3] DurationShort term or long term[1] CausesViruses, alcohol, toxins, autoimmune[2][3] PreventionVaccination (for viral hepatitis),[2] avoiding excessive alcohol TreatmentMedication, liver transplant[1][4] Frequency> 500 million cases[3] Deaths> One million a year[3] Hepatitis is inflammation of the liver tissue.[5][3] Some people with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea.[1][2] Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months.[1][6] Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure.[7] Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.[3] Hepatitis is most commonly caused by the viruses hepatitis A, B, C, D, and E.[3][2] Other causes include heavy alcohol use, certain medications, toxins, other infections, autoimmune diseases,[2][3] and non-alcoholic steatohepatitis (NASH).[8] Hepatitis A and E are mainly spread by contaminated food and water.[3] Hepatitis B is mainly sexually transmitted, but may also be passed from mother to baby during pregnancy or childbirth and spread through infected blood.[3] Hepatitis C is commonly spread through infected blood such as may occur during needle sharing by intravenous drug users.[3] Hepatitis D can only infect people already infected with hepatitis B.[3] Hepatitis A, B, and D are preventable with immunization.[2] Medications may be used to treat chronic viral hepatitis.[1] Antiviral medications are recommended in all with chronic hepatitis C, except those with conditions that limit their life expectancy.[9] There is no specific treatment for NASH; however, physical activity, a healthy diet, and weight loss are recommended.[8] Autoimmune hepatitis may be treated with medications to suppress the immune system.[10] A liver transplant may be an option in both acute and chronic liver failure.[4] Worldwide in 2015, hepatitis A occurred in about 114 million people, chronic hepatitis B affected about 343 million people and chronic hepatitis C about 142 million people.[11] In the United States, NASH affects about 11 million people and alcoholic hepatitis affects about 5 million people.[8][12] Hepatitis results in more than a million deaths a year, most of which occur indirectly from liver scarring or liver cancer.[3][13] In the United States, hepatitis A is estimated to occur in about 2,500 people a year and results in about 75 deaths.[14] The word is derived from the Greek hêpar (ἧπαρ), meaning "liver", and -itis (-ῖτις), meaning "inflammation".[15] ## Contents * 1 Signs and symptoms * 1.1 Acute hepatitis * 1.2 Fulminant hepatitis * 1.3 Chronic hepatitis * 2 Causes * 2.1 Infectious * 2.1.1 Viral hepatitis * 2.1.2 Parasitic hepatitis * 2.1.3 Bacterial hepatitis * 2.2 Metabolic * 2.2.1 Alcoholic hepatitis * 2.2.2 Toxic and drug-induced hepatitis * 2.2.3 Non-alcoholic fatty liver disease * 2.3 Autoimmune * 2.4 Genetic * 2.5 Ischemic hepatitis * 2.6 Other * 3 Mechanism * 3.1 Viral hepatitis * 3.2 Steatohepatitis * 4 Diagnosis * 4.1 Viral hepatitis * 4.2 Alcoholic versus non-alcoholic * 4.3 Screening for viral hepatitis * 4.3.1 Hepatitis A * 4.3.2 Hepatitis B * 4.3.3 Hepatitis C * 5 Prevention * 5.1 Vaccines * 5.1.1 Hepatitis A * 5.1.2 Hepatitis B * 5.1.3 Other * 5.2 Behavioral changes * 5.2.1 Hepatitis A * 5.2.2 Hepatitis B and C * 5.2.3 Hepatitis D * 5.2.4 Hepatitis E * 5.2.5 Alcoholic hepatitis * 5.3 Successes * 5.3.1 Hepatitis A * 5.3.2 Hepatitis B * 5.3.3 Hepatitis C * 5.3.4 Alcoholic hepatitis * 6 Treatment * 6.1 Hepatitis A * 6.2 Hepatitis B * 6.2.1 Acute * 6.2.2 Chronic * 6.3 Hepatitis C * 6.4 Hepatitis D * 6.5 Hepatitis E * 6.6 Alcoholic hepatitis * 7 Prognosis * 7.1 Acute hepatitis * 7.1.1 Fulminant hepatitis * 7.2 Chronic hepatitis * 8 Epidemiology * 8.1 Viral hepatitis * 8.1.1 Hepatitis A * 8.1.2 Hepatitis B * 8.1.3 Hepatitis C * 8.1.4 Hepatitis D * 8.1.5 Hepatitis E * 8.2 Alcoholic hepatitis * 8.3 Non-alcoholic steatohepatitis * 9 History * 9.1 Early observations * 9.2 Willowbrook State School experiments * 9.3 The Australia antigen * 10 Society and culture * 10.1 Economic burden * 10.2 Notable cases * 11 Special populations * 11.1 HIV co-infection * 11.2 Pregnancy * 11.2.1 Hepatitis B * 11.2.2 Hepatitis C * 11.2.3 Hepatitis E * 12 See also * 13 References * 14 External links ## Signs and symptoms[edit] Jaundiced eyes Hepatitis has a broad spectrum of presentations that range from a complete lack of symptoms to severe liver failure.[16][17][18] The acute form of hepatitis, generally caused by viral infection, is characterized by constitutional symptoms that are typically self-limiting.[16][17] Chronic hepatitis presents similarly, but can manifest signs and symptoms specific to liver dysfunction with long-standing inflammation and damage to the organ.[18][19] ### Acute hepatitis[edit] Acute viral hepatitis follows three distinct phases: 1. The initial prodromal phase (preceding symptoms) involves non-specific and flu-like symptoms common to many acute viral infections. These include fatigue, nausea, vomiting, poor appetite, joint pain, and headaches.[16][17] Fever, when present, is most common in cases of hepatitis A and E.[16] Late in this phase, people can experience liver-specific symptoms, including choluria (dark urine) and clay-colored stools.[16][17] 2. Yellowing of the skin and whites of the eyes follow the prodrome after about 1–2 weeks and can last for up to 4 weeks.[16][17] The non-specific symptoms seen in the prodromal typically resolve by this time, but people will develop an enlarged liver and right upper abdominal pain or discomfort.[16] 10–20% of people will also experience an enlarged spleen, while some people will also experience a mild unintentional weight loss.[16][18] 3. The recovery phase is characterized by resolution of the clinical symptoms of hepatitis with persistent elevations in liver lab values and potentially a persistently enlarged liver.[16] All cases of hepatitis A and E are expected to fully resolve after 1–2 months.[16] Most hepatitis B cases are also self-limiting and will resolve in 3–4 months. Few cases of hepatitis C will resolve completely.[16] Both drug-induced hepatitis and autoimmune hepatitis can present very similarly to acute viral hepatitis, with slight variations in symptoms depending on the cause.[20][21] Cases of drug-induced hepatitis can manifest with systemic signs of an allergic reaction including rash, fever, serositis (inflammation of membranes lining certain organs), elevated eosinophils (a type of white blood cell), and suppression of bone marrow activity.[20] ### Fulminant hepatitis[edit] Fulminant hepatitis, or massive hepatic cell death, is a rare and life-threatening complication of acute hepatitis that can occur in cases of hepatitis B, D, and E, in addition to drug-induced and autoimmune hepatitis.[16][20][21] The complication more frequently occurs in instances of hepatitis B and D co-infection at a rate of 2–20% and in pregnant women with hepatitis E at rate of 15–20% of cases.[16][17] In addition to the signs of acute hepatitis, people can also demonstrate signs of coagulopathy (abnormal coagulation studies with easy bruising and bleeding) and encephalopathy (confusion, disorientation, and sleepiness).[16][17] Mortality due to fulminant hepatitis is typically the result of various complications including cerebral edema, gastrointestinal bleeding, sepsis, respiratory failure, or kidney failure.[16] ### Chronic hepatitis[edit] Acute cases of hepatitis are seen to be resolved well within a six-month period. When hepatitis is continued for more than six months it is termed chronic hepatitis.[22] Chronic hepatitis is often asymptomatic early in its course and is detected only by liver laboratory studies for screening purposes or to evaluate non-specific symptoms.[18][19] As the inflammation progresses, patients can develop constitutional symptoms similar to acute hepatitis, including fatigue, nausea, vomiting, poor appetite, and joint pain.[19] Jaundice can occur as well, but much later in the disease process and is typically a sign of advanced disease.[19] Chronic hepatitis interferes with hormonal functions of the liver which can result in acne, hirsutism (abnormal hair growth), and amenorrhea (lack of menstrual period) in women.[19] Extensive damage and scarring of the liver over time defines cirrhosis, a condition in which the liver's ability to function is permanently impeded.[18] This results in jaundice, weight loss, coagulopathy, ascites (abdominal fluid collection), and peripheral edema (leg swelling).[19] Cirrhosis can lead to other life-threatening complications such as hepatic encephalopathy, esophageal varices, hepatorenal syndrome, and liver cancer.[18] ## Causes[edit] Causes of hepatitis can be divided into the following major categories: infectious, metabolic, ischemic, autoimmune, genetic, and other. Infectious agents include viruses, bacteria, and parasites. Metabolic causes include prescription medications, toxins (most notably alcohol), and non-alcoholic fatty liver disease. Autoimmune and genetic causes of hepatitis involve genetic predispositions and tend to affect characteristic populations. ### Infectious[edit] #### Viral hepatitis[edit] Main article: Viral hepatitis Viral hepatitis is the most common type of hepatitis worldwide.[23] Viral hepatitis is caused by five different viruses (hepatitis A, B, C, D, and E).[16] Hepatitis A and hepatitis E behave similarly: they are both transmitted by the fecal–oral route, are more common in developing countries, and are self-limiting illnesses that do not lead to chronic hepatitis.[16][24][25] Hepatitis B, hepatitis C, and hepatitis D are transmitted when blood or mucous membranes are exposed to infected blood and body fluids, such as semen and vaginal secretions.[16] Viral particles have also been found in saliva and breastmilk. However, kissing, sharing utensils, and breastfeeding do not lead to transmission unless these fluids are introduced into open sores or cuts.[26] Hepatitis B and C can present either acutely or chronically.[16] Hepatitis D is a defective virus that requires hepatitis B to replicate and is only found with hepatitis B co-infection.[16] In adults, hepatitis B infection is most commonly self-limiting, with less than 5% progressing to chronic state, and 20 to 30% of those chronically infected developing cirrhosis or liver cancer.[27] However, infection in infants and children frequently leads to chronic infection.[27] Unlike hepatitis B, most cases of hepatitis C lead to chronic infection.[28] Hepatitis C is the second most common cause of cirrhosis in the US (second to alcoholic hepatitis).[29] In the 1970s and 1980s, blood transfusions were a major factor in spreading hepatitis C virus.[28] Since widespread screening of blood products for hepatitis C began in 1992, the risk of acquiring hepatitis C from a blood transfusion has decreased from approximately 10% in the 1970s to 1 in 2 million currently.[16] #### Parasitic hepatitis[edit] Echinococcus granulosus Parasites can also infect the liver and activate the immune response, resulting in symptoms of acute hepatitis with increased serum IgE (though chronic hepatitis is possible with chronic infections).[30] Of the protozoans, Trypanosoma cruzi, Leishmania species, and the malaria-causing Plasmodium species all can cause liver inflammation.[30] Another protozoan, Entamoeba histolytica, causes hepatitis with distinct liver abscesses.[30] Of the worms, the cestode Echinococcus granulosus, also known as the dog tapeworm, infects the liver and forms characteristic hepatic hydatid cysts.[30] The liver flukes Fasciola hepatica and Clonorchis sinensis live in the bile ducts and cause progressive hepatitis and liver fibrosis.[30] #### Bacterial hepatitis[edit] Bacterial infection of the liver commonly results in pyogenic liver abscesses, acute hepatitis, or granulomatous (or chronic) liver disease.[31] Pyogenic abscesses commonly involve enteric bacteria such as Escherichia coli and Klebsiella pneumoniae and are composed of multiple bacteria up to 50% of the time.[31] Acute hepatitis is caused by Neisseria meningitidis, Neisseria gonorrhoeae, Bartonella henselae, Borrelia burgdorferi, salmonella species, brucella species and campylobacter species.[31] Chronic or granulomatous hepatitis is seen with infection from mycobacteria species, Tropheryma whipplei, Treponema pallidum, Coxiella burnetii, and rickettsia species.[31] ### Metabolic[edit] #### Alcoholic hepatitis[edit] Main article: Alcoholic hepatitis Excessive alcohol consumption is a significant cause of hepatitis and is the most common cause of cirrhosis in the U.S.[29] Alcoholic hepatitis is within the spectrum of alcoholic liver disease. This ranges in order of severity and reversibility from alcoholic steatosis (least severe, most reversible), alcoholic hepatitis, cirrhosis, and liver cancer (most severe, least reversible).[29] Hepatitis usually develops over years-long exposure to alcohol, occurring in 10 to 20% of alcoholics.[32] The most important risk factors for the development of alcoholic hepatitis are quantity and duration of alcohol intake.[32] Long-term alcohol intake in excess of 80 grams of alcohol a day in men and 40 grams a day in women is associated with development of alcoholic hepatitis (1 beer or 4 ounces of wine is equivalent to 12g of alcohol).[29] Alcoholic hepatitis can vary from asymptomatic hepatomegaly (enlarged liver) to symptoms of acute or chronic hepatitis to liver failure.[29] #### Toxic and drug-induced hepatitis[edit] Many chemical agents, including medications, industrial toxins, and herbal and dietary supplements, can cause hepatitis.[33][34] The spectrum of drug-induced liver injury varies from acute hepatitis to chronic hepatitis to acute liver failure.[33] Toxins and medications can cause liver injury through a variety of mechanisms, including direct cell damage, disruption of cell metabolism, and causing structural changes.[35] Some drugs such as paracetamol exhibit predictable dose-dependent liver damage while others such as isoniazid cause idiosyncratic and unpredictable reactions that vary among individuals.[33] There are wide variations in the mechanisms of liver injury and latency period from exposure to development of clinical illness.[29] Many types of drugs can cause liver injury, including the analgesic paracetamol; antibiotics such as isoniazid, nitrofurantoin, amoxicillin-clavulanate, erythromycin, and trimethoprim-sulfamethoxazole; anticonvulsants such as valproate and phenytoin; cholesterol-lowering statins; steroids such as oral contraceptives and anabolic steroids; and highly active anti-retroviral therapy used in the treatment of HIV/AIDS.[29] Of these, amoxicillin-clavulanate is the most common cause of drug-induced liver injury, and paracetamol toxicity the most common cause of acute liver failure in the United States and Europe.[33] Herbal remedies and dietary supplements are another important cause of hepatitis; these are the most common causes of drug-induced hepatitis in Korea.[36] The United-States-based Drug Induced Liver Injury Network linked more than 16% of cases of hepatotoxicity to herbal and dietary supplements.[37] In the United States, herbal and dietary supplements – unlike pharmaceutical drugs – are unregulated by the Food and Drug Administration.[37] However, the National Institutes of Health maintains the LiverTox database for consumers to track all known prescription and non-prescription compounds associated with liver injury.[38] Exposure to other hepatotoxins can occur accidentally or intentionally through ingestion, inhalation, and skin absorption. The industrial toxin carbon tetrachloride and the wild mushroom Amanita phalloides are other known hepatotoxins.[33][34][39] #### Non-alcoholic fatty liver disease[edit] Main article: Non-alcoholic fatty liver disease Non-alcoholic hepatitis is within the spectrum of non-alcoholic liver disease (NALD), which ranges in severity and reversibility from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) to cirrhosis to liver cancer, similar to the spectrum of alcoholic liver disease.[40] Non-alcoholic liver disease occurs in people with little or no history of alcohol use, and is instead strongly associated with metabolic syndrome, obesity, insulin resistance and diabetes, and hypertriglyceridemia.[29] Over time, non-alcoholic fatty liver disease can progress to non-alcoholic steatohepatitis, which additionally involves liver cell death, liver inflammation and possible fibrosis.[29] Factors accelerating progression from NAFLD to NASH are obesity, older age, non-African American ethnicity, female gender, diabetes mellitus, hypertension, higher ALT or AST level, higher AST/ALT ratio, low platelet count, and an ultrasound steatosis score.[29] In the early stages (as with NAFLD and early NASH), most patients are asymptomatic or have mild right upper quadrant pain, and diagnosis is suspected on the basis of abnormal liver function tests.[29] As the disease progresses, symptoms typical of chronic hepatitis may develop.[41] While imaging can show fatty liver, only liver biopsy can demonstrate inflammation and fibrosis characteristic of NASH.[42] 9 to 25% of patients with NASH develop cirrhosis.[29] NASH is recognized as the third most common cause of liver disease in the United States.[41] ### Autoimmune[edit] Main article: Autoimmune hepatitis Autoimmune hepatitis is a chronic disease caused by an abnormal immune response against liver cells.[43] The disease is thought to have a genetic predisposition as it is associated with certain human leukocyte antigens involved in the immune response.[44] As in other autoimmune diseases, circulating auto-antibodies may be present and are helpful in diagnosis.[45] Auto-antibodies found in patients with autoimmune hepatitis include the sensitive but less specific anti-nuclear antibody (ANA), smooth muscle antibody (SMA), and atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA).[45] Other autoantibodies that are less common but more specific to autoimmune hepatitis are the antibodies against liver kidney microsome 1 (LKM1) and soluble liver antigen (SLA).[45] Autoimmune hepatitis can also be triggered by drugs (such as nitrofurantoin, hydralazine, and methyldopa), after liver transplant, or by viruses (such as hepatitis A, Epstein-Barr virus, or measles).[29] Autoimmune hepatitis can present anywhere within the spectrum from asymptomatic to acute or chronic hepatitis to fulminant liver failure.[29] Patients are asymptomatic 25–34% of the time, and the diagnosis is suspected on the basis of abnormal liver function tests.[45] Up to 40% of cases present with signs and symptoms of acute hepatitis.[29] As with other autoimmune diseases, autoimmune hepatitis usually affects young women (though it can affect patients of either sex of any age), and patients can exhibit classic signs and symptoms of autoimmunity such as fatigue, anemia, anorexia, amenorrhea, acne, arthritis, pleurisy, thyroiditis, ulcerative colitis, nephritis, and maculopapular rash.[29] Autoimmune hepatitis increases the risk for cirrhosis, and the risk for liver cancer is increased by about 1% for each year of the disease.[29] Many people with autoimmune hepatitis have other autoimmune diseases.[46] Autoimmune hepatitis is distinct from the other autoimmune diseases of the liver: primary biliary cirrhosis and primary sclerosing cholangitis. However, all of these diseases can lead to scarring, fibrosis, and cirrhosis of the liver.[29][45] ### Genetic[edit] Genetic causes of hepatitis include alpha-1-antitrypsin deficiency, hemochromatosis, and Wilson's disease.[29] In alpha-1-antitrypsin deficiency, a co-dominant mutation in the gene for alpha-1-antitrypsin results in the abnormal accumulation of the mutant AAT protein within liver cells, leading to liver disease.[47] Hemochromatosis and Wilson's disease are both autosomal recessive diseases involving abnormal storage of minerals.[29] In hemochromatosis, excess amounts of iron accumulate in multiple body sites, including the liver, which can lead to cirrhosis.[29] In Wilson's disease, excess amounts of copper accumulate in the liver and brain, causing cirrhosis and dementia.[29] When the liver is involved, alpha-1-antitrypsin deficiency and Wilson's disease tend to present as hepatitis in the neonatal period or in childhood.[29] Hemochromatosis typically presents in adulthood, with the onset of clinical disease usually after age 50.[29] ### Ischemic hepatitis[edit] Main article: Ischemic hepatitis Ischemic hepatitis (also known as shock liver) results from reduced blood flow to the liver as in shock, heart failure, or vascular insufficiency.[48] The condition is most often associated with heart failure but can also be caused by shock or sepsis. Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT). The condition usually resolves if the underlying cause is treated successfully. Ischemic hepatitis rarely causes permanent liver damage.[49] ### Other[edit] Main article: Neonatal hepatitis Hepatitis can also occur in neonates and is attributable to a variety of causes, some of which are not typically seen in adults.[50] Congenital or perinatal infection with the hepatitis viruses, toxoplasma, rubella, cytomegalovirus, and syphilis can cause neonatal hepatitis.[50] Structural abnormalities such as biliary atresia and choledochal cysts can lead to cholestatic liver injury leading to neonatal hepatitis.[50] Metabolic diseases such as glycogen storage disorders and lysosomal storage disorders are also implicated.[50] Neonatal hepatitis can be idiopathic, and in such cases, biopsy often shows large multinucleated cells in the liver tissue.[51] This disease is termed giant cell hepatitis and may be associated with viral infection, autoimmune disorders, and drug toxicity.[52][53] ## Mechanism[edit] The specific mechanism varies and depends on the underlying cause of the hepatitis. Generally, there is an initial insult that causes liver injury and activation of an inflammatory response, which can become chronic, leading to progressive fibrosis and cirrhosis.[16] ### Viral hepatitis[edit] Stages of liver disease The pathway by which hepatic viruses cause viral hepatitis is best understood in the case of hepatitis B and C.[16] The viruses do not directly activate apoptosis (cell death).[16][54] Rather, infection of liver cells activates the innate and adaptive arms of the immune system leading to an inflammatory response which causes cellular damage and death, including viral-induced apoptosis via the induction of the death receptor-mediated signaling pathway.[16][54][55][56] Depending on the strength of the immune response, the types of immune cells involved and the ability of the virus to evade the body's defense, infection can either lead to clearance (acute disease) or persistence (chronic disease) of the virus.[16] The chronic presence of the virus within liver cells results in multiple waves of inflammation, injury and wound healing that over time lead to scarring or fibrosis and culminate in hepatocellular carcinoma.[54][57] Individuals with an impaired immune response are at greater risk of developing chronic infection.[16] Natural killer cells are the primary drivers of the initial innate response and create a cytokine environment that results in the recruitment of CD4 T-helper and CD8 cytotoxic T-cells.[58][59] Type I interferons are the cytokines that drive the antiviral response.[59] In chronic Hepatitis B and C, natural killer cell function is impaired.[58] ### Steatohepatitis[edit] Steatohepatitis is seen in both alcoholic and non-alcoholic liver disease and is the culmination of a cascade of events that began with injury. In the case of non-alcoholic steatohepatitis, this cascade is initiated by changes in metabolism associated with obesity, insulin resistance, and lipid dysregulation.[60][61] In alcoholic hepatitis, chronic excess alcohol use is the culprit.[62] Though the inciting event may differ, the progression of events is similar and begins with accumulation of free fatty acids (FFA) and their breakdown products in the liver cells in a process called steatosis.[60][61][62] This initially reversible process overwhelms the hepatocyte's ability to maintain lipid homeostasis leading to a toxic effect as fat molecules accumulate and are broken down in the setting of an oxidative stress response.[60][61][62] Over time, this abnormal lipid deposition triggers the immune system via toll-like receptor 4 (TLR4) resulting in the production of inflammatory cytokines such as TNF that cause liver cell injury and death.[60][61][62] These events mark the transition to steatohepatitis and in the setting of chronic injury, fibrosis eventually develops setting up events that lead to cirrhosis and hepatocellular carcinoma.[60] Microscopically, changes that can be seen include steatosis with large and swollen hepatocytes (ballooning), evidence of cellular injury and cell death (apoptosis, necrosis), evidence of inflammation in particular in zone 3 of the liver, variable degrees of fibrosis and Mallory bodies.[60][63][64] ## Diagnosis[edit] Most elevated aminotransferase Cause ALT Chronic hepatitis B, C, and D Nonalcoholic liver disease Acute viral hepatitis Medications/toxins Autoimmune hepatitis Wilson's disease Alpha-1-antitrypsin deficiency Hemochromatosis Ischemic hepatitis (severe elevation up to thousands) AST Alcoholic liver disease Cirrhosis Histopathology of acute hepatitis with lobular disarray and associated lymphocytic inflammation, acidophil body formation (arrow) and bilirubinostasis. Diagnosis of hepatitis is made on the basis of some or all of the following: a person's signs and symptoms, medical history including sexual and substance use history, blood tests, imaging, and liver biopsy.[29] In general, for viral hepatitis and other acute causes of hepatitis, the person's blood tests and clinical picture are sufficient for diagnosis.[16][29] For other causes of hepatitis, especially chronic causes, blood tests may not be useful.[29] In this case, liver biopsy is the gold standard for establishing the diagnosis: histopathologic analysis is able to reveal the precise extent and pattern of inflammation and fibrosis.[29] However, liver biopsy is typically not the initial diagnostic test because it is invasive and is associated with a small but significant risk of bleeding that is increased in people with liver injury and cirrhosis.[65] Blood testing includes liver enzymes, serology (i.e. for autoantibodies), nucleic acid testing (i.e. for hepatitis virus DNA/RNA), blood chemistry, and complete blood count.[29] Characteristic patterns of liver enzyme abnormalities can point to certain causes or stages of hepatitis.[66][67] Generally, AST and ALT are elevated in most cases of hepatitis regardless of whether the person shows any symptoms.[29] However, the degree of elevation (i.e. levels in the hundreds vs. in the thousands), the predominance for AST vs. ALT elevation, and the ratio between AST and ALT are informative of the diagnosis.[29] Ultrasound, CT, and MRI can all identify steatosis (fatty changes) of the liver tissue and nodularity of the liver surface suggestive of cirrhosis.[68][69] CT and especially MRI are able to provide a higher level of detail, allowing visualization and characterize such structures as vessels and tumors within the liver.[70] Unlike steatosis and cirrhosis, no imaging test is able to detect liver inflammation (i.e. hepatitis) or fibrosis.[29] Liver biopsy is the only definitive diagnostic test that is able to assess inflammation and fibrosis of the liver.[29] ### Viral hepatitis[edit] Main article: Viral hepatitis Viral hepatitis is primarily diagnosed through blood tests for levels of viral antigens (such as the hepatitis B surface or core antigen), anti-viral antibodies (such as the anti-hepatitis B surface antibody or anti-hepatitis A antibody), or viral DNA/RNA.[16][29] In early infection (i.e. within 1 week), IgM antibodies are found in the blood.[29] In late infection and after recovery, IgG antibodies are present and remain in the body for up to years.[29] Therefore, when a patient is positive for IgG antibody but negative for IgM antibody, he is considered immune from the virus via either prior infection and recovery or prior vaccination.[29] In the case of hepatitis B, blood tests exist for multiple virus antigens (which are different components of the virion particle) and antibodies.[71] The combination of antigen and antibody positivity can provide information about the stage of infection (acute or chronic), the degree of viral replication, and the infectivity of the virus.[71] ### Alcoholic versus non-alcoholic[edit] The most apparent distinguishing factor between alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) is a history of alcohol use or abuse.[72] Thus, in patients who have no or negligible alcohol use, the diagnosis is unlikely to be alcoholic hepatitis. However, in those who use alcohol, the diagnosis may just as likely be alcoholic or nonalcoholic hepatitis especially if there is concurrent obesity, diabetes, and metabolic syndrome. In this case, alcoholic and nonalcoholic hepatitis can be distinguished by the pattern of liver enzyme abnormalities; specifically, in alcoholic steatohepatitis AST>ALT with ratio of AST:ALT>2:1 while in nonalcoholic steatohepatitis ALT>AST with ratio of ALT:AST>1.5:1.[72] Of note, liver biopsy shows identical findings in patients with ASH and NASH, specifically, the presence of polymorphonuclear infiltration, hepatocyte necrosis and apoptosis in the form of ballooning degeneration, Mallory bodies, and fibrosis around veins and sinuses.[29] ### Screening for viral hepatitis[edit] The purpose of screening for viral hepatitis is to identify people infected with the disease as early as possible, even before symptoms and transaminase elevations may be present. This allows for early treatment, which can both prevent disease progression and decrease the likelihood of transmission to others. #### Hepatitis A[edit] Hepatitis A causes an acute illness that does not progress to chronic liver disease. Therefore, the role of screening is to assess immune status in people who are at high risk of contracting the virus, as well as in people with known liver disease for whom hepatitis A infection could lead to liver failure.[73][74] People in these groups who are not already immune can receive the hepatitis A vaccine. Those at high risk and in need of screening include:[75][76][77] * People with poor sanitary habits such as not washing hands after using the restroom or changing diapers * People who do not have access to clean water * People in close contact (either living with or having sexual contact) with someone who has hepatitis A * People who use illicit drugs * People with liver disease * People traveling to an area with endemic hepatitis A The presence of anti-hepatitis A IgG in the blood indicates past infection with the virus or prior vaccination.[78] #### Hepatitis B[edit] Hepatitis B virus v2 The CDC, WHO, USPSTF, and ACOG recommend routine hepatitis B screening for certain high-risk populations.[79][80][81][82] Specifically, these populations include people who are: * Born in countries where the prevalence of hepatitis B is high (defined as ≥2% of the population), whether or not they have been vaccinated[79][80] * Born in the United States whose parents are from countries where the prevalence of hepatitis B is very high (defined as ≥8% of the population), and who were not vaccinated[79][80] * HIV positive[79][80][81] * Intravenous drug users[79][80][81] * Men who have sex with men[79][80][81] * In close contact with (i.e. live or have sex with) people known to have hepatitis B[79][80][81] * Pregnant[79][80][82] * Beginning immunosuppressive or cytotoxic therapy[79] * Found to have elevated liver enzymes without a known cause[79] * Blood, organ, or tissue donors[81] * Incarcerated[81] * On hemodialysis[79] Screening consists of a blood test that detects hepatitis B surface antigen (HBsAg). If HBsAg is present, a second test – usually done on the same blood sample – that detects the antibody for the hepatitis B core antigen (anti-HBcAg) can differentiate between acute and chronic infection.[79][83] People who are high-risk whose blood tests negative for HBsAg can receive the hepatitis B vaccine to prevent future infection.[79][80][81][82] #### Hepatitis C[edit] HCV structure Play media ABHD5CGI-58-the-Chanarin-Dorfman-Syndrome-Protein-Mobilises-Lipid-Stores-for-Hepatitis-C-Virus-ppat.1005568.s014 The CDC, WHO, USPSTF, AASLD, and ACOG recommend screening people at high risk for hepatitis C infection.[82][84][85][86][9] These populations include people who are: * Intravenous drug users (past or current)[84][85][86][9] * Intranasal illicit drug users[84][85][86][9] * HIV-positive[84][85][86][9] * Men who have sex with men[9] * Incarcerated, or who have been in the past[84][85][86][9] * On long-term hemodialysis, or who have been in the past[84][85][86][9] * Recipients of tattoos in an "unregulated setting"[86][9] * Recipients of blood products or organs prior to 1992 in the United States[84][86][9] * Adults in the United States born between 1945 and 1965[86][9] * Born to HCV-positive mothers[9] * Pregnant, and engaging in high-risk behaviors[82] * Workers in a healthcare setting who have had a needlestick injury[9] * Blood or organ donors.[9] * Sex workers[85] For people in the groups above whose exposure is ongoing, screening should be "periodic," though according to the USPSTF, research has not defined the optimal screening interval.[86] The AASLD recommends screening men who have sex with men who are HIV-positive annually.[9] People born in the US between 1945 and 1965 should be screened once (unless they have other exposure risks).[84][86][9] Screening consists of a blood test that detects anti-hepatitis C virus antibody. If anti-hepatitis C virus antibody is present, a confirmatory test to detect HCV RNA indicates chronic disease.[85][9] ## Prevention[edit] ### Vaccines[edit] #### Hepatitis A[edit] Main article: Hepatitis A vaccine Havrix vaccine The CDC recommends the hepatitis A vaccine for all children beginning at age one, as well as for those who have not been previously immunized and are at high risk for contracting the disease.[75][76] For children 12 months of age or older, the vaccination is given as a shot into the muscle in two doses 6–18 months apart and should be started before the age 24 months.[87] The dosing is slightly different for adults depending on the type of the vaccine. If the vaccine is for hepatitis A only, two doses are given 6–18 months apart depending on the manufacturer.[77] If the vaccine is combined hepatitis A and hepatitis B, up to 4 doses may be required.[77] #### Hepatitis B[edit] Main article: Hepatitis B vaccine WHO-UNICEF estimates of hepatitis B vaccine (HepB-BD) coverage in countries from the European WHO region in the years 2000-2015 The CDC recommends the routine vaccination of all children under the age of 19 with the hepatitis B vaccine.[88] They also recommend it for those who desire it or are at high risk.[76] Routine vaccination for hepatitis B starts with the first dose administered as a shot into the muscle before the newborn is discharged from the hospital. An additional two doses should be administered before the child is 18 months.[87] For babies born to a mother with hepatitis B surface antigen positivity, the first dose is unique – in addition to the vaccine, the hepatitis immune globulin should also be administered, both within 12 hours of birth. These newborns should also be regularly tested for infection for at least the first year of life.[87] There is also a combination formulation that includes both hepatitis A and B vaccines.[89] #### Other[edit] There are currently no vaccines available in the United States for hepatitis C or E.[85][90][91] In 2015, a group in China published an article regarding the development of a vaccine for hepatitis E.[92] As of March 2016, the United States government was in the process of recruiting participants for the phase IV trial of the hepatitis E vaccine.[93] ### Behavioral changes[edit] #### Hepatitis A[edit] Because hepatitis A is transmitted primarily through the oral-fecal route, the mainstay of prevention aside from vaccination is good hygiene, access to clean water and proper handling of sewage.[76] #### Hepatitis B and C[edit] As hepatitis B and C are transmitted through blood and multiple bodily fluids, prevention is aimed at screening blood prior to transfusion, abstaining from the use of injection drugs, safe needle and sharps practices in healthcare settings, and safe sex practices.[27][85] #### Hepatitis D[edit] Worldwide prevalence of HDV among HBV carriers in 2015. Eight genotypes have been identified worldwide by comparative phylogenetic analysis. Genotype 1 is the most frequent and has variable pathogenicity, Genotypes 2 and 4 are found in East Asia causing relatively mild disease. Genotype 3 is found in South America in association with severe hepatitis. Genotypes 5, 6, 7, 8 have been found only in Africa.[94] The hepatitis D virus requires that a person first be infected with hepatitis B virus, so prevention efforts should focus on limiting the spread of hepatitis B. In people who have chronic hepatitis B infection and are at risk for superinfection with the hepatitis D virus, the preventive strategies are the same as for hepatitis B.[91] #### Hepatitis E[edit] Hepatitis E is spread primarily through the oral-fecal route but may also be spread by blood and from mother to fetus. The mainstay of hepatitis E prevention is similar to that for hepatitis A (namely, good hygiene and clean water practices).[90] #### Alcoholic hepatitis[edit] As excessive alcohol consumption can lead to hepatitis and cirrhosis, the following are maximal recommendations for alcohol consumption:[95] * Women – ≤ 3 drinks on any given day and ≤ 7 drinks per week * Men – ≤ 4 drinks on any given day and ≤ 14 drinks per week ### Successes[edit] #### Hepatitis A[edit] In the United States, universal immunization has led to a two-thirds decrease in hospital admissions and medical expenses due to hepatitis A.[96] #### Hepatitis B[edit] In the United States new cases of hepatitis B decreased 75% from 1990 to 2004.[97] The group that saw the greatest decrease was children and adolescents, likely reflecting the implementation of the 1999 guidelines.[98] #### Hepatitis C[edit] Hepatitis C infections each year had been declining since the 1980s, but began to increase again in 2006.[99] The data are unclear as to whether the decline can be attributed to needle exchange programmes.[100] #### Alcoholic hepatitis[edit] Depiction of a liver failure patient Because people with alcoholic hepatitis may have no symptoms, it can be difficult to diagnose and the number of people with the disease is probably higher than many estimates.[101] Programs such as Alcoholics Anonymous have been successful in decreasing death due to cirrhosis, but it is difficult to evaluate their success in decreasing the incidence of alcoholic hepatitis.[102] ## Treatment[edit] The treatment of hepatitis varies according to the type, whether it is acute or chronic, and the severity of the disease. * Activity - Many people with hepatitis prefer bed rest, though it is not necessary to avoid all physical activity while recovering.[16] * Diet -A high-calorie diet is recommended.[16] Many people develop nausea and cannot tolerate food later in the day, so the bulk of intake may be concentrated in the earlier part of the day.[16] In the acute phase of the disease, intravenous feeding may be needed if patients cannot tolerate food and have poor oral intake subsequent to nausea and vomiting.[16] * Drugs - People with hepatitis should avoid taking drugs metabolized by the liver.[16] Glucocorticoids are not recommended as a treatment option for acute viral hepatitis and may even cause harm, such as development of chronic hepatitis.[16] * Precautions - Universal precautions should be observed. Isolation is usually not needed, except in cases of hepatitis A and E who have fecal incontinence, and in cases of hepatitis B and C who have uncontrolled bleeding.[16] ### Hepatitis A[edit] Main article: Hepatitis A Hepatitis A usually does not progress to a chronic state, and rarely requires hospitalization.[16][75] Treatment is supportive and includes such measures as providing intravenous (IV) hydration and maintaining adequate nutrition.[16][75] Rarely, people with the hepatitis A virus can rapidly develop liver failure, termed fulminant hepatic failure, especially the elderly and those who had a pre-existing liver disease, especially hepatitis C.[16][75] Mortality risk factors include greater age and chronic hepatitis C.[16] In these cases, more aggressive supportive therapy and liver transplant may be necessary.[16] ### Hepatitis B[edit] Main article: Hepatitis B #### Acute[edit] In healthy patients, 95–99% recover with no long-lasting effects, and antiviral treatment is not warranted.[16] Age and comorbid conditions can result in a more prolonged and severe illness. Certain patients warrant hospitalization, especially those who present with clinical signs of ascites, peripheral edema, and hepatic encephalopathy, and laboratory signs of hypoglycemia, prolonged prothrombin time, low serum albumin, and very high serum bilirubin.[16] In these rare, more severe acute cases, patients have been successfully treated with antiviral therapy similar to that used in cases of chronic hepatitis B, with nucleoside analogues such as entecavir or tenofovir. As there is a dearth of clinical trial data and the drugs used to treat are prone to developing resistance, experts recommend reserving treatment for severe acute cases, not mild to moderate.[16] #### Chronic[edit] Chronic hepatitis B management aims to control viral replication, which is correlated with progression of disease.[19] Seven drugs are approved in the United States:[19] * Injectable interferon alpha was the first therapy approved for chronic hepatitis B.[19] It has several side effects, most of which are reversible with removal of therapy, but it has been supplanted by newer treatments for this indication.[19] These include long-acting interferon bound to polyethylene glycol (pegylated interferon) and the oral nucleoside analogues.[19] * Pegylated interferon (PEG IFN) is dosed just once a week as a subcutaneous injection and is both more convenient and effective than standard interferon.[19] Although it does not develop resistance as do many of the oral antivirals, it is poorly tolerated and requires close monitoring.[19] PEG IFN is estimated to cost about $18,000 per year in the United States, compared to $2,500-8,700 for the oral medications; however, its treatment duration is 48 weeks as opposed to the oral antivirals, which require indefinite treatment for most patients (minimum 1 year).[19] PEG IFN is not effective in patients with high levels of viral activity and cannot be used in immunosuppressed patients or those with cirrhosis.[19] * Lamivudine was the first approved oral nucleoside analogue.[19] While effective and potent, lamivudine has been replaced by newer, more potent treatments in the Western world and is no longer recommended as first-line treatment.[19] However, it is still used in areas where newer agents either have not been approved or are too costly.[19] Generally, the course of treatment is a minimum of one year with a minimum of six additional months of "consolidation therapy."[19] Based on viral response, longer therapy may be required, and certain patients require indefinite long-term therapy.[19] Due to a less robust response in Asian patients, consolidation therapy is recommended to be extended to at least a year.[19] All patients should be monitored for viral reactivation, which if identified, requires restarting treatment.[19] Lamivudine is generally safe and well tolerated.[19] Many patients develop resistance, which is correlated with longer treatment duration.[19] If this occurs, an additional antiviral is added.[19] Lamivudine as a single treatment is contraindicated in patients coinfected with HIV, as resistance develops rapidly, but it can be used as part of a multidrug regimen.[19] * Adefovir dipivoxil, a nucleotide analogue, has been used to supplement lamivudine in patients who develop resistance, but is no longer recommended as first-line therapy.[19] * Entecavir is safe, well tolerated, less prone to developing resistance, and the most potent of the existing hepatitis B antivirals; it is thus a first-line treatment choice.[19] It is not recommended for lamivudine-resistant patients or as monotherapy in patients who are HIV positive.[19] * Telbivudine is effective but not recommended as first-line treatment; as compared to entecavir, it is both less potent and more resistance prone.[19] * Tenofovir is a nucleotide analogue and an antiretroviral drug that is also used to treat HIV infection.[19] It is preferred to adefovir both in lamivudine-resistant patients and as initial treatment since it is both more potent and less likely to develop resistance.[19] First-line treatments currently used include PEG IFN, entecavir, and tenofovir, subject to patient and physician preference.[19] Treatment initiation is guided by recommendations issued by The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) and is based on detectable viral levels, HBeAg positive or negative status, ALT levels, and in certain cases, family history of HCC and liver biopsy.[19] In patients with compensated cirrhosis, treatment is recommended regardless of HBeAg status or ALT level, but recommendations differ regarding HBV DNA levels; AASLD recommends treating at DNA levels detectable above 2x103 IU/mL; EASL and WHO recommend treating when HBV DNA levels are detectable at any level.[19][81] In patients with decompensated cirrhosis, treatment and evaluation for liver transplantation are recommended in all cases if HBV DNA is detectable.[19][81] Currently, multidrug treatment is not recommended in treatment of chronic HBV as it is no more effective in the long term than individual treatment with entecavir or tenofovir.[19] ### Hepatitis C[edit] Main article: Hepatitis C The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) recommend antiviral treatment for all patients with chronic hepatitis C infection except for those with additional chronic medical conditions that limit their life expectancy.[9] Once it is acquired, persistence of the hepatitis C virus is the rule, resulting in chronic hepatitis C. The goal of treatment is prevention of hepatocellular carcinoma (HCC).[103] The best way to reduce the long-term risk of HCC is to achieve sustained virological response (SVR).[103] SVR is defined as an undetectable viral load at 12 weeks after treatment completion and indicates a cure.[104][105] Currently available treatments include indirect and direct acting antiviral drugs.[104][105] The indirect acting antivirals include pegylated interferon (PEG IFN) and ribavirin (RBV), which in combination have historically been the basis of therapy for HCV.[104][105] Duration of and response to these treatments varies based on genotype.[104][105] These agents are poorly tolerated but are still used in some resource-poor areas.[104][105] In high-resource countries, they have been supplanted by direct acting antiviral agents, which first appeared in 2011; these agents target proteins responsible for viral replication and include the following three classes:[104][105] * NS3/4A protease inhibitors, including telaprevir, boceprevir, simeprevir, and others * NS5A inhibitors, including ledipasvir, daclatasvir, and others * NS5B polymerase inhibitors, including sofosbuvir, dasabuvir, and others These drugs are used in various combinations, sometimes combined with ribavirin, based on the patient's genotype, delineated as genotypes 1–6.[105] Genotype 1 (GT1), which is the most prevalent genotype in the United States and around the world, can now be cured with a direct acting antiviral regimen.[105] First-line therapy for GT1 is a combination of sofosbuvir and ledipasvir (SOF/LDV) for 12 weeks for most patients, including those with advanced fibrosis or cirrhosis.[105] Certain patients with early disease need only 8 weeks of treatment while those with advanced fibrosis or cirrhosis who have not responded to prior treatment require 24 weeks.[105] Cost remains a major factor limiting access to these drugs, particularly in low-resource nations; the cost of the 12-week GT1 regimen (SOF/LDV) has been estimated at US$94,500.[104] ### Hepatitis D[edit] Main article: Hepatitis D Hepatitis D is difficult to treat, and effective treatments are lacking. Interferon alpha has proven effective at inhibiting viral activity but only on a temporary basis.[106] ### Hepatitis E[edit] Main article: Hepatitis E Hepatitis E virus Similar to hepatitis A, treatment of hepatitis E is supportive and includes rest and ensuring adequate nutrition and hydration.[107] Hospitalization may be required for particularly severe cases or for pregnant women.[107] ### Alcoholic hepatitis[edit] First-line treatment of alcoholic hepatitis is treatment of alcoholism.[32] For those who abstain completely from alcohol, reversal of liver disease and a longer life are possible; patients at every disease stage have been shown to benefit by prevention of additional liver injury.[32][62] In addition to referral to psychotherapy and other treatment programs, treatment should include nutritional and psychosocial evaluation and treatment.[32][62][108] Patients should also be treated appropriately for related signs and symptoms, such as ascites, hepatic encephalopathy, and infection.[62] Severe alcoholic hepatitis has a poor prognosis and is notoriously difficult to treat.[32][62][108] Without any treatment, 20-50% of patients may die within a month, but evidence shows treatment may extend life beyond one month (i.e., reduce short-term mortality).[32][108][109] Available treatment options include pentoxifylline (PTX), which is a nonspecific TNF inhibitor, corticosteroids, such as prednisone or prednisolone (CS), corticosteroids with N-acetylcysteine (CS with NAC), and corticosteroids with pentoxifylline (CS with PTX).[108] Data suggest that CS alone or CS with NAC are most effective at reducing short-term mortality.[108] Unfortunately, corticosteroids are contraindicated in some patients, such as those who have active gastrointestinal bleeding, infection, kidney failure, or pancreatitis.[32][62] In these cases PTX may be considered on a case-by-case basis in lieu of CS; some evidence shows PTX is better than no treatment at all and may be comparable to CS while other data show no evidence of benefit over placebo.[108][109] Unfortunately, there are currently no drug treatments that decrease these patients' risk of dying in the longer term, at 3–12 months and beyond.[108] Weak evidence suggests milk thistle extracts may improve survival in alcoholic liver disease and improve certain liver tests (serum bilirubin and GGT) without causing side effects, but a firm recommendation cannot be made for or against milk thistle without further study.[110] ## Prognosis[edit] ### Acute hepatitis[edit] Nearly all patients with hepatitis A infections recover completely without complications if they were healthy prior to the infection. Similarly, acute hepatitis B infections have a favorable course towards complete recovery in 95–99% of patients.[16] However, certain factors may portend a poorer outcome, such as co-morbid medical conditions or initial presenting symptoms of ascites, edema, or encephalopathy.[16] Overall, the mortality rate for acute hepatitis is low: ~0.1% in total for cases of hepatitis A and B, but rates can be higher in certain populations (super infection with both hepatitis B and D, pregnant women, etc.).[16] In contrast to hepatitis A & B, hepatitis C carries a much higher risk of progressing to chronic hepatitis, approaching 85–90%.[111] Cirrhosis has been reported to develop in 20–50% of patients with chronic hepatitis C. Other rare complications of acute hepatitis include pancreatitis, aplastic anemia, peripheral neuropathy, and myocarditis.[16] #### Fulminant hepatitis[edit] Despite the relatively benign course of most viral cases of hepatitis, fulminant hepatitis represents a rare but feared complication. Fulminant hepatitis most commonly occurs in hepatitis B, D, and E. About 1–2% of cases of hepatitis E can lead to fulminant hepatitis, but pregnant women are particularly susceptible, occurring in up to 20% of cases.[112] Mortality rates in cases of fulminant hepatitis rise over 80%, but those patients that do survive often make a complete recovery. Liver transplantation can be life-saving in patients with fulminant liver failure.[113] Hepatitis D infections can transform benign cases of hepatitis B into severe, progressive hepatitis, a phenomenon known as superinfection.[114] ### Chronic hepatitis[edit] Acute hepatitis B infections become less likely to progress to chronic forms as the age of the patient increases, with rates of progression approaching 90% in vertically transmitted cases of infants compared to 1% risk in young adults.[19] Overall, the 5-year survival rate for chronic hepatitis B ranges from 97% in mild cases to 55% in severe cases with cirrhosis.[19] Most patients who acquire hepatitis D at the same time as hepatitis B (co-infection) recover without developing a chronic infection; however, in people with hepatitis B who later acquire hepatitis D (superinfection), chronic infection is much more common at 80-90%, and liver disease progression is accelerated.[106][115] Chronic hepatitis C progresses towards cirrhosis, with estimates of cirrhosis prevalence of 16% at 20 years after infection.[116] While the major causes of mortality in hepatitis C is end stage liver disease, hepatocellular carcinoma is an important additional long term complication and cause of death in chronic hepatitis. Rates of mortality increase with progression of the underlying liver disease. Series of patients with compensated cirrhosis due to HCV have shown 3,5, and 10-year survival rates of 96, 91, and 79% respectively.[117] The 5-year survival rate drops to 50% upon if the cirrhosis becomes decompensated. ## Epidemiology[edit] ### Viral hepatitis[edit] #### Hepatitis A[edit] Hepatitis A is found throughout the world and manifests as large outbreaks and epidemics associated with fecal contamination of water and food sources.[98] Hepatitis A viral infection is predominant in children ages 5–14 with rare infection of infants.[98] Infected children have little to no apparent clinical illness, in contrast to adults in whom greater than 80% are symptomatic if infected.[118] Infection rates are highest in low resource countries with inadequate public sanitation and large concentrated populations.[16][119] In such regions, as much as 90% of children younger than 10 years old have been infected and are immune, corresponding both to lower rates of clinically symptomatic disease and outbreaks.[98][119][120] The availability of a childhood vaccine has significantly reduced infections in the United States, with incidence declining by more than 95% as of 2013.[121] Paradoxically, the highest rates of new infection now occur in young adults and adults who present with worse clinical illness.[16] Specific populations at greatest risk include: travelers to endemic regions, men who have sex with men, those with occupational exposure to non-human primates, individuals with clotting disorders who have received clotting factors, individuals with a history of chronic liver disease where co-infection with hepatitis A can lead to fulminant hepatitis, and intravenous drug users (rare).[98] #### Hepatitis B[edit] Main article: Hepatitis B HBV replication Hepatitis B is the most common cause of viral hepatitis in the world with more than 240 million chronic carriers of the virus, 1 million of whom are in the United States.[27][98] In approximately two-thirds of patients who develop acute hepatitis B infection, no identifiable exposure is evident.[16] Of those acutely infected, 25% become lifetime carriers of the virus.[98] Risk of infection is highest among intravenous drug users, individuals with high-risk sexual behaviors, healthcare workers, individuals with a history of multiple transfusions, organ transplant patients, dialysis patients and newborns infected during the birthing process.[98] Close to 780,000 deaths in the world are attributed to hepatitis B.[27] The most endemic regions are in sub-Saharan Africa and East Asia, where as many as 10% of adults are chronic carriers.[27] Carrier rates in developed nations are significantly lower, encompassing less than 1% of the population.[27] In endemic regions, transmission is thought to be associated with exposure during birth and close contact between young infants.[16][27] #### Hepatitis C[edit] Main article: Hepatitis C HepC replication Chronic hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma.[122] It is a common medical reason for liver transplantation due to its severe complications.[122] It is estimated that 130–180 million people in the world are affected by this disease representing a little more than 3% of the world population.[85][98][122] In the developing regions of Africa, Asia and South America, prevalence can be as high as 10% of the population.[98] In Egypt, rates of hepatitis C infection as high as 20% have been documented and are associated with iatrogenic contamination related to schistosomiasis treatment in the 1950s–1980s.[16][98] Currently in the United States, approximately 3.5 million adults are estimated to be infected.[123] Hepatitis C is particularly prevalent among people born between 1945 and 1965, a group of about 800,000 people, with prevalence as high as 3.2% versus 1.6% in the general U.S. population.[16] Most chronic carriers of hepatitis C are unaware of their infection status.[16] The most common mode of transmission of hepatitis C virus is exposure to blood products via blood transfusions (prior to 1992) and intravenous drug injection.[16][98] A history of intravenous drug injection is the most important risk factor for chronic hepatitis C.[122] Other susceptible populations include individuals with high-risk sexual behavior, infants of infected mothers, and healthcare workers.[98] #### Hepatitis D[edit] Main article: Hepatitis D The hepatitis D virus causes chronic and fulminant hepatitis in the context of co-infection with the hepatitis B virus.[98] It is primarily transmitted via non-sexual contact and via needles.[16][98] Susceptibility to hepatitis D differs by geographic region.[16][98] In the United States and Northern Europe, populations at risk are intravenous drug users and individuals who receive multiple transfusions.[16][98] In the Mediterranean, hepatitis D is predominant among hepatitis B virus co-infected individuals.[16][98] #### Hepatitis E[edit] Main article: Hepatitis E Similar to Hepatitis A, hepatitis E manifests as large outbreaks and epidemics associated with fecal contamination of water sources.[16] It accounts for more than 55,000 deaths annually with approximately 20 million people worldwide thought to be infected with the virus.[90] It affects predominantly young adults, causing acute hepatitis.[16][124] In infected pregnant women, Hepatitis E infection can lead to fulminant hepatitis with third trimester mortality rates as high as 30%.[98][124] Individuals with weakened immune systems, such as organ transplant recipients, are also susceptible.[124] Infection is rare in the United States but rates are high in the developing world (Africa, Asia, Central America, Middle East).[16][124] Many genotypes exist and are differentially distributed around the world.[90] There is some evidence of hepatitis E infection of animals, serving as a reservoir for human infection.[98] ### Alcoholic hepatitis[edit] Alcoholic hepatitis (AH) in its severe form has a one-month mortality as high as 50%.[62][63][125] Most people who develop AH are men but women are at higher risk of developing AH and its complications likely secondary to high body fat and differences in alcohol metabolism.[63] Other contributing factors include younger age <60, binge pattern drinking, poor nutritional status, obesity and hepatitis C co-infection.[63] It is estimated that as much as 20% of people with AH are also infected with hepatitis C.[126] In this population, the presence of hepatitis C virus leads to more severe disease with faster progression to cirrhosis, hepatocellular carcinoma and increased mortality.[63][126][127] Obesity increases the likelihood of progression to cirrhosis in individuals with alcoholic hepatitis.[63] It is estimated that a high proportion of individuals (70%) who have AH will progress to cirrhosis.[63] ### Non-alcoholic steatohepatitis[edit] Non-alcoholic steatohepatitis (NASH) is projected to become the top reason for liver transplantation in the United States by the year 2020, supplanting chronic liver disease due to hepatitis C.[128] About 20–45% of the U.S. population have NAFLD and 6% have NASH.[29][40] The estimated prevalence of NASH in the world is 3–5%.[129] Of NASH patients who develop cirrhosis, about 2% per year will likely progress to hepatocellular carcinoma.[129] Worldwide, the estimated prevalence of hepatocellular carcinoma related to NAFLD is 15–30%.[130] NASH is thought to be the primary cause of cirrhosis in approximately 25% of patients in the United States, representing 1–2% of the general population.[130] ## History[edit] ### Early observations[edit] Initial accounts of a syndrome that we now think is likely to be hepatitis begin to occur around 3000 B.C. Clay tablets that served as medical handbooks for the ancient Sumerians described the first observations of jaundice. The Sumerians believed that the liver was the home of the soul, and attributed the findings of jaundice to the attack of the liver by a devil named Ahhazu.[131] Around 400 B.C., Hippocrates recorded the first documentation of an epidemic jaundice, in particular noting the uniquely fulminant course of a cohort of patients who all died within two weeks. He wrote, "The bile contained in the liver is full of phlegm and blood, and erupts...After such an eruption, the patient soon raves, becomes angry, talks nonsense and barks like a dog."[132] Given the poor sanitary conditions of war, infectious jaundice played a large role as a major cause of mortality among troops in the Napoleonic Wars, the American Revolutionary War, and both World Wars.[133] During World War II, estimates of soldiers affected by hepatitis were upwards of 10 million. During World War II, soldiers received vaccines against diseases such as yellow fever, but these vaccines were stabilized with human serum, presumably contaminated with hepatitis viruses, which often created epidemics of hepatitis.[134] It was suspected these epidemics were due to a separate infectious agent, and not due to the yellow fever virus itself, after noting 89 cases of jaundice in the months after vaccination out of a total 3,100 patients that were vaccinated. After changing the seed virus strain, no cases of jaundice were observed in the subsequent 8,000 vaccinations.[135] ### Willowbrook State School experiments[edit] A New York University researcher named Saul Krugman continued this research into the 1950s and 1960s, most infamously with his experiments on mentally disabled children at the Willowbrook State School in New York, a crowded urban facility where hepatitis infections were highly endemic to the student body. Krugman injected students with gamma globulin, a type of antibody. After observing the temporary protection against infection this antibody provided, he then tried injected live hepatitis virus into students. Krugman also controversially took feces from infected students, blended it into milkshakes, and fed it to newly admitted children.[136] His research was received with much controversy, as people protested the questionable ethics surrounding the chosen target population. Henry Beecher was one of the foremost critics in an article in the New England Journal of Medicine in 1966, arguing that parents were unaware to the risks of consent and that the research was done to benefit others at the expense of children.[137] Moreover, he argued that poor families with mentally disabled children often felt pressured to join the research project to gain admission to the school, with all of the educational and support resources that would come along with it.[138] Others in the medical community spoke out in support of Krugman's research in terms of its widespread benefits and understanding of the hepatitis virus, and Willowbrook continues to be a commonly cited example in debates about medical ethics.[139] ### The Australia antigen[edit] The next insight regarding hepatitis B was a serendipitous one by Dr. Baruch Blumberg, a researcher at the NIH who did not set out to research hepatitis, but rather studied lipoprotein genetics. He travelled across the globe collecting blood samples, investigating the interplay between disease, environment, and genetics with the goal of designing targeted interventions for at-risk individuals that could prevent them from getting sick.[140] He noticed an unexpected interaction between the blood of a patient with hemophilia that had received multiple transfusions and a protein found in the blood of an Australian aborigine.[141] He named the protein the "Australia antigen" and made it the focus of his research. He found a higher prevalence of the protein in the blood of patients from developing countries, compared to those from developed ones, and noted associations of the antigen with other diseases like leukemia and Down Syndrome.[142] Eventually, he came to the unifying conclusion that the Australia antigen was associated with viral hepatitis. In 1970, David Dane first isolated the hepatitis B virion at London's Middlesex Hospital, and named the virion the 42-nm "Dane particle".[138] Based on its association with the surface of the hepatitis B virus, the Australia antigen was renamed to "hepatitis B surface antigen" or HBsAg. Blumberg continued to study the antigen, and eventually developed the first hepatitis B vaccine using plasma rich in HBsAg, for which he received the Nobel Prize in Medicine in 1976.[143] ## Society and culture[edit] ### Economic burden[edit] Overall, hepatitis accounts for a significant portion of healthcare expenditures in both developing and developed nations, and is expected to rise in several developing countries.[144][145] While hepatitis A infections are self-limited events, they are associated with significant costs in the United States.[146] It has been estimated that direct and indirect costs are approximately $1817 and $2459 respectively per case, and that an average of 27 work days is lost per infected adult.[146] A 1997 report demonstrated that a single hospitalization related to hepatitis A cost an average of $6,900 and resulted in around $500 million in total annual healthcare costs.[147] Cost effectiveness studies have found widespread vaccination of adults to not be feasible, but have stated that a combination hepatitis A and B vaccination of children and at risk groups (people from endemic areas, healthcare workers) may be.[148] Hepatitis B accounts for a much larger percentage of health care spending in endemic regions like Asia.[149][150] In 1997 it accounted for 3.2% of South Korea's total health care expenditures and resulted in $696 million in direct costs.[150] A large majority of that sum was spent on treating disease symptoms and complications.[151] Chronic hepatitis B infections are not as endemic in the United States, but accounted for $357 million in hospitalization costs in the year 1990.[144] That number grew to $1.5 billion in 2003, but remained stable as of 2006, which may be attributable to the introduction of effective drug therapies and vaccination campaigns.[144][145] People infected with chronic hepatitis C tend to be frequent users of the health care system globally.[152] It has been estimated that a person infected with hepatitis C in the United States will result in a monthly cost of $691.[152] That number nearly doubles to $1,227 for people with compensated (stable) cirrhosis, while the monthly cost of people with decompensated (worsening) cirrhosis is almost five times as large at $3,682.[152] The wide-ranging effects of hepatitis make it difficult to estimate indirect costs, but studies have speculated that the total cost is $6.5 billion annually in the United States.[144] In Canada, 56% of HCV related costs are attributable to cirrhosis and total expenditures related to the virus are expected to peak at CAD$396 million in the year 2032.[153] ### Notable cases[edit] The largest outbreak of hepatitis A virus in United States history occurred among people who ate at a now-defunct Mexican food restaurant located in Monaca, Pennsylvania in late 2003.[154] Over 550 people who visited the restaurant between September and October 2003 were infected with the virus, three of whom died as a direct result.[154] The outbreak was brought to the attention of health officials when local emergency medicine physicians noticed a significant increase in cases of hepatitis A in the county.[155] After conducting its investigation, the CDC attributed the source of the outbreak to the use of contaminated raw green onion. The restaurant was purchasing its green onion stock from farms in Mexico at the time.[154] It is believed that the green onions may have been contaminated through the use of contaminated water for crop irrigation, rinsing, or icing or by handling of the vegetables by infected individuals.[154] Green onion had caused similar outbreaks of hepatitis A in the southern United States prior to this, but not to the same magnitude.[154] The CDC believes that the restaurant's use of a large communal bucket for chopped raw green onion allowed non-contaminated plants to be mixed with contaminated ones, increasing the number of vectors of infection and amplifying the outbreak.[154] The restaurant was closed once it was discovered to be the source, and over 9,000 people were given hepatitis A immune globulin because they had either eaten at the restaurant or had been in close contact with someone who had.[154] ## Special populations[edit] ### HIV co-infection[edit] Persons infected with HIV have a particularly high burden of HIV-HCV co-infection.[156][157] In a recent study by the WHO, the likelihood of being infected with hepatitis C virus was six times greater in individuals who also had HIV.[157] The prevalence of HIV-HCV co-infection worldwide was estimated to be 6.2% representing more than 2.2 million people.[157] Intravenous drug use was an independent risk factor for HCV infection.[122] In the WHO study, the prevalence of HIV-HCV co-infection was markedly higher at 82.4% in those who injected drugs compared to the general population (2.4%).[157] In a study of HIV-HCV co-infection among HIV positive men who have sex with men (MSM), the overall prevalence of anti-hepatitis C antibodies was estimated to be 8.1% and increased to 40% among HIV positive MSM who also injected drugs.[156] ### Pregnancy[edit] #### Hepatitis B[edit] Vertical transmission is a significant contributor of new HBV cases each year, with 35–50% of transmission from mother to neonate in endemic countries.[82][158] Vertical transmission occurs largely via a neonate's exposure to maternal blood and vaginal secretions during birth.[158] While the risk of progression to chronic infection is approximately 5% among adults who contract the virus, it is as high as 95% among neonates subject to vertical transmission.[82][159] The risk of viral transmission is approximately 10–20% when maternal blood is positive for HBsAg, and up to 90% when also positive for HBeAg.[82] Given the high risk of perinatal transmission, the CDC recommends screening all pregnant women for HBV at their first prenatal visit.[82][160] It is safe for non-immune pregnant women to receive the HBV vaccine.[82][158] Based on the limited available evidence, the American Association for the Study of Liver Diseases (AASLD) recommends antiviral therapy in pregnant women whose viral load exceeds 200,000 IU/mL.[161] A growing body of evidence shows that antiviral therapy initiated in the third trimester significantly reduces transmission to the neonate.[158][161] A systematic review of the Antiretroviral Pregnancy Registry database found that there was no increased risk of congenital anomalies with Tenofovir; for this reason, along with its potency and low risk of resistance, the AASLD recommends this drug.[161][162] A 2010 systematic review and meta-analysis found that Lamivudine initiated early in the third trimester also significantly reduced mother-to-child transmission of HBV, without any known adverse effects.[163] The ACOG states that the evidence available does not suggest any particular mode of delivery (i.e. vaginal vs. cesarean) is better at reducing vertical transmission in mothers with HBV.[82] The WHO and CDC recommend that neonates born to mothers with HBV should receive hepatitis B immune globulin (HBIG) as well as the HBV vaccine within 12 hours of birth.[79][81] For infants who have received HBIG and the HBV vaccine, breastfeeding is safe.[82][158] #### Hepatitis C[edit] Estimates of the rate of HCV vertical transmission range from 2–8%; a 2014 systematic review and meta-analysis found the risk to be 5.8% in HCV-positive, HIV-negative women.[82][164] The same study found the risk of vertical transmission to be 10.8% in HCV-positive, HIV-positive women.[164] Other studies have found the risk of vertical transmission to be as high as 44% among HIV-positive women.[82] The risk of vertical transmission is higher when the virus is detectable in the mother's blood.[164] Evidence does not indicate that mode of delivery (i.e. vaginal vs. cesarean) has an effect on vertical transmission.[82] For women who are HCV-positive and HIV-negative, breastfeeding is safe; however, CDC guidelines suggest avoiding breastfeeding if a woman's nipples are "cracked or bleeding" to reduce the risk of transmission.[82][84] #### Hepatitis E[edit] Pregnant women who contract HEV are at significant risk of developing fulminant hepatitis with maternal mortality rates as high as 20–30%, most commonly in the third trimester .[16][82][158] A 2016 systematic review and meta-analysis of 47 studies that included 3968 people found maternal case-fatality rates (CFR) of 20.8% and fetal CFR of 34.2%; among women who developed fulminant hepatic failure, CFR was 61.2%.[165] ## See also[edit] * World Hepatitis Day ## References[edit] 1. ^ a b c d e f "Hepatitis". 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PMID 26939626. ## External links[edit] Classification D * ICD-10: K75.9 * ICD-9-CM: 573.3 * MeSH: D006505 * DiseasesDB: 20061 External resources * MedlinePlus: 001154 * WHO fact sheet of hepatitis * Viral Hepatitis at the Centers for Disease Control * 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 Authority control * GND: 4024427-1 * NARA: 10641635 * NDL: 00564863 * NSK: 002104740 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hepatitis	c0019158	1,298	wikipedia	https://en.wikipedia.org/wiki/Hepatitis	2021-01-18T18:38:18	{"mesh": ["D006505"], "umls": ["C0019158"], "wikidata": ["Q131742"]}
A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-1A (CMS1A) is caused by heterozygous mutation in the CHRNA1 gene (100690) on chromosome 2q31. There are rare reports of recessive inheritance. Mutation in the CHRNA1 gene can also cause fast-channel CMS1B (608930). Description Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003). Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic NMJ characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). ### Genetic Heterogeneity of Congenital Myasthenic Syndromes Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13. CMS5 (603034) is caused by mutation in the COLQ gene (603033) on 3p25; CMS6 (254210) is caused by mutation in the CHAT gene (118490) on 10q; CMS7 (616040) is caused by mutation in the SYT2 gene (600104) on 1q32; CMS8 (615120) is caused by mutation in the AGRN gene (103320) on 1p; CMS9 (616325) is caused by mutation in the MUSK gene (601296) on 9q31; CMS10 (254300) is caused by mutation in the DOK7 gene (610285) on 4p; CMS11 (616326) is caused by mutation in the RAPSN gene (601592) on 11p11; CMS12 (610542) is caused by mutation in the GFPT1 gene (138292) on 2p14; CMS13 (614750) is caused by mutation in the DPAGT1 gene (191350) on 11q23; CMS14 (616228) is caused by mutation in the ALG2 gene (607905) on 9q22; CMS15 (616227) is caused by mutation in the ALG14 gene (612866) on 1p21; CMS16 (614198) is caused by mutation in the SCN4A gene (603967) on 17q; CMS17 (616304) is caused by mutation in the LRP4 gene (604270) on 11p12; CMS18 (616330) is caused by mutation in the SNAP25 gene (600322) on 20p11; CMS19 (616720) is caused by mutation in the COL13A1 gene (120350) on 10q22; CMS20 (617143) is caused by mutation in the SLC5A7 gene (608761) on 2q12; CMS21 (617239) is caused by mutation in the SLC18A3 gene (600336) on 10q11; CMS22 (616224) is caused by mutation in the PREPL gene (609557) on 2p21; CMS23 (618197) is caused by mutation in the SLC25A1 gene (190315) on 22q11; CMS24 (618198) is caused by mutation in the MYO9A gene (604875) on 15q22; and CMS25 (618323) is caused by mutation in the VAMP1 gene (185880) on 12p13. Nomenclature An international workshop (Middleton, 1996) classified the congenital myasthenia syndromes on the basis of their genetic and clinical features: type Ia (254210); Ib, limb-girdle myasthenia (254300); Ic, endplate AChR deficiency (603034); Id, AChR deficiency; and Ie, CMS with facial dysmorphism, which has since been shown to be caused by AChR deficiency. Type IIa is autosomal dominant slow-channel syndrome, and type III is sporadic. These designations have largely been replaced by a classification according to the location of the defect (presynaptic, synaptic, or postsynaptic), as well as by pathologic mechanism (i.e., AChR deficiency) (Engel et al., 2003) and genetic defect (Engel et al., 2015). Lambert-Eaton myasthenic syndrome is a distinct, acquired disorder in which patients develop autoantibodies against several putative antigens associated with P/Q-type voltage-gated calcium channels (see, e.g., CACNA1A, 601011 and CACNB2, 600003). Clinical Features Engel et al. (1982) reported 5 patients from 2 families and 1 sporadic patient who had a congenital myasthenic syndrome characterized by selective involvement of cervical, scapular, and finger extensor muscles and ophthalmoparesis from infancy or early childhood. Laboratory studies showed a decremental compound muscle action potential (CMAP) response to stimulus, prolonged endplate potentials, and prolonged miniature endplate potentials (MEPPs) and endplate currents (MEPCs). Quantal content and acetylcholinesterase activity were normal. Muscle biopsy showed predominance of type I fibers, atrophic type 2 fibers, and abnormal endplate configuration. Electron microscopy showed a decrease in the size of nerve terminals, a reduction in the length of postsynaptic membranes, and focal degeneration of junctional folds with loss of acetylcholine receptors. Engel et al. (1982) suggested that the defect was a prolonged open time of the acetylcholine-induced ion channel. Whiteley et al. (1976) described 2 brothers, aged 19 and 29, with myasthenic symptoms beginning within the first 2 years of life. Ptosis and ophthalmoplegia responded poorly to oral anticholinesterase therapy and to thymectomy. The brothers had 2 different HLA haplotypes, and neither had the A1-B8-Dw3 haplotypes commonly associated with adult-onset myasthenia gravis (MG; 254200). Oosterhuis et al. (1987) reported a woman (case 1) who developed weakness of the upper arm in the eighth month of her first pregnancy at age 23 years. She showed generalized myasthenic weakness and mild hand muscle wasting. Antibodies to AChR were absent, and she reacted adversely to anticholinesterase drugs. Electrophysiologic studies showed a repetitive muscle response to a single nerve stimulation, and in vitro microelectrode studies showed a prolonged decay time of MEPPs. The authors concluded that there was prolonged open time of the ACh-induced ion channel. Chauplannaz and Bady (1994) reported 2 unrelated women (cases 1 and 2) with SCCMS who had onset of symptoms in childhood and at age 16 years, respectively. They had generalized weakness and prominent wasting and weakness of the finger extensor muscles. One patient also had marked weakness and atrophy of the cervical muscles and developed respiratory problems. A single nerve stimulus elicited repetitive CMAP responses, and repetitive nerve stimulation showed a myasthenic decrement in finger extensor muscles. Similar symptoms were noted in first-degree relatives of both women. Croxen et al. (1997) noted that both women reported by Chauplannaz and Bady (1994) had deterioration of symptoms during or after pregnancy. Engel et al. (1996) reported a 30-year-old woman with SCCMS who had ocular muscle weakness since early childhood, limb muscle weakness with difficulty climbing stairs since age 8, and scoliosis since age 10. Family history was consistent with autosomal dominant inheritance spanning 3 generations. Electrophysiologic studies showed prolonged endplate currents and prolonged AChR channel-opening episodes, with a repetitive CMAP response to a single nerve stimulus. Ultrastructural studies of muscle biopsies showed an endplate myopathy with loss of AChR from degenerating junctional folds. Croxen et al. (1997) reported a 34-year-old man who became aware of lower limb weakness at the age of 14. He later developed facial, neck, and upper limb weakness, with wasting of the forearm and hand muscles, and slight difficulty with chewing and swallowing. Serum antibodies to AChR were absent. Shen et al. (2006) reported a 24-year-old man with SCCMS who had lid ptosis since birth, high-arched palate, pectus carinatum, and moderate limitation of eye movements. As a young adult, he developed fatigable weakness of the lower extremities with selective severe distal upper and lower limb weakness. EMG studies showed a decremental response on repetitive stimulation, and single nerve stimuli showed a repetitive CMAP, consistent with slow-channel CMS. He had no family history of a similar disorder. Clinical Management Engel et al. (1996) noted that acetylcholinesterase inhibitors would not be an effective treatment for SCCMS because they would result in exacerbated desensitization of mutant AChRs. The authors suggested that long-lived AChR channel blockers would be of greater benefit. Fukudome et al. (1998) noted that quinidine is a long-lived open-channel blocker of the endplate AChR. In vitro, quinidine shortened the AChR channel-opening burst in cells expressing mutant SCCMS AChRs. Harper and Engel (1998) reported successful treatment of 6 SCCMS patients with quinidine sulfate. After 30 days of therapy, patients showed an improvement in muscle strength and in decrement of the CMAP. Harper et al. (2003) found that fluoxetine significantly shortened the prolonged opening bursts of SCCMS AChR expressed in fibroblasts. Treatment of 2 SCCMS patients, who were allergic to quinidine, with fluoxetine resulted in marked subjective and objective improvement in muscle strength. Movaghar and Slavin (2000) studied the effects of heat versus ice application on eyelid ptosis in 4 patients with ocular or systemic myasthenia. Transient complete improvement of ptosis was found in 3 patients and marked improvement in 1 patient after each test. The results of heat, ice, and modified sleep tests were identical. The authors concluded that the common denominator among these 3 tests, rest, seemed to be the relevant factor in the study. Pathogenesis In studies of muscle tissue from patients with SCCMS, Engel et al. (1996) found a decrease in the rate of AChR ion channel closure and an increase in apparent affinity of the receptor for ACh, resulting in a prolonged channel-opening time. Cationic overloading of the postsynaptic region results in an endplate myopathy with loss of AChR due to destruction of the junctional folds. The temporal summation of endplate potentials predicted a depolarization block, also suggesting desensitization in the presence of acetylcholinesterase inhibitors. Zhou et al. (1999) found that mutant AChRs that cause SCCMS were activated by serum choline and by transient exposure to synaptically released transmitter. The high frequency of openings in serum was reduced by treatment with choline oxidase. Single-channel kinetic analysis indicated that the increased response to choline is caused by a reduced intrinsic stability of the closed channel. The results suggested that a mutation that destabilizes the inactive conformation of the AChR, together with the sustained exposure of endplates to serum choline, results in continuous channel activity that contributes to the pathophysiology of the disease. Molecular Genetics In 5 members of a family and another unrelated individual with SCCMS (Engel et al., 1982), Sine et al. (1995) identified a heterozygous missense mutation in the CHRNA1 gene (G153S; 100690.0004). Electrophysiologic analysis of endplates revealed prolonged decay of miniature endplate currents and prolonged activation episodes of single AChR channels. Single-channel kinetic analysis of engineered alpha-G153S AChR showed a markedly decreased rate of acetylcholine dissociation, indicating an increased affinity for ACh and causing the mutant AChR to open repeatedly during ACh occupancy. In addition, ACh binding measurements combined with the kinetic analysis indicated increased desensitization of the mutant AChR. Sine et al. (1995) concluded that ACh binding affinity can dictate the time course of the synaptic response. In a 30-year-old woman with SCCMS, Engel et al. (1996) identified a heterozygous missense mutation in the CHRNA1 gene (N217K; 100690.0001). In 4 patients with SCCMS, 3 of whom were previously reported by Oosterhuis et al. (1987) and Chauplannaz and Bady (1994), Croxen et al. (1997) identified different heterozygous missense mutations in the CHRNA1 gene (100690.0002-100690.0005). In a 24-year-old man with SCCMS, Shen et al. (2006) identified a de novo heterozygous missense mutation in the CHRNA1 gene (C418W; 100690.0012). Functional kinetic expression studies in HEK cells showed that the AChR with the mutant alpha-subunit increased the channel-opening equilibrium as well as the mean duration of open durations and bursts characteristic of a slow-channel mutation. ### Associations Pending Confirmation For discussion of a possible association between congenital myasthenic syndrome and variation in the UNC13A gene, see 609894.0001. For discussion of a possible association between presynaptic congenital myasthenic syndrome and variation in the LAMA5 gene, see 601033.0001. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Ophthalmoplegia \- Ptosis Mouth \- High-arched palate (in some patients) RESPIRATORY \- Respiratory insufficiency, episodic ABDOMEN Gastrointestinal \- Feeding difficulties \- Dysphagia MUSCLE, SOFT TISSUES \- Generalized muscle weakness due to defect at the neuromuscular junction \- Cervical muscle weakness \- Scapular muscle weakness \- Extensor finger muscle weakness \- Atrophy of affected muscles, especially intrinsic hand muscles \- Chronic fatigable muscles \- Dysarthria \- Repetitive compound muscle action potentials (CMAP) in response to single stimulus \- Decremental CMAP response to repetitive nerve stimulation seen on EMG \- Prolonged miniature endplate potentials (MEPP) \- Prolonged miniature endplate currents (MEPC) \- Increased opening duration of acetylcholine receptor (AChR)-induced ion channels \- Focal degeneration of junctional folds ('honeycombed' appearance) seen on muscle biopsy \- Thickened endplate basal lamina seen on muscle biopsy \- Decreased size of nerve terminals seen on muscle biopsy \- Progressive widening of synaptic clefts that are filled with amorphous debris seen on muscle biopsy \- Calcium accumulation in junctional folds seen on muscle biopsy \- Secondary loss of AChR from junctional folds seen on muscle biopsy MISCELLANEOUS \- Variable age at onset \- Usually symptomatic in adulthood with history of weakness since infancy or childhood \- Exacerbation of symptoms during or after pregnancy \- Progressive disorder due to secondary myopathy \- Poor response to acetylcholinesterase inhibitors \- Quinidine therapy may be effective \- Fluoxetine therapy may be effective MOLECULAR BASIS \- Caused by mutation in the cholinergic receptor, nicotinic, alpha polypeptide-1 gene (CHRNA1, 100690.0001 ) ▲ 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	MYASTHENIC SYNDROME, CONGENITAL, 1A, SLOW-CHANNEL	c0751882	1,299	omim	https://www.omim.org/entry/601462	2019-09-22T16:14:42	{"doid": ["0110663"], "mesh": ["D020294"], "omim": ["601462"], "orphanet": ["98913", "590"], "synonyms": ["CMS IIa, FORMERLY", "Alternative titles", "MYASTHENIC SYNDROME, CONGENITAL, TYPE IIa, FORMERLY"], "genereviews": ["NBK1168"]}

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