Datasets:

findzebra
/

corpus

Dataset card Data Studio Files Files and versions Community

Split (1)

train · 30.7k rows

text stringlengths 297 230k	title stringlengths 4 145	cui stringlengths 4 10	idx int64 0 30.7k	source stringclasses 6 values	source_url stringlengths 33 155	retrieved_date timestamp[s]	classification_map stringlengths 2 1.45k
CK syndrome is a rare, genetic, X-linked syndromic intellectual disability disorder characterized by mild to severe intellectual disability, infancy-onset seizures, post-natal microcephaly, cerebral cortical malformations, dysmorphic facial features (including long, narrow face, almond-shaped palpebral fissures, epicanthic folds, high nasal bridge, malar flattening, posteriorly rotated ears, high arched palate, crowded teeth, micrognathia) and thin body habitus. Long and slim fingers/toes, strabismus, hypotonia, spasticity, optic disc atrophy, and behavioral problems (aggression, attention deficit hyperactivity disorder and irritability) are additional features. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	CK syndrome	c3151781	1,500	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251383	2021-01-23T17:39:36	{"omim": ["300831"], "synonyms": ["X-linked intellectual disability-microcephaly-cortical malformation-thin habitus syndrome"]}
Nisan et al. (1988) described agenesis of 5 cervical vertebrae in a 7-year-old son of first-cousin parents. The patient had a webbed neck, and a diagnosis of Klippel-Feil syndrome was made before x-rays were taken. Spine \- Cervical vertebrae agenesis Neck \- Webbed 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	CERVICAL VERTEBRAE, AGENESIS OF	c0432160	1,501	omim	https://www.omim.org/entry/214290	2019-09-22T16:29:47	{"mesh": ["C562952"], "omim": ["214290"]}
Ectodermal dysplasia-blindness syndrome is characterized by intellectual deficit, blindness caused by ocular malformations (microphthalmia, microcornea and sclerocornea), short stature, dysmorphic facial features (narrow nasal bridge and prominent ears), hypotrichosis, and malaligned teeth. It has been described in two siblings (brother and sister) and is likely to be transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Ectodermal dysplasia-blindness syndrome	c1849332	1,502	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1806	2021-01-23T18:57:44	{"gard": ["2045"], "mesh": ["C535865"], "omim": ["268320"], "umls": ["C1849332"], "icd-10": ["Q87.8"]}
The 1951 Pont-Saint-Esprit mass poisoning, also known as Le Pain Maudit, was a mass poisoning on 15 August 1951, in the small town of Pont-Saint-Esprit in southern France. More than 250 people were involved, including 50 people interned in asylums and 7 deaths. A foodborne illness was suspected, and among these it was originally believed to be a case of "cursed bread" (pain maudit). A majority of academic sources accept ergot poisoning as the cause of the epidemic,[1][2][3][4][5] while a few theorize other causes such as poisoning by mercury, mycotoxins, or nitrogen trichloride. ## Contents * 1 Background * 1.1 Previous sanitary events * 2 Mass poisoning * 2.1 Epidemiological investigation * 3 Criminal investigation * 3.1 Inquiry * 3.2 Maurice Maillet * 4 Arrests and trial * 5 Scientific publishing * 6 Other theories * 6.1 Conspiracy theory * 7 In popular culture * 8 References ## Background[edit] During the Vichy government, the supply of grains from field to mill to bakery was directed by the government's grain control board, the Office National Interprofessionnel des Céréales (ONIC), and later the Union Meuniere. Essentially, this created a government monopoly on the sale of flour, allowing the government a measure of control over wartime supply shortages.[6] This also meant that flour would be purchased directly from ONIC, and delivered to the baker for a set price, without the baker being able to have any control on quality.[7] Following the end of the second world war, this system was relaxed, allowing for bakers to have some choice over their flour supply. The ONIC retained its monopoly on inter-departmental exportation and importation. By this system, millers in departments with more supply than demand could sell the excess to ONIC. In practice, this meant that the higher-quality flour would be delivered to local bakers and lower-quality flour would be exported to other departments. Thus, departments with net flour deficits, like the Gard department in which Pont-Saint-Esprit was located, would be supplied with lower-quality flour from other departments via ONIC, with the bakers having virtually no choice of the provenance or quality of their flour.[8]:224-225 ### Previous sanitary events[edit] In the weeks preceding the outbreak, several villages near Pont-Saint-Esprit reported outbreaks of food poisoning via bread. These outbreaks were all linked to bakeries that made their bread with most if not all of their flour supplied by the mill of Maurice Maillet, in Saint-Martin-la-Riviere. The symptoms reported were milder than those reported in Pont-Saint-Esprit. At Issirac, at least 20 people reported cutaneous eruptions, diarrhea, vomiting and headaches. Similar symptoms were reported in Laval-Saint-Roman. Multiple families were reported sick in Goudargues and Lamotte-du-Rhone. In Connaux, the town’s baker received reports from his clients that they believed his bread was causing violent diarrhea. He reported that his family, as well as himself, were all suffering from the same afflictions. The baker was quick to blame his flour, which he described as “bad, forming a sticky dough with acid fermentation” and which made gray and sticky bread. In Saint-Genies-de-Comolas, the town’s mayor was alerted by one of the town’s two bakers that he received flour that was gray and full of worms. The mayor banned making bread with that flour, and referred the situation to the region's prefect, as well as to the driver that delivered the flour. The delivery driver, Jean Bousquet, sent the prefect a copy of a remark made to his employer, the miller’s union in Nimes, on 9 August. The note said that “almost every baker of Centre de Bagnols/Cèze has complained of the quality of the flour provided by Mr. Maillet”. Following the incident at Connaux, Bousquet requested immediate written instructions from his employer regarding the situation. On the 13th of August, he requested that samples be taken to determine if the flour was contaminated. During this period, 42 bakers complained of the flour delivered by Bousquet.[8]:438 ## Mass poisoning[edit] On 16 August 1951, the local offices of the town's two doctors filled with patients reporting similar food poisoning symptoms; nausea, vomiting, cold chills, heat waves. These symptoms eventually worsened, with added hallucinatory crises and convulsions. The situation in the town deteriorated in the following days. On the night of 24 August, a man believed himself to be an airplane and died by jumping from a second-storey window and across town, an 11-year old boy strangled his mother. One of the town's two doctors would name the night nuit d'apocalypse; apocalyptic night.[9] ### Epidemiological investigation[edit] Doctors Vieu and Gabbai investigated the epidemiology of the disease. On 19 August, they came to the conclusion that bread was to blame; all patients interrogated had purchased their bread at the Briand bakery in Pont-Saint-Esprit. In a family from a neighboring village four of whose nine members fell ill, all members who ate bread from the Briand bakery fell ill, whereas none of the others who ate bread from another bakery did. Another family shared a loaf of Briand’s bread among five of its seven members, the others preferring biscottes, with only the five falling ill. On the morning of the 20th, the health service, the prefecture, the prosecutor of the Republic and the police were notified. Roch Briand was interrogated, and the sickness in the town was blamed on his bread.[8] ## Criminal investigation[edit] The police investigation would eventually center on the second of three batches of bread made at Briand's bakery on the day of 16 August. The flour composition of each batch varied, as having run out of flour during the preparation of the second batch, Briand had borrowed flour from two other local bakers, Jaussent and Fallavet. Briand’s assistant stated that when he picked up flour from Jaussent, the baker was out ill, and that he took the flour from his assistant instead. Both Briand and his assistant agreed that the first batch was constituted of the previous day’s flour mixed with flour borrowed from Jaussent. They disagreed on the second and third batches. Whereas Briand stated that the second was made with Jaussent’s flour and the third with Fallavet’s flour, the assistant stated that both latter batches were made with a mix of the two. The investigation led police to interrogate many of the town’s residents, who gave inconsistent ratings of Briand’s tainted batch. Some reported that the taste was perfectly normal, while others reported chemical smells (one described an odor of gasoline, another of bleach). Some reported that the bread looked normal, while others stated that its appearance was grayish.[8]:319 ### Inquiry[edit] On the 23rd of August, a judge of inquiry opened a formal investigation, and tasked commissaire Georges Sigaud with finding the cause of the mass poisoning event. The tainted bread made by Briand was made with only four ingredients: flour, yeast, water and salt. All of the ingredients but the flour could be easily discounted as sources of the illness. The water used to make the bread was from a municipal source, the same that also supplied the rest of the village. Both the salt and the yeast used by Briand were sourced from the same suppliers as all other bakers in the region, and subsequent testing of the supplies found no toxicity.[8]:432 The investigation of the provenance of the flour led Sigaud to the UM-Gard flour distribution centre, in Bagnols-sur-Cèze. The chief of the distribution network, Jean Bousquet, stated that since the end of July, the vast majority of the flour supplying the region was from two mills; one in Châtillon-sur-Indre, and the other being the mill of Maurice Maillet in Saint-Martin-la-Rivière, the latter of which was the subject of numerous complaints about the quality of its flour.[8]:436 ### Maurice Maillet[edit] In an interrogation that lasted multiple hours, Maurice Maillet denied mixing rye (which is highly susceptible to ergot) into his flour, opting instead to cut his product with 2% of bean flour. This was unusual, given that owing to a shortage of wheat, ONIC had mandated that rye flour be mixed in. However, in the Vienne department, rye of good quality was often more expensive than wheat, and accordingly, bean flour was authorised by ONIC as a replacement.[8]:459 Despite this, it came to light that the supply of grains to be milled for export was sometimes mixed with grains milled in an informal agreement called échangisme. Under this type of agreement, often practiced at the time, a farmer would bring a baker grain he grew himself in exchange for bread that would later be made with his grain. The baker would bring the grain to the miller, who would mill it. The miller and baker would each take a cut for sale.[8]:452-458 During the interrogation, Maillet admitted that he had made a deal with a baker, Guy Bruère, who had brought in bags to be milled. Since this was near the end of the season, the bags were filled with leftover grain that sometimes contained a high proportion of rye. The rye was not the only problem with the flour, as the miller also noted the presence of weevils, mites and dust. The baker was concerned that he would lose business should he refuse the grain on the basis of quality. Despite the miller having noticed the low quality of the grains, he agreed to exchange the grain for a lower quantity of flour already milled from grain marked for export. Given that the quantity of lower-quality grain was much lower than that of the grain for export, the miller thought that it would be possible to mix it all without reducing the overall quality of the flour.[8]:461-467 ## Arrests and trial[edit] On August 31, around 14:30, Sigaud addressed the media, announcing the arrests of Maillet and Bruère for involuntary manslaughter and involuntary injuries arising from their negligence in trading improper flour. Further arrests were made in the following days: an employee of Maillet, André Bertrand, was arrested, but released on bail as he was the head of a family of nine whose wife was about to give birth. The owners of the bakery at which Bruère was employed, Clothaire and Denise Audidier, were also arrested for infractions of fiscal legislation and of legislation governing wheat and flour.[8]:471 ## Scientific publishing[edit] Shortly after the incident, in September 1951, Dr. Gabbai and colleagues published a paper in the British Medical Journal declaring that "the outbreak of poisoning" was produced by ergot fungus.[10] The victims appeared to have one common connection. They had eaten bread from the bakery of Roch Briand, who was subsequently blamed for having used flour made from contaminated rye. Animals who had eaten the bread were also found to have perished.[10] According to reports at the time, the flour had been contaminated by the fungus Claviceps purpurea (ergot), which produces alkaloids similar to the hallucinogenic drug lysergic acid diethylamide (LSD). ## Other theories[edit] Later investigations suggested mercury poisoning due to the use of Panogen or other fungicides to treat grain and seeds.[11] This type of contamination was considered owing to the presence of fluorescent stains on the outside of some used empty flour bags returned to the distributor. Panogen was sold containing a red colorant as a safety measure, to ensure that seeds coated with it would be used only for planting. Subsequent scientific tests showed that this coloring would not penetrate flour bags but that the active ingredient could do so. This would allow contamination of the flour, but it would appear to be limited to the bags. Further testing showed that if bread were to be baked using Panogen-contaminated flour, the rising of the bread could be partially or totally inhibited, depending on the concentration. This hypothesis was considered thoroughly in a French civil trial arising from the accident, with the contamination mechanism being a train wagon carrying flour that could have previously carried concentrated cylinders of Panogen intended for agricultural uses.[8] It was later discovered that pre-treating the seeds in Panogen could lead to mercury accumulation in the plants growing from those seeds. For this reason, Panogen, made by a Swedish company, was banned in Sweden in 1966. A revised version of the ban, in 1970, would prohibit the exportation of Panogen, leading to its removal from the market.[12] In 1982, a French researcher suggested Aspergillus fumigatus, a toxic fungus produced in grain silos, as a potential culprit.[13] Historian Steven Kaplan's 2008 book, Le Pain Maudit argues that the poisoning might have been caused by nitrogen trichloride used to artificially (and illegally) bleach flour.[8][14] ### Conspiracy theory[edit] In his 2009 book, A Terrible Mistake, author Hank P. Albarelli Jr originated a conspiracy theory claiming that the Special Operations Division of the Central Intelligence Agency (CIA) tested the use of LSD on the population of Pont-Saint-Esprit as part of its MKNAOMI biological warfare program in a field test called "Project SPAN".[15][16] ## In popular culture[edit] Barbara Comyns wrote her third novel, Who Was Changed and Who Was Dead (1954), after reading about the poisoning.[17] ## References[edit] 1. ^ Gabbai, Lisbonne and Pourquier (15 September 1951). "Ergot Poisoning at Pont St. Esprit". British Medical Journal. 2 (4732): 650–651. doi:10.1136/bmj.2.4732.650. PMC 2069953. PMID 14869677. 2. ^ Stanley Finger (2001). Origins of Neuroscience: A History of Explorations into Brain Function. Oxford University Press. p. 221. ISBN 978-0-19-514694-3. 3. ^ Jeffrey C. Pommerville; I. Edward Alcamo (2012). Alcamo's Fundamentals of Microbiology: Body Systems Edition. Jones & Bartlett Publishers. p. 734. ISBN 978-1-4496-0594-0. 4. ^ Istituto internazionale di storia economica F. Datini. Settimana di studio; Simonetta Cavaciocchi (2010). Economic and biological interactions in pre-industrial Europe, from the 13th to the 18th century. Firenze University Press. p. 82. ISBN 978-88-8453-585-6. 5. ^ Frederick Burwick (2010). Poetic Madness and the Romantic Imagination. Penn State Press. p. 180. ISBN 978-0-271-04296-1. 6. ^ Fuller, John G. (1968). The Day of St. Anthony's Fire (PDF). Signet Books. p. 15. ISBN 9780090954605. "...the Union Meuniere, the giant distribution organization of France that supplies flour to the bakers through its distributors at strategically located centers throughout the country. It is not a union in the labor sense of the word. As a state-supervised private monopoly, its responsibilities are well defined, and its distribution is patterned so that if one department -as the regional sections of France are called -is lacking in flour, another will provide what is necessary to keep the distribution on an even keel." 7. ^ Jacobson, Jonathan (8 March 2019). "What drove an entire French town mad on a summer day in 1951". Haaretz.com. Retrieved 26 July 2020. 8. ^ a b c d e f g h i j k l Kaplan, Steven (2008). Fayard (ed.). Le Pain Maudit. ISBN 978-2-213-63648-1. 9. ^ Lamoureux, Nathalie (9 July 2012). "1951 : trip sous acide à Pont-Saint-Esprit". Le Point (in French). Retrieved 21 July 2020. 10. ^ a b Gabbai; Lisbonne; Pourquier (15 September 1951). "Ergot Poisoning at Pont St. Esprit". British Medical Journal. 2 (4732): 650–651. doi:10.1136/bmj.2.4732.650. PMC 2069953. PMID 14869677. 11. ^ Jonathan Ott, Pharmacotheon: Entheogenic Drugs, their Plant Sources and History (Kennewick, W.A.: Natural Products Co., 1993), pg. 145. See also Dr. Albert Hofmann, LSD: My Problem Child (New York, N.Y.: McGraw-Hill Book Company, 1980), Chapter 1: "How LSD Originated," pg. 6. 12. ^ United States. Congress. Senate. Commerce. (1973). Offshore Marine Environment Protection Act of 1973, hearings before ..., 93-1, march 5, 6, and 12, 1973. pp. 135–136. OCLC 77647957. 13. ^ Moreau, C. (1982). "Les mycotoxines neurotropes de l'Aspergillus fumigatus; une hypothèse sur le "pain maudit" de Pont-Saint-Esprit". Bulletin de la Société Mycologique de France (98): 261–273. 14. ^ Quand le pain empoisonne, La Vie des idées, 3 September 2008 (in French) 15. ^ Josset, Christophe. "Did the CIA poison a French town with LSD?". france24.com. France 24. Retrieved 21 July 2020. 16. ^ "CIA spiked baguettes with LSD, new evidence suggests". www.rfi.fr. Radio France Internationale. Retrieved 21 July 2020. 17. ^ Comyns, Barbara (1981). The Vet's Daughter. Virago. pp. xv. * v * t * e Conspiracy theories List of conspiracy theories Core topics * Antiscience * Cabals * Civil * Criminal * Deception * Espionage * Fiction * Political * Pseudoscience * Secrecy * Secret societies * Urban legend Psychology * Attitude polarization * Cognitive dissonance * Communal reinforcement * Confirmation bias * Locus of control * Mass hysteria * Paranoia * Psychological projection Assassinations and avoidable accidents * Geoffrey Chaucer (1400) * Princes in the Tower (1483) * Kaspar Hauser (1833) * Abraham Lincoln (1865) * Ludwig II of Bavaria (1886) * Franz Ferdinand (1914) * Lord Kitchener (1916) * Michael Collins (1922) * Sergey Kirov (1934) * Władysław Sikorski (1943) * Subhas Chandra Bose (1945) * Dag Hammarskjöld (1961) * Patrice Lumumba (1961) * Marilyn Monroe (1962) * John F. Kennedy (1963) * Lee Harvey Oswald (1963) * Dorothy Kilgallen (1965) * Martin Luther King Jr. (1968) * Robert F. Kennedy (1968) * Juscelino Kubitschek (1976) * Pope John Paul I (1978) * Airey Neave (1979) * Francisco de Sá Carneiro and Adelino Amaro da Costa (1980) * Olof Palme (1986) * Zia-ul-Haq (1988) * Vince Foster (1993) * Yitzhak Rabin (1995) * Diana, Princess of Wales (1997) * Nepalese royal family (2001) * Jeffrey Epstein (2019) * Chan Yin-lam (2019) False flag attacks * USS Maine (1898) * RMS Lusitania (1915) * Reichstag fire (1933) * Pearl Harbor (1941) * USS Liberty (1967) * Widerøe Flight 933 (1982) * KAL Flight 007 (1983) * Mozambican presidential jet (1986) * Pan Am Flight 103 (1988) * Oklahoma City bombing (1995) * 9/11 attacks (2001) * Advance knowledge * WTC collapse * Madrid train bombing (2004) * London bombings (2005) * Malaysia Airlines Flight 17 (2014) Various deaths and disappearances * RMS Titanic (1912) * Phar Lap (1932) * Gas chambers for Poles in Warsaw (1940s) * Mass murder of German POWs after World War II (1940s) * Adolf Hitler's death (1945) * Yemenite Children (1948–54) * Cairo Fire (1952) * Dyatlov Pass incident (1959) * Lost Cosmonauts (1950s / 1960s) * Elvis Presley's death (1977) * Jonestown (1978) * Satanic ritual abuse * MS Estonia (1994) * Kurt Cobain (1994) * Hello Garci scandal * Osama bin Laden (2011) * Lahad Datu, Malaysia standoff (2013) * Zamboanga City crisis (2013) * Malaysia Airlines Flight 370 (2014) New World Order * Black helicopters * Cultural Marxists theories * Denver International Airport * Eurabia * Georgia Guidestones * Illuminati * Judeo-Masonic plot * Jews * The Protocols of the Elders of Zion * Kalergi Plan * Freemasons * North American Union * Catholics * Jesuits * Vatican * ODESSA * Rothschild family * Skull and Bones * The Fellowship * Zionist Occupation Government By region * Conspiracy theories in the Arab world * Israeli animal theories * Conspiracy theories in Turkey UFOs * Alien abduction * Area 51 * Bermuda Triangle * Black Knight satellite * Cryptoterrestrial hypothesis * Extraterrestrial hypothesis * Interdimensional hypothesis * Dulce Base * Estimate of the Situation (1948) * Majestic 12 * Men in black * Nazi UFOs * Project Serpo * Reptilian humanoids Incidents * Tunguska (1908) * Foo Fighters (1940s) * Los Angeles (1942) * Ghost Rockets (1946) * Maury Island (1947) * Roswell (1947) * Gorman Dogfight (1948) * Mantell (1948) * McMinnville (1950) * Lubbock (1951) * Washington, D.C. (1952) * Barney and Betty Hill Abduction (1961) * Kecksburg (1965) * Westall (1966) * Jimmy Carter (1969) * Frederick Valentich (1978) * Rendlesham Forest (1980) * Cash-Landrum (1980) * Japan Air Lines (1986) * Varginha (1996) * Phoenix Lights (1997) * USS Nimitz (2004) * Chicago (2006) United States government * 1951 Pont-Saint-Esprit mass poisoning * Apollo Moon landings * Barack Obama's citizenship / religion / parentage * Belgrade Chinese embassy bombing (1999) * Black genocide * Business Plot * Clinton Body Count * CIA-Kennedy assassination link * Allegations of CIA assistance to Osama bin Laden * Dulles' Plan * FEMA concentration camps * HAARP * Jade Helm 15 (2015) * Montauk Project * October Surprise (1980) * Pizzagate (2016) * Philadelphia Experiment (1943) * Project Azorian (1974) * QAnon * Sandy Hook shooting (2012) * Seth Rich (2016) * Sovereign citizen / Redemption movement * Stop the Steal (2020) * Spygate (2016,18) * Vast right-wing conspiracy * Vietnam War POW / MIA issue * TWA Flight 800 (1996) Health * Big Pharma conspiracy theory * HIV/AIDS denialism * Discredited HIV/AIDS origins theories * OPV AIDS hypothesis * SARS (2003) * COVID-19 pandemic * Anti-vaccination * Vaccines and autism * MMR vaccine and autism * Chemtrail conspiracy theory * Water fluoridation controversy * GMO conspiracy theories * Wind turbine syndrome * Electronic harassment Energy, environment * Free energy suppression conspiracy theory * Global warming conspiracy theory Other * 2012 phenomenon * Agenda 21 (1992) * Andinia Plan * Black genocide * Cancellation of the Avro Arrow (1959) * Bible * Clockwork Orange (1970s) * Conspiracy Encyclopedia * "Death" of Paul McCartney (1969) * Judeo-Bolshevism * Judeopolonia * Homintern * Homosexual recruitment * Kalergi Plan * Knights Templar * Lilla Saltsjöbadsavtalet (1987) * Love Jihad * Mexican Reconquista * New Coke (1985) * Phantom time / New Chronology * Red mercury * Soft coup * George Soros * War against Islam * White genocide See also * Denial of mass killings (list) * Genocide denial [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	1951 Pont-Saint-Esprit mass poisoning	None	1,503	wikipedia	https://en.wikipedia.org/wiki/1951_Pont-Saint-Esprit_mass_poisoning	2021-01-18T19:10:29	{"wikidata": ["Q13420313"]}
Sexually transmitted disease caused by the invasive serovars L1, L2, L2a or L3 of Chlamydia trachomatis This article is about the sexually transmitted disease caused by certain types of chlamydia. For the ulcerative disease caused by Klebsiella granulomatis, see Granuloma inguinale. Lymphogranuloma venereum Lymphogranuloma venereum in a young adult who experienced acute onset of tender, enlarged lymph nodes in both groins. SpecialtyInfectious disease Lymphogranuloma venereum (LGV; also known as Climatic bubo,[1] Durand–Nicolas–Favre disease,[1] Poradenitis inguinale,[1] Lymphogranuloma inguinale, and Strumous bubo)[1] is a sexually transmitted disease caused by the invasive serovars L1, L2, L2a, L2b, or L3 of Chlamydia trachomatis.[2] LGV is primarily an infection of lymphatics and lymph nodes. Chlamydia trachomatis is the bacteria responsible for LGV. It gains entrance through breaks in the skin, or it can cross the epithelial cell layer of mucous membranes. The organism travels from the site of inoculation down the lymphatic channels to multiply within mononuclear phagocytes of the lymph nodes it passes. In developed nations, it was considered rare before 2003.[3] However, a recent outbreak in the Netherlands among gay men has led to an increase of LGV in Europe and the United States.[4][5] LGV was first described by Wallace in 1833[6] and again by Durand, Nicolas, and Favre in 1913.[7][8] Since the 2004 Dutch outbreak many additional cases have been reported, leading to greater surveillance.[9] Soon after the initial Dutch report, national and international health authorities launched warning initiatives and multiple LGV cases were identified in several more European countries (Belgium, France, the UK,[10] Germany, Sweden, Italy and Switzerland) and the US and Canada. All cases reported in Amsterdam and France and a considerable percentage of LGV infections in the UK and Germany were caused by a newly discovered Chlamydia variant, L2b, a.k.a. the Amsterdam variant. The L2b variant could be traced back and was isolated from anal swabs of men who have sex with men (MSM) who visited the STI city clinic of San Francisco in 1981. This finding suggests that the recent LGV outbreak among MSM in industrialised countries is a slowly evolving epidemic. The L2b serovar has also been identified in Australia.[11] ## Contents * 1 Signs and symptoms * 1.1 Primary stage * 1.2 Secondary stage * 2 Diagnosis * 3 Treatment * 3.1 Further recommendations * 4 Prognosis * 4.1 Long-term complications * 5 Notes * 6 References * 7 External links ## Signs and symptoms[edit] The clinical manifestation of LGV depends on the site of entry of the infectious organism (the sex contact site) and the stage of disease progression. * Inoculation at the mucous lining of external sex organs (penis and vagina) can lead to the inguinal syndrome named after the formation of buboes or abscesses in the groin (inguinal) region where draining lymph nodes are located. These signs usually appear from 3 days to a month after exposure. * The rectal syndrome (Lymphogranuloma venereum proctitis, or LGVP) arises if the infection takes place via the rectal mucosa (through anal sex) and is mainly characterized by proctocolitis or proctitis symptoms.[12] * The pharyngeal syndrome is rare. It starts after infection of pharyngeal tissue, and buboes in the neck region can occur. ### Primary stage[edit] LGV may begin as a self-limited painless genital ulcer that occurs at the contact site 3–12 days after infection. Women rarely notice a primary infection because the initial ulceration where the organism penetrates the mucosal layer is often located out of sight, in the vaginal wall. In men fewer than one-third of those infected notice the first signs of LGV. This primary stage heals in a few days. Erythema nodosum occurs in 10% of cases. ### Secondary stage[edit] The secondary stage most often occurs 10–30 days later, but can present up to six months later. The infection spreads to the lymph nodes through lymphatic drainage pathways. The most frequent presenting clinical manifestation of LGV among males whose primary exposure was genital is unilateral (in two-thirds of cases) lymphadenitis and lymphangitis, often with tender inguinal and/or femoral lymphadenopathy because of the drainage pathway for their likely infected areas. Lymphangitis of the dorsal penis may also occur and resembles a string or cord. If the route was anal sex, the infected person may experience lymphadenitis and lymphangitis noted above. They may instead develop proctitis, inflammation limited to the rectum (the distal 10–12 cm) that may be associated with anorectal pain, tenesmus, and rectal discharge, or proctocolitis, inflammation of the colonic mucosa extending to 12 cm above the anus and associated with symptoms of proctitis plus diarrhea or abdominal cramps. In addition, symptoms may include inflammatory involvement of the perirectal or perianal lymphatic tissues. In females, cervicitis, perimetritis, or salpingitis may occur as well as lymphangitis and lymphadenitis in deeper nodes. Because of lymphatic drainage pathways, some patients develop an abdominal mass which seldom suppurates, and 20–30% develop inguinal lymphadenopathy. Systemic signs which can appear include fever, decreased appetite, and malaise. Diagnosis is more difficult in women and men who have sex with men (MSM) who may not have the inguinal symptoms. Over the course of the disease, lymph nodes enlarge, as may occur in any infection of the same areas as well. Enlarged nodes are called buboes. Buboes are commonly painful. Nodes commonly become inflamed, thinning and fixation of the overlying skin. These changes may progress to necrosis, fluctuant and suppurative lymph nodes, abscesses, fistulas, strictures, and sinus tracts. During the infection and when it subsides and healing takes place, fibrosis may occur. This can result in varying degrees of lymphatic obstruction, chronic edema, and strictures. These late stages characterised by fibrosis and edema are also known as the third stage of LGV, and are mainly permanent. ## Diagnosis[edit] The diagnosis usually is made serologically (through complement fixation) and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Serologic testing has a sensitivity of 80% after two weeks. Serologic testing may not be specific for serotype (has some cross reactivity with other chlamydia species) and can suggest LGV from other forms because of their difference in dilution, 1:64 more likely to be LGV and lower than 1:16 is likely to be other chlamydia forms (emedicine). For identification of serotypes, culture is often used. Culture is difficult. Requiring a special medium, cycloheximide-treated McCoy or HeLa cells, and yields are still only 30-50%. DFA, or direct fluorescent antibody test, PCR of likely infected areas and pus, are also sometimes used. DFA test for the L-type serovar of C. trachomatis is the most sensitive and specific test, but is not readily available. If polymerase chain reaction (PCR) tests on infected material are positive, subsequent restriction endonuclease pattern analysis of the amplified outer membrane protein A gene can be done to determine the genotype. Recently a fast realtime PCR (TaqMan analysis) has been developed to diagnose LGV.[13] With this method an accurate diagnosis is feasible within a day. It has been noted that one type of testing may not be thorough enough.[citation needed] ## Treatment[edit] Treatment involves antibiotics and may involve drainage of the buboes or abscesses by needle aspiration or incision. Further supportive measure may need to be taken: dilatation of the rectal stricture, repair of rectovaginal fistulae, or colostomy for rectal obstruction. Common antibiotic treatments include tetracycline (doxycycline)[14][15] (all tetracyclines, including doxycycline, are contraindicated during pregnancy and in children due to effects on bone development and tooth discollloration), and erythromycin.[citation needed] Azithromycin is also a drug of choice in LGV. ### Further recommendations[edit] As with all STIs, sex partners of patients who have LGV should be examined and tested for urethral or cervical chlamydial infection. After a positive culture for chlamydia, clinical suspicion should be confirmed with testing to distinguish serotype. Antibiotic treatment should be started if they had sexual contact with the patient during the 30 days preceding onset of symptoms in the patient. Patients with a sexually transmitted disease should be tested for other STDs due to high rates of comorbid infections. Antibiotics are not without risks and prophylactic broad antibiotic coverage is not recommended.[citation needed] ## Prognosis[edit] Prognosis is highly variable. Spontaneous remission is common. Complete cure can be obtained with proper antibiotic treatments to kill the causative bacteria, such as tetracycline, doxycycline, or erythromycin. Prognosis is more favorable with early treatment. Bacterial superinfections may complicate course. Death can occur from bowel obstruction or perforation, and follicular conjunctivitis due to autoinoculation of infectious discharge can occur. ### Long-term complications[edit] Genital elephantiasis or esthiomene, which is the dramatic end-result of lymphatic obstruction, which may occur because of the strictures themselves, or fistulas. This is usually seen in females, may ulcerate and often occurs 1–20 years after primary infection. Fistulas of, but not limited to, the penis, urethra, vagina, uterus, or rectum. Also, surrounding edema often occurs. Rectal or other strictures and scarring. Systemic spread may occur, possible results are arthritis, pneumonitis, hepatitis, or perihepatitis.[citation needed] ## Notes[edit] 1. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Ward H, Martin I, MacDonald N, et al. (January 1, 2007). "Lymphogranuloma Venereum in the United Kingdom". Clinical Infectious Diseases. Infectious Diseases Society of America. 44 (1): 26–32. doi:10.1086/509922. ISSN 1058-4838. JSTOR 4485191. PMC 1764657. PMID 17143811. 3. ^ Richardson D; Goldmeier D (January 2007). "Lymphogranuloma venereum: an emerging cause of proctitis in men who have sex with men". International Journal of STD & AIDS. 18 (1): 11–4, quiz 15. doi:10.1258/095646207779949916. PMID 17326855. S2CID 36269503. 4. ^ Thomas H. Maugh II. Virulent Chlamydia Detected Largely Among Gay Men in U.S. Los Angeles Times: 11 May 2006 5. ^ Michael Brown. LGV in the UK: almost 350 cases reported and still predominantly affecting HIV-positive gay men Aidsmap: 17 May 2006 6. ^ Lymphogranuloma Venereum at eMedicine 7. ^ synd/1431 at Who Named It? 8. ^ Durand N.J.; Nicolas J.; Favre M. (January 1913). "Lymphogranulomatose inguinale subaiguë d'origine génitale probable, peut-être vénérienne". Bulletin de la Société des Médecins des Hôpitaux de Paris. 35: 274–288. 9. ^ Kivi M; Koedijk FD; van der Sande M; van de Laar MJ (April 2008). "Evaluation prompting transition from enhanced to routine surveillance of lymphogranuloma venereum (LGV) in the Netherlands". Eurosurveillance. 13 (14). PMID 18445453. 10. ^ Jebbari H, Alexander S, Ward H, et al. (July 2007). "Update on lymphogranuloma venereum in the United Kingdom". Sexually Transmitted Infections. 83 (4): 324–6. doi:10.1136/sti.2007.026740. PMC 2598681. PMID 17591663. 11. ^ Stark D; van Hal S; Hillman R; Harkness J; Marriott D (March 2007). "Lymphogranuloma venereum in Australia: anorectal Chlamydia trachomatis serovar L2b in men who have sex with men". Journal of Clinical Microbiology. 45 (3): 1029–31. doi:10.1128/JCM.02389-06. PMC 1829134. PMID 17251405. 12. ^ de Vries, Henry J. C.; van der Bij, Akke K.; Fennema, Johan S. A.; Smit, Colette; de Wolf, Frank; Prins, Maria; Coutinho, Roel A.; MorrÉ, Servaas A. (February 2008). "Lymphogranuloma Venereum Proctitis in Men Who Have Sex With Men Is Associated With Anal Enema Use and High-Risk Behavior" (PDF). Sexually Transmitted Diseases. 35 (2): 203–8. doi:10.1097/OLQ.0b013e31815abb08. ISSN 0148-5717. PMID 18091565. S2CID 2065170. 13. ^ Schaeffer A; Henrich B (2008). "Rapid detection of Chlamydia trachomatis and typing of the Lymphogranuloma venereum associated L-Serovars by TaqMan PCR". BMC Infectious Diseases. 8: 56. doi:10.1186/1471-2334-8-56. PMC 2387162. PMID 18447917. 14. ^ Kapoor S (April 2008). "Re-emergence of lymphogranuloma venereum". Journal of the European Academy of Dermatology and Venereology: JEADV. 22 (4): 409–16. doi:10.1111/j.1468-3083.2008.02573.x. PMID 18363909. S2CID 10325217. 15. ^ McLean CA, Stoner BP, Workowski KA (April 1, 2007). "Treatment of Lymphogranuloma Venereum". Clinical Infectious Diseases. Infectious Diseases Society of America. 44 (Supplement 3, Sexually Transmitted Diseases Treatment Guidelines): S147–S152. doi:10.1086/511427. ISSN 1058-4838. JSTOR 4485305. PMID 17342667. ## References[edit] * Original article from the public domain resource "1998 guidelines for treatment of sexually transmitted diseases. Centers for Disease Control and Prevention". MMWR Recomm Rep. 47 (RR–1): 1–111. January 1998. PMID 9461053. here — note that this has not been modified since 1998, and may be out of date. * "Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention: Proctitis, proctocolitis, and enteritis". MMWR Recomm Rep. 51 (RR–6): 66–7. May 2002. PMID 12184549. * Fitzpatrick, Thomas B; Wolff, Klaus; Suurmond, Dick; Johnson, Richard Allen, eds. (2005). Fitzpatrick's color atlas and synopsis of clinical dermatology (5th ed.). New York: McGraw-Hill Medical. OCLC 225739682. Archived from the original (Continually Updated Resource, Computer File) on 2011-08-11. Retrieved 2011-04-23. * Rosen T, Brown TJ (October 1998). "Genital ulcers. Evaluation and treatment". Dermatol Clin. 16 (4): 673–85, x. doi:10.1016/S0733-8635(05)70032-2. PMID 9891666. * Wolkerstorfer A, de Vries HJ, Spaargaren J, Fennema JS, van Leent EJ (December 2004). "[Inguinal lymphogranuloma venereum in a man having sex with men: perhaps an example of the missing link to explain the transmission of the recently identified anorectal epidemic]". Ned Tijdschr Geneeskd (in Dutch). 148 (51): 2544–6. PMID 15636477. * Rampf J, Essig A, Hinrichs R, Merkel M, Scharffetter-Kochanek K, Sunderkötter C (2004). "Lymphogranuloma venereum—a rare cause of genital ulcers in central Europe". Dermatology. 209 (3): 230–2. doi:10.1159/000079896. PMID 15459539. S2CID 27167098. * Centers for Disease Control and Prevention (CDC) (October 2004). "Lymphogranuloma venereum among men who have sex with men—Netherlands, 2003-2004". MMWR Morb. Mortal. Wkly. Rep. 53 (42): 985–8. PMID 15514580. * Sarkar R, Kaur C, Thami GP, Kanwar AJ (June 2002). "Genital elephantiasis". Int J STD AIDS. 13 (6): 427–9. doi:10.1258/095646202760029886. PMID 12015020. S2CID 31776970. * Spaargaren J, Fennema HS, Morré SA, de Vries HJ, Coutinho RA (July 2005). "New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam". Emerging Infect. Dis. 11 (7): 1090–2. doi:10.3201/eid1107.040883. PMC 3371808. PMID 16022786. * Morré SA, Spaargaren J, Fennema JS, de Vries HJ, Coutinho RA, Peña AS (August 2005). "Real-time polymerase chain reaction to diagnose lymphogranuloma venereum". Emerging Infect. Dis. 11 (8): 1311–2. doi:10.3201/eid1108.050535. PMC 3320474. PMID 16110579. * Spaargaren J, Schachter J, Moncada J, et al. (November 2005). "Slow epidemic of lymphogranuloma venereum L2b strain". Emerging Infect. Dis. 11 (11): 1787–8. doi:10.3201/eid1111.050821. PMC 3367337. PMID 16318741. * van der Bij AK, Spaargaren J, Morré SA, et al. (January 15, 2006). "Diagnostic and Clinical Implications of Anorectal Lymphogranuloma Venereum in Men Who Have Sex with Men: A Retrospective Case-Control Study" (PDF). Clinical Infectious Diseases. Infectious Diseases Society of America. 42 (2): 186–94. doi:10.1086/498904. ISSN 1058-4838. JSTOR 4484555. PMID 16355328. ## External links[edit] Classification D * ICD-10: A55 * ICD-9-CM: 099.1 * MeSH: D008219 * DiseasesDB: 29101 External resources * MedlinePlus: 000634 * eMedicine: emerg/304 med/1356 derm/617 * Sexually transmitted infections (BMJ publishing) * v * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill 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	Lymphogranuloma venereum	c0024286	1,504	wikipedia	https://en.wikipedia.org/wiki/Lymphogranuloma_venereum	2021-01-18T18:59:46	{"gard": ["9545"], "mesh": ["D008219"], "umls": ["C0024286"], "icd-10": ["A55"], "wikidata": ["Q694552"]}
Davies et al. (1994) and Cordell et al. (1995) observed linkage between the X chromosome and type I diabetes. Cucca et al. (1998) examined the male-female bias in type I diabetes. Contrary to assumption, the male:female (M:F) ratio in patients with IDDM is not 1. Karvonen et al. (1997) found that high-incidence countries (mainly European) have a high M:F ratio and low-incidence countries (Asian and African) have a low M:F ratio. Cucca et al. (1998) analyzed the M:F ratio according to genotype at the major locus for type I diabetes (IDDM1), the major histocompatibility complex (MHC). There are 2 main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. Cucca et al. (1998) found that in medium-/high-incidence Caucasian populations, the bias in male incidence was largely restricted to the DR3/X category of patients (where X is any allele other than DR4) with a M:F ratio of 1.7, compared with a ratio of 1.0 in the DR4/Y category (where Y is any allele other than DR3). This provided additional evidence for significant heterogeneity between the etiology of 'DR4-associated' and 'DR3-associated' diabetes. Cucca et al. (1998) analyzed linkage of type I diabetes to the X chromosome, and as expected found that most of the linkage to Xp21-p11 was in the DR3/X affected-sib-pair families. In a personal communication, Todd (1998) noted that, due to typographical error, the linkage assignment in the report of Cucca et al. (1998) appeared incorrectly as Xp13-p11. Bassuny et al. (2003) demonstrated association between a polymorphism in the promoter/enhancer region of the FOXP3 gene (300292), which maps to the same region of chromosome Xp11 as the IDDMX locus, and type I diabetes in the Japanese population. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	DIABETES MELLITUS, INSULIN-DEPENDENT, X-LINKED, SUSCEPTIBILITY TO	c1848042	1,505	omim	https://www.omim.org/entry/300136	2019-09-22T16:20:50	{"omim": ["300136"], "synonyms": ["Alternative titles", "IDDMX", "INSULIN-DEPENDENT DIABETES MELLITUS, X-LINKED, SUSCEPTIBILITY TO"]}
Meromelia is a birth defect characterized by the lacking of a part, but not all, of one or more limbs with the presence of a hand or foot. It results in a shrunken and deformed extremity. [1] ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 Etymology * 5 See also * 6 References ## Cause[edit] Such defects are mainly the results of genetic disorders, but some teratogenic (or environmental) factors have been identified, such as the use of thalidomide from 1957 to 1962 for morning sickness (NVP).[1] ## Diagnosis[edit] Meromelia a birth defect characterization by the lacking of a part, but all, of one or more limbs with the presence of a hand or foot.[citation needed] ## Treatment[edit] This section is empty. You can help by adding to it. (October 2017) ## Etymology[edit] Gk, meros ("part") + melia ("limb") ## See also[edit] * Amelia (birth defect) * Phocomelia * Polymelia * Thalidomide * Amniotic Band Syndrome ## References[edit] 1. ^ a b Sadler, T. W. Langman's Medical Embryology Eleventh Ed.. LWW, p. 140. This article about a congenital malformation is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Meromelia	c0265549	1,506	wikipedia	https://en.wikipedia.org/wiki/Meromelia	2021-01-18T18:33:35	{"wikidata": ["Q6819940"]}
Gastrointestinal perforation Other namesRuptured bowel,[1] gastrointestinal rupture Free air under the right diaphragm from a perforated bowel. SpecialtyGastroenterology, emergency medicine SymptomsAbdominal pain, tenderness[2] ComplicationsSepsis, abscess[2] Usual onsetSudden or more gradual[2] CausesTrauma, following colonoscopy, bowel obstruction, colon cancer, diverticulitis, stomach ulcers, ischemic bowel, C. difficile infection[2] Diagnostic methodCT scan, plain X-ray[2] TreatmentEmergency surgery in the form of an exploratory laparotomy[2] MedicationIntravenous fluids, antibiotics[2] Gastrointestinal perforation, also known as ruptured bowel,[1] is a hole in the wall of part of the gastrointestinal tract.[2] The gastrointestinal tract includes the esophagus, stomach, small intestine, and large intestine.[2][1] Symptoms include severe abdominal pain and tenderness.[2] When the hole is in the stomach or early part of the small intestine the onset of pain is typically sudden while with a hole in the large intestine onset may be more gradual.[2] The pain is usually constant in nature.[2] Sepsis, with an increased heart rate, increased breathing rate, fever, and confusion may occur.[2] The cause can include trauma such as from a knife wound, eating a sharp object, or a medical procedure such as colonoscopy, bowel obstruction such as from a volvulus, colon cancer, or diverticulitis, stomach ulcers, ischemic bowel, and a number of infections including C. difficile.[2] A hole allows intestinal contents to enter the abdominal cavity.[2] The entry of bacteria results in a condition known as peritonitis or in the formation of an abscess.[2] A hole in the stomach can also lead to a chemical peritonitis due to gastric acid.[2] A CT scan is typically the preferred method of diagnosis; however, free air from a perforation can often be seen on plain X-ray.[2] Perforation anywhere along the gastrointestinal tract typically requires emergency surgery in the form of an exploratory laparotomy.[2] This is usually carried out along with intravenous fluids and antibiotics.[2] A number of different antibiotics may be used such as piperacillin/tazobactam or the combination of ciprofloxacin and metronidazole.[3][4] Occasionally the hole can be sewn closed while other times a bowel resection is required.[2] Even with maximum treatment the risk of death can be as high as 50%.[2] A hole from a stomach ulcer occurs in about 1 per 10,000 people per year, while one from diverticulitis occurs in about 0.4 per 10,000 people per year.[1][5] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Signs and symptoms may include a sudden pain in the epigastrium to the right of the midline indicating the perforation of a duodenal ulcer, while a gastric ulcer perforation reveals itself by burning pain in epigastrium, with flatulence and dyspepsia. In intestinal perforation, pain starts from the site of perforation and spreads across the abdomen. Gastrointestinal perforation results in severe abdominal pain intensified by movement, nausea, vomiting and hematemesis. Later symptoms include fever and or chills.[6] In any case, the abdomen becomes rigid with tenderness and rebound tenderness. After some time the abdomen becomes silent and heart sounds can be heard all over. Patient stops passing flatus and motion, abdomen is distended. The symptoms of esophageal rupture may include sudden onset of chest pain. ## Causes[edit] Underlying causes include gastric ulcers, duodenal ulcers, appendicitis, gastrointestinal cancer, diverticulitis, inflammatory bowel disease, superior mesenteric artery syndrome, trauma, vascular Ehlers–Danlos syndrome,[7] and ascariasis. Typhoid fever,[8] non-steroidal anti-inflammatory drugs,[9][10] ingestion of corrosives may also be responsible.[11] Eating multiple magnets can also lead to perforation if the magnets attract and stick to one another through different loops of the intestine.[12] ## Diagnosis[edit] On x-rays, gas may be visible in the abdominal cavity. Gas is easily visualized on x-ray while the patient is in an upright position. The perforation can often be visualised using computed tomography. White blood cells are often elevated. ## Treatment[edit] Surgical intervention is nearly always required in form of exploratory laparotomy and closure of perforation with peritoneal wash. Occasionally they may be managed laparoscopically.[13] A Graham patch may be used for duodenal perforations. Conservative treatment including intravenous fluids, antibiotics, nasogastric aspiration and bowel rest is indicated only if the person is nontoxic and clinically stable.[citation needed] ## References[edit] 1. ^ a b c d Domino, Frank J.; Baldor, Robert A. (2013). The 5-Minute Clinical Consult 2014. Lippincott Williams & Wilkins. p. 1086. ISBN 9781451188509. Archived from the original on 17 August 2016. Retrieved 4 August 2016. 2. ^ a b c d e f g h i j k l m n o p q r s t u v Langell, JT; Mulvihill, SJ (May 2008). "Gastrointestinal perforation and the acute abdomen". The Medical Clinics of North America. 92 (3): 599–625, viii–ix. doi:10.1016/j.mcna.2007.12.004. PMID 18387378. 3. ^ Wong, PF; Gilliam, AD; Kumar, S; Shenfine, J; O'Dair, GN; Leaper, DJ (18 April 2005). "Antibiotic regimens for secondary peritonitis of gastrointestinal origin in adults". The Cochrane Database of Systematic Reviews (2): CD004539. doi:10.1002/14651858.CD004539.pub2. PMID 15846719. 4. ^ Wilson, William C.; Grande, Christopher M.; Hoyt, David B. (2007). Trauma: Resuscitation, Perioperative Management, and Critical Care. CRC Press. p. 882. ISBN 9781420015263. Archived from the original on 2016-08-17. 5. ^ Yeo, Charles J.; McFadden, David W.; Pemberton, John H.; Peters, Jeffrey H.; Matthews, Jeffrey B. (2012). Shackelford's Surgery of the Alimentary Tract (7 ed.). Elsevier Health Sciences. p. 701. ISBN 978-1455738076. Archived from the original on 2016-08-17. 6. ^ Ansari, Parswa. "Acute Perforation". Merck Manuals. Archived from the original on July 10, 2016. Retrieved June 30, 2016. 7. ^ Byers, Peter H. (21 February 2019). "Vascular Ehlers-Danlos Syndrome". University of Washington, Seattle. Retrieved 8 January 2020. 8. ^ Sharma AK, Sharma RK, Sharma SK, Sharma A, Soni D (2013). "Typhoid Intestinal Perforation: 24 Perforations in One Patient". Annals of Medical and Health Sciences Research. 3 (Suppl1): S41–S43. doi:10.4103/2141-9248.121220. PMC 3853607. PMID 24349848. 9. ^ R I Russell (2001). "Non-steroidal anti-inflammatory drugs and gastrointestinal damage—problems and solutions". Postgrad Med J. 77 (904): 82–88. doi:10.1136/pmj.77.904.82. PMC 1741894. PMID 11161072. 10. ^ Carlos Sostres; Carla J Gargallo; Angel Lanas (2013). "Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage". Arthritis Res. Ther. 15 (Suppl 3): S3. doi:10.1186/ar4175. PMC 3890944. PMID 24267289. 11. ^ Ramasamy, Kovil; Gumaste, Vivek V. (2003). "Corrosive Ingestion in Adults". Journal of Clinical Gastroenterology. 37 (2): 119–124. doi:10.1097/00004836-200308000-00005. PMID 12869880. 12. ^ Lima, Mario (2016). Pediatric Digestive Surgery. Springer. p. 239. ISBN 9783319405254. 13. ^ Rustagi, T; McCarty, TR; Aslanian, HR (2015). "Endoscopic Treatment of Gastrointestinal Perforations, Leaks, and Fistulae". Journal of Clinical Gastroenterology. 49 (10): 804–9. doi:10.1097/mcg.0000000000000409. PMID 26325190. S2CID 38323381. ## External links[edit] Classification D * ICD-10: K63.1, S36.9 * ICD-9-CM: 569.83, 863.9 * DiseasesDB: 34042 External resources * MedlinePlus: 000235 * eMedicine: med/2822 * Gastrointestinal perforation—MedlinePlus * 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 * v * t * e Nonmusculoskeletal injuries of abdomen and pelvis Abdomen / GI * Ruptured spleen * Blunt splenic trauma * Traumatic diaphragmatic hernia * Gastrointestinal perforation * Liver injury * Pancreatic injury Pelvic * Uterine perforation * Penile fracture Authority control * GND: 4359655-1 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Gastrointestinal perforation	c0151664	1,507	wikipedia	https://en.wikipedia.org/wiki/Gastrointestinal_perforation	2021-01-18T19:06:47	{"icd-9": ["863.9", "569.83"], "icd-10": ["K63.1"], "wikidata": ["Q279324"]}
Livedoid vasculopathy is a blood vessel disorder that causes painful ulcers and scarring (atrophie blanche) on the feet and lower legs. These symptoms can persist for months to years and the ulcers often recur. Livedoid vasculopathy lesions appear as painful red or purple marks and spots that may progress to small, tender, irregular ulcers. Symptoms tend to worsen in the winter and summer months, and affect women more often then men. Livedoid vasculopathy may occur alone or in combination with another condition, such as lupus or thrombophilia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Livedoid vasculopathy	c0857794	1,508	gard	https://rarediseases.info.nih.gov/diseases/12784/livedoid-vasculopathy	2021-01-18T17:59:21	{"icd-9": ["709.1"], "synonyms": ["Segmental hyalinizing vasculopathy", "Livedo vasculitis", "Livedoid vasculitis", "Livedo reticularis with summer ulcerations", "Livedo reticularis with winter ulcerations"]}
A number sign (#) is used with this entry because of evidence that early-onset neurodegeneration with choreoathetoid movements and microcytic anemia (NDCAMA) is caused by compound heterozygous mutation in the iron responsive element-binding protein-2 gene (IREB2; 147582) on chromosome 15q25. One such patient has been reported. Description Early-onset neurodegeneration with choreoathetoid movements and microcytic anemia (NDCAMA) is an autosomal recessive disorder characterized by severe psychomotor developmental abnormalities and functional iron deficiency (Costain et al., 2019). Clinical Features Costain et al. (2019) reported a 16-year-old boy, born of unrelated Filipino parents, with a severe neurodegenerative disorder. He was born at term with normal parameters, with some neonatal feeding difficulties in retrospect. Around 3 months of age, he was noted to have delayed psychomotor development and significant motor abnormalities, including poor head control, hypotonia, and dystonic posturing. He never achieved rolling or crawling and had no speech and minimal eye contact. In childhood, he developed choreoathetoid movements with involvement of the upper limbs and face, including orofacial dyskinesias, as well as hypertonia and spasticity of the lower limbs. He developed tonic-clonic seizures at age 9, which could be controlled. EEG showed diffuse slowing of background activity. At age 16, he was fully dependent for care, had a feeding tube, paucity of voluntary movement, and prominent involuntary movements and corticospinal tract signs such as hyperreflexia and extensor plantar responses. He had mild dysmorphic features, including ptosis, short philtrum, low-set ears, midface hypoplasia, and thick, unruly scalp and body hair. Brain imaging showed progressive cerebral volume loss, enlarged ventricles, delayed myelination, and loss of white matter volume. Retinal examination was normal, but ERG suggested retinal dysfunction. Laboratory studies showed chronic refractory microcytic, hypochromic iron-deficient anemia, although serum transferrin and iron levels were normal. Serum ferritin was mildly increased. Inheritance The transmission pattern of NDCAMA in the family reported by Costain et al. (2019) was consistent with autosomal recessive inheritance. Molecular Genetics In a 16-year-old boy, born of unrelated Filipino parents, with NDCAMA, Costain et al. (2019) identified compound heterozygous nonsense mutations in the IREB2 gene (R419X, 147582.0001 and G357X, 147582.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. Neither variant was found in the gnomAD database. Western blot analysis of patient cells showed undetectable IREB2 protein. Patient cells also showed upregulation of ferritin heavy chain (FTH1; 134770) expression and downregulation of transferrin receptor (TFRC; 190010) expression, consistent with absence of IREB2 activity. There was a compensatory increase in IREB1 (ACO1; 100880) activity, as well as evidence of mitochondrial dysfunction with decreased activities of respiratory chain complexes, likely resulting from decreased availability of iron. The abnormalities in patient cells could be rescued in vitro by restoration of IREB2. Costain et al. (2019) noted that the phenotype was similar to that observed in mice with homozygous knockdown of the Ireb2 gene (see ANIMAL MODEL). Animal Model LaVaute et al. (2001) showed that in mice, targeted disruption of the Ireb2 gene resulted in misregulation of iron metabolism in the intestinal mucosa and neurodegenerative disease of the central nervous system. In adulthood, Ireb2 -/- mice developed a movement disorder characterized by ataxia, bradykinesia, and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain preceded the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulated in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalized with iron accumulations in populations of neurons that degenerated. Ireb2 -/- mice initially grew and developed normally. Mice older than 6 months of age developed a progressive neurodegenerative disorder characterized initially by an unsteady, wide-based gait and subtle kyphosis followed by gradual onset of ataxia, vestibular dysfunction, tremor, bradykinesia, and postural abnormalities. Balance and grip strength measured using the hanging wire test indicated severe impairment, whereas heterozygous mice showed an intermediate degree of impairment. Ghosh et al. (2008) reported that administration of tempol, a stable nitroxide, to Irp2-null mice attenuated the progression of neuromuscular impairment. In cell lines derived from Irp2-null mice and in the cerebellum, brainstem, and forebrain of animals maintained on the tempol diet, Irp1 (100880) was converted from a cytosolic aconitase to an IRE-binding protein that stabilized the transferrin receptor-1 (TFRC; 190010) transcript and repressed ferritin synthesis. Ghosh et al. (2008) suggested that tempol protected Irp2-null mice by disassembling the cytosolic iron-sulfur cluster of Irp1 and activating IRE binding activity, which stabilized the Tfrc transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain. In a review of the role of IRP proteins in iron regulation, Ghosh et al. (2015) noted that Ireb2-null mice developed progressive neurodegeneration and microcytic anemia. Mitochondrial abnormalities, including respiratory chain defects, indicated a functional iron deficiency. There were also increased ferritin and decreased transferrin receptor levels compared to controls. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Short philtrum \- Midface hypoplasia \- Orofacial dyskinesia Ears \- Low-set ears Eyes \- Ptosis \- Poor eye contact \- Retinal dysfunction ABDOMEN Gastrointestinal \- Tube feeding MUSCLE, SOFT TISSUES \- Hypotonia, axial \- Hypertonia, limbs \- Poor head control NEUROLOGIC Central Nervous System \- Global developmental delay \- Impaired intellectual development, profound \- Absent speech \- Dystonia \- Choreoathetosis \- Chorea \- Lack of voluntary movements \- Inability to roll or crawl \- Corticospinal tract signs \- Spasticity \- Hyperreflexia \- Extensor plantar responses \- Seizures \- Abnormal EEG \- Cortical atrophy, progressive \- Decreased white matter volume \- Delayed myelination HEMATOLOGY \- Microcytic anemia \- Hypochromic anemia LABORATORY ABNORMALITIES \- Normal serum transferrin \- Normal total iron \- Mitochondrial abnormalities due to functional iron deficiency \- Impaired activities of mitochondrial respiratory chain complexes MISCELLANEOUS \- Onset in infancy \- Progressive disorder \- Anemia is refractory to iron supplementation \- One patient has been reported (last curated May 2019) MOLECULAR BASIS \- Caused by mutation in the iron-responsive element-binding protein 2 gene (IREB2, 147582.0001 ) ▲ 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	NEURODEGENERATION, EARLY-ONSET, WITH CHOREOATHETOID MOVEMENTS AND MICROCYTIC ANEMIA	None	1,509	omim	https://www.omim.org/entry/618451	2019-09-22T15:41:53	{"omim": ["618451"]}
A rare genetic eye disease characterized by congenital profound excavation of the optic nerve head with diminished visual field, in the absence of elevated intraocular pressure. Many patients lack a well-formed retinal artery and have multiple radial cilioretinal arteries instead. The condition is mostly bilateral, may worsen progressively, and is often complicated by serous macular detachment with profound visual loss. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Familial cavitary optic disc anomaly	c1969063	1,510	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=464760	2021-01-23T18:59:36	{"mesh": ["C566924"], "omim": ["611543"], "synonyms": ["Familial CODA"]}
A number sign (#) is used with this entry because non-Hodgkin lymphoma is associated with somatic mutations in a number of genes, including CASP10 (601762), ATM (607585), RAD54L (603615), BRAF (164757), CARD11 (607210), and RAD54B (604289). Inheritance Wiernik et al. (2000) analyzed 11 published reports of multigenerational familial non-Hodgkin lymphoma (NHL) and 18 previously unreported families with familial NHL for evidence of anticipation. They determined the difference in disease-free survival between generations and the difference in the age of onset for each affected parent-child pair. To avoid ascertainment bias, the analyses were also performed separately using only parent-child pairs with age of onset greater than 25 years. In addition, the age-of-onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) program using data for 1973 to 1998. The median age of onset in the child and parent generations of all families (48.5 and 78.3 years, respectively) and in the selected pairs (52.5 and 71.5 years, respectively) was significantly different. A significant difference was observed between the ages of onset between the child generation and that of the SEER population but not between the parent generation and the SEER population. Wiernik et al. (2000) concluded that anticipation in familial NHL is a genuine phenomenon and suggests a genetic role in the disorder. Using the Swedish Family-Cancer Database, Altieri et al. (2005) calculated standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in 4,455 offspring with NHL whose parents or sibs were affected with different types of lymphoproliferative malignancies. SIRs for affected patients with a parental history of NHL were significantly increased for NHL (1.8) and diffuse large B-cell lymphoma (2.3). SIRs for affected patients with a sib history of NHL were significantly increased for NHL (1.9), follicular lymphoma (2.3), and B-cell lymphoma not otherwise specified (3.4). With a parental history of histopathology-specific concordant cancer, familial risks were significantly increased for diffuse large B-cell lymphoma, follicular NHL, plasma cell myeloma, and chronic lymphocytic leukemia (SIRs of 11.8, 6.1, 2.5, and 5.9, respectively). Altieri et al. (2005) concluded that there is a strong familial association in NHL. Pathogenesis Roughly 10% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCLs) have mutant CARD11 (607210) isoforms that activate NF-kappa-B (see 164011). Davis et al. (2010) used an RNA interference genetic screen to show that the BCR signaling component Bruton tyrosine kinase (BTK; 300300) is essential for the survival of ABC DLBCLs with wildtype CARD11. In addition, knockdown of proximal BCR subunits (IgM, see 147020; Ig-kappa, see 147200; CD79A, 112205; and CD79B, 147245) killed ABC DLBCLs with wildtype CARD11 but not other lymphomas. The B cell receptors in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signaling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine at position 196, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase (165120), a feedback inhibitor of BCR signaling. Davis et al. (2010) concluded that their findings establish chronic active BCR signaling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies. Molecular Genetics Clementi et al. (2005) reported 4 patients with non-Hodgkin lymphoma with features of hemophagocytic lymphohistiocytosis (603533) who had mutations in the perforin gene (see 170280.0002; 170280.0009; 170280.0011). DLBCL is the most common form of non-Hodgkin lymphoma, accounting for 30 to 40% of cases (Lenz et al., 2008). DLBCL consists of 3 subtypes: germinal center B cell-like (GCB) DLBCL, ABC DLBCL, and primary mediastinal B cell lymphoma. The ABC DLBCL subtype accounts for roughly one-third of the cases and has an inferior prognosis. A characteristic feature of ABC DLBCL is constitutive activation of the NF-kappa-B (see 164011) pathway, which plays a pivotal role in proliferation, differentiation, and survival of normal lymphoid cells. In normal B cells, antigen receptor-induced NF-kappa-B activation requires CARD11 (607210), a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, Lenz et al. (2008) sequenced the CARD11 gene in human DLBCL tumors. Lenz et al. (2008) detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappa-B activation and enhanced the NF-kappa-B activity upon antigen receptor stimulation. Lenz et al. (2008) concluded that CARD11 is a bona fide oncogene in DLBCL. Compagno et al. (2009) showed that greater than 50% of ABC DLBCL and a smaller fraction of germinal center B cell-like (GCB) DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3; 191163) and positive (including CARD11 and TRAF2, 601895) regulators of NF-kappa-B. Of these, the TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappa-B. Compagno et al. (2009) concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses. Morin et al. (2010) identified recurrent somatic mutations affecting the tyr641 residue of the conserved SET domain in the EZH2 gene (601573) in cases of follicular lymphoma and diffuse large B-cell lymphoma of only the GCB subtype. Their data indicated that mutation involving this tyrosine was among the most frequent genetic events observed in GCB malignancies, after t(14;18)(q32;q21) translocations. Pasqualucci et al. (2011) reported that the 2 most common types of B cell non-Hodgkin lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP (600140) and, more rarely, EP300 (602700), 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. Pasqualucci et al. (2011) demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (109565) and activation of the p53 tumor suppressor (191170). Morin et al. (2011) sequenced tumor and matched control DNA from 13 DLBCL cases and 1 follicular lymphoma case to identify genes with mutations in B-cell NHL. Morin et al. (2011) analyzed RNA sequencing data from these and another 113 NHLs to identify genes with candidate mutations, and then resequenced tumor and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of follicular lymphoma cases had somatic mutations in MLL2 (602113), which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and follicular lymphoma cases, respectively, had mutations in MEF2B (601661), a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Morin et al. (2011) concluded that their analysis suggested a previously unappreciated disruption of chromatin biology in lymphomagenesis. In their analysis, Morin et al. (2011) found that the 8 most significant genes included 7 with strong selective pressure for nonsense mutations, including the known tumor suppressor genes TP53 and TNFRSF14 (602746). CREBBP also showed some evidence for acquisition of nonsense mutations and coding single-nucleotide variants. Morin et al. (2011) observed enrichment for nonsense mutations in BCL10 (603517), a positive regulator of NF-kappa-B in which oncogenic truncated products have been described in lymphomas. The remaining strongly significant genes (BTG1, 109580; GNA13, 604406; SGK1, 602958; and MLL2, 602113) had no reported role in lymphoma. GNA13 encodes the alpha subunit of a heterotrimeric G protein-coupled receptor responsible for modulating RhoA activity. SGK1 encodes a phosphatidylinositol-3-hydroxy kinase-regulated kinase with functions including regulation of FOXO transcription factors, regulation of NF-kappa-B by phosphorylating I-kappa-B kinase (see 600664), and negative regulation of NOTCH (190198) signaling. SGK1 also resides within a region of chromosome 6 commonly deleted in DLBCL. Both SGK1 and GNA13 mutations were found only in germinal center B-cell lymphomas. MEF2B and TNFRSF14, which had no previously described role in DLBCL, were similarly restricted to germinal center B-cell lymphomas. To identify tumor suppressor genes in lymphoma, Scuoppo et al. (2012) screened a short hairpin RNA library targeting genes deleted in human lymphomas and functionally confirmed those in a mouse lymphoma model. Of the 9 tumor suppressors identified, 8 corresponded to genes occurring in 3 physically linked 'clusters,' suggesting that the common occurrence of large chromosomal deletions in human tumors reflects selective pressure to attenuate multiple genes. Among the new tumor suppressors are adenosylmethionine decarboxylase-1 (AMD1; 180980) and eukaryotic translation initiation factor 5A (eIF5A; 600187), 2 genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, Scuoppo et al. (2012) established the polyamine-hypusine axis as a new tumor suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas, and cosuppression of both genes promotes lymphomagenesis in mice. Thus, Scuoppo et al. (2012) concluded that some tumor suppressor functions can be disabled through a 2-step process targeting different genes acting in the same pathway. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	LYMPHOMA, NON-HODGKIN, FAMILIAL	c0024305	1,511	omim	https://www.omim.org/entry/605027	2019-09-22T16:11:38	{"doid": ["0060060"], "mesh": ["D008228"], "omim": ["605027"], "orphanet": ["547"], "synonyms": ["Alternative titles", "NON-HODGKIN LYMPHOMA"]}
Alopecia totalis A woman with alopecia totalis SpecialtyDermatology Alopecia totalis is the loss of all skull and facial hair. Its causes are unclear, but believed to be autoimmune. Research suggests there may be a genetic component linked to developing alopecia totalis; the presence of DRB10401 and DQB10301, both of which are Human Leukocyte Antigens (HLA), were found to be associated with long-standing alopecia totalis.[1] ## Contents * 1 Treatment * 2 See also * 3 References * 4 External links ## Treatment[edit] Methotrexate and corticosteroids are proposed treatments.[2] Scalp cooling has specifically been used to prevent alopecia in docetaxel chemotherapy,[3] although it has been found prophylactic in other regimens as well.[4][5][6] Treatment effects may take time to resolve, with one study showing breast cancer survivors wearing wigs up to 2 years after chemotherapy.[7] ## See also[edit] * Alopecia areata * Alopecia universalis ## References[edit] 1. ^ Colombe, Beth W.; Lou, Calvin D.; Price, Vera H. (December 1999). "The Genetic Basis of Alopecia Areata: HLA Associations with Patchy Alopecia Areata Versus Alopecia Totalis and Alopecia Universalis". Journal of Investigative Dermatology Symposium Proceedings. 4 (3): 216–219. doi:10.1038/sj.jidsp.5640214. ISSN 1087-0024. 2. ^ Joly, Pascal (2006). "The use of methtrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis". Journal of the American Academy of Dermatology. 55 (4): 632–6. doi:10.1016/j.jaad.2005.09.010. PMID 17010743. 3. ^ Hurk, C. J. G.; Breed, W. P. M.; Nortier, J. W. R. (2012). "Short post-infusion scalp cooling time in the prevention of docetaxel-induced alopecia". Supportive Care in Cancer. 20 (12): 3255–3260. doi:10.1007/s00520-012-1465-0. PMID 22539051. 4. ^ Lemieux, J. (2012). "Reducing chemotherapy-induced alopecia with scalp cooling". Clinical Advances in Hematology & Oncology. 10 (10): 681–682. PMID 23187775. 5. ^ Van Den Hurk, C. J.; Peerbooms, M.; Van De Poll-Franse, L. V.; Nortier, J. W.; Coebergh, J. W. W.; Breed, W. P. (2012). "Scalp cooling for hair preservation and associated characteristics in 1411 chemotherapy patients - Results of the Dutch Scalp Cooling Registry". Acta Oncologica. 51 (4): 497–504. doi:10.3109/0284186X.2012.658966. PMID 22304489. 6. ^ Yeager, C. E.; Olsen, E. A. (2011). "Treatment of chemotherapy-induced alopecia". Dermatologic Therapy. 24 (4): 432–442. doi:10.1111/j.1529-8019.2011.01430.x. PMID 21910801. 7. ^ Oshima, Y.; Watanabe, T.; Nakagawa, S.; Endo, A.; Shiga, C. (2012). "A questionnaire survey about hair loss after chemotherapy for breast cancer". Gan to kagaku ryoho. Cancer & chemotherapy. 39 (9): 1375–1378. PMID 22996772. ## External links[edit] Classification D * ICD-10: L63.0 * v * t * e Human hair Classification by type * Lanugo * Androgenic * Terminal * Vellus by location * Body * Ear * Nose * Eyebrow * unibrow * Eyelash * Underarm * Chest * Abdominal * Pubic * Leg Head hairstyles (list) * Afro * Afro puffs * Asymmetric cut * Bald * Bangs * Beehive * Big hair * Blowout * Bob cut * Bouffant * Bowl cut * Braid * Brush cut * Bun (odango) * Bunches * Burr * Businessman cut * Butch cut * Buzz cut * Caesar cut * Chignon * Chonmage * Chupryna * Comb over * Conk * Cornrows * Crew cut * Crochet braids * Croydon facelift * Curly hair * Curtained hair * Devilock * Dido flip * Digital perm * Dreadlocks * Duck's ass * Eton crop * Extensions * Feathered hair * Finger wave * Flattop * Fontange * French braid * French twist * Fringe * Frosted tips * Hair crimping * Harvard clip * High and tight * Hime cut * Historical Christian hairstyles * Hi-top fade * Induction cut * Ivy League * Jewfro * Jheri curl * Kiss curl * Layered hair * Liberty spikes * Long hair * Lob cut * Marcelling * Mod cut * Mohawk * Mullet * 1950s * 1980s * Pageboy * Part * Payot * Pigtail * Pixie cut * Polish halfshaven head * Pompadour * Ponytail * Punch perm * Princeton * Professional cut * Queue * Quiff * Rattail * Razor cut * Regular haircut * Ringlets * Shag * Shape-Up * Shimada * Short back and sides * Short brush cut * Short hair * Spiky hair * Straight hair * Standard haircut * Surfer hair * Taper cut * Temple Fade * Tonsure * Updo * Undercut * Waves * Widow's peak * Wings Facial hair (list) * Beard * Chinstrap * Goatee * Shenandoah * Soul patch * Van Dyke * Moustache * Fu Manchu * handlebar * horseshoe * pencil * toothbrush * walrus * Designer stubble * Sideburns Hair loss cosmetic * Removal * waxing * threading * plucking * chemical * electric * laser * IPL * Shaving * head * leg * cream * brush * soap * Razor * electric * safety * straight other * Alopecia * areata * totalis * universalis * Frictional alopecia * Male-pattern hair loss * Hypertrichosis * Management * Trichophilia * Trichotillomania * Pogonophobia Haircare products * Brush * Clay * Clipper * Comb * Conditioner * Dryer * Gel * Hot comb * Iron * Mousse * Pomade * Relaxer * Rollers * Shampoo * Spray * Wax Haircare techniques * Backcombing * Crimping * Curly Girl Method * Hair cutting * Perm * Shampoo and set * Straightening Related topics * Afro-textured hair (kinky hair) * Beard and haircut laws by country * Bearded lady * Barber (pole) * Eponymous hairstyle * Frizz * Good hair * Hairdresser * Hair fetishism (pubic) * Hair follicle * Hair growth * Hypertrichosis * Trichotillomania * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Alopecia totalis	c0263504	1,512	wikipedia	https://en.wikipedia.org/wiki/Alopecia_totalis	2021-01-18T19:06:41	{"gard": ["613"], "umls": ["C0263504"], "icd-10": ["L63.0"], "orphanet": ["700"], "wikidata": ["Q4734614"]}
A number sign (#) is used with this entry because of evidence that keratoconus-9 (KCTN9) is caused by heterozygous mutation in the TUBA3D gene (617878) on chromosome 2q21. Description Keratoconus-9, a degenerative corneal disease with onset during adolescence, is characterized by corneal ectasia, thinning, and cone-shaped protrusion that results in reduced vision (Hao et al., 2017). For a discussion of genetic heterogeneity of keratoconus, see 148300. Clinical Features Hao et al. (2017) studied a Chinese family in which 23-year-old twin sisters had keratoconus. The proband began noticing vision loss at age 16 years, with a significant decrease by age 23. Examination revealed bilateral corneal ectasia, thinning, and a cone-shaped protrusion with Vogt striae and Fleischer ring. Videokeratography showed the typical findings of keratoconus. The parents were unaffected. Molecular Genetics In Chinese twin sisters with keratoconus who were negative for mutation in 3 candidate genes, Hao et al. (2017) performed exome sequencing and identified heterozygosity for a de novo nonsense mutation in the TUBA3D gene (Q11X; 617878.0001) that was not found in their unaffected parents, in 200 Chinese controls, or in public variant databases. Analysis of the TUBA3D gene in 200 unrelated patients with sporadic keratoconus identified 2 more patients with heterozygous mutations (see, e.g., 617878.0002). Functional analysis showed that the mutant proteins result in higher expression of matrix metalloproteinase genes and higher levels of oxidative stress, which the authors suggested would reduce the amount of extracellular matrix in the corneas and contribute to the stromal thinning and Bowman layer/basement membrane breaks that are observed in keratoconus. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Reduced visual acuity \- Corneal ectasia \- Corneal thinning \- Cone-shaped protrusion \- Vogt striae \- Fleischer ring MISCELLANEOUS \- Clinical details based on report of monozygotic twins (last curated April 2018) MOLECULAR BASIS \- Caused by mutation in the alpha-3D tubulin gene (TUBA3D, 617878.0001 ) ▲ 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	KERATOCONUS 9	c4693660	1,513	omim	https://www.omim.org/entry/617928	2019-09-22T15:44:22	{"omim": ["617928"]}
Skeletal fluorosis Fluorosis victim of the industrial city of Raigarh, Chhattisgarh SpecialtyRheumatology Skeletal fluorosis is a bone disease caused by excessive accumulation of fluoride leading to weakened bones.[1] In advanced cases, skeletal fluorosis causes painful damage to bones and joints. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 3.1 Skeletal fluorosis phases * 4 Treatment * 5 Epidemiology * 6 Effects on animals * 7 See also * 8 References * 9 Further reading * 10 External links ## Symptoms[edit] Symptoms are mainly promoted in the bone structure. Due to a high fluoride concentration in the body, the bone is hardened and thus less elastic, resulting in an increased frequency of fractures. Other symptoms include thickening of the bone structure and accumulation of bone tissue, which both contribute to impaired joint mobility. Ligaments and cartilage can become ossified.[2] Most patients suffering from skeletal fluorosis show side effects from the high fluoride dose such as ruptures of the stomach lining and nausea.[3] Fluoride can also damage the parathyroid glands, leading to hyperparathyroidism, the uncontrolled secretion of parathyroid hormones. These hormones regulate calcium concentration in the body. An elevated parathyroid hormone concentration results in a depletion of calcium in bone structures and thus a higher calcium concentration in the blood. As a result, bone flexibility decreases making the bone more susceptible to fractures.[4] ## Causes[edit] Common causes of fluorosis include inhalation of fluoride dusts/fumes by workers in industry, consumption of fluoride from drinking water (levels of fluoride in excess of levels that are considered safe.[5]) In India, especially the Nalgonda region (Telangana), a common cause of fluorosis is fluoride-rich drinking water that is sourced from deep-bore wells. Over half of groundwater sources in India have fluoride above recommended levels.[6] Fluorosis can also occur as a result of volcanic activity. The 1783 eruption of the Laki volcano in Iceland is estimated to have killed about 22% of the Icelandic population, and 60% of livestock, as a result of fluorosis and sulfur dioxide gases.[7] The 1693 eruption of Hekla also led to fatalities of livestock under similar conditions.[8] ## Diagnosis[edit] [citation needed] ### Skeletal fluorosis phases[edit] Osteosclerotic phase Ash concentration (mgF/kg) Symptoms and signs Normal Bone 500 to 1,000 Normal Preclinical Phase 3,500 to 5,500 Asymptomatic; slight radiographically-detectable increases in bone mass Clinical Phase I 6,000 to 7,000 Sporadic pain; stiffness of joints; osteosclerosis of pelvis and vertebral column Clinical Phase II 7,500 to 9,000 Chronic joint pain; arthritic symptoms; slight calcification of ligaments' increased osteosclerosis and cancellous bones; with/without osteoporosis of long bones Clinical Phase III 8,400 Limitation of joint movement; calcification of ligaments of neck vertebral column; crippling deformities of the spine and major joints; muscle wasting; neurological defects/compression of spinal cord ## Treatment[edit] As of now, there are no established treatments for skeletal fluorosis patients.[9] However, it is reversible in some cases, depending on the progression of the disease. If fluorine intake is stopped, the amount in bone will decrease and be excreted via urine. However, it is a very slow process to eliminate the fluorine from the body completely. Minimal results are seen in patients. Treatment of side effects is also very difficult. For example, a patient with a bone fracture cannot be treated according to standard procedures, because the bone is very brittle. In this case, recovery will take a very long time and a pristine healing cannot be guaranteed.[10] However, further fluorosis can be prevented by drinking defluoridated water. It is recently suggested that drinking of defluoridated water from the ″calcium amended-hydroxyapatite″ defluoridation method may help in the fluorosis reversal.[11] Defluoridated water from this suggested method provides calcium-enriched alkaline drinking water as generally fluoride contaminated water has a low amount of calcium mineral and drinking alkaline water helps in eliminating the toxic fluoride from the body.[11] ## Epidemiology[edit] In some areas, skeletal fluorosis is endemic. While fluorosis is most severe and widespread in the two largest countries – India and China – UNICEF estimates that "fluorosis is endemic in at least 25 countries across the globe. The total number of people affected is not known, but a conservative estimate would number in the tens of millions."[12] In India, 20 states have been identified as endemic areas, with an estimated 60 million people at risk and 6 million people disabled; about 600,000 might develop a neurological disorder as a consequence.[6] ## Effects on animals[edit] Moroccan cow with fluorosis The histological changes which are induced through fluorine on rats resemble those of humans.[13] ## See also[edit] * Dental fluorosis * Fluoride poisoning * Kaj Roholm ## References[edit] 1. ^ Whitford GM (1994). "Intake and Metabolism of Fluoride". Advances in Dental Research. 8 (1): 5–14. doi:10.1177/08959374940080011001. PMID 7993560. 2. ^ Kalia LV, Lee L, Kalia SK, Pirouzmand F, Rapoport MJ, Aviv RI, Mozeg D, Symons SP. Thoracic myelopathy from coincident fluorosis and epidural lipomatosis. Canadian Journal of Neurological Sciences. 2010 March; 37(2):276–278. 3. ^ Gönnewicht, Daniela (2005). "Untersuchung eines Zusammenhanges von Fluoridkonzentrationen in privaten Trinkwasserversorgungsanlagen und Kariesentwicklung im Raum Ascheberg (Südliches Münsterland/Westfalen)" (PDF). Dissertation. Universität Münster, Fachbereich Medizinische Fakultät. 4. ^ Teotia SP, Teotia M (March 1973). "Secondary hyperparathyroidism in patients with endemic skeletal fluorosis". Br Med J. 1 (5854): 637–40. doi:10.1136/bmj.1.5854.637. PMC 1588649. PMID 4692708. 5. ^ "CDC – National Research Council (NRC) Report – Safety – Community Water Fluoridation – Oral Health". Cdc.gov. Retrieved 2013-09-04. 6. ^ a b Reddy DR (2009). "Neurology of endemic skeletal fluorosis". Neurol India. 57 (1): 7–12. doi:10.4103/0028-3886.48793. PMID 19305069. 7. ^ Thordarson, Thorvaldur; Self, Stephen (2003). "Atmospheric and environmental effects of the 1783–1784 Laki eruption: A review and reassessment" (PDF). Journal of Geophysical Research. 108 (D1): 4011. Bibcode:2003JGRD..108.4011T. doi:10.1029/2001JD002042. 8. ^ Eruption History 9. ^ Whyte MP, Essmyer K, Gannon FH, Reinus WR (January 2005). "Skeletal fluorosis and instant tea". Am. J. Med. 118 (1): 78–82. doi:10.1016/j.amjmed.2004.07.046. PMID 15639213. 10. ^ Grandjean P, Thomsen G (November 1983). "Reversibility of skeletal fluorosis". Br J Ind Med. 40 (4): 456–61. doi:10.1136/oem.40.4.456. PMC 1009220. PMID 6626475. 11. ^ a b Sankannavar, Ravi; Chaudhari, Sanjeev (2019). "An imperative approach for fluorosis mitigation: Amending aqueous calcium to suppress hydroxyapatite dissolution in defluoridation". Journal of Environmental Management. 245: 230–237. doi:10.1016/j.jenvman.2019.05.088. PMID 31154169. 12. ^ "UNICEF – Water, environment and sanitation – Common water and sanitation-related diseases". Retrieved 2007-09-17. 13. ^ Franke J, Runge H, Fengler F, Wanka C (1972). "[Experimental bone fluorosis]". Int Arch Arbeitsmed (in German). 30 (1): 31–48. doi:10.1007/bf00539123. PMID 5084923. ## Further reading[edit] * Fluorosis from drinking very large amounts of tea: Naveen Kakumanu, M.D. & Sudhaker D. Rao, M.B., B.S. (2013-03-21). "Skeletal Fluorosis Due to Excessive Tea Drinking". New England Journal of Medicine. 368 (12): 1140. doi:10.1056/NEJMicm1200995. PMID 23514291.CS1 maint: multiple names: authors list (link) ## External links[edit] Classification D * ICD-10: M85.1 * ICD-9-CM: 733.9 * 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	Skeletal fluorosis	c0410447	1,514	wikipedia	https://en.wikipedia.org/wiki/Skeletal_fluorosis	2021-01-18T19:00:02	{"icd-9": ["733.9"], "icd-10": ["M85.1"], "wikidata": ["Q3266880"]}
A number sign (#) is used with this entry because of evidence that 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN), also referred to as 3-methylglutaconic aciduria type VII (MGCA7), is caused by homozygous or compound heterozygous mutation in the CLPB gene (616254) on chromosome 11q13. Description 3-Methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections (summary by Wortmann et al., 2015 and Saunders et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950). Clinical Features Wortmann et al. (2015) reported 14 individuals from 9 unrelated families with an inborn error of metabolism characterized by increased urinary excretion of 3-MGA. Additional features were highly variable, with some patients having no neurologic involvement or infections and others having neonatal or even prenatal onset of progressive neurologic symptoms and/or severe neutropenia with progression to leukemia and death in the first months of life. Common features included delayed psychomotor development/variable intellectual disability (12 patients), congenital neutropenia (10 patients), brain atrophy (7 patients), microcephaly (7 patients), movement disorder (7 patients), and cataracts (5 patients). The oldest living patient was 18 years old and the youngest was 2; 6 patients died between 24 days and 46 months of age. The least severely affected children were a pair of sibs ascertained due to neutropenia. One sib had congenital nuclear cataracts and the other had attention deficit-hyperactivity disorder, dyslexia, and dysgraphia; however, both showed normal overall growth and development at ages 8 and 10 years, respectively. Most of the other patients showed neonatal hypotonia that progressed to spasticity, suggesting pyramidal tract dysfunction. Patients with a moderate phenotype had hypotonia, feeding difficulties, microcephaly, delayed psychomotor development, ataxia, and dystonia. Four patients had the most severe phenotype, with onset in utero or at birth of increased muscle tension ('stiff babies'), lack of eye contact, complete absence of development, and death in the first months of life. Eleven patients had swallowing difficulties, and 4 had seizures. Results of brain imaging also varied significantly, and included normal findings, isolated cerebellar atrophy, cerebral atrophy, and abnormalities of the basal ganglia. Ten patients had neutropenia, but only some patients had recurrent severe infections. Two sibs developed acute myeloid leukemia and myelodysplastic syndrome, respectively. Less common features, occurring in only a few patients, included facial dysmorphism, cardiomyopathy or hypertrophy, and hypothyroidism. Studies of patient cells did not show defects in mitochondrial oxidative phosphorylation. Saunders et al. (2015) reported 4 children, including 2 sibs, of Greenlandic descent, and an unrelated child of northern European and Asian descent, with 3-MGA and neutropenia. The 4 children of Greenlandic origin showed regression of psychomotor development after a few months of normal early development; all died within the first years of life. The fifth child presented at birth with growth retardation, microcephaly, rigidity, contractures, and abnormal facial features, and died from respiratory failure on day 8 of life. Additional variable features among all patients included cataracts, hypotonia, extrapyramidal symptoms such as myoclonus, dystonia, choreoathetosis, opisthotonus, and seizures. Bone marrow biopsies showed maturational arrest of granulopoiesis. Brain imaging was either normal or showed cerebral atrophy; 1 patient had lesions in the basal ganglia. Capo-Chichi et al. (2015) reported 4 sibs, born of consanguineous Cambodian parents, with a severe form of MEGCANN. They did not move or breathe spontaneously at birth. Appendicular tone was increased, and they showed sustained clonic movements induced by minimal tactile stimulation. EEG showed burst suppression. Brain imaging in 1 patient showed gyral simplification. All were ventilator-dependent and died in the first week of life after removal of respiratory support. Laboratory studies showed increased serum lactate, increased urinary 3-methylglutaconic acid and methylglutaric acid, neutropenia, and coagulation defects. Neuropathologic examination showed neuronal loss in several brain regions, diffuse gliosis, and microvacuolization, which are nonspecific changes consistent with a defect in energy metabolism. Inheritance The transmission pattern of MEGCANN in the families reported by Wortmann et al. (2015) and Saunders et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In 14 individuals from 9 unrelated families with MEGCANN Wortmann et al. (2015) identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., 616254.0001-616254.0007). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; 616254.0006) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity. In 4 patients, including 2 sibs, of Greenlandic descent with MEGCANN, Saunders et al. (2015) identified a homozygous missense mutation in the CLPB gene (T268M; 616254.0008). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (616254.0007 and 616254.0009). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. In 4 sibs, born of consanguineous Cambodian parents, with MEGCANN, Capo-Chichi et al. (2015) identified a homozygous truncating mutation in the CLPB gene (616254.0010) that segregated with the disorder in the family. The mutation was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. Animal Model Wortmann et al. (2015) found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Microcephaly Face \- Dysmorphic facial features (in some patients) Eyes \- Cataracts (in most patients) ABDOMEN Gastrointestinal \- Poor feeding MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Increased muscle tone, neonatal (in severely affected patients) NEUROLOGIC Central Nervous System \- Delayed psychomotor development (in most patients) \- Intellectual disability \- Developmental regression (in some patients) \- Spasticity \- Pyramidal signs \- Extrapyramidal signs \- Abnormal movements \- Seizures (in some patients) \- Cerebellar atrophy \- Cerebral atrophy \- Atrophy of the basal ganglia IMMUNOLOGY \- Neutropenia (in most patients) \- Bone marrow shows deficient granulopoiesis \- Recurrent infections (in some patients) LABORATORY ABNORMALITIES \- Increased urinary 2-methylglutaconic acid MISCELLANEOUS \- Onset at birth \- Onset in utero in severely affected patients \- Highly variable phenotype \- Progressive disorder \- Death often in childhood MOLECULAR BASIS \- Caused by mutation in the caseinolytic peptidase B gene (CLPB, 616254.0001 ) ▲ 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	3-METHYLGLUTACONIC ACIDURIA WITH CATARACTS, NEUROLOGIC INVOLVEMENT, AND NEUTROPENIA	c4225393	1,515	omim	https://www.omim.org/entry/616271	2019-09-22T15:49:25	{"doid": ["0110003"], "omim": ["616271"], "orphanet": ["445038"], "synonyms": ["Alternative titles", "3-METHYLGLUTACONIC ACIDURIA, TYPE VII", "MGA7", "3-methylglutaconic aciduria-cataract-neurologic involvement-neutropenia syndrome"], "genereviews": ["NBK396257"]}
A rare vascular anomaly characterized by congenital narrowing of the inferior vena cava mostly at the diaphragmatic level or hepatic segment, with or without web formation. Patients may present with deep vein thrombosis below the obstructed segment, lower extremity swellings, pain, and varices, abdominal pain/varices, or hematochezia. Presence of collateral veins between upper and lower segments of the stenosis, as well as venous aneurysms are typical associated findings. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: 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 stenosis of the inferior vena cava	c0265934	1,516	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99122	2021-01-23T16:59:52	{"umls": ["C0265934", "C0340757"], "icd-10": ["Q26.0"], "synonyms": ["Congenital stenosis of the IVC", "Congenital stenosis of the inferior caval vein"]}
A rare vascular tumor characterized by a solitary lesion in the superficial or deep soft tissue of the extremities, most often originating from a small vein as a fusiform intravascular mass also infiltrating surrounding tissues. It is composed of epithelioid endothelial cells arranged in short cords and nests in a myxohyaline stroma. Patients present with an often painful nodule which may be associated with edema or thrombophlebitis. In classic epithelioid hemangioendothelioma lacking atypical histological features metastatic rate and mortality are low. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Epithelioid hemangioendothelioma	c0206732	1,517	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=157791	2021-01-23T18:40:53	{"mesh": ["D018323"], "umls": ["C0206732"], "icd-10": ["D18.0"]}
A number sign (#) is used with this entry because of evidence that X-linked hypoparathyroidism (HYPX) is caused by an interstitial deletion/insertion on chromosome Xq27.1, which may have a position effect on expression of SOX3 (313430). Clinical Features Peden (1960) reported a family in which multiple males had neonatal idiopathic hypoparathyroidism in an X-linked pattern of inheritance. No affected males reproduced. Peden (1960) suggested that most familial cases with early onset are of the X-linked type, the autosomal type (146200) having a later onset. Whyte and Weldon (1981) performed extensive studies of a second kindred from Missouri (where Peden's family also lived) with neonatal or infantile onset of X-linked isolated hypoparathyroidism. No ancestor common to the 2 kindreds could be identified. Whyte et al. (1986) reported the autopsy findings in a member of the family of Peden (1960) who had died as a teenager after an automobile crash. A careful search for parathyroid tissue was made. Dissection of the thyroid gland and tissue from elsewhere in the neck, including between the trachea and esophagus and in the retroesophageal space, and histologic study of the soft tissue from these areas showed no parathyroid tissue whatever; thus, the pathology appears to be agenesis of the parathyroid glands. The patient was receiving phenobarbital and diphenylhydantoin for treatment of seizures as well as calcium supplements and vitamin D. Mumm et al. (1997) investigated the relatedness of the 2 seemingly unrelated Missouri kindreds. Both kindreds lived in eastern Missouri and were known to have migrated there from Kentucky in the 1880s. Despite genealogic studies of 5 generations, no common ancestor had been identified. Mumm et al. (1997) compared the DNA sequence of the mitochondrial D-loop among several individuals in both kindreds. The mtDNA sequence was identical among affected males and their maternal lineage for individuals in both kindreds. Conversely, the mtDNA sequence of the fathers of the affected males differed from that of the maternal lineage at 3 to 6 positions. These results demonstrated that the 2 kindreds exhibiting X-linked recessive hypoparathyroidism are indeed related and that an identical gene defect is responsible for the disease. Mumm et al. (1997) suggested that this approach may be important in investigating common ancestry in other X-linked disorders. Buchs (1957) reported 3 affected brothers who presented with neonatal tetany. Although maternal hyperparathyroidism with fetal parathyroid suppression was not excluded, it is unlikely because subsequent children were normal. Teebi et al. (1992) reported a Bedouin family with 4 affected male sibs including a set of triplets. The mother had a brother who died in early infancy of unknown causes. Mapping In the family reported by Whyte and Weldon (1981), Thakker et al. (1988, 1989) established linkage of X-linked hypoparathyroidism with a RFLP located at Xq26-q27. Zucchi et al. (1996) reported a YAC/STS map from the distal portion of Xq and suggested that the locus for X-linked hypoparathyroidism is in a segment 3 Mb telomeric to the factor IX locus (F9; 300746). Trump et al. (1998) performed further linkage analysis and suggested that the HYPX locus lies within a 1.5-Mb interval flanked centromerically by marker F9 and telomerically by DXS984. Molecular Genetics Nesbit et al. (2004) noted that the region on Xq26-q27 to which X-linked recessive hypoparathyroidism had been linked contained 3 genes: ATP11C (300516), U7snRNA, and SOX3 (313430). Sequence analyses of these 3 genes revealed no abnormalities. Nesbit et al. (2004) raised the possibility that other genomic abnormalities such as duplications or translocations, which could cause altered gene function (Kleinjan and van Heyningen, 2005), may underlie the etiology of X-linked recessive hypoparathyroidism. In studies in the affected members of the Missouri family with X-linked hypoparathyroidism reported by Peden (1960), Bowl et al. (2005) undertook a detailed characterization of the genomic region containing the HYPX locus by combined analysis of single-nucleotide polymorphisms and sequence-tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber-FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome-specific libraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that the insertion originated from 2p25 and contained a segment of the SNTG2 gene (608715) that lacked an open reading frame. However, the deletion-insertion, which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, Sox3 expression was demonstrated, by in situ hybridization, in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days postcoitum. Thus, the results indicated a likely role for SOX3 in the embryonic development of the parathyroid glands. Endocrine \- Neonatal true idiopathic hypoparathyroidism Neuro \- Tetany \- Seizures Neck \- Absent parathyroid glands Inheritance \- X-linked ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	HYPOPARATHYROIDISM, X-LINKED	c1832648	1,518	omim	https://www.omim.org/entry/307700	2019-09-22T16:18:10	{"doid": ["11199"], "mesh": ["C537156"], "omim": ["307700"], "orphanet": ["2238", "2239"], "synonyms": ["Alternative titles", "PARATHYROID GLANDS, AGENESIS OF"]}
Wilson et al. (1989) described the single case of a 2-year-old girl with virtual absence of body and scalp hair, rounded nails, thin dental enamel, preaxial polydactyly of the feet, and an unusual facial appearance consisting of dystopia canthorum, thickened frenulum giving an appearance of slight median cleft of the upper lip (pseudocleft), and a long, flat philtrum. The patient had 2 unaffected sibs, there was no parental consanguinity, and the karyotype was normal. Some of the features resembled those of OFD I (311200) and OFD II (252100), but the patient lacked cleft, tongue abnormalities, and radiographic irregularities sometimes seen in OFD. Further, OFD patients do not have the severe degree of alopecia that was present in this patient. INHERITANCE \- Isolated cases HEAD & NECK Face \- Micrognathia \- Flat philtrum \- Malar hypoplasia Eyes \- Dystopia canthorum \- Sparse eyebrows \- Sparse eyelashes Nose \- Flat nasal bridge Mouth \- Thin upper lip \- Thickened frenulum \- Midline notch of upper alveolar ridge Teeth \- Thin dental enamel \- Dental caries SKELETAL Hands \- Fifth finger clinodactyly Feet \- Preaxial polydactyly \- Duplicated halluces \- Duplicated first metatarsals SKIN, NAILS, & HAIR Nails \- Rounded nails Hair \- Scalp alopecia \- Body alopecia \- Sparse eyebrows \- Sparse eyelashes NEUROLOGIC Central Nervous System \- Language delay ▲ 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	ECTODERMAL DYSPLASIA SYNDROME WITH DISTINCTIVE FACIAL APPEARANCE AND PREAXIAL POLYDACTYLY OF FEET	c1851851	1,519	omim	https://www.omim.org/entry/129540	2019-09-22T16:42:01	{"mesh": ["C565067"], "omim": ["129540"]}
Infantile Refsum disease (IRD) is the mildest variant of the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD- ZSS; see this term), characterized by hypotonia, retinitis pigmentosa, developmental delay, sensorineural hearing loss and liver dysfunction. Phenotypic overlap is seen between IRD and neonatal adrenoleukodystrophy (NALD) (see this term). ## Epidemiology The birth prevalence of PBD-ZSS is estimated to be around 1/50,000 in North America and 1/500,000 in Japan. More than ½ of patients with PBD-ZSS have the NALD-IRD forms. ## Clinical description IRD has an onset at birth or early infancy but manifestations may be subtle enough that diagnosis is not until adulthood. In infancy, symptoms may include nystagmus, hypotonia, sensorineural hearing loss, growth retardation, mild facial dysmorphism, and hepatomegaly. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to coagulopathy. In childhood, progressive retinitis pigmentosa, developmental deficits and hypotonia are seen. Most achieve motor milestones, though delayed, and communicate in a few words or signs. Osteoporosis and fractures can occur in the less mobile. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Leukodystrophy with loss of previously acquired skills can occur at any age and may stabilize, or progress and be fatal. Atypical presentations (visual and hearing loss with preservation of intellect and cerebellar ataxia with/without peripheral neuropathy) have been described. ## Etiology PBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis. ## Diagnostic methods IRD is suspected on physical exam and definitively confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are usually reduced, but can be normal. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Occasionally, VLCFA levels and enzymatic assays in fibroblasts can be within the normal range, requiring additional assessment in expert laboratories. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify myelin changes. ## Differential diagnosis The main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. IRD should not be confused with adult Refsum disease (see this term). ## Antenatal diagnosis Prenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis. ## Genetic counseling IRD is inherited autosomal recessively, so genetic counseling is possible. ## Management and treatment There is no cure for IRD. Cataracts should be removed in early infancy and glasses used. Hearing aids should be provided to those with hearing impairment and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Standard epileptic drugs are used for seizures. Lifelong follow up monitors changes in hearing, vision and liver function. ## Prognosis Great variation is seen with respect to life expectancy, medical complications and preservation of neurological function. Many patients survive childhood, and survival to adulthood is possible. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Infantile Refsum disease	c0282527	1,520	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=772	2021-01-23T17:49:51	{"gard": ["4648"], "mesh": ["D052919"], "omim": ["202370", "266510", "601539", "614863", "614867", "614871", "614873", "614877", "614885", "614920", "617370"], "umls": ["C0282527"], "icd-10": ["G60.1"], "synonyms": ["IRD"]}
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see 168600. Mapping Soon after a form of autosomal dominant Parkinson disease was mapped to 4q21-q22 and was shown to be due to mutations in the alpha-synuclein gene (SNCA; 163890), genetic heterogeneity became apparent, as in other families the disorder was not linked to 4q and was not associated with SNCA mutations. Gasser et al. (1998) described a genetic locus on 2p13 in familial parkinsonism with clinical features closely resembling those of sporadic Parkinson disease, including a similar mean age of onset: 59 years in these families, 59.7 years in sporadic PD (Di Rocco et al., 1996). The maximum multipoint lod score for all 6 families in their study was 3.96, considering affected members only. The most likely location of the locus for this form of familial parkinsonism was considered to be at D2S441, with a 100-to-1 likelihood ratio support interval ranging from D2S134 to D2S286, spanning 10.3 cM on 2p13. The maximum 2-point lod score was 3.20 with marker D2S441 at theta = 0.03. Two of the 6 families were genealogically traced to southern Denmark and northern Germany and were found to share a common haplotype, suggesting a founder effect. West et al. (2001) determined that the 2 families reported by Gasser et al. (1998) with the common haplotype shared 8 markers corresponding to a genetic distance of 3.2 cM. Construction of a BAC-based physical map covering the PARK3 locus genotyping 17 microsatellite markers allowed refinement of the minimum common haplotype for PARK3 to a region spanning a physical distance of approximately 2.5 Mb. All 14 known genes within the critical region were sequenced from at least 2 affected persons from each family and no potentially pathogenic mutations were detected, implying that none of these genes are likely candidates for PARK3. Klein et al. (1999) evaluated 85 German Parkinson disease patients and 85 ethnically matched controls for shared markers on chromosome 2p that might indicate a founder haplotype. No evidence of linkage disequilibrium was found, suggesting that a previously postulated founder mutation on 2p is not a common cause of Parkinson disease in the population studied by Klein et al. (1999). Furthermore, no patient carried the ala30-to-pro change (163890.0002) in the alpha-synuclein gene, supporting earlier findings that mutations in this gene are very rare. Parkinson disease is characteristically a late-onset neurodegenerative disorder with a mean age at onset of 61 years, but the disorder can range from juvenile cases to cases in the eighth or ninth decade of life. DeStefano et al. (2002) performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives, mainly affected sib pairs. The highest evidence of linkage was found with 2p (maximum multipoint lod = 2.08), a location previously reported as influencing PD affection status. Association between the age at onset of PD and allele 174 of marker D2S1394, located on 2p13, was observed (P = 0.02). This 174 allele was common to the PD haplotype observed in 2 families that showed linkage to PARK3 and had autosomal dominant PD, suggesting that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD. By studying 281 sib pairs with Parkinson disease, Karamohamed et al. (2003) fine-mapped the PARK3 locus to a 2.2-Mb region on chromosome 2p13. Patients with the TT genotype at rs1876487 had an average 7.4-year earlier age at onset compared to patients with the GT or GG genotype (p = 0.005). The authors suggested that the sepiapterin reductase gene (SPR; 182125) may be involved. Sharma et al. (2006) found that DNA polymorphisms in a highly intercorrelated linkage disequilibrium block that included the SPR gene appeared to be associated with both sporadic and familial Parkinson disease. Pankratz et al. (2004) found evidence for linkage of PD to a 15-cM region on 2p overlapping the PARK3 locus in a group of 151 PD families with an average age at disease onset of 61.9 years. They obtained a maximum multipoint lod score of 4.8 at marker D2S337. In index patients from 4 families that define the PARK3 locus, Strauss et al. (2005) found no mutation in the HTRA2 gene, mutations in which cause another form, PARK13 (610297). Indeed, the data of West et al. (2001) narrowing the PARK3 locus exclude the HTRA2 locus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PARKINSON DISEASE 3, AUTOSOMAL DOMINANT	c1865581	1,521	omim	https://www.omim.org/entry/602404	2019-09-22T16:13:49	{"doid": ["0111250"], "mesh": ["C566552"], "omim": ["602404"], "orphanet": ["2828"], "synonyms": ["PARKINSON DISEASE 3, AUTOSOMAL DOMINANT LEWY BODY", "Alternative titles", "YOPD", "Early-onset Parkinson disease"]}
Rapid onset of confusion caused by alcohol withdrawal "DTs" redirects here. For other uses, see DTS (disambiguation). For other uses, see Delirium tremens (disambiguation). Delirium tremens An alcoholic man with delirium tremens on his deathbed, surrounded by his terrified family. The text "L'Alcool Tue" means "Alcohol Kills" in French. SpecialtyPsychiatry, critical care medicine SymptomsConfusion, hallucination, shaking, shivering, irregular heart rate, sweating[1][2] ComplicationsVery high body temperature, seizures[2] Usual onsetRapid[2] Duration2–3 days[2] CausesWithdrawal from alcohol[2] Differential diagnosisBenzodiazepine withdrawal syndrome, barbiturate withdrawal[3] TreatmentIntensive care unit, benzodiazepines, thiamine[2] PrognosisRisk of death ~2% (treatment), 25% (no treatment)[4] Frequency~4% of those withdrawing from alcohol[2] Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol.[2] When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days.[2] Physical effects may include shaking, shivering, irregular heart rate, and sweating.[1] People may also hallucinate.[2] Occasionally, a very high body temperature or seizures may result in death.[2] Alcohol is one of the most dangerous drugs from which to withdraw.[5] Delirium tremens typically only occurs in people with a high intake of alcohol for more than a month.[6] A similar syndrome may occur with benzodiazepine and barbiturate withdrawal.[3] Withdrawal from stimulants such as cocaine do not have major medical complications.[7] In a person with delirium tremens it is important to rule out other associated problems such as electrolyte abnormalities, pancreatitis, and alcoholic hepatitis.[2] Prevention is by treating withdrawal symptoms.[2] If delirium tremens occurs, aggressive treatment improves outcomes.[2] Treatment in a quiet intensive care unit with sufficient light is often recommended.[2] Benzodiazepines are the medication of choice with diazepam, lorazepam, chlordiazepoxide, and oxazepam all commonly used.[6] They should be given until a person is lightly sleeping.[2] The antipsychotic haloperidol may also be used.[2] The vitamin thiamine is recommended.[2] Mortality without treatment is between 15% and 40%.[4] Currently death occurs in about 1% to 4% of cases.[2] About half of people with alcoholism will develop withdrawal symptoms upon reducing their use.[2] Of these, 3% to 5% develop DTs or have seizures.[2] The name delirium tremens was first used in 1813; however, the symptoms were well described since the 1700s.[6] The word "delirium" is Latin for "going off the furrow," a plowing metaphor.[4] It is also called shaking frenzy and Saunders-Sutton syndrome.[4] Nicknames include the shakes, barrel-fever, blue horrors, bottleache, bats, drunken horrors, elephants, gallon distemper, quart mania, heebie jeebies, pink spiders and riding the ghost train.[8] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Society and culture * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] The main symptoms of delirium tremens are nightmares, agitation, global confusion, disorientation, visual and[9] auditory hallucinations, tactile hallucinations, fever, high blood pressure, heavy sweating, and other signs of autonomic hyperactivity (fast heart rate and high blood pressure). These symptoms may appear suddenly, but typically develop two to three days after the stopping of heavy drinking, being worst on the fourth or fifth day.[10] Also, these symptoms are characteristically worse at night.[11] In general, DT is considered the most severe manifestation of alcohol withdrawal and occurs 3–10 days following the last drink.[9] Other common symptoms include intense perceptual disturbance such as visions of insects, snakes, or rats. These may be hallucinations or illusions related to the environment, e.g., patterns on the wallpaper or in the peripheral vision that the patient falsely perceives as a resemblance to the morphology of an insect, and are also associated with tactile hallucinations such as sensations of something crawling on the subject—a phenomenon known as formication. Delirium tremens usually includes extremely intense feelings of "impending doom". Severe anxiety and feelings of imminent death are common DT symptoms. DT can sometimes be associated with severe, uncontrollable tremors of the extremities and secondary symptoms such as anxiety, panic attacks and paranoia. Confusion is often noticeable to onlookers as those with DT will have trouble forming simple sentences or making basic logical calculations. DT should be distinguished from alcoholic hallucinosis, the latter of which occurs in approximately 20% of hospitalized alcoholics and does not carry a significant mortality. In contrast, DT occurs in 5–10% of alcoholics and carries up to 15% mortality with treatment and up to 35% mortality without treatment.[12] DT is characterized by the presence of altered sensorium; that is, a complete hallucination without any recognition of the real world. DT has extreme autonomic hyperactivity (high pulse, blood pressure, and rate of breathing), and 35-60% of patients have a fever. Some patients experience seizures.[citation needed] ## Causes[edit] Delirium tremens is mainly caused by a long period of drinking being stopped abruptly. Withdrawal leads to a biochemical regulation cascade. Another cause of delirium tremens is abrupt stopping of tranquilizer drugs of the barbiturate or benzodiazepine classes in a person with a relatively strong addiction to them.[citation needed] Because these tranquilizers' primary pharmacological and physiological effects stem from their manipulation of the GABA chemical and transmitter somatic system, the same neurotransmitter system affected by alcohol, delirium tremens can occur upon abrupt decrease of dosage in those who are heavily dependent. These DTs are much the same as those caused by alcohol and so is the attendant withdrawal syndrome of which they are a manifestation. That is the primary reason benzodiazepines are such an effective treatment for DTs, despite also being the cause of them in many cases. Because ethanol and tranquilizers such as barbiturates and benzodiazepines function as positive allosteric modulators at GABAA receptors, the brain, in its desire to equalize an unbalanced chemical system, triggers the abrupt stopping of the production of endogenous GABA. This decrease becomes more and more marked as the addiction becomes stronger and as higher doses are needed to cause intoxication. In addition to having sedative properties, GABA is an immensely important regulatory neurotransmitter that controls the heart rate, blood pressure, and seizure threshold among myriad other important autonomic nervous subsystems.[citation needed] Delirium tremens is most common in people who have a history of alcohol withdrawal, especially in those who drink the equivalent of 7 to 8 US pints (3 to 4 l) of beer or 1 US pint (0.5 l) of distilled beverage daily. Delirium tremens also commonly affects those with a history of habitual alcohol use or alcoholism that has existed for more than 10 years.[13] ## Pathophysiology[edit] Delirium tremens is a component of alcohol withdrawal hypothesized to be the result of compensatory changes in response to chronic alcohol abuse. Alcohol positively allosterically modulates the binding of GABA, enhancing its effect and resulting in inhibition of neurons projecting into the nucleus accumbens, as well as inhibiting NMDA receptors. This combined with desensitization of alpha-2 adrenergic receptors, results in a homeostatic upregulation of these systems in chronic alcohol use. When alcohol use ceases, the unregulated mechanisms result in hyperexcitability of neurons as natural GABAergic systems are down-regulated and excitatory glutamatergic systems are unregulated. This combined with increased noradrenergic activity results in the symptoms of delirium tremens.[14] ## Diagnosis[edit] Diagnosis is mainly based on symptoms. In a person with delirium tremens it is important to rule out other associated problems such as electrolyte abnormalities, pancreatitis, and alcoholic hepatitis.[2] ## Treatment[edit] Delirium tremens due to alcohol withdrawal can be treated with benzodiazepines. High doses may be necessary to prevent death.[15] Amounts given are based on the symptoms. Typically the person is kept sedated with benzodiazepines, such as diazepam, lorazepam, chlordiazepoxide, or oxazepam. In some cases antipsychotics, such as haloperidol may also be used. Older drugs such as paraldehyde and clomethiazole were formerly the traditional treatment but have now largely been superseded by the benzodiazepines. Acamprosate is occasionally used in addition to other treatments, and is then carried on into long-term use to reduce the risk of relapse. If status epilepticus occurs it is treated in the usual way. It can also be helpful to provide a well lit room as people often have hallucinations.[16] Alcoholic beverages can also be prescribed as a treatment for delirium tremens,[17] but this practice is not universally supported.[18] High doses of thiamine often by the intravenous route is also recommended.[2] ## Society and culture[edit] Drawing by Donald Ogden Stewart published in 1921 showing Little Elmer's father with DTs and seeing pink elephants Nicknames include "the horrors", "the shakes", "the bottleache", "quart mania", "ork orks", "gallon distemper", "the zoots", "barrel fever", "the 750 itch", "pint paralysis", “seeing pink elephants”. Another nickname is "the Brooklyn Boys" found in Eugene O'Neill's one-act play Hughie set in Times Square in the 1920s.[19] Writer Jack Kerouac details his experiences with delirium tremens in his book Big Sur.[20] One of the characters in Joseph Conrad's novel Lord Jim experiences "DTs of the worst kind" with symptoms that include seeing millions of pink frogs. In the 1995 film Leaving Las Vegas, Nicolas Cage plays a suicidal alcoholic who rids himself of all his possessions and travels to Las Vegas to drink himself to death. During his travels he experiences delirium tremens on a couch after waking up from a binge and crawls in pain to the refrigerator for more vodka. Cage's performance as Ben Sanderson in the film won the Academy Award for Best Actor in 1995. In the 1945 film The Lost Weekend, Ray Milland won the Academy Award for Best Actor for his depiction of a character who experiences delirium tremens after being hospitalized, hallucinating that he saw a bat fly in and eat a mouse poking through a wall.[21][22][23] English author George Eliot provides a case involving delirium tremens in her novel Middlemarch (1871–72). Alcoholic scoundrel John Raffles, both an abusive stepfather of Joshua Riggs and blackmailing nemesis of financier Nicholas Bulstrode, dies, whose "death was due to delirium tremens" while at Peter Featherstone's Stone Court property. Housekeeper Mrs Abel provides Raffles’ final night of care per Bulstrode's instruction whose directions given to Abel stand adverse to Dr Tertius Lydgate's orders. Pages 700–710, Chapters 69-70: "‘Remember, if he calls for liquors of any sort, not to give it to him.’" (Lydgate to Bulstrode). "...he gave directions to Bulstrode as to the doses, and the point at which they should cease. He insisted on the risk of not ceasing, and repeated his order that no alcohol should be given.’ (Bulstrode reflecting): "The thought was, that he had not told Mrs Abel when the dose of opium must cease. ... He walked up-stairs, candle in hand, not knowing whether he should straitaway enter his own room and go to bed, or turn to the patient’s room and rectify his omission. ... He turned to his own room. Before he had quite undressed, Mrs Abel rapped at his door ...‘If you please sir, should I have no brandy nor nothing to give the poor creetur? ...When I nursed my poor master, Mr Robisson, I had to give him port-wine and brandy constant, and a big glass at a time,’ added Mrs Abel with a touch of remonstrance in her tone. ...a key was thrust through the inch of doorway, and Mr Bulstrode said huskily, ‘That is the key of the wine-cooler. You will find plenty of brandy there.’" American writer Mark Twain describes an episode of delirium tremens in his book The Adventures of Huckleberry Finn (1884). In Chapter 6, Huck states about his father, "After supper pap took the jug, and said he had enough whisky there for two drunks and one delirium tremens. That was always his word." Subsequently, Pap Finn runs around with hallucinations of snakes and chases Huck around their cabin with a knife in an attempt to kill him, thinking Huck is the "Angel of Death". French writer Émile Zola's novel The Drinking Den (L'Assommoir) includes a character who suffers delirium tremens by the end of the book. It is Coupeau, the main character Gervaise's husband. The MASH (TV series) episode "Bottoms Up" (Season 9, Episode 15) featured a side story about a nurse (Cpt. Helen Whitfield) who was found to be drinking heavily off-duty. By the culmination of the episode, after a confrontation by Maj. Margaret Houlihan, the character swears off her alcoholism and presumably quits immediately. At mealtime, an unspecified time later (roughly 48 hours, according to Maj. Houlihan), Whitfield becomes hysterical upon being served food in the Mess tent, claiming that there are things crawling onto her from it. Margaret and Col. Sherman Potter subdue her. Potter, having recognized the symptoms of delirium tremens (which he abbreviates "the DTs"), orders 5 ml of paraldehyde from a witnessing nurse. Russian composer Modest Mussorgsky died of delirium tremens.[24] The Belgian beer "Delirium Tremens" is named after delirium tremens and is also using a pink elephant as its logo to highlight one of the symptoms of delirium tremens.[25] ## See also[edit] Psychiatry portal * Alcohol dementia * Alcohol detoxification * Delusional parasitosis * Excited delirium * On the wagon ## References[edit] 1. ^ a b Healy, David (3 December 2008). Psychiatric Drugs Explained. Elsevier Health Sciences. p. 237. ISBN 978-0-7020-2997-4. Archived from the original on 8 September 2017. 2. ^ a b c d e f g h i j k l m n o p q r s t u v w Schuckit, MA (27 November 2014). "Recognition and management of withdrawal delirium (delirium tremens)". The New England Journal of Medicine. 371 (22): 2109–13. doi:10.1056/NEJMra1407298. PMID 25427113. 3. ^ a b Posner, Jerome B. (2007). Plum and Posner's Diagnosis of Stupor and Coma (4 ed.). Oxford: Oxford University Press, USA. p. 283. ISBN 9780198043362. Archived from the original on 2016-03-04. 4. ^ a b c d Blom, Jan Dirk (2010). A dictionary of hallucinations (. ed.). New York: Springer. p. 136. ISBN 9781441912237. Archived from the original on 2016-03-04. 5. ^ Fisher, Gary L. (2009). Encyclopedia of substance abuse prevention, treatment, & recovery. Los Angeles: SAGE. p. 1005. ISBN 9781452266015. Archived from the original on 2015-12-22. 6. ^ a b c Stern, TA; Gross, AF; Stern, TW; Nejad, SH; Maldonado, JR (2010). "Current approaches to the recognition and treatment of alcohol withdrawal and delirium tremens: "old wine in new bottles" or "new wine in old bottles"". Primary Care Companion to the Journal of Clinical Psychiatry. 12 (3). doi:10.4088/PCC.10r00991ecr. PMC 2947546. PMID 20944765. 7. ^ Galanter, Marc; Kleber, Herbert D (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 58. ISBN 978-1-58562-276-4. Archived from the original on 4 March 2016. 8. ^ Baldwin, Dan (2002). Just the FAQ's, Please, About Alcohol and Drug Abuse: Frequently Asked Questions from Families. America Star Books. pp. Chapter four. ISBN 9781611028706. Archived from the original on 2016-03-04. 9. ^ a b Delirium Tremens (DTs)~clinical at eMedicine 10. ^ Hales, R.; Yudofsky, S.; Talbott, J. (1999). Textbook of Psychiatry (3rd ed.). London: The American Psychiatric Press.[page needed] 11. ^ Gelder et al, 2005 p188 Psychiatry 3rd Ed. oxford: New York.[page needed] 12. ^ Delirium Tremens (DTs): Prognosis at eMedicine 13. ^ MedlinePlus Encyclopedia: Delirium Tremens 14. ^ Stern, Theodore A.; Gross, Anne F.; Stern, Thomas W.; Nejad, Shamim H.; Maldonado, Jose R. (1 January 2010). "Current Approaches to the Recognition and Treatment of Alcohol Withdrawal and Delirium Tremens: "Old Wine in New Bottles" or "New Wine in Old Bottles"". Primary Care Companion to the Journal of Clinical Psychiatry. 12 (3). doi:10.4088/PCC.10r00991ecr. ISSN 1523-5998. PMC 2947546. PMID 20944765. 15. ^ Wolf KM, Shaughnessy AF, Middleton DB (1993). "Prolonged delirium tremens requiring massive doses of medication". J Am Board Fam Pract. 6 (5): 502–4. PMID 8213241. 16. ^ NCLEX-RN in a Flash. Jones & Bartlett Learning. 2009. ISBN 9780763761974. 17. ^ Rosenbaum M, McCarty T (2002). "Alcohol prescription by surgeons in the prevention and treatment of delirium tremens: Historic and current practice". General Hospital Psychiatry. 24 (4): 257–259. doi:10.1016/S0163-8343(02)00188-3. PMID 12100836. 18. ^ Sattar SP, Qadri SF, Warsi MK, Okoye C, Din AU, Padala PR, Bhatia SC (2006). "Use of alcoholic beverages in VA medical centers". Substance Abuse Treatment, Prevention, and Policy. 1: 30. doi:10.1186/1747-597X-1-30. PMC 1624810. PMID 17052353. 19. ^ Paulson, Michael, "Gambling on O’Neill: Forest Whitaker Makes His Broadway Debut in ‘Hughie’" Archived 2016-02-29 at the Wayback Machine, New York Times, February 3, 2016. Retrieved 2016-02-03. 20. ^ Summary and analysis of novel Archived 2011-06-28 at the Wayback Machine 21. ^ Bailey, Blake. "Weekend in the Sun; Hollywood went wild over Charles Jackson and his 1944 best-seller, The Lost Weekend. Jackson reciprocated, thrilled that the celebrated Billy Wilder wanted to direct his dark, autobiographical novel of addiction. But would the result—a cinematic classic—destroy his literary achievement?" Archived 2016-04-13 at the Wayback Machine, Vanity Fair (magazine), February 28, 2013. Accessed February 15, 2017. "That summer, Hollywood columns had buzzed with rumors about who would play Don Birnam, the genteel alcoholic who ends up howling with delirium tremens. The role had been turned down by everyone from Cary Grant to Gary Cooper before the Welshman Ray Milland took it, refusing to heed an all but universal warning that he was committing 'career suicide.'" 22. ^ Cameron, Kate. "The Lost Weekend effectively portrays the damage caused by alcoholism on screen" Archived 2017-02-16 at the Wayback Machine, New York Daily News, January 2, 1945, reprinted February 17, 2015. Accessed February 15, 2017. "If you read the book, which was a best-seller last year, you know that Jackson did a remarkable job of recording the actions of Birnam, during a weekend binge of monumental proportions, and in setting down in graphic prose the effects produced on him by liquor. In adapting the book to the screen, Brackett and Wilder have accomplished an equally remarkable feat of projecting a case of delirium tremens on screen." 23. ^ Armstrong, Richard. Billy Wilder, American Film Realist Archived 2017-02-17 at the Wayback Machine, p. 41. McFarland & Company, 2004. ISBN 9780786421190. Accessed February 15, 2017. "Finally, Don's hallucination in which a wheeling bat devours a mouse places The Lost Weekend in a direct line of descent from the Gothicism of the '30s Universal horror cycle." 24. ^ Алкогольная трагедия легендарного композитора Мусоргского 25. ^ Belgian, Beers (2020-05-29). "The Pink Elephant beer: Delirium Tremens". Belgian Beers. Retrieved 2020-05-29. ## External links[edit] Classification D * ICD-10: F10.4 * ICD-9-CM: 291.0 * MeSH: D000430 * DiseasesDB: 3543 External resources * MedlinePlus: 000766 * eMedicine: med/524 * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse * v * t * e Alcohol and health Alcohol use Alcohol-related crimes * Drunk drivers * Alcohol-related traffic crashes in the United States * Driving under the influence (DUI) * Drunk driving in the United States * Public intoxication * Rum-running * Adulterated moonshine/Denatured alcohol * List of methanol poisoning incidents Alcoholism * Alcohol and Native Americans * Alcoholism in adolescence * Alcoholism in family systems * Collaborative Study on the Genetics of Alcoholism * College student alcoholism * Disease theory of alcoholism * High-functioning alcoholic (HFA) * Seeing pink elephants Chemistry * Beer chemistry * Congener * Alcohol congener analysis * Ethanol * Blood alcohol content * Breathalyzer * Fusel alcohol * Wine chemistry Effects * Short-term effects of alcohol consumption * Long-term effects of alcohol * On memory * Subjective response to alcohol Interactions * Aging * Brain * Cancer * breast cancer * Cortisol * Pregnancy * Sleep * Tolerance/intolerance * Weight * Beverage-specific * Beer: Potomania * Red wine: Red wine headache Social issues * Alcohol advertising * on college campuses * Sex * Alcohol myopia * Alcohol abuse among college students * Binge drinking * Epidemiology * Blackout (alcohol-related amnesia) * Blackout Wednesday * Drinking game * list * pregaming * Drinking in public * Drunk dialing * Drunk walking * Drunkorexia * Dry drunk * French paradox * Hair of the dog * Nightcap * Pantsdrunk * Passive drinking * Binge drinking devices * Beer bong * Yard of ale * Routes of administration * Alcohol enema * Alcohol inhalation * Sconcing * Surrogate alcohol * Related issues * Balconing * Suicide History * Dionysian Mysteries * Dipsomania * Gin Craze * List of deaths through alcohol * Rum ration * Speakeasy General * Beer day * Drinking culture * Apéritif and digestif * Hangover remedies * Health effects of wine * Wine and food matching * Long-distance race involving alcohol * List of countries by alcohol consumption per capita * Alcohol consumption by youth in the United States * Nip joint Alcohol control Alcohol law * Administrative license suspension (ALS) * Alcohol packaging warning messages * Drunk driving law by country * DWI court * Field sobriety testing * Hip flask defence * Ignition interlock device * Legal drinking age * Age controversy in US * Underage drinking in US * List of alcohol laws of US Alcohol prohibition * List of countries with alcohol prohibition * Neo-prohibitionism * Temperance movement Sobriety * Alcohol detoxification * Alcohol-free zone * Dry campus * United States open-container laws * Designated driver * Alcohol rehabilitation * Drunk tank * Managed alcohol program * Non-alcoholic drink * List of cocktails * List of mixed drinks * Spritzer * Malt drinks * Teetotalism * Temperance bar * Twelve-step groups * Al-Anon/Alateen * Alcoholics Anonymous (AA): * Adult Children of Alcoholics (ACA) Alcohol limitation * 0-0-1-3 * Alcohol education * Alcohol server training * FRAMES * Dry January * Foundation for Advancing Alcohol Responsibility * Campaigns * Get Your Sexy Back * Liquor license * Low-alcohol drinks * Fermented tea * Low-alcohol beer * Low-alcoholic malt drinks * Small beer * Measurement * Alcoholic spirits measure * Standard drink * Recommended maximum intake of alcoholic beverages Addiction medicine * Disulfiram-like drugs: disulfiram, calcium carbimide, cyanamide. Sulfonic acids: Acamprosate Religion and alcohol * Christian views on alcohol * alcohol in the Bible * Islam and alcohol History * Bratt System Related * Index of alcohol-related articles * Austrian syndrome * Ban on caffeinated alcoholic beverages * Brief intervention * Gateway drug effect * Last call * Mood disorder * Non-alcoholic fatty liver disease * Self-medication * Spins * Sober companion * Sober living houses * Sobering center * Town drunk * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Delirium tremens	c0001957	1,522	wikipedia	https://en.wikipedia.org/wiki/Delirium_tremens	2021-01-18T18:40:10	{"mesh": ["D000430"], "icd-9": ["291.0"], "icd-10": ["F10.4"], "wikidata": ["Q209647"]}
Cernunnos-XLF deficiency is a rare form of combined immunodeficiency characterized by microcephaly, growth retardation, and T and B cell lymphopenia. ## Epidemiology Prevalence is unknown. To date, five cases have been reported. ## Clinical description Patients present in childhood with growth retardation, microcephaly, uro-genital and bone malformations, dysmorphic features, including ''bird-like'' facial dysmorphism, and features of combined immunodeficiency including recurrent opportunistic, viral and bacterial infections. Some patients may also present with autoimmune cytopenia (anemia and thrombocytopenia). Patients share several clinical features with Nijmegen breakage syndrome and LIG 4 deficiency (see these terms). ## Etiology This disease is caused by mutations in the NHEJ1 (or Cernunos) gene (2q35). The resulting defect of Cernunnos/XLF, a core protein of the non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair. ## Diagnostic methods Diagnosis is based on the combination of clinical features with evidence of B and T cell lymphocytopenia with normal levels of natural killer (NK) cells. Fibroblasts also exhibit increased radiosensitivity. ## Differential diagnosis Differential diagnoses include Nijmegen breakage syndrome and LIG4 syndrome (see these terms). ## Genetic counseling Transmission is autosomal recessive. ## Management and treatment Treatment is based on antibiotic treatment of infections, immunoglobulin replacement, antiviral prophylaxis and allogeneic hematopoietic stem-cell transplantation (HSCT). Radiotherapy as part of conditioning regimens should be avoided. Reduced intensity conditioning regimens are favored. ## Prognosis Without treatment, the immunodeficiency may result in severe infection, sepsis and early 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	Cernunnos-XLF deficiency	c1969799	1,523	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=169079	2021-01-23T18:17:19	{"mesh": ["C566970"], "omim": ["611291"], "icd-10": ["D81.1"], "synonyms": ["Cernunnos XLFD", "Cernunnos deficiency", "Combined immunodeficiency-microcephaly-growth retardation-sensitivity to ionizing radiation syndrome", "NHEJ1 deficiency"]}
A rare congenital malformation characterized by a unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, ipsilateral breast and nipple anomalies, hypoplasia of the pectoral subcutaneous tissue, absence of pectoral and axillary hair, and possibly accompanied by chest wall and/or upper limb defects. ## Epidemiology The incidence is estimated at 1/30,000, but this is likely an underestimate. It affects more frequently men (male/female ratio of 2:1). ## Clinical description The major feature of Poland syndrome (PS) is complete or partial (sternocostal head) agenesis of the pectoralis major muscle, manifesting as an asymmetric appearance. Generally, the pectoralis minor muscle is also absent. The malformation is typically unilateral with the right side predominantly affected; bilateral involvement is possible but rare (1% of cases). The associated upper limb and rib anomalies determine the severity of PS. According to the combination of these additional features, three forms of PS can be described: type-1 (minimal form) is defined as an isolated pectoral muscle defect, type-2 (partial form) is defined by pectoral muscle defect associated with either upper limb (2a, upper limb variant) or rib (2b, thoracic variant) anomaly, and type-3 (complete form) by pectoral muscle defect associated with both upper limb and rib anomalies. Additional muscle involvement may include the serratus anterior, latissimus dorsi and trapezius. Chest defects can include absence of the anterior part of the rib with lung herniation, rib hypoplasia, contralateral pectus carinatum and/or pectus excavatum. Dextrocardia occurs in 10% of cases, associated with left rib agenesis. Upper limb anomalies are present in 56% of the patients, including brachydactyly, syndactyly or a combination of the two; aplasia/hypoplasia of the middle phalanges of the hand is frequently observed. Hypoplastic/absent hand(s) and short forearm are rarely observed. In all females, the breast and nipple areola complex is aplasitic or hypoplasitic with superolateral localization of the nipple. ## Etiology The etiology is unknown. ## Diagnostic methods Diagnosis is by clinical evaluation. The pectoral muscle anomaly is generally observed by asking the patient to push the palms of the hands against each other with the arms positioned in front of the body. Cough or other maneuvers increasing thoracic pressure will demonstrate lung herniation in case of rib agenesis. Echography can confirm the diagnosis and delineate the extent of the muscular anomaly and detect cartilage rib anomaly and, in postpubertal females, breast anomaly. Chest X-ray can confirm rib agenesis and dextrocardia. ## Differential diagnosis Differential diagnosis includes other chest wall anomalies, breast/nipple anomalies, isolated thoracic lipoatrophy, and isolated hand/upper limb anomalies without pectoralis major muscle involvement. Syndromes rarely associated with PS include Moebius, Klippe Feil, Pierre-Robin, Sprengel deformity and Carey-Fineman-Ziter. ## Antenatal diagnosis Antenatal diagnosis is rare; however, suspicion may arise if hand anomaly is detected. ## Genetic counseling PS is typically a sporadic condition but around 4% of cases are familial. Most cases are probably multifactorial with a low recurrence risk. Autosomal dominant and recessive patterns are described in literature. ## Management and treatment Usually, the aim of surgical treatment is cosmetic. However, in a minority of cases thoracic surgery is required to improve respiratory dynamics due to rib cage defect or heart compression by sternal compression. TNB (thorax, breast and nipple) classification guides surgical choice. Patients should be evaluated for surgery at the beginning of puberty (and before complete growth). A combined approach (pediatric/thoracic and plastic surgery) is beneficial. In case of multiple rib agenesis, non-absorbable mesh or metallic or custom prostheses can be used. Breast/pectoral, custom-made, implants can be used to correct the soft tissue and breast defect. Breast/pectoral expander can be used as first step. Fat grafting is beneficial either as first step or to improve final result. For symmetry reasons, surgery to the contralateral breast can be considered. Muscle transpositions require careful evaluation of the benefits and risks, and should only be considered in selected cases and never in children. Correction of syndactyly should generally begin between 12 and 24 months of life. In case of phalangeal absence, non-microvascular free phalangeal transfer from the foot, or microvascular digital transfer from the foot can be proposed. ## Prognosis Aesthetic achievement after surgery is typically satisfactory. Usually, there is not a significant muscle weakness. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Poland syndrome	c0032357	1,524	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2911	2021-01-23T17:04:55	{"gard": ["7412"], "mesh": ["D011045"], "omim": ["173800"], "umls": ["C0032357"], "icd-10": ["Q79.8"], "synonyms": ["Poland anomaly", "Poland sequence"]}
A number sign (#) is used with this entry because some cases of Rothmund-Thomson syndrome (RTS) are caused by compound heterozygous mutation in the DNA helicase gene RECQL4 (603780) on chromosome 8q24. Description Rothmund-Thomson syndrome is rare autosomal recessive disorder characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease (Simon et al., 2010). ### Genetic Heterogeneity of Rothmund-Thomson Syndrome Wang et al. (2003) analyzed the RECQL4 gene in 33 RTS patients and found an absence of RECQL4 mutations in 10 patients. Analysis of a family with an affected sib pair excluded RECQL4 as a recessive locus for RTS in the family, arguing strongly for genetic heterogeneity in RTS. Simon et al. (2010) stated that only 40 to 66% of patients with RTS have been found to have mutation in the RECQL4 gene, indicating genetic heterogeneity. Clinical Features Rothmund (1868) described 2 related consanguineous families in the small Walser valley in Austria in which 4 girls and 1 boy had lenticular opacities with skin disease. According to Waardenburg et al. (1961), this family was further investigated by Siemens. Waardenburg et al. (1961) described the disorder as a hereditary dermatosis characterized by atrophy, pigmentation, and telangiectasia and frequently accompanied by juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, and hypogonadism. Prognosis for survival is fairly good. In the disorder described by Thomson (1936), saddle nose was not present and cataract did not occur. An excellent color illustration was provided by Thomson (1936). Greaves and Inman (1969) described a brother and sister, born of healthy unrelated parents, as having Morquio syndrome (253000, 253010) with previously unrecognized cutaneous manifestations. However, specific enzyme assays later excluded this diagnosis. Spellacy et al. (1981) reported extensive investigations which appeared to delineate the condition as a 'new' disorder. In addition to having severe skeletal dysplasia, the sibs had cutaneous atrophy with striking telangiectases and shallow indolent cutaneous ulcers, mesodermal dysgenesis of the iris, and joint abnormalities. The 15-year-old brother had severe kyphoscoliosis and hypermobility of some joints, with a restricted range of motion in other joints. His 17-year-old sister, who had bilateral congenitally dislocated hips, was less severely affected. The telangiectasia in both patients was generalized and associated with sensitivity to the sun. The odontoid process was normal and there was no corneal clouding. Moss (1990) reviewed the 2 patients when they were aged 25 and 27 years and concluded it was 'now clear that their disorder is the Rothmund-Thomson syndrome.' At 25 years of age, the brother was 97 cm tall, and photographs demonstrated saddle-nose. The telangiectasia on the face and extensor surfaces of the limbs, most marked on the hands and with wrinkling of the affected skin, was striking. In addition to the previously described changes in the iris, there were bilateral nuclear and posterior cortical lens opacities precluding a clear view of the fundus. The sister had iris atrophy but no cataracts. Starr et al. (1985) reported 2 cases and emphasized the less well-known nondermatologic features, namely, hypodontia, soft tissue contractures, proportionate short stature, hypogonadism, anemia, and osteogenic sarcoma. Birth weight in the 2 cases was 3 kg and 2.83 kg. Drouin et al. (1993) described osteosarcoma of the distal femoral metaphysis in an 11-year-old French Canadian boy with RTS. Several such cases had previously been reported. Pujol et al. (2000) reported 2 patients with variable presentations of Rothmund-Thomson syndrome. Initial presenting symptoms included growth deficiency and absent thumbs in 1 patient and osteogenic sarcoma and poikiloderma in the other. The growth-deficient patient was found to have growth hormone deficiency and a subnormal response to growth hormone supplementation. Neither malformations nor growth deficiency was present in the patient with osteogenic sarcoma and her only other manifestation of RTS was poikiloderma. Pujol et al. (2000) suggested that RTS should be considered in all patients with osteogenic sarcoma, particularly if associated with skin changes. The authors pointed out that Lindor et al. (1996) had reported a brother and sister of Mexican descent with marked short stature, poikiloderma, absent or hypoplastic thumbs, osteogenic sarcoma, and no cataracts. They stated that these were the sibs in whom Kitao et al. (1999) had found mutations in the RECQL4 gene. Wang et al. (2001) identified a cohort of 41 patients with RTS to better define the clinical profile, diagnostic criteria, and management of the disorder. Patients diagnosed with RTS were ascertained by referrals from dermatology, ophthalmology, genetics, and oncology or through direct contact with the patient's family. Medical information was obtained from interviews with physicians, patients, and their parents and a review of medical records. Age at ascertainment ranged from 9 months to 42 years. There were 28 males and 13 females. All subjects displayed a characteristic rash. Thirteen subjects had osteosarcoma (32%), 8 had radial defects (20%), 7 had gastrointestinal findings (17%), 2 had cataracts (6%), and 1 had skin cancer (2%). The gastrointestinal findings were feeding problems as infants, including chronic emesis or diarrhea, with some patients requiring tube feeding. One had documented duodenal stenosis, but the others had no clear explanation for the symptoms. Of the patients without osteosarcoma, 22 of 28 were less than 15 years old and thus remained at significant risk for this tumor. Compared with historical reports, this study showed a clinical profile of RTS that included a higher prevalence of osteosarcoma and fewer cataracts. ### Clinical Variability On the basis of their analysis of the clinical and molecular spectra of RTS, Wang et al. (2003) suggested that there may be at least 2 forms of the disorder: a form as originally described by Rothmund (1868), associated with the characteristic poikiloderma but not with osteosarcoma, which they designated 'type 1;' and a form characterized by poikiloderma with an increased risk of osteosarcoma and deleterious mutations in the RECQL4 gene (603780), which they designated 'type 2.' Hilhorst-Hofstee et al. (2000) described a syndrome observed in 3 isolated patients, the features of which included bilateral radial aplasia, short stature, an inflammatory based 'elastic' pyloric stenosis, a panenteric inflammatory gut disorder that appears to be due to an autoimmune process, and poikiloderma. Other features in individual cases included cleft palate, micrognathia, anal atresia, patellar aplasia/hypoplasia, and sensorineural deafness. Hilhorst-Hofstee et al. (2000) suggested that the combination may represent a severe form of Rothmund-Thomson syndrome or possibly a previously unrecognized condition. Inheritance Rothmund-Thomson syndrome is inherited as an autosomal recessive disorder (Rothmund, 1868; Kitao et al., 1999). Clinical Management Wang et al. (2001) recommended baseline skeletal radiographs of the long bones by age 5 years for all patients with RTS, since patients often have underlying skeletal dysplasias and subsequent films based on clinical suspicion of osteosarcoma can be interpreted more easily in comparison to baseline findings. They stated that it is unclear whether RTS patients are more sensitive to the effects of chemotherapy and radiation. There had been no reports of increased toxicity to treatment comparable to that experienced by ataxia-telangiectasia (208900) patients treated for cancer. Cytogenetics Ying et al. (1990) described trisomy 8 mosaicism in association with Rothmund-Thomson syndrome. Der Kaloustian et al. (1990) found mosaic trisomy 8 and mosaic supernumerary i(2q) in fibroblasts from normal skin; lymphocytes, however, had a normal karyotype. Orstavik et al. (1994) likewise found instability of lymphocyte chromosomes in a young girl who had severe skeletal abnormalities of the upper limbs with absence of both radii, short dysmorphic ulnae, a rudimentary right thumb, and aplasia of the left thumb. She also had anal atresia with a rectovaginal fistula. Poikiloderma developed on the face and extensor surfaces of the limbs beginning at the age of 3 months. Mental development was normal. Lindor et al. (1996) reported a brother and sister with typical clinical manifestations of RTS and tibial sarcoma. Three cell lines [46,XY; 47,XY,+8; 47,XY,+i(8q)] were found in lymphocyte cultures of the brother and 2 cell lines [46,XX; 47,XX,+i(8q)] were detected in the sister. FISH studies with a probe specific for the chromosome 8 centromere showed 3 chromosome 8 signals in 4 to 16% of uncultivated lymphocytes and buccal cells of these patients, suggesting the in vivo presence of abnormal cell lines. RTS may be associated with clonal rearrangements causing acquired somatic mosaicism. Molecular Genetics Kitao et al. (1999) identified compound heterozygous mutations in the helicase gene RECQL4 (603780) in 2 sibs with Rothmund-Thomson syndrome and in an isolated case. In 4 other patients, no mutation was found. In 2 brothers with RTS, Lindor et al. (2000) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0005 and 603780.0006). One brother died at age 9 years from osteosarcoma of the right calcaneus and right iliac wing, whereas the other brother was diagnosed at age 21 years with osteoblastic osteosarcoma of the distal radius. In a 19-year-old Caucasian male patient with RTS, Beghini et al. (2003) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0005 and 603780.0008). Wang et al. (2003) analyzed the RECQL4 gene in 33 RTS patients and identified 23 patients, including all 11 patients with osteosarcoma, who carried at least 1 of 19 truncating mutations (see, e.g., 603780.0002). The authors concluded that RECQL4 loss-of-function mutations occur in approximately two-thirds of RTS patients and are associated with the risk of osteosarcoma. Simon et al. (2010) reported a 21-year-old male with RTS who was compound heterozygous for mutations in the RECQL4 gene (603780.0015 and 603780.0016) and who developed 4 malignant diseases: large-cell anaplastic T-cell lymphoma with histologic features of the syncytial variant of nodular sclerosing Hodgkin lymphoma at age 9.3 years; diffuse large B-cell lymphoma, centroblastic variant, at age 14.3 years; osteosarcoma at age 14.6; and acute leukemia at age 21.6 years. Despite achieving remission with the first 3 malignancies, including spontaneous remission of the diffuse large cell lymphoma, the patient died from leukemia progression at age 21.9 years. Animal Model Mann et al. (2005) created a viable Recql4-mutant mouse model. Mutant mice exhibited a distinctive skin abnormality, birth defects of the skeletal system, genomic instability, and increased cancer susceptibility in a sensitized genetic background. Cells from Recql4-mutant mice had high frequencies of premature centromere separation and aneuploidy. The authors proposed a role for Recql4 in sister-chromatid cohesion, and suggested that chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Face \- Frontal bossing \- Prognathism Eyes \- Juvenile zonular cataracts \- Microphthalmia \- Microcornea \- Strabismus \- Glaucoma \- Mesodermal iris dysgenesis (in some patients) Nose \- Small, saddle nose Teeth \- Microdontia \- Delayed eruption \- Supernumerary teeth \- Missing teeth \- Multiple crown malformations ABDOMEN Pancreas \- Annular pancreas Gastrointestinal \- Anteriorly placed anus GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Osteoporosis Spine \- Kyphoscoliosis (in some patients) Pelvis \- Congenital hip dislocation (rare) Limbs \- Forearm reduction defects \- Absence of patella \- Hypermobile joints (rare) \- Restricted range of movement in some joints (rare) Hands \- Hypoplastic thumbs \- Small hands Feet \- Small feet \- Club feet SKIN, NAILS, & HAIR Skin \- Erythematous skin lesions in infancy \- Poikiloderma (atrophic plaques with telangiectasia) \- Telangiectasia \- Skin atrophy \- Sun sensitivity \- Shallow indolent cutaneous ulcers (in some patients) Nails \- Atrophic nails Hair \- Sparse hair \- Alopecia \- Premature graying of hair NEUROLOGIC Central Nervous System \- Mental retardation in 5-13% ENDOCRINE FEATURES \- Hypogonadism NEOPLASIA \- Basal cell carcinoma \- Squamous cell carcinoma \- Osteogenic sarcoma MOLECULAR BASIS \- Caused by mutation in the Req-like DNA helicase type 4 gene (RECQL4, 603780.0001 ) ▲ 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	ROTHMUND-THOMSON SYNDROME	c0032339	1,525	omim	https://www.omim.org/entry/268400	2019-09-22T16:22:32	{"doid": ["2732"], "mesh": ["D011038"], "omim": ["268400"], "icd-10": ["Q82.8"], "orphanet": ["221016", "221008", "2909"], "synonyms": ["Poikiloderma of Rothmund-Thomson type 2", "RTS2", "RTS1", "Poikiloderma of Rothmund-Thomson type 1", "Alternative titles", "POIKILODERMA ATROPHICANS AND CATARACT"], "genereviews": ["NBK1237"]}
## Summary ### Clinical characteristics. CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (e.g., loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The mean age of onset is usually in the fourth decade. Affected individuals eventually become bedridden with spasticity and rigidity. The disease course ranges from two to 30 or more years (mean: 8 years). ### Diagnosis/testing. The diagnosis is suspected in individuals with characteristic clinical and brain MRI findings and is confirmed by identification of a heterozygous pathogenic variant in CSF1R. ### Management. Treatment of manifestations: Supportive management includes: attention to general care and nutritional requirements; antiepileptic drugs for seizures; and antibiotic treatment for general and recurrent infections. Prevention of secondary complications: Information about and support systems for the social problems and suicidal tendencies often associated with disease progression. Surveillance: Periodic brain MRI and clinical evaluation to monitor disease progression. Agents/circumstances to avoid: Use of first-generation neuroleptics due to increased seizure risk and risk of additional parkinsonian signs; medications used to treat multiple sclerosis as they are of no benefit and have major side effects. ### Genetic counseling. CSF1R-related ALSP is inherited in an autosomal dominant manner. Individuals with CSF1R-related ALSP usually have an affected parent; de novo mutation can occur. Each child of an individual with CSF1R-related ALSP has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in a family is known. ## Diagnosis ### Suggestive Findings CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) should be suspected in individuals with the following clinical and brain findings. Clinical * Progressive neurologic decline; presenting signs may include the following: * Personality changes, cognitive impairments, memory decline, and depression * Motor impairments including paresis, gait dysfunction, bradykinesia, rigidity, and tremor * On rare occasions, seizures Later signs usually include dementia, seizures, and pyramidal and extrapyramidal signs. * Family history consistent with autosomal dominant inheritance Brain * On MRI [Van Gerpen et al 2008, Sundal et al 2012b, Bender et al 2014, Konno et al 2014, Konno et al 2017] * The white matter lesions are hyperintense on T2-weighted and FLAIR images, and hypointense on T1-weighted images. * Bifrontal or bifrontoparietal T2-weighted/FLAIR hyperintensities in the deep, subcortical, and periventricular areas are typical. The white matter lesions are often asymmetric, especially in the early stages of the disease. Early lesions are patchy and focal, but with time become confluent. T2-weighted and FLAIR hyperintensities are present in other areas, including the corpus callosum and corticospinal tracts. * Cerebral atrophy manifesting as enlarged ventricles is typical, as is cerebral atrophy corresponding to the white matter lesions. * The following are absent: * Significant gray matter pathology * Brain stem atrophy * Contrast uptake in the parenchyma * Cerebellar abnormalities are minimal. * On CT. Brain calcifications in the white matter are seen in up to half of individuals. Frequently they have a characteristic pattern of “stepping stone appearance” in the frontal pericallosal area, and punctate appearance in the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter [Konno et al 2017]. ### Establishing the Diagnosis The diagnosis of CSF1R-related ALSP is established in a proband by identification of a heterozygous pathogenic variant in CSF1R by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of CSF1R is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes CSF1R and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in CSF1R-Related ALSP View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method CSF1RSequence analysis 3~100% 4 Gene targeted deletion/duplication analysis 5None detected 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. To date more than 50 pathogenic variants have been reported, including deletions and missense, frameshift, nonsense, and splice site variants. Almost all pathogenic variants are located in the intracellular tyrosine kinase domain of exons 12-22 of CSF1R (see Molecular Genetics). 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. ## Clinical Characteristics ### Clinical Description CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (including loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The presenting problems and rate of progression vary among individuals and even within a family harboring the same pathogenic variant. The mean age of onset is usually in the fourth decade, but ranges from early adulthood to the eighth decade of life [Sundal et al 2012b]. The disease course may be from two to 30 years or more with a mean of eight years. Signs and symptoms that usually occur during the disease course include the following: * Personality problems, memory decline, executive dysfunction * Disturbances of higher cortical function such as motor aphasia, agraphia, acalculia, and apraxia * Depression * Gait disturbance * Pyramidal signs such as spasticity, hyperreflexia, extensor plantar response, hemiparesis, or quadriparesis * Sensory deficits including some impairment of vibration, position, tactile, and pain perception. The higher integrative sensory functions such as graphesthesia, stereognosis, and double simultaneous stimulation are also impaired. * Parkinsonian signs such as rigidity, bradykinesia, tremor (resting and/or kinetic), shuffling gait, and postural instability. Hypomimic face and hypophonic voice are common. Lack of beneficial response to levodopa defines the parkinsonian signs as atypical. * Bulbar/pseudobulbar signs: dysphagia, dysarthria, slurred speech, and palatal myoclonus * Cerebellar signs with ataxia, dysmetria, and intention tremor * Visual field defects such as homonymous quadrantanopsia or hemianopsia * Other signs of a movement disorder: dystonia, myoclonic twitches, dyskinesia, and akathisia * Seizures in some individuals (at times only a single episode at the onset of the illness) * Progressive course Affected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movements, and appear to be generally unaware of their surroundings. In the last stage of the disease, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp and mouth-opening reflex, as well as the sucking reflex, are present. Death most commonly results from pneumonia or other infections. Other findings. Cerebrospinal fluid (CSF): * Normal cell count, glucose concentration, and proteins * No inflammatory cells * Usually normal isoelectric focusing and no oligoclonal bands; however, oligoclonal bands have been demonstrated in samples from affected individuals with the pathogenic variant p.Asn854Lys or p.Val 838Leu [Karle et al 2013, Levin et al 2014, Schuberth et al 2014, Sundal et al 2015]. * No identified CSF biomarker. The following preliminary findings in four persons with ALSP need to be interpreted cautiously and require further research [Sundal et al 2012a, Sundal et al 2015]: * Normal Aβ42 protein concentrations * Minimally increased levels of total Tau protein concentrations * Borderline normal phospho-Tau protein concentrations * Elevated neurofilament light chain (NF-L) proteins (Note that NF-L proteins are markers of neuronal death and axonal damage.) * Slight increase in glial fibrillary acidic protein, indicating gliosis or astroglial cell damage Brain pathology. The following features may be seen on brain biopsy or at autopsy: * White matter changes that are typically vacuolated and demyelinated * Axonal spheroids in the white matter lesions that are immunoreactive for neurofilament, amyloid precursor protein, and ubiquitin * Bizarre astrocytes and lipid-laden and myelin-laden macrophages * Unaffected or very mildly affected basal ganglia, thalamus, hypothalamus, hippocampus, substantia nigra, raphe nucleus, reticular formation, and cerebellar gray matter * Absence or only traces of amyloid angiopathy in parenchymal or leptomeningeal vessels * Pigmented changes of either iron or lipofuscin found in macrophages and other glia cells ### Genotype-Phenotype Correlations No genotype-phenotype correlation exists: individuals from the same family harboring the same CSF1R pathogenic variant do not necessarily share the same phenotype. In the end stage all have devastating multiple neurologic impairments. ### Penetrance Penetrance appears to be incomplete [Karle et al 2013, Sundal et al 2015, Konno et al 2017]; estimates have not been calculated given the limited number of families reported to date. Although CSF1R-related ALSP is a dominantly inherited disease, de novo mutation occurs and variable expressivity in terms of the phenotype and the disease course can be found in members of the same family sharing the same pathogenic variant. ### Nomenclature Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is within the same disease spectrum as familial pigmentary orthochromatic leukodystrophy (POLD) [Wider et al 2009]. Because of the phenotypic and radiologic similarities of the two disorders, Wider et al [2009] proposed the following terminology for the combined entity: "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)." Families with POLD have recently been found to have CSF1R pathogenic variants [Nicholson et al 2013], providing evidence that HDLS and POLD are a single disease entity. Because a similar phenotype has been reported in individuals with biallelic AARS2 pathogenic variants, the authors propose new nomenclature: CSF1R-related ALSP. ### Prevalence CSF1R-related ALSP was previously thought to be a rare disease. However, recent expanded publications in this field have demonstrated that it is more common than previously recognized: it is now estimated to be responsible for 10%-25% of adult-onset leukodystrophy. However, actual prevalence figures have not been reported [Lynch et al 2016]. ## Differential Diagnosis The clinical presentation of CSF1R-related ALSP often overlaps with other neurologic disorders. CSF1R-related ALSP should be considered in previously healthy individuals who develop cognitive decline, memory problems, and personality changes in midlife with a progressive course and white matter lesions evident on brain MRI. Because the signs and symptoms in the early stages of CSF1R-related ALSP are nonspecific, ALSP can often be confused with the inherited and sporadic disorders listed below. In individuals with CSF1R-related ALSP, laboratory and/or genetic testing for these other disorders are normal. ### Table 2. Disorders to Consider in the Differential Diagnosis of CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) View in own window DisorderGene(s)Clinical Features of This Disorder Overlapping w/CSF1R-Related ALSPDistinguishing from CSF1R-Related ALSP Autosomal dominant disorders Alexander diseaseGFAPBulbar/pseudobulbar signs, ataxia, spasticityPalatal myoclonus; cognitive function in adults frequently normal; infratentorial atrophy on MRI Adult-onset autosomal dominant leukodystrophy (OMIM 169500)LMNB1Cognitive impairment, pyramidal & cerebellar signsEarly autonomic dysfunction; a periventricular normal rim on MRI CADASILNOTCH3Frontal lobe syndrome, WMLStroke-like clinical signs; multiple cerebral infarcts & WML incl the characteristic temporal pools MAPT-related disorders (OMIM 157140)MAPTProgresses over a few years into profound dementia w/mutismFrontal &/or temporal atrophy w/far fewer WML Frontotemporal dementia, chromosome 3-linkedCHMP2BFrontal lobe affected; pyramidal &/or extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML GRN-related frontotemporal dementiaGRNFrontal lobe affected; pyramidal/extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML C9orf72-related FTDC9orf72Frontal lobe affected; pyramidal/extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML Early-onset Alzheimer diseaseAPP, PSEN1, PSEN2Executive dysfunction & personality changes; similar onset ageEpisodic memory loss; WM changes present but much less pronounced Autosomal recessive disorders PLOSL (Nasu-Hakola disease)TREM2, TYROBPInsidious personality changes, frontal lobe syndrome, motor impairments, dementia & progression to vegetative stagePain/tenderness of feet/wrists, polycystic osseous lesions, pathologic fractures; U-fibers partially affected Vanishing white matterEIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5Cognitive decline, spastic paraparesis, cerebellar ataxiaStress-induced deterioration w/minor trauma or infections; more widespread & diffuse WM changes & atrophy than in ALSP; cystic breakdown of the WM Adult type of metachromatic leukodystrophyARSAExecutive dysfunction, personality changes, memory problems, pyramidal signs and seizuresPeripheral neuropathy; spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes Adult form of Krabbe diseaseGALCPyramidal signs, developing into para- or tetraparesisPeripheral neuropathy; MRI w/predominance in the posterior part of the WM. MRI detects demyelination in the brain stem & cerebellum. T2-weighted value is progressively prolonged in the occipital deep WM & posterior part of central semiovale in late-onset disease. LBSLDARS2Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction; deterioration of motor skillsPeripheral neuropathy; WML are either non-homogeneous/spotty or homogeneous & confluent. Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts. AARS2-related ALSPAARS2Cognitive, neuropsychiatric, & upper motor neuron signs; symmetric leukoencephalopathy w/punctate regions of restricted diffusionEarlier age of onset of symptoms (mean age 26 yrs); ovarian failure in all women. WM demonstrates rarefaction [Lakshmanan et al 2017]. X-linked disorders X-linked adrenoleukodystrophyABCD1Cognitive decline, dementia, spastic paraparesisNeuropathy & slowly spastic paraparesis. WML are contrast enhancing. Corticospinal tracts are involved from cranial to medulla. Fabry diseaseGLAWMLGray matter pathology Mitochondrial disorders (caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA) Leigh syndromemtDNA deletionPsychomotor regression; WML may be present in adult mt diseasesStrikingly different clinical presentation; brain MRI in mt diseases may demonstrate symmetric T1-weighted hypointense & T2-weighted hyperintense signal abnormalities in deep gray matter; abnormalities are not restricted to vascular territories; lesions often fluctuate over the course of the disease. Varying degrees of cerebral & cerebellar atrophy may also be present. MELASMT-TL1 or other mtDNA genes Alpers-Huttenlocher syndromePOLG 1 MNGIETYMP 1 Other (complex multifactorial inheritance/sporadic) Primary progressive multiple sclerosis (PPMS)WMLCognitive decline occurs later; callosomarginal lesions occur. Confluent WML in frontoparietal areas are more consistent w/CSF1R-related ALSP than w/PPMS 2. Susac syndromeCognitive impairment, behavioral changesBranch retinal artery inclusions, tinnitus, hearing loss, vertigo; gray matter lesions Frontotemporal lobar degenerationThe combination of FTD & atypical parkinsonism is characterized by multisystem atrophy & progressive supranuclear palsy; the addition of ALS can mimic clinical ALSP.MRI demonstrates mainly cerebral atrophy w/out the characteristic WML found in CSF1R-related ALSP. ALS = amyotrophic lateral sclerosis; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; FTD = frontotemporal dementia; LBSL = leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MNGIE = mitochondrial neurogastrointestinal encephalopathy; PLOSL = polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy; WM = white matter; WML = white matter lesions 1\. Alpers-Huttenlocher syndrome and MNGIE are inherited in an autosomal recessive manner. 2\. Sundal et al [2015] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), the following evaluations are recommended if they have not already been completed: * Complete neurologic assessment * Psychological and psychiatric assessments * Brain MRI to determine the extent and localization of white matter changes, presence of cortical atrophy, and involvement of the corpus callosum and corticospinal tracts * Assessment of feeding/eating, digestive problems (constipation, incontinence), and nutrition based on clinical history * EEG or video EEG if a seizure disorder is suspected; evaluation of the need for antiepileptic drugs * Lumbar puncture to measure neurofilament light protein (NFL) in the cerebrospinal fluid (CSF) to follow the disease progression. An increased level of NFL on repeat CSF examinations may suggest faster disease course and thus worse prognosis. * Assessment of family and social structure to determine the availability of adequate support systems * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations No specific therapy is currently available for ALSP. However, as CSF1R-related ALSP is a microglia-associated neurodegenerative disease it is suggested that hematopoietic stem cell transplantation may have a therapeutic role for this disease [Eichler et al 2016]. Management is supportive and includes attention to general care and nutritional requirements, antiepileptic drugs for seizures, and antibiotic treatment for general and recurrent infections such as pneumonia or urinary tract infections. Other: * L-dopa or other dopaminergic therapies have not been beneficial in individuals with ALSP or in those with an atypical parkinsonian phenotype, but may be worth trying. * Antidepressant medications may be prescribed for depression, although reports to date have demonstrated no long-term benefit. * Antipsychotics are in general not recommended due to extrapyramidal side effects, but may be used in aggressive individuals. * Anti-seizure medications should be initiated in any individual with seizures and are reported to be beneficial. ### Prevention of Secondary Complications Social problems (unemployment, divorce, financial troubles, and alcoholism) and suicidal tendencies are often associated with the progression of the disease. Some of the social consequences may be avoided if family members are informed early about the nature of the disorder. ### Surveillance Periodic clinical evaluation to monitor for the following is appropriate: * Changes in mobility, communication, and behavior, which could indicate a need to alter care and support systems (wheelchair / personal assistance) * Onset of seizures and need for antiepileptic therapy * Contractures, which could indicate a need to change medical management and physical therapy * Behavioral changes, inappropriate emotions and actions, problems following directions, memory loss, incontinence, which indicate curtailing of independence * Difficulties in swallowing or weight loss, which trigger consideration for gastrostomy * Need for physical therapy to minimize contractures and maintain locomotion Longitudinal MRI studies every year can potentially help with prognosis, as during the disease course the more rapid the confluence of patchy or focal T2-weighted hyperintensities and the progression of cortical atrophy, the poorer the prognosis appears to be [Van Gerpen et al 2008, Sundal et al 2012b]. ### Agents/Circumstances to Avoid The following should be avoided: * Use of first-generation neuroleptics, which increase seizure risk and risk of additional parkinsonian signs * Treatment agents for multiple sclerosis, as these medications are of no benefit and have major side effects ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia	None	1,526	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK100239/	2021-01-18T21:37:27	{"synonyms": ["CSF1R-Related ALSP"]}
A number sign (#) is used with this entry because of evidence that cataract-18 (CTRCT18) is caused by homozygous mutation in the FYCO1 gene (607182) on chromosome 3p21.3. Description Mutations in the FYCO1 gene have been identified in families with autosomal recessive cataract described as congenital and congenital nuclear. The preferred title/symbol of this entry was formerly 'Cataract, Autosomal Recessive Congenital 2; CATC2.' Clinical Features Chen et al. (2011) studied 12 consanguineous Pakistani families segregating autosomal recessive congenital cataract. All affected individuals available for examination had bilateral nuclear cataracts that were either present at birth or developed in infancy. No other ocular or systemic abnormalities were present in these families. Mapping Pras et al. (2001) mapped a locus for autosomal recessive cataract to chromosome 3p in 3 inbred Arab families. All affected individuals had been diagnosed with cataract within a few weeks after birth, and operated upon during the first 3 months of life. The parents of the affected sibs were first cousins in all 3 families. One of the families had been reported by Pras et al. (2000). A SNP-based genomewide search was performed on a pooled DNA sample from 6 affected family members in a search for regions showing homozygosity. Using conventional microsatellite markers, regions of homozygosity were further analyzed in all families. A region on chromosome 3p spanning 43 Mb showed homozygosity with 13 consecutive SNPs. Three microsatellite markers from this region yielded lod scores greater than 3.00. A maximal 2-point lod of 4.83 was obtained with the marker D3S1298 at theta = 0.004. Haplotype analysis placed the disease gene in a 20-Mb interval between D3S1768 and D3S2409. In 8 unrelated consanguineous Pakistani families segregating autosomal recessive congenital cataract, Chen et al. (2011) performed genomewide linkage analysis and fine mapping and found significant or suggestive linkage to chromosome 3p22-p21. Chen et al. (2011) noted that the 3.5-cM (12-Mb) linked region, flanked by D3S3685 and D3S1289, overlapped the CATC2 locus previously described by Pras et al. (2001). Molecular Genetics In affected members of a consanguineous Pakistani family segregating autosomal recessive congenital cataract (arCC) that mapped to chromosome 3p22-p21, Chen et al. (2011) analyzed 35 candidate genes and identified homozygosity for a nonsense mutation in the FYCO1 gene (607182.0001); analysis of FYCO1 in 7 additional Pakistani families with arCC mapping to 3p22-p21 revealed homozygosity for 5 different mutations in FYCO1 (see, e.g., 607182.0002 and 607182.0004-607182.0005). Chen et al. (2011) also sequenced FYC01 in 1 affected individual from each of 63 Pakistani families with arCC that did not obtain a lod score greater than 3 at 3p22-p21 and identified homozygous mutations in 4 of the probands (see, e.g., 607182.0003-607182.0005). The mutations segregated with disease in all of the families and were not found in 300 unrelated ethnically matched control chromosomes. In addition, homozygosity for a nonsense mutation in FYC01 was identified in an affected member of a consanguineous Arab Israeli family with congenital cataracts originally reported by Pras et al. (2001) ('family 1'; 607182.0006). Chen et al. (2011) stated that the 43 mutation-positive Pakistani patients represented approximately 10% of the total genetic load of cataracts in their ongoing collaborative study of arCC in Pakistan involving 125 families, suggesting that FYCO1 mutations are among the most common causes of inherited congenital cataracts in the Pakistani population as a whole. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Cataracts, bilateral nuclear, present at birth or developing in infancy MOLECULAR BASIS \- Caused by mutation in the fyve and coiled-coil domain containing-1 gene (FYCO1, 607182.0001 ) ▲ 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	CATARACT 18	c0392557	1,527	omim	https://www.omim.org/entry/610019	2019-09-22T16:05:15	{"doid": ["0110238"], "mesh": ["C535342"], "omim": ["610019"], "icd-10": ["Q12.0"], "orphanet": ["98992", "91492", "98995", "98991"], "synonyms": ["CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 2", "Alternative titles"]}
Charcot-Marie-Tooth disease type 4B2 (CMT4B2) is a disorder that affects the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves can result in loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands. CMT4B2 can also cause glaucoma (damage to the eye’s optic nerve). There is currently no cure for CMT4B2, but physical therapy, occupational therapy, braces and other orthopedic devices, pain medication, and orthopedic surgery can help manage and improve symptoms. CMT4B2 is inherited in an autosomal recessive fashion. It is caused by mutations in the SBF1 gene. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Charcot-Marie-Tooth disease type 4B2	c1858278	1,528	gard	https://rarediseases.info.nih.gov/diseases/9200/charcot-marie-tooth-disease-type-4b2	2021-01-18T18:01:30	{"mesh": ["C535421"], "omim": ["604563"], "umls": ["C1858278"], "orphanet": ["99956"], "synonyms": ["CMT 4B2", "Charcot Marie Tooth disease type 4B2", "CHARCOT-MARIE-TOOTH DISEASE, WITH FOCALLY FOLDED MYELIN SHEATHS, AUTOSOMAL RECESSIVE, TYPE 4B2", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 4B2"]}
A rare, hereditary endocrine tumor characterized by a benign pituitary adenoma that is either secreting (e.g. prolactin, growth hormone, thyroid stimulating hormone) or non-secreting. Symptoms may occur due to either the hormonal hypersecretion and/or the mass effect of the lesion on local structures in the brain. ## Epidemiology Familial isolated pituitary adenoma (FIPA) prevalence is unknown. However, FIPA represents around 2-5% of pituitary adenoma cases. A female predominance is reported. ## Clinical description In FIPA, pituitary adenomas can be of any secretory type (e.g. prolactinoma, acromegaly, Cushing's disease, TSH-secreting) or can be non-secreting. FIPA kindreds usually have 2-4 members affected with pituitary adenomas, while larger numbers of affected patients per family can occur infrequently. In FIPA, pituitary adenomas generally begin at a younger age and are larger than corresponding sporadic non-FIPA cases. Pituitary adenomas in FIPA can cause symptoms due to hormonal hypersecretion and/or due to the mass effect of the pituitary adenoma on local structures in the brain (e.g. visual disturbance). In FIPA families with AIP mutations pituitary adenoma growth characteristics are often aggressive and hormonal hypersecretion may be marked. ## Etiology In up to 80% of FIPA families, the etiology of pituitary adenomas is unknown. However, mutations in the gene AIP (11q13.2 ) account for about 20% of FIPA kindreds. AIP is thought to act as a tumor suppressor gene. Pituitary adenomas due to germline AIP mutations are accompanied by a second hit of the other allele (e.g. deletion or mutation) and this is thought to favor or stimulate tumorigenesis. ## Diagnostic methods FIPA kindreds usually have 2-4 members affected with pituitary adenomas. Hormonal testing is used to identify abnormal hormonal secretion in FIPA. Magnetic resonance imaging (MRI) is used to confirm the presence and dimensions of a pituitary adenoma. AIP mutations can lead to pituitary apoplexy in FIPA kindreds, so MRI and hormonal signs of apoplexy may be present in affected family members. ## Differential diagnosis Differential diagnosis include multiple endocrine neoplasia type 1 and familial infantile gigantism, which may present as FIPA. ## Genetic counseling In children of FIPA cases with AIP mutations, the pattern of inheritance is autosomal dominant and, thus, there is a 50% risk of inheriting the mutation from an affected parent. For families with unidentified gene, an autosomal dominant inheritance pattern has been suggested. Large international studies have shown that only about 20% of AIP mutation carriers eventually develop a pituitary adenoma. ## Management and treatment Pituitary adenomas in the setting of FIPA are generally managed according to guideline recommendations for non-FIPA pituitary adenomas. However, in FIPA families with AIP mutations, pituitary adenomas (often growth hormone secreting) can be large and poorly responsive to treatment with surgery and medical therapy. ## Prognosis Formal outcome studies for patients with FIPA as compared with sporadic pituitary adenoma patients have not been performed. However, due to larger tumor size, younger age at onset and lower responses to medical therapies (particularly in FIPA families with AIP mutations), hormonal and tumoral effects may be more difficult to control and may require a larger burden of 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	Familial isolated pituitary adenoma	c1863340	1,529	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314777	2021-01-23T18:48:51	{"gard": ["10959"], "mesh": ["C566321"], "omim": ["102200", "600634"], "umls": ["C1863340"], "icd-10": ["D35.2"], "synonyms": ["FIPA"]}
Semicircular canal dehiscence (SCD) syndrome is a rare otorhinolaryngologic disease characterized by the uni- or bilateral dehiscence of the bone(s) overlying the superior (most common), lateral or posterior semicircular canal(s). Patients present audiological (autophony, aural fullness, conductive hearing loss, pulsatile tinnitus) and/or vestibular symptoms (sound or pressure-evoked oscillopsia or vertigo, characteristic vertical-torsional eye movements), depending on which semicircular canal is affected. Posterior SCD syndrome is associated with high-riding jugular bulb and fibrous dysplasia, while lateral SCD syndrome is associated with chronic otitis media and cholesteatoma, with or without audiological and vestibular symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Semicircular canal dehiscence syndrome	c4708600	1,530	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=420402	2021-01-23T17:24:32	{"icd-10": ["H83.8"], "synonyms": ["SCD syndrome"]}
Purpura of the nail beds usually result from trauma, with causes of toe involvement including physical pressure on the toes, such as that seen in surfboarding or windsurfing in which one must maintain balance with the toes, or when exogenous pressure is exerted from poorly fitting shoes.[1]:791–2 Purpura beneath the nails may present similar to a melanoma, a confusion that may result if the patient does not communicate the acuteness of onset.[1]:792 ## See also[edit] * Nail anatomy * List of cutaneous conditions ## References[edit] 1. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Purpura of the nail bed	None	1,531	wikipedia	https://en.wikipedia.org/wiki/Purpura_of_the_nail_bed	2021-01-18T18:34:04	{"wikidata": ["Q7261509"]}
A rare genetic form of low-renin hypertension characterized by hypertension associated with decreased plasma levels of potassium and aldosterone. ## Epidemiology Liddle syndrome prevalence is unknown. The condition is considered rare with less than 80 families reported worldwide. ## Clinical description The disease can be clinically heterogeneous, ranging from mild to severe. Most patients are diagnosed in young adulthood, although the diagnosis may be made as early as in infancy, especially when family screening of an affected patient is performed. The typical clinical features are resistance to treatment with conventional anti-hypertensives, salt-sensitive arterial hypertension, hypokalemia and metabolic alkalosis often associated with a family history of early-onset hypertension and sudden death. Associated manifestations of hypokalemia may include muscular weakness, polyuria/polydipsia. Sudden death due to stroke or myocardial infarction or associated with malignant arrhythmias elicited by severe hypokalemia has been reported. Mild forms with essential normal plasma electrolytes have also been reported. ## Etiology Liddle syndrome is due to gain-of-function mutations in the genes SCNN1A (16p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12.2), encoding, respectively, the alpha, beta and gamma subunits of the epithelial sodium channel (ENaC), a key protein involved in sodium reabsorption in the distal renal tubules. Physiologically, ENaC channel abundance is regulated by aldosterone. The gain-of-function mutations causing Liddle syndrome impair the retrieval from the apical membrane and subsequent degradation of ENaC by the ubiquitin proteasome pathway. The prolonged tenancy of mutated ENaC in the membrane results in increased sodium reabsorption independent of aldosterone with consequent hypertension. ## Diagnostic methods Diagnosis is suspected by the detection of hypertension, associated with hypokalemic alkalosis and suppressed renin and aldosterone, especially in the presence of a relevant family history. It can be confirmed by genetic testing. ## Differential diagnosis Liddle syndrome needs to be distinguished from other forms of hypertension with hypokalemic alkalosis. The suppressed renin and aldosterone levels separate it from primary and secondary forms of hyperaldosteronism, such as Conn syndrome or renovascular hypertension. A family history consistent with dominant inheritance, a urine steroid profile and genetic testing can separate it from apparent mineralocorticoid excess and glucocorticoid remediable hypertension. ## Genetic counseling The pattern of inheritance is autosomal dominant, the risk to offspring of inheriting the mutation from an affected parent is 50%. Given the variable phenotype reported in some families, genetic screening should be performed in first-degree relatives of a mutation carrier. ## Management and treatment Treatment is based on administration of potassium-sparing diuretics, such as amiloride or triamterene, which act by blocking ENaC activity. This results in reduction of blood pressure and correction of hypokalemia and metabolic alkalosis. Conventional antihypertensive therapies are not effective. Patients must also follow a low sodium diet. ## Prognosis With adequate treatment, prognosis is good. Without treatment, cardiovascular and renal complications usually occur. * 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	Liddle syndrome	c0221043	1,532	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=526	2021-01-23T17:49:20	{"gard": ["7381"], "mesh": ["D056929"], "omim": ["177200", "618114", "618126"], "umls": ["C0221043"], "icd-10": ["I15.1"], "synonyms": ["Pseudoaldosteronism", "Pseudohyperaldosteronism type 1"]}
This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (July 2015) (Learn how and when to remove this template message) Baggio–Yoshinari syndrome Other namesBYS SpecialtyInfectious disease The Baggio–Yoshinari syndrome , formerly known as the Brazilian Lyme-like disease and Brazilian human borreliosis, is a disease transmitted by the Amblyomma cajennense tick, but the organism that causes the infection is still unknown.[1] Clinical features resemble those of Lyme disease (LD).[2] ## Contents * 1 Presentation * 2 Diagnosis * 3 History * 4 References ## Presentation[edit] A distinct feature of the syndrome is its prolonged clinical evolution, with relapsing episodes and autoimmune dysfunction. If diagnosed in its early stages, the symptoms respond well to antibiotics. If the disease evolves to a chronic phase, it can potentially cause oligoarthritis, cognitive impairment, meningoencephalitis and erythema nodosum, with the patient risking to develop both articular and neurological sequelae.[2] The neurological manifestations of BYS were first described by Yoshinari et al. including patients with peripheral neuritis, meningitis and cranial neuritis (facial nerve palsy, diplopia and deafness).[1] Likely transmission vectors of BYS belong to the Amblyomma and Rhipicephalus genera, which could help to explain all the particularities observed in BYS versus LD.[1] Some features of BYS also resemble those found in the Southern tick-associated rash illness (STARI, also known as Masters' disease), which is found in the Southern USA.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (March 2018) ## History[edit] In 1989, Brazilian researchers Professors Domingos Baggio (an entomologist from the Biomedical Sciences Institute of the University of São Paulo), Paulo Yasuda (a microbiologist from the same institute) and Natalino Hajime Yoshinari (a physician from the Rheumatology Department at University of São Paulo's Medical School[1]) started research on Lyme disease in Brazil, by suggestion of Dr. Allen Steere. At that time, LD was almost unknown among Brazilian physicians.[3] The first cases were described in Brazil in 1992 in siblings from Cotia, São Paulo that developed symptoms as a migrating redness, general flu-like symptoms and arthritis after being bitten by ticks. Although the symptoms were similar to those presented by patients of Lyme disease, clinical and laboratorial results were considerably different. Ticks of the Ixodes ricinus complex were not found at the risk areas; bacteria from the Borrelia burgdorferi sensu lato complex —that cause Lyme disease— were not found in biological fluids and tissues of the siblings.[4] Blood analysis of the patients on electron microscopy exhibited structures resembling microorganisms of the spirochaete phylum. For these reasons, the Brazilian zoonosis was considered a new disease and named Baggio–Yoshinari Syndrome (BYS), defined as: "Exotic and emerging Brazilian infectious disease, transmitted by ticks not belonging to the Ixodes ricinus complex, caused by latent spirochetes with atypical morphology, which originates LD-like symptoms, except for occurrence of relapsing episodes and auto-immune disorders".[4] ## References[edit] 1. ^ a b c d e Revista Brasileira de Reumatologia, vol.49 no.5, São Paulo, Sept./Oct. 2009: Neurological manifestations in Baggio-Yoshinari Syndrome (Brazilian Lyme-like disease syndrome) 2. ^ a b Revista Brasileira de Reumatologia, Vol.54, Issue 2, March–April 2014, Pages 148–151. Chronic lymphomonocytic meningoencephalitis, oligoarthritis and erythema nodosum: report of Baggio-Yoshinari syndrome of long and relapsing evolution 3. ^ Revista Brasileira de Pesquisas Médicas e Biológicas vol.40 no.4 Ribeirão Preto Apr. 2007: Description of Lyme disease-like syndrome in Brazil. Is it a new tick borne disease or Lyme disease variation? 4. ^ a b Revista da Associação Médica Brasileira vol.56 no.3 São Paulo, 2010: Brazilian Lyme-like disease or Baggio-Yoshinari syndrome: exotic and emerging Brazilian tick-borne zoonosis * v * t * e Tick-borne diseases and infestations Diseases Bacterial infections Rickettsiales * Anaplasmosis * Boutonneuse fever * Ehrlichiosis (Human granulocytic, Human monocytotropic, Human E. ewingii infection) * Scrub typhus * Spotted fever rickettsiosis * Pacific Coast tick fever * American tick bite fever * rickettsialpox * Rocky Mountain spotted fever) Spirochaete * Baggio–Yoshinari syndrome * Lyme disease * Relapsing fever borreliosis Thiotrichales * Tularemia Viral infections * Bhanja virus * Bourbon virus * Colorado tick fever * Crimean–Congo hemorrhagic fever * Heartland bandavirus * Kemerovo tickborne viral fever * Kyasanur Forest disease * Omsk hemorrhagic fever * Powassan encephalitis * Severe fever with thrombocytopenia syndrome * Tete orthobunyavirus * Tick-borne encephalitis Protozoan infections * Babesiosis Other diseases * Tick paralysis * Alpha-gal allergy * Southern tick-associated rash illness Infestations * Tick infestation Species and bites Amblyomma * Amblyomma americanum * Amblyomma cajennense * Amblyomma triguttatum Dermacentor * Dermacentor andersoni * Dermacentor variabilis Ixodes * Ixodes cornuatus * Ixodes holocyclus * Ixodes pacificus * Ixodes ricinus * Ixodes scapularis Ornithodoros * Ornithodoros gurneyi * Ornithodoros hermsi * Ornithodoros moubata Other * Rhipicephalus sanguineus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Baggio–Yoshinari syndrome	None	1,533	wikipedia	https://en.wikipedia.org/wiki/Baggio%E2%80%93Yoshinari_syndrome	2021-01-18T19:06:08	{"wikidata": ["Q20736850"]}
Holt (1975) described hypothenar radial arches in 2 families and concluded that the inheritance is probably recessive. Inheritance \- Autosomal recessive Skin \- Hypothenar radial arches \- Abnormal dermatoglyphics ▲ 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	DERMATOGLYPHICS--HYPOTHENAR RADIAL ARCH	c1857315	1,534	omim	https://www.omim.org/entry/221780	2019-09-22T16:28:47	{"omim": ["221780"]}
Twin twin transfusion syndrome (TTTS) is a rare condition seen in twin monochorionic pregnancies, typically developing during the 15-26 week gestation period and usually due to unbalanced intertwin placental anastomoses, where an unequal exchange of blood between twins causes oligohydramnios in one sac and polyhydramnios in the other which can lead to a high perinatal mortality rate and a high rate of disability in survivors if left untreated [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Twin to twin transfusion syndrome	c2909036	1,535	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95431	2021-01-23T18:26:04	{"gard": ["325"], "mesh": ["D005330"], "icd-10": ["O43.0"], "synonyms": ["Feto-fetal transfusion syndrome"]}
Segmental odontomaxillary dysplasia (SOD) is a rare disorder characterized by unilateral enlargement of the right or left maxillary alveolar bone and gingiva in the region from the back of the canines to the maxillary tuberosity. In the enlarged region, dental abnormalities such as missing teeth, abnormal spacing and delayed eruption occur. ## Epidemiology The term segmental odontomaxillary dysplasia was introduced by Danforth et al. in 1990. Up to 2005, 32 cases of SOD had been described. SOD is often diagnosed in childhood both in males and females. ## Clinical description The main clinical features include: 1) an alveolar process characterized by unilateral enlargement of the maxillary alveolar bone and gingiva. Buccal as well as palatal enlargement of the alveolar bone is observed, although it is more pronounced on the buccal side. 2) Dentition is marked by abnormal spacing between erupted primary molars and adjacent teeth. The first permanent molars are often distally displaced. A depression in the palate can appear in the molar region. The canines erupt normally. Malformations of the primary molars, absence of one or both premolars and delayed eruption of adjacent teeth are regular findings. 3) On radiograph, the bone appears dense and sclerotic. Decreased size of the maxillary sinus in the affected side is observed. 4) Histological findings reveal immature bone with irregular trabecular and basophilic cemental lines resulting from alternating bone resorption and bone formation. Sparse narrow spaces with only a few fat cells are observed. The gingiva shows slight fibrosis without pathological changes. Primary teeth are characterized by enlargement of pulps and an irregular pulp/dentin interface. Tubular defects in the coronal dentine are present. A deficient osteoblast layer and widespread external resorption is also observed. ## Etiology The etiology of SOD remains unknown. There is however a vascular theory for the origin of regional odontodysplasia. ## Differential diagnosis Differential diagnosis includes hemimaxillofacial dysplasia (HMD), regional odontodysplasia, fibrous dysplasia, focal cemento-osseous dysplasia, and hemifacial hyperplasia. In HMD, ipsilateral facial hypertrichosis is present in addition to the SOD symptoms. Some authors consider SOD and HMD to be different manifestations of the same syndrome. Regional odontodysplasia is characterized by delayed eruption or failure of eruption of discoloured and atypically shaped teeth. It is similar to SOD, but the incisors and canines of the permanent dentition are commonly involved and agenesis of premolars is not a typical feature. In regional odontodysplasia the radiographic appearance is described as teeth showing poorly demarcated enamel and dentition with a blotchy appearance. The pulp chambers are large and the roots short with open apices. Both primary and permanent teeth are said to be affected in this condition. Fibrous dysplasia also causes enlargement of bone tissue, but in this case affected bone growth is out of proportion with that of unaffected bones, and tooth malformations and missing premolars are not characteristics of the disease. Focal cemento-osseous dysplasia occurs in adults. Gingival enlargements and absence of teeth does not occur. Hemifacial hyperplasia results in unilateral facial enlargement and precocious eruption and enlarged teeth in the affected region. Absence of premolars has not been reported. ## Genetic counseling The condition does not appear to be inherited. SOD is apparently a non progressive developmental disorder. ## Management and treatment Treatement of SOD should include long-term follow-up as it is important for guidance in the management of this disorder. Due to the possibility of a vascular origin for regional odontodysplasia, all patients with this syndrome must be carefully examined in the face and neck region for vascular malformations of any type, bearing in mind that vascular skin lesions (birthmarks) may fade during childhood. Implants have been successful in one reported case. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Segmental odontomaxillary dysplasia	c3698531	1,536	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=67039	2021-01-23T17:14:56	{"icd-10": ["K00.4"]}
Viral meningitis Other namesAseptic meningitis Viral meningitis causes inflammation of the meninges. SpecialtyNeurology Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges (the membranes covering the brain and spinal cord). Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.[1] Viruses are the most common cause of aseptic meningitis.[2] Most cases of viral meningitis are caused by enteroviruses (common stomach viruses).[3][4][5] However, other viruses can also cause viral meningitis, such as West Nile virus, mumps, measles, herpes simplex types I and II, varicella and lymphocytic choriomeningitis (LCM) virus.[4][6] Based on clinical symptoms, viral meningitis cannot be reliably differentiated from bacterial meningitis, although viral meningitis typically follows a more benign clinical course. Viral meningitis has no evidence of bacteria present in cerebral spinal fluid (CSF). Therefore, lumbar puncture with CSF analysis is often needed to identify the disease.[7] In most cases, there is no specific treatment, with efforts generally aimed at relieving symptoms (headache, fever or nausea).[8] A few viral causes, such as HSV, have specific treatments. In the United States, viral meningitis is the cause of more than half of all cases of meningitis.[9] With the prevalence of bacterial meningitis in decline, the viral disease is garnering more and more attention.[10] The estimated incidence has a considerable range, from 0.26 to 17 cases per 100,000 people. For enteroviral meningitis, the most common cause of viral meningitis, there are up to 75,000 cases annually in the United States alone.[10] While the disease can occur in both children and adults, it is more common in children.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 Recent research * 8 References * 9 External links ## Signs and symptoms[edit] Symptoms of Meningitis Viral meningitis characteristically presents with fever, headache and neck stiffness.[11] Fever is the result of cytokines released that affect the thermoregulatory (temperature control) neurons of the hypothalamus. Cytokines and increased intracranial pressure stimulate nociceptors in the brain that lead to headaches. Neck stiffness is the result of inflamed meninges stretching due to flexion of the spine.[12] The various layers of meninges act form a separation between the brain and the skull.[13] In contrast to bacterial meningitis, symptoms associated with viral meningitis are often less severe and do not progress as quickly.[11] Nausea, vomiting and photophobia (light sensitivity) also commonly occur, as do general signs of a viral infection, such as muscle aches and malaise.[11] Increased cranial pressure from viral meningitis stimulates the area postrema, which causes nausea and vomiting. Widened pulse pressure (systolic - diastolic blood pressure), bradycardia, and irregular respiration would be alarming for Cushing's reflex, a sign of acutely elevated intracranial pressure.[14] Photophobia is due to meningeal irritation.[12] In severe cases, people may experience concomitant encephalitis (meningoencephalitis), which is suggested by symptoms such as altered mental status, seizures or focal neurologic deficits.[15] Babies with viral meningitis may only appear irritable, sleepy or have trouble eating.[7] Infection in the neonatal period may be the result of infection during pregnancy.[1] In severe cases, people may experience concomitant encephalitis (meningoencephalitis), which is suggested by symptoms such as altered mental status, seizures or focal neurologic deficits.[15] The pediatric population may show some additional signs and symptoms that include jaundice and bulging fontanelles.[12] A biphasic fever is more often seen in children compared to adults. The first fever arrives with the onset of general constitutional symptoms, and the second accompanying the onset of the neurological symptoms.[16] Symptoms can vary depending on the virus responsible for infection. Enteroviral meningitis (the most common cause) typically presents with the classic headache, photophobia, fever, nausea, vomiting, and nuchal rigidity.[17] With coxsackie and echo virus' specifically, a maculopapular rash may be present, or even the typical vesicles seen with Herpangina.[17] Lymphocytic choriomeningitis virus (LCMV) can be differentiated from the common presenting meningeal symptoms by the appearance of a prodromal influenza-like sickness about 10 days before other symptoms begin.[17] Mumps meningitis can present similarly to isolated mumps, with possible parotid and testicular swelling.[17] Interestingly, research has shown that HSV-2 meningitis most often occurs in people with no history of genital herpes, and that a severe frontal headache is among the most common presenting symptoms.[18][17] Patients with varicella zoster meningitis may present with herpes zoster (Shingles) in conjunction with classic meningeal signs.[17] Meningitis can be an indication that an individual with HIV is undergoing seroconversion, the time when the human body is forming antibodies in response to the virus.[1] ## Causes[edit] The most common causes of viral meningitis in the United States are non-polio enteroviruses. The viruses that cause meningitis are typically acquired from sick contacts. However, in most cases, people infected with viruses that may cause meningitis do not actually develop meningitis.[7] Viruses that can cause meningitis include:[19] * Enteroviruses * Enterovirus 71 * Echovirus * Poliovirus (PV1, PV2, PV3) * Coxsackie A virus (CAV); also causes Hand foot and mouth disease * Herpesviridae (HHV) * Herpes simplex virus type 1 (HSV-1 / HHV-1) or type 2 (HSV-2 / HHV-2); also cause cold sores or genital herpes * Varicella zoster (VZV / HHV-3); also causes chickenpox and shingles (herpes zoster) * Epstein–Barr virus (EBV / HHV-4); also causes infectious mononucleosis/"mono" * Cytomegalovirus (CMV / HHV-5) * Human immunodeficiency virus (HIV); causes AIDS * La Crosse virus * Lymphocytic choriomeningitis virus (LCMV) * Measles * Mumps * St. Louis encephalitis virus * West Nile virus ## Mechanism[edit] Play media Meningitis Viral Meningitis is mostly caused by an infectious agent that has colonized somewhere in its host.[20] People who are already in an immunocompromised state are at the highest risk of pathogen entry.[12] Some of the most common examples of immunocompromised individuals include those with HIV, cancer, diabetes, malnutrition, certain genetic disorders, and patients on chemotherapy.[12] Potential sites for this include the skin, respiratory tract, gastrointestinal tract, nasopharynx, and genitourinary tract. The organism invades the submucosa at these sites by invading host defenses, such as local immunity, physical barriers, and phagocytes or macrophages.[20] After pathogen invasion, the immune system is activated.[12] An infectious agent can enter the central nervous system and cause meningeal disease via invading the bloodstream, a retrograde neuronal pathway, or by direct contiguous spread.[21] Immune cells and damaged endothelial cells release matrix metalloproteinases (MMPs), cytokines, and nitric oxide. MMPs and NO induce vasodilation in the cerebral vasculature. Cytokines induce capillary wall changes in the blood brain barrier, which leads to expression of more leukocyte receptors, thus increasing white blood cell binding and extravasation.[12] The barrier that the meninges create between the brain and the bloodstream are what normally protect the brain from the body's immune system. Damage to the meninges and endothelial cells increases cytotoxic reactive oxygen species production, which damages pathogens as well as nearby cells.[12] In meningitis, the barrier is disrupted, so once viruses have entered the brain, they are isolated from the immune system and can spread.[22] This leads to elevated intracranial pressure, cerebral edema, meningeal irritation, and neuronal death.[12] ## Diagnosis[edit] Lumbar Puncture The diagnosis of viral meningitis is made by clinical history, physical exam, and several diagnostic tests.[23] Kernig and Brudzinski signs may be elucidated with specific physical exam maneuvers, and can help diagnose meningitis at the bedside.[17] Most importantly however, cerebrospinal fluid (CSF) is collected via lumbar puncture (also known as spinal tap). This fluid, which normally surrounds the brain and spinal cord, is then analyzed for signs of infection.[24] CSF findings that suggest a viral cause of meningitis include an elevated white blood cell count (usually 10-100 cells/µL) with a lymphocytic predominance in combination with a normal glucose level.[25] Increasingly, cerebrospinal fluid PCR tests have become especially useful for diagnosing viral meningitis, with an estimated sensitivity of 95-100%.[26] Additionally, samples from the stool, urine, blood and throat can also help to identify viral meningitis.[24] CSF vs serum c-reactive protein and procalcitonin have not been shown to elucidate whether meningitis is bacterial or viral.[16] In certain cases, a CT scan of the head should be done before a lumbar puncture such as in those with poor immune function or those with increased intracranial pressure.[1] If the patient has focal neurological deficits, papilledema, a Glasgow Coma Score less than 12, or a recent history of seizures, lumbar puncture should be reconsidered.[16] Differential diagnosis for viral meningitis includes meningitis caused by bacteria, mycoplasma, fungus, and drugs such as NSAIDS, TMP-SMX, IVIG. Further considerations include brain tumors, lupus, vasculitis, and Kawasaki disease in the pediatric population.[16] ## Treatment[edit] Aciclovir Because there is no clinical differentiation between bacterial and viral meningitis, people with suspected disease should be sent to the hospital for further evaluation.[1] Treatment for viral meningitis is generally supportive. Rest, hydration, antipyretics, and pain or anti-inflammatory medications may be given as needed.[27] However, if there is initial uncertainty as to whether the meningitis is bacterial or viral in origin, empiric antibiotics are often given until bacterial infection is ruled out.[16] Herpes simplex virus, varicella zoster virus and cytomegalovirus have a specific antiviral therapy. For herpes the treatment of choice is aciclovir.[28] If encephalitis is suspected, empiric treatment with IV aciclovir is often warranted.[16] Surgical management is indicated where there is extremely increased intracranial pressure, infection of an adjacent bony structure (e.g. mastoiditis), skull fracture, or abscess formation.[12] The majority of people that have viral meningitis get better within 7–10 days.[29] ## Epidemiology[edit] From 1988–1999, about 36,000 cases occurred each year.[30] As recently as 2017, the incidence in the U.S. alone increased to 75,000 cases per year for enteroviral meningitis.[10] With the advent and implementation of vaccinations for organisms such as Streptococcus pneumoniae, Haemophilus influenza type B, and Neisseria meningitis, rates of bacterial meningitis have been in decline, making viral meningitis more common.[16] Countries without high rates of immunization still carry higher rates of bacterial disease.[16] While the disease can occur in both children and adults, it is more common in children.[1] Rates of infection tend to reach a peak in the summer and fall. [31] During an outbreak in Romania and in Spain viral meningitis was more common among adults.[32] While, people aged younger than 15 made up 33.8% of cases.[32] In contrast in Finland in 1966 and in Cyprus in 1996, Gaza 1997, China 1998 and Taiwan 1998, the incidences of viral meningitis were more common among children.[33][34][35][36] ## Recent research[edit] It has been proposed that viral meningitis might lead to inflammatory injury of the vertebral artery wall.[37] The Meningitis Research Foundation is conducting a study to see if new genomic techniques can improve the speed, accuracy and cost of diagnosing meningitis in children in the UK. The research team will develop a new method to be used for the diagnosis of meningitis, analysing the genetic material of microorganisms found in CSF (cerebrospinal fluid). The new method will first be developed using CSF samples where the microorganism is known, but then will be applied to CSF samples where the microorganism is unknown (estimated at around 40%) to try and identify a cause.[38] There is also research investigating whether high-throughput sequencing, wherein the investigator does not need to compare DNA results with known genomic sequences, could be used in specifically diagnosing unknown causes of viral meningitis.[39] While there is some emerging evidence that bacterial meningitis may have a negative impact on cognitive function, there is no such evidence for viral meningitis.[40] ## References[edit] 1. ^ a b c d e f g Logan SA, MacMahon E (January 2008). "Viral meningitis". BMJ. 336 (7634): 36–40. doi:10.1136/bmj.39409.673657.ae. PMC 2174764. PMID 18174598. 2. ^ "Aseptic Meningitis". Healthline. 2012-08-07. Retrieved 10 March 2017. 3. ^ "Epidemiology". Alaska Department of Health and Social Services. 4. ^ a b Logan SA, MacMahon E (January 2008). "Viral meningitis". BMJ. 336 (7634): 36–40. doi:10.1136/bmj.39409.673657.ae. PMC 2174764. PMID 18174598. 5. ^ Ratzan KR (March 1985). "Viral meningitis". The Medical Clinics of North America. 69 (2): 399–413. doi:10.1016/s0025-7125(16)31051-3. PMID 3990441. 6. ^ "Meningitis, Viral" (PDF). lacounty.gov. Acute Communicable Disease Control Manual. County of Los Angeles Dept. of Public Health. March 2015. Retrieved January 2, 2019. 7. ^ a b c "Meningitis \| Viral \| CDC". www.cdc.gov. Retrieved 2017-03-02. 8. ^ "Viral Meningitis - Meningitis Research Foundation". www.meningitis.org. Retrieved 2017-03-02. 9. ^ Bartt R (December 2012). "Acute bacterial and viral meningitis". Continuum. 18 (6 Infectious Disease): 1255–70. doi:10.1212/01.CON.0000423846.40147.4f. PMID 23221840. S2CID 24087895. 10. ^ a b c McGill F, Griffiths MJ, Solomon T (April 2017). "Viral meningitis: current issues in diagnosis and treatment". Current Opinion in Infectious Diseases. 30 (2): 248–256. doi:10.1097/QCO.0000000000000355. PMID 28118219. S2CID 6003618. 11. ^ a b c "Viral Meningitis - Brain, Spinal Cord, and Nerve Disorders - Merck Manuals Consumer Version". Merck Manuals Consumer Version. Retrieved 2017-03-04. 12. ^ a b c d e f g h i j "Meningitis \| McMaster Pathophysiology Review". www.pathophys.org. Retrieved 2017-12-12. 13. ^ Weller RO, Sharp MM, Christodoulides M, Carare RO, Møllgård K (March 2018). "The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS". Acta Neuropathologica. 135 (3): 363–385. doi:10.1007/s00401-018-1809-z. PMID 29368214. 14. ^ Dinallo S, Waseem M (2019). "Cushing Reflex". StatPearls. StatPearls Publishing. PMID 31747208. Retrieved 2020-01-16. 15. ^ a b Cho TA, Mckendall RR (2014-01-01). "Clinical approach to the syndromes of viral encephalitis, myelitis, and meningitis". In Tselis AC, Booss J (eds.). Neurovirology. Handbook of Clinical Neurology. Neurovirology. 123. Elsevier. pp. 89–121. doi:10.1016/B978-0-444-53488-0.00004-3. ISBN 9780444534880. PMID 25015482. 16. ^ a b c d e f g h Cantu RM, Das JM (2019). "Viral Meningitis". StatPearls Publishing. StatPearls. PMID 31424801. Retrieved 2020-01-16. 17. ^ a b c d e f g Wright WF, Pinto CN, Palisoc K, Baghli S (March 2019). "Viral (aseptic) meningitis: A review". Journal of the Neurological Sciences. 398: 176–183. doi:10.1016/j.jns.2019.01.050. PMID 30731305. S2CID 72334384. 18. ^ Landry ML, Greenwold J, Vikram HR (July 2009). "Herpes simplex type-2 meningitis: presentation and lack of standardized therapy". The American Journal of Medicine. 122 (7): 688–91. doi:10.1016/j.amjmed.2009.02.017. PMID 19559173. 19. ^ Viral Meningitis at eMedicine 20. ^ a b "Viral Meningitis: Background, Pathophysiology, Etiology". 2017-11-29. Cite journal requires `\|journal=` (help) 21. ^ Klimpel, Gary R. (1996). "Immune Defenses". In Baron, Samuel (ed.). Medical Microbiology (4th ed.). Galveston (TX): University of Texas Medical Branch at Galveston. ISBN 978-0963117212. PMID 21413332. 22. ^ Chadwick DR (2005-01-01). "Viral meningitis". British Medical Bulletin. 75–76 (1): 1–14. doi:10.1093/bmb/ldh057. PMID 16474042. 23. ^ "Diagnosis - Meningitis - Mayo Clinic". www.mayoclinic.org. Retrieved 2017-03-04. 24. ^ a b "CSF analysis: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2017-03-04. 25. ^ "CSF Analysis - Neurology - UMMS Confluence". wiki.umms.med.umich.edu. Retrieved 2017-03-04. 26. ^ Fomin, Dean A. Seehusen\|Mark Reeves\|Demitri (2003-09-15). "Cerebrospinal Fluid Analysis". American Family Physician. 68 (6): 1103–1108. PMID 14524396. Retrieved 2017-03-04. 27. ^ "Viral Meningitis Treatment & Management: Approach Considerations, Pharmacologic Treatment and Medical Procedures, Patient Activity". 2017-11-29. Cite journal requires `\|journal=` (help) 28. ^ Tyler KL (June 2004). "Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's". Herpes. 11 Suppl 2 (Suppl 2): 57A–64A. PMID 15319091. 29. ^ "Meningitis \| Viral \| CDC". www.cdc.gov. 2017-12-04. Retrieved 2017-12-11. 30. ^ Khetsuriani N, Quiroz ES, Holman RC, Anderson LJ (Nov–Dec 2003). "Viral meningitis-associated hospitalizations in the United States, 1988-1999". Neuroepidemiology. 22 (6): 345–52. doi:10.1159/000072924. PMID 14557685. S2CID 27311344. 31. ^ Logan SA, MacMahon E (January 2008). "Viral meningitis". BMJ. 336 (7634): 36–40. doi:10.1136/bmj.39409.673657.AE. PMC 2174764. PMID 18174598. 32. ^ a b Jiménez Caballero PE, Muñoz Escudero F, Murcia Carretero S, Verdú Pérez A (October 2011). "Descriptive analysis of viral meningitis in a general hospital: differences in the characteristics between children and adults". Neurologia. 26 (8): 468–73. doi:10.1016/j.nrleng.2010.12.004. PMID 21349608. 33. ^ Rantakallio P, Leskinen M, von Wendt L (1986). "Incidence and prognosis of central nervous system infections in a birth cohort of 12,000 children". Scandinavian Journal of Infectious Diseases. 18 (4): 287–94. doi:10.3109/00365548609032339. PMID 3764348. 34. ^ "1998—Enterovirus Outbreak in Taiwan, China—update no. 2". WHO. 35. ^ "1997—Viral meningitis in Gaza". WHO. 36. ^ "1996—Viral meningitis in Cyprus". WHO. 37. ^ Pan, Xudong (2012). "Vertebral artery dissection associated with viral meningitis". BMC Neurology. 12: 79. doi:10.1186/1471-2377-12-79. PMC 3466159. PMID 22909191. 38. ^ "Using new genomic techniques to identify the causes of meningitis in UK children \| Meningitis Research Foundation". www.meningitis.org. Retrieved 2017-12-12. 39. ^ Zanella MC, Lenggenhager L, Schrenzel J, Cordey S, Kaiser L (April 2019). "High-throughput sequencing for the aetiologic identification of viral encephalitis, meningoencephalitis, and meningitis. A narrative review and clinical appraisal". Clinical Microbiology and Infection. 25 (4): 422–430. doi:10.1016/j.cmi.2018.12.022. PMC 7129948. PMID 30641229. 40. ^ Christie D, Rashid H, El-Bashir H, Sweeney F, Shore T, Booy R, Viner RM (2017). "Impact of meningitis on intelligence and development: A systematic review and meta-analysis". PLOS ONE. 12 (8): e0175024. Bibcode:2017PLoSO..1275024C. doi:10.1371/journal.pone.0175024. PMC 5570486. PMID 28837564. ## External links[edit] Classification D * ICD-10: G0.2 * ICD-10-CM: A87 * ICD-9-CM: 321.2 * MeSH: D008587 External resources * eMedicine: article/1168529 * v * t * e Infectious diseases – viral systemic diseases Oncovirus DNA virus HBV Hepatocellular carcinoma HPV Cervical cancer Anal cancer Penile cancer Vulvar cancer Vaginal cancer Oropharyngeal cancer KSHV Kaposi's sarcoma EBV Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin lymphoma Follicular dendritic cell sarcoma Extranodal NK/T-cell lymphoma, nasal type MCPyV Merkel-cell carcinoma RNA virus HCV Hepatocellular carcinoma Splenic marginal zone lymphoma HTLV-I Adult T-cell leukemia/lymphoma Immune disorders * HIV * AIDS Central nervous system Encephalitis/ meningitis DNA virus Human polyomavirus 2 Progressive multifocal leukoencephalopathy RNA virus MeV Subacute sclerosing panencephalitis LCV Lymphocytic choriomeningitis Arbovirus encephalitis Orthomyxoviridae (probable) Encephalitis lethargica RV Rabies Chandipura vesiculovirus Herpesviral meningitis Ramsay Hunt syndrome type 2 Myelitis * Poliovirus * Poliomyelitis * Post-polio syndrome * HTLV-I * Tropical spastic paraparesis Eye * Cytomegalovirus * Cytomegalovirus retinitis * HSV * Herpes of the eye Cardiovascular * CBV * Pericarditis * Myocarditis Respiratory system/ acute viral nasopharyngitis/ viral pneumonia DNA virus * Epstein–Barr virus * EBV infection/Infectious mononucleosis * Cytomegalovirus RNA virus * IV: Human coronavirus 229E/NL63/HKU1/OC43 * Common cold * MERS coronavirus * Middle East respiratory syndrome * SARS coronavirus * Severe acute respiratory syndrome * SARS coronavirus 2 * Coronavirus disease 2019 * V, Orthomyxoviridae: Influenza virus A/B/C/D * Influenza/Avian influenza * V, Paramyxoviridae: Human parainfluenza viruses * Parainfluenza * Human orthopneumovirus * hMPV Human digestive system Pharynx/Esophagus * MuV * Mumps * Cytomegalovirus * Cytomegalovirus esophagitis Gastroenteritis/ diarrhea DNA virus Adenovirus Adenovirus infection RNA virus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNA virus HBV (B) RNA virus CBV HAV (A) HCV (C) HDV (D) HEV (E) HGV (G) Pancreatitis * CBV Urogenital * BK virus * MuV * Mumps * v * t * e Meningitis and other diseases of meninges Meningitis * Arachnoiditis * Bacterial * Tuberculous * Haemophilus * Pneumococcal * Viral * Herpesviral * Fungal * Cryptococcal * Aseptic * Drug-induced Other * Meningoencephalitis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Viral meningitis	c0025297	1,537	wikipedia	https://en.wikipedia.org/wiki/Viral_meningitis	2021-01-18T19:06:14	{"mesh": ["D008587"], "umls": ["C0025297"], "wikidata": ["Q3301664"]}
Charcot-Marie-Tooth disease type 4F (CMT4F) is a severe, demyelinating subtype of Charcot-Marie-Tooth disease type 4 characterized by the childhood onset of a slowly-progressing typical CMT phenotype (i.e. distal muscle weakness and atrophy, as well as pes cavus) that presents severe sensory loss (frequently with sensory ataxia), moderately to severely reduced motor nerve conduction velocities and almost invariable absence of sensory nerve action potentials, and delayed motor milestones. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Charcot-Marie-Tooth disease type 4F	c3540453	1,538	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99952	2021-01-23T18:07:26	{"gard": ["12441"], "omim": ["614895"], "icd-10": ["G60.0"], "synonyms": ["CMT4F"]}
Hall (1965) described 5 families in which 14 cases of myxedema occurred in addition to the 5 probands. In 1 of these families, a case of thyrotoxicosis was also observed, and in each of 2 families a relative had nontoxic goiter. A sixth proband had a daughter with thyrotoxicosis. In the families of 32 other patients with myxedema, no thyroid dysfunction was detected. Environmental factors, such as viral infection, cannot be excluded in the causation of such familial aggregation. However, the findings were considered compatible with sex-influenced recessive inheritance and also with the previous suggestion of a genetic relationship of myxedema to hyperthyroidism and to nontoxic goiter. In 1 family, 'bilateral inheritance of thyroid disease' was demonstrated. Voice \- Husky Neuro \- Paresthesias \- Decreased memory Lab \- Low free T4 \- High TSH Inheritance \- Autosomal recessive, sex-influenced \- environmental factors not excluded Skin \- Coarse, dry skin \- Puffy, non-pitting swelling of face, hands and limbs \- Decreased sweating Endocrine \- Hypothyroidism Muscle \- Muscle cramps Misc \- Weakness \- Fatigue \- Lethargy \- Cold intolerance \- Thyrotoxicosis in relatives \- Nontoxic goiter in relatives GI \- Constipation ▲ 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	MYXEDEMA	c0027145	1,539	omim	https://www.omim.org/entry/255900	2019-09-22T16:24:38	{"doid": ["11634"], "mesh": ["D009230"], "omim": ["255900"], "icd-10": ["E03.9"]}
Abortion in Costa Rica is severely restricted by criminal law. Currently, abortions are allowed in Costa Rica only in order to preserve the life or physical health of the woman. Abortions are illegal in almost all cases, including when the pregnancy is a result of rape or incest and when the fetus suffers from medical problems or birth defects. Both social and economic factors have led to this legal status. It remains unclear whether abortions are legal to preserve the mental health of the woman,[1] though the 2013 United Nations abortion report says Costa Rica does allow abortions concerning mental health of a woman.[2] Currently under the Carlos Alvarado Quesada administration, the discussion of the "Technical Norm" to regulate the already legal therapeutic abortion is a hot issue, as the Evangelical parties (who have a large bloc in the Legislative Assembly) vigorously oppose it. ## Contents * 1 Statistics * 2 Legal issues * 3 Public opinion * 4 "Rosa" * 5 References ## Statistics[edit] Abortions in Costa Rica are most commonly practiced in secret, either in private clinics or by other means where statistics of maternal deaths are difficult to obtain. In 2007, data revealed that the number of illegal abortions is on the rise, up to 22.3 for every 1,000 from 10.6 for every 1,000 women. This comes out to about 27,000 illegal abortions being performed in Costa Rica annually.[3] ## Legal issues[edit] The Costa Rican Penal Code in its article 121 establishes that no abortion performed to protect the life or health of the mother, carried with the consent of the woman and participation of an authorized physician or obstetrician, can be punished.[4] This is known as “abortion with impunity”. However as mentioned before the lack of a regulatory norm makes difficult the application. Article 93 allows the judges to grant judicial pardon to a woman who has caused her own abortion as a consequence of rape.[4] Articles 118, 119, 120 and 122 punish different types of abortion from three months to ten years of prison depending on the circumstances. In all cases the law increases the penalty if the fetus had more than six months of development.[4] Induced abortion is classified as a crime in the Penal Code of 1970, included in the crimes against life. Doctors who suspect that a woman has had an abortion are obligated to report them to the Organization of Judicial Investigation (Organizacion de Investigacion Judicial). Punishment varies depending on whether the woman consented or not to the procedure and whether the fetus had reached six months' gestation at the time. Although the United Nations Human Rights Council recommended in 1999 that Costa Rica should introduce more exceptions to the prohibition of abortions, the actual Costa Rican legislature intended to increase penalties for abortions due to their Roman Catholic background.[5] Laura Chinchilla, strictly opposed to the legalization of abortion, was president of Costa Rica from 2010 to 2014, during which reforms to the law were not expected.[6] According to the Center for Reproductive Rights (translated from Spanish), "therapeutic abortion is legal according to Article 121 of the Penal Code; however, adequate measures have not been taken to guarantee this right. Specifically, there are no specialized protocols or guides that tell health care workers how to proceed with an abortion if the life or physical or mental health of the woman is at risk. There are also no effective judicial or administrative mechanisms through which this procedure can be demanded to be performed."[7] In 2003, there were no women or doctors in prison for having or performing an abortion. However, there was one lay woman, an untrained midwife, who was accused of carrying out abortions and served a three-year sentence.[citation needed] ## Public opinion[edit] According to Planned Parenthood public opinion is heavily influenced by the Roman Catholic Church. Given the influence of Catholic doctrine on public policy and culture, abortion under any circumstance is illegal and understood as murder. Accordingly, almost all doctors will not carry out an abortion for any reason at all.[8] According to a survey made by the University of Costa Rica whilst most Costa Rican support therapeutic abortion (55%) very few support completely free abortion (only 11%).[9][10] The poll showed that 55% support abortion to save the mother’s life, against 45% who oppose. 49% supports it in case of non-life threatening health problems against 39%, 43% in case the fetus has life-incompatible malformation versus 49% against, only 29% supports it in case of pregnancy of a child versus 57% against, only 28% in cases of rape against 61% opposing, and only 11% supports only on the woman’s request against 78% opposing it. The poll also show that half Costa Rican have no knowledge of what is therapeutic abortion and of such almost all opposed it.[11][12] Support is bigger among unreligious people, younger generations and people with higher education.[12] A 2013-2014 investigation made with focus groups with different religious samples showed that most non-religious Costa Ricans support free abortion on woman's request only, non-practicing Catholics and most non-Christian religious minorities (except for Tibetan Buddhists) support abortion in some cases including for saving the woman's life and health and cases of rape particularly in the case of children, whilst most practicing Catholics, Mainline Protestants and Neo-Pentecostal oppose any kind of abortion even in life threatening situation.[13] ## "Rosa"[edit] In 2003, a nine-year-old girl living in Costa Rica, known to the media as "Rosa", became pregnant after being a victim of sexual abuse. Consequently, Rosa was left in a state where her physical and emotional state was very delicate. The authorities denied her the opportunity to have an abortion, as they alleged that the consequences of an induced abortion would be worse than her carrying the pregnancy to term. Eventually, Rosa was able to travel to Nicaragua, where, despite much controversy, she had an abortion in a private clinic.[5][14] ## References[edit] 1. ^ "Summary of Abortion Laws Around the World". Pregnant Pause. Archived from the original on 19 November 2014. Retrieved 19 October 2014. 2. ^ https://web.archive.org/web/20160415084202/http://www.un.org/en/development/desa/population/publications/pdf/policy/WorldAbortionPolicies2013/WorldAbortionPolicies2013_WallChart.pdf 3. ^ Ertelt, Steven (23 September 2008). "Costa Rica Report Indicates Number of Illegal Abortions Supposedly Rising". Lifenews.com. Life News. Retrieved 19 October 2014. 4. ^ a b c Asamblea Legislativa (1972). "Código Penal de Costa Rica" (PDF). Retrieved 10 September 2016. Cite journal requires `\|journal=` (help) 5. ^ a b Francoeur, Robert T. The International Encyclopedia of Sexuality. The Continuum Publishing Company. Retrieved 19 October 2014. 6. ^ "Costa Rican presidential candidate reveals opposition to abortion and same-sex 'marriage'". Catholic News Agency. 4 February 2010. Retrieved 19 October 2014. 7. ^ "Derecho a la Salud de la Mujeres Embarazadas" (PDF), Center for Reproductive Rights (in Spanish), retrieved 21 March 2018 8. ^ "Costa Rica Country Program". Planned Parenthood. Planned Parenthood Federation of America. Archived from the original on 2 November 2014. Retrieved 19 October 2014. 9. ^ Redaccion (23 August 2018). "El 55% de los costarricenses apoya el aborto terapéutico, según encuesta". Teletica. Retrieved 1 April 2019. 10. ^ Umaña, Paula (15 January 2019). "Mitad de la población costarricense apoya el aborto si la madre se encuentra en peligro de muerte". UCR. Retrieved 1 April 2019. 11. ^ "Encuesta UCR: 50% de los ticos no sabe lo que es el aborto terapéutico". Repretel. 21 December 2018. Retrieved 1 April 2019. 12. ^ a b Chinchilla, Aaron (22 December 2018). "Encuesta UCR: "Mitad de los costarricenses desconocen sobre aborto terapéutico"". El Periódico. Retrieved 1 April 2019. 13. ^ Fuentes Belgrave, Laura (2013–2014). "¿Un menú de creencias a fuego lento?: Acercamiento sociológico a la religión en Costa Rica". Revistas Universidad Nacional. Retrieved 1 April 2019. 14. ^ Chan, Sue (23 March 2003). "Nicaragua Shaken By Child's Abortion". CBS News. Retrieved 29 March 2011. * v * t * e Abortion in North America Sovereign states * Antigua and Barbuda * Bahamas * Barbados * Belize * Canada * Costa Rica * Cuba * Dominica * Dominican Republic * El Salvador * Grenada * Guatemala * Haiti * Honduras * Jamaica * Mexico * Nicaragua * Panama * Saint Kitts and Nevis * Saint Lucia * Saint Vincent and the Grenadines * Trinidad and Tobago * United States Dependencies and other territories * Anguilla * Aruba * Bermuda * Bonaire * British Virgin Islands * Cayman Islands * Curaçao * Greenland * Guadeloupe * Martinique * Montserrat * Puerto Rico * Saint Barthélemy * Saint Martin * Saint Pierre and Miquelon * Saba * Sint Eustatius * Sint Maarten * Turks and Caicos Islands * United States Virgin Islands * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Abortion in Costa Rica	None	1,540	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Costa_Rica	2021-01-18T18:34:15	{"wikidata": ["Q4668447"]}
A number sign (#) is used with this entry because type A2 brachydactyly (BDA2) is caused by heterozygous mutation in the BMPR1B gene (603248) on chromosome 4q or in the GDF5 gene (601146) on chromosome 20q11. It can also be caused by heterozygous duplication of a proposed regulatory element on chromosome 20p12 that affects the expression of BMP2 (112261) in the developing limb. Description Brachydactyly type A2 is an autosomal dominant disorder characterized by malformations of the middle phalanx of the index finger and by anomalies of the second toe (summary by Su et al., 2011). Clinical Features In brachydactyly type A2, shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. Temtamy and McKusick (1978) noted that this rare form of brachydactyly had been described in 3 different kindreds of German, Norwegian, and Swiss descent (Ziegner, 1903; Mohr and Wriedt, 1919; Hanhart, 1940). The family of Mohr and Wriedt (1919) contained a possible homozygote. Temtamy and McKusick (1978) provided details of a fourth affected family, of African American descent, originally reported by Edelson (1972). Seemann et al. (2005) described a large Norwegian pedigree with short index fingers and variable clinodactyly. X-rays showed hypoplasia or aplasia of the second phalanx of the second digit and, to a variable extent, shortening and shape abnormalities of the middle phalanx of the fifth digit. Kjaer et al. (2006) studied 37 living members of the then 9-generation Norwegian family of Danish descent with BDA2 originally described by Mohr and Wriedt (1919), including 2 individuals who had been examined by Mohr and Wriedt when they were children. Nineteen family members had a shortened or absent middle phalanx of the index finger, and other fingers were occasionally involved. The fourth finger was characteristically spared, leading the authors to suggest that the phenotype in this family represented a subtype of brachydactyly type A2. Ploger et al. (2008) studied 14 affected and 14 unaffected members of a 6-generation family with BDA2. All 5 affected individuals who were radiologically evaluated had a metacarpophalangeal profile that demonstrated a second mesophalanx that was shorter than mesophalanges 3, 4, and 5, consistent with a diagnosis of BDA2. Other occasional findings included a relatively short first metacarpal or first proximal phalanx. Hands were more commonly affected than feet. The phenotype was variable, with some affected individuals showing an almost normal pattern, whereas others had additional features such as mild hypoplasia of middle phalanges of fingers 3 and 4, indicating overlap with BDA1 (112500) and BDC (113100). Mapping In 2 unrelated German families with type A2 brachydactyly, Lehmann et al. (2003) performed linkage analysis and mapped a locus for type A2 brachydactyly to chromosome 4q21-q25, an interval that includes the BMPR1B gene. ### Duplication of a Regulatory Element Downstream of BMP2 In a large Brazilian kindred of German origin segregating brachydactyly type A2, originally described by Freire-Maia et al. (1980), Dathe et al. (2009) performed linkage analysis and found a novel locus on chromosome 20p12.3 that incorporated the BMP2 gene (112261). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence about 110 kb downstream of BMP2 was detected. Screening of other patients by quantitative PCR revealed a similar duplication in a second family of European origin. The duplicated region contained evolutionarily highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model, Dathe et al. (2009) showed that this sequence is able to drive expression of an X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicated that a limb-specific enhancer of Bmp2 is located within the identified duplication. In affected members of a 6-generation Chinese family with brachydactyly type A2, Su et al. (2011) identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20: 6,809,382-6,814,044, NCBI36). There was a 2.1-kb fragment that overlapped with the duplications reported by Dathe et al. (2009). Luciferase activity assays showed that the 2.1-kb fragment was associated with a 2.21-fold (p = 0.00011) reduction of transcription activity in osteosarcoma U2OS cells and a 3.25-fold (p = 0.0018) reduction in transcription activity in HeLa cells, suggesting a repressive effect on BMP2 expression. These findings were opposite to the functional effects observed by Dathe et al. (2009), but Su et al. (2011) concluded that the findings overall identified cis-regulatory sequences in the duplication 3-prime to the BMP2 gene. Molecular Genetics ### Mutations in BMPR1B In affected members of a German family with BDA2, Lehmann et al. (2003) identified an ile200-to-lys mutation in the BMPR1B gene (I200K; 603248.0001), and in affected members of the another German family, they identified an arg486-to-trp mutation (R486W; 603248.0002). In a 26-month-old boy with typical BDA2, Lehmann et al. (2006) identified an arg486-to-gln (R486Q) mutation in the BMPR1B gene (603248.0004). They identified the same mutation in an unrelated 34-year-old German woman with a brachydactyly C (BDC; 113100)/symphalangism-1 (SYM1; 185800)-like phenotype who was negative for mutations in the coding regions of the GDF5 and NOG (602991) genes. A possible modifying mutation in the IHH gene (600726), which causes type A1 brachydactyly (112500), was excluded in both patients. Lehmann et al. (2006) suggested that the phenotypic variability between the 2 patients is due to unknown modifiers and/or stochastic effects, and that the phenotypic overlap in the female patient reflects interactions within the BMP/GDF pathway among the ligand (GDF5), its receptor (BMPR1B), and the inhibitor (NOG). ### Mutations in GDF5 In affected members of a Norwegian family with a BDA2 phenotype, Seemann et al. (2005) found no mutations in the BMPR1B gene. By screening for candidate genes, they identified heterozygosity for a mutation in the GDF5 gene (L441P; 601146.0010). Kjaer et al. (2006) studied 37 living members of the then 9-generation Norwegian family of Danish descent with BDA2 originally described by Mohr and Wriedt (1919), including 2 individuals who had been examined by Mohr and Wriedt when they were children. Heterozygosity for the L441P mutation in the GDF5 gene was identified in 22 family members, 3 of whom were clinically unaffected. The mutation was also identified in a similarly affected Danish individual. In 14 affected individuals from a 6-generation family with BDA2, in whom no mutations in the BMPR1B gene were identified, Ploger et al. (2008) identified heterozygosity for a missense mutation in the GDF5 gene (R380Q; 601164.0021) that was not found in unaffected members of the family. INHERITANCE \- Autosomal dominant SKELETAL Hands \- Brachydactyly \- Medially deviated index finger \- Short index finger \- Variable fifth finger clinodactyly \- Hypoplastic/aplastic middle phalanx (2nd finger) \- Hypoplastic middle phalanx (5th finger) Feet \- Short, broad laterally deviated halluces \- Medially deviated second toe \- Syndactyly (2-3) MOLECULAR BASIS \- Caused by mutation in the bone morphogenetic protein receptor, type 1B gene (BMPR1B, 603248.0001 ) \- Caused by mutation in the growth/differentiation factor 5 gene (GD5, 601146.0005 ) \- Caused by mutation in the bone morphogenetic protein 2 gene (BMP2, 112261.0001 ) ▲ 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	BRACHYDACTYLY, TYPE A2	c1832702	1,541	omim	https://www.omim.org/entry/112600	2019-09-22T16:44:07	{"doid": ["0110965"], "mesh": ["C537089"], "omim": ["112600"], "orphanet": ["93396"], "synonyms": ["Alternative titles", "BRACHYMESOPHALANGY II", "MOHR-WRIEDT TYPE BRACHYDACTYLY"]}
Spinocerebellar ataxia type 15/16 (SCA15/16) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar ataxia, tremor and cognitive impairment. ## Epidemiology Prevalence is unknown. Fewer than 80 patients affected by the disease have been identified to date. ## Clinical description Age of onset is from 20 to 66 years (mean age = 39.6 years). ## Etiology Genetic testing has shown that patients originally classified under SCA15 and SCA16 have the same subtype caused by a deletion in the inositol 1,4,5-triphosphate receptor 1 ITPR1 gene (3p26.1). ## Prognosis Prognosis is generally good and life-shortening events do not usually occur. Some patients live beyond 80 years of 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	Spinocerebellar ataxia type 15/16	c1847725	1,542	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98769	2021-01-23T17:31:41	{"gard": ["10477"], "mesh": ["C564685"], "omim": ["606658"], "icd-10": ["G11.2"], "synonyms": ["SCA15/16"]}
Recombinant chromosome 8 syndrome is a condition that involves heart and urinary tract abnormalities, moderate to severe intellectual disability, and a distinctive facial appearance. Many children with recombinant chromosome 8 syndrome do not survive past early childhood, usually due to complications related to their heart abnormalities. Most people with this condition are descended from a Hispanic population originating in the San Luis Valley area of southern Colorado and northern New Mexico. Recombinant chromosome 8 syndrome is caused by a rearrangement of chromosome 8 that results in a missing piece of the short (p) arm and an extra piece of the long (q) arm. Most affected individuals have at least one parent with a change in chromosome 8 called an 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	Recombinant chromosome 8 syndrome	c0795822	1,543	gard	https://rarediseases.info.nih.gov/diseases/9698/recombinant-chromosome-8-syndrome	2021-01-18T17:58:00	{"mesh": ["C535296"], "omim": ["179613"], "umls": ["C0795822"], "orphanet": ["96167"], "synonyms": ["Rec8 syndrome", "San Luis Valley recombinant chromosome 8 syndrome", "San Luis Valley syndrome"]}
A number sign (#) is used with this entry because karyomegalic interstitial nephritis (KMIN) is caused by homozygous or compound heterozygous mutation in the FAN1 gene (613534) on chromosome 15q. Description Karyomegalic tubulointerstitial nephritis (KTN) is a rare kidney disease characterized clinically by onset in the third decade of progressive renal failure. Renal biopsy shows chronic tubulointerstitial nephritis and interstitial fibrosis associated with enlarged and atypical tubular epithelial cell nuclei (summary by Baba et al., 2006). Clinical Features Spoendlin et al. (1995) reported 3 unrelated adult patients who presented with asymptomatic slowly progressive renal dysfunction identified by routine laboratory investigation. Two patients had proteinuria, and 1 had hypertension. All had a history of recurrent infections earlier in life. Urine cytology of a son of 1 of the patients showed a few cells with enlarged nuclei; his renal function was normal. Renal biopsy in the 3 probands showed markedly enlarged and hyperchromatic nuclei in tubular epithelial cells in all parts of the nephron. Electron microscopy showed bizarrely enlarged nuclei with an irregular distribution of chromatin. In all cases, there was interstitial fibrosis surrounding atrophic tubules, and some of the glomeruli were completely sclerosed. Immunohistochemical studies showed significantly increased PCNA (176740), suggesting active DNA synthesis and perhaps an inhibition of mitosis in these cells. Spoendlin et al. (1995) postulated a genetic defect causing an induction of DNA repair. Godin et al. (1996) reported a French brother and sister with onset of progressive renal failure at ages 32 and 42 years, respectively. Neither had a history of recurrent infections. Both had mild proteinuria and glycosuria. Both had persistent elevation of liver enzymes, which was more marked in the brother, but his liver biopsy was normal. Renal biopsies of both patients showed enlarged and hyperchromatic nuclei in tubular epithelial cells as well as in endothelial cells of the peritubular capillaries. Both had high levels of blood and urine ochratoxin A, a mycotoxin known to be nephrotoxic. The brother underwent renal transplantation and had normal renal function 10 years later. Baba et al. (2006) reported a 39-year-old man who presented with asymptomatic progressive renal failure. He also had mild hypertension and mildly increased liver enzymes. Renal biopsy showed globally sclerosed glomeruli, interstitial fibrosis with tubular atrophy, and karyomegaly in tubular epithelial cells. Electron microscopy showed uneven chromatin distribution in the nuclei. The disorder progressed to stage IV chronic renal failure and the patient was worked-up for transplantation. Monga et al. (2006) reported 2 Italian sibs, born of consanguineous parents, with karyomegalic interstitial nephritis. The patients presented at ages 31 and 22 years, respectively. The older sister had a history of repeated respiratory infections. At age 38, she had severe renal failure. Renal biopsy showed hyalinized glomeruli, large nuclei in tubular epithelial cells, atrophic tubules, and interstitial fibrosis. Karyomegalic changes were also noted in a skin biopsy and liver biopsy. She underwent kidney transplant at age 42, but died 20 days later. Postmortem examination showed karyomegalic cells in multiple tissues, including endothelial cells in the brain and lung, fibroblasts of the thyroid and myocardium, Schwann cells, the esophagus, and smooth muscle cells of the aorta. Her younger brother had severe chronic renal failure and chronic liver disease with increased liver enzymes and cholestasis. Renal biopsy was similar to his sister's, with hyperchromatic nuclei and nuclei with dispersed chromatin. Karyomegalic cells were also observed in a duodenal biopsy. He developed chronic renal failure requiring dialysis and died 6 years after presentation. Monga et al. (2006) also reported an unrelated Italian man with a less severe form of the disorder. Palmer et al. (2007) reported a 44-year-old Maori woman who presented with pneumonia and was found to have renal insufficiency on biochemical studies. She also had normocytic anemia requiring transfusion. Renal ultrasound showed atrophic and echogenic kidneys, and urinalysis showed protein and glucose. Renal biopsy revealed karyomegalic changes in the tubules, dilated tubules, and tubular atrophy. Cytology of the urine showed irregular, large, vesicular nuclei with prominent nucleoli and atypical features, which Palmer et al. (2007) noted could mimic carcinoma. Family history revealed a brother with karyomegalic interstitial nephritis. Inheritance The transmission pattern in the families with karyomegalic interstitial nephritis reported by Zhou et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of 9 unrelated families with karyomegalic interstitial nephritis, Zhou et al. (2012) identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene (see, e.g., 613534.0001-613534.0008). Eight of the 12 mutations resulted in a truncated protein. The first mutation was identified by homozygosity mapping and exome sequencing in an affected family reported by Palmer et al. (2007). Other families with mutations had been reported by Godin et al. (1996), Spoendlin et al. (1995), and Baba et al. (2006). Upon exposure to mitomycin C, FAN1 mutant cells showed genomic instability, as manifest by increased chromatid breaks and radial chromosomes on metaphase spreads. Although the results of the test for Fanconi anemia (see, e.g., 227650), diepoxybutane-induced breakage, were negative in FAN1-mutant cells lines, these cells still showed decreased survival compared to wildtype in response to either inducer of interstrand crosslink repair (ICL). None of the FAN1 mutant proteins was able to correct mitomycin C-induced decreased survival in cells lacking FAN1 nuclease activity. Morpholino knockdown of Fan1 in zebrafish embryos resulted in a nephronophthisis (NPHP; 256100)-like phenotype, with shortened and curved body axis, as well as a Fanconi anemia-like phenotype, with microcephaly, microphthalmia, and massive apoptosis. There was evidence of activation of the DNA damage repair pathway, as demonstrated by increased signaling for gamma-H2AX (H2AFX; 601772). Knockdown of both Fan1 and p53 (191170) in zebrafish caused renal cysts, reminiscent of a ciliopathy. In the fawn-hooded hypertensive rat, an animal model of chronic kidney disease, as well as in kidney samples from humans with genetically heterogeneous forms of chronic kidney disease, Zhou et al. (2012) found increased nuclear staining for gamma-H2AX, indicating activation of the DNA damage response pathway. These findings supported the hypothesis that DNA lesions and DNA damage response pathways may partially drive renal damage in NPHP-related ciliopathies and in chronic kidney disease. INHERITANCE \- Autosomal recessive GENITOURINARY Kidneys \- Chronic renal failure \- End-stage renal disease \- Atrophic kidneys \- Large nuclei (karyomegaly) in renal tubules seen renal biopsy \- Hyperchromatic nuclei \- Glomerular sclerosis \- Interstitial fibrosis \- Atrophic tubules \- Cystic dilation of tubules (in some patients) \- Chronic inflammatory infiltrate, mild \- Nephronophthisis LABORATORY ABNORMALITIES \- Proteinuria \- Glycosuria \- Increased BUN \- Increased creatinine \- Abnormal liver function tests (in some patients) \- Hematuria (less common) \- Karyomegaly may be found in other visceral organs MISCELLANEOUS \- Onset of renal failure in adulthood (range twenties to fifties) \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the FANCD2/FANCI-associated nuclease 1 gene (FAN1, 613534.0001 ) ▲ 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	INTERSTITIAL NEPHRITIS, KARYOMEGALIC	c3553774	1,544	omim	https://www.omim.org/entry/614817	2019-09-22T15:54:18	{"doid": ["0060911"], "omim": ["614817"], "orphanet": ["401996"], "synonyms": ["KIN", "Systemic karyomegaly"]}
Distal 7q11.23 microdeletion syndrome is a rare chromosomal anomaly characterized by epilepsy, neurodevelopmental disorder variably including developmental delays and intellectual disabilities of variable severity, learning disability and neurobehavioral abnormalities (autism spectrum disorder, hyperactivity, impulsivity, aggression, self-abusive behaviors, depression). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Distal 7q11.23 microdeletion syndrome	c3150999	1,545	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254351	2021-01-23T18:19:54	{"omim": ["613729"], "icd-10": ["Q93.5"], "synonyms": ["Distal del(7)(q11.23)", "Distal monosomy 7q11.23"]}
Hereditary hyperferritinemia with congenital cataracts is characterized by the association of early onset (although generally absent at birth) cataract with persistently raised plasma ferritin concentrations in the absence of iron overload. ## Epidemiology Prevalence still needs to be precisely determined but is estimated to be at least 1 in 200 000. ## Etiology The syndrome is caused by a mutation in a translational regulatory element of the gene coding for the L-ferritin subunit, located on 19q13.4-qter. Messenger RNAs for ferritin have a stem-loop structure called an 'iron responsive element' (IRE) in their 5' non-coding region. In the absence of iron, a cytoplasmic protein called the 'iron regulatory protein' (IRP) binds to the IRE and represses ferritin synthesis. As a result of the mutation on the IRE, the IRP no longer recognizes the binding site leading to constitutive L-ferritin expression in tissues and an increase in ferritin levels in the plasma, although there is no iron overload. The mutations that have been identified affect bases on the IRE loop or in the bulge in the middle of the IRE stem. Two partial deletions of either half of the IRE have also been reported. ## Differential diagnosis In cases for which no IRE mutations have been detected but the hyperferritinemia persists, hemochromatosis type 4 (which may be caused by ferroportin mutations) should be suspected. ## Genetic counseling The syndrome is an autosomal dominant inherited disease. ## Management and treatment There is no treatment for cataract-hyperferritinemia syndrome, but venesections should be avoided as they are not well tolerated. ## Prognosis Besides cataracts, there are no other clinical manifestations associated with this syndrome and the prognosis is good. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hereditary hyperferritinemia-cataract syndrome	c1833213	1,546	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163	2021-01-23T18:43:45	{"gard": ["2806"], "mesh": ["C538137"], "omim": ["600886"], "umls": ["C1833213"], "icd-10": ["H26.0"], "synonyms": ["Bonneau-Beaumont syndrome", "HHCS", "Hereditary hyperferritinemia with congenital cataracts"]}
A number sign (#) is used with this entry because of evidence that X-linked mental retardation-72 (MRX72) is caused by hemizygous mutation in the RAB39B gene (300774) on chromosome Xq28. Mutation in the RAB39B gene can also cause X-linked recessive mental retardation with early-onset Parkinson disease, known as Waisman syndrome (WSMN; 311510). Clinical Features Russo et al. (2000) reported a 3-generation Sardinian family segregating X-linked mental retardation. Three affected individuals had seizures and 1 had features of autism (see 209850). Giannandrea et al. (2010) reported a large family with X-linked mental retardation spanning 2 generations. There were 6 affected males, all with macrocephaly. One had obesity and 2 had features of autism. Inheritance The transmission pattern of mental retardation in the family reported by Russo et al. (2000) was consistent with X-linked recessive inheritance. Mapping In a 4-generation Sardinian family, Russo et al. (2000) observed 8 males with nonspecific X-linked mental retardation and 6 carrier females. Two-point linkage analysis demonstrated linkage to markers in Xq28; maximum lod score = 2.71 at theta = 0.00. The authors excluded involvement of the GDI1 gene (300104), which maps to the same region and is mutated in other families with nonspecific mental retardation (MRX41; 300849). Molecular Genetics In 2 unrelated families with X-linked mental retardation, including the family reported by Russo et al. (2000), Giannandrea et al. (2010) identified different hemizygous loss-of-function mutations in the RAB39B gene (300774.0001-300774.0002) that segregated with the disorder. INHERITANCE \- X-linked recessive GROWTH Other \- Developmental delay HEAD & NECK Head \- Dolichocephaly \- Macrocephaly Face \- Long face NEUROLOGIC Central Nervous System \- Mental retardation (range mild to severe) \- Seizures \- Limited memory, attention, language Behavioral Psychiatric Manifestations \- Stereotypic behavior \- Hyperactivity \- Autistic features (rare) MISCELLANEOUS \- Motor skills less affected than cognitive skills MOLECULAR BASIS \- Caused by mutation in the Ras-associated protein RAB39B ( 300774.0001 ) ▲ 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	MENTAL RETARDATION, X-LINKED 72	c2931498	1,547	omim	https://www.omim.org/entry/300271	2019-09-22T16:20:35	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300271"], "orphanet": ["777"]}
## Description Preeclampsia, which along with chronic hypertension and gestational hypertension comprise the hypertensive disorders of pregnancy, is characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks' gestation with clinically relevant proteinuria. Preeclampsia is 1 of the top 4 causes of maternal mortality and morbidity worldwide (summary by Payne et al., 2011). Preeclampsia is otherwise known as gestational proteinuric hypertension (Davey and MacGillivray, 1988). A high proportion of patients with preeclampsia have glomerular endotheliosis, the unique histopathologic feature of the condition (Fisher et al., 1981). A distinct form of severe preeclampsia is characterized by hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) (Brown et al., 2000). ### Genetic Heterogeneity of Preeclampsia/Eclampsia Susceptibility loci for preeclampsia/eclampsia include PEE1 on chromosome 2p13, PEE2 (609402) on chromosome 2p25, and PEE3 (609403) on chromosome 9p13. PEE4 (609404) is caused by mutation in the STOX1 gene (609397) on chromosome 10q22. PEE5 (614595) is caused by mutation in the CORIN gene (605236) on chromosome 4p12. An association with PEE has been found with the EPHX1 gene (132810) on chromosome 1q. Inheritance Humphries (1960) presented a systematic study of hypertensive toxemia of pregnancy in mother-daughter pairs delivered at The Johns Hopkins Hospital. Toxemia occurred in 28% of daughters of women who had toxemia in the pregnancy in which they were delivered as compared with 13% in a comparison group. Chesley et al. (1968) did a similar study with similar results. In cases in which 2 or more daughters of an eclamptic woman have been tested in pregnancy, toxemia developed in the first pregnancy of at least 1 daughter in 53% of the families. No definite conclusions on genetic heterogeneity, role of maternal versus fetal genotype, and possible genotype-genotype interaction were reached by Cooper and Liston (1979). Editorials published in The Lancet (Anonymous (1980, 1988)) and in the British Medical Journal (Anonymous, 1980) gave excellent reviews of genetic studies on eclampsia. Cooper et al. (1988) reported several examples of 3- and 4-generation involvement. Despite this, pedigree analysis by Chesley and Cooper (1986) suggested autosomal recessive inheritance with a frequency of the 'abnormal' allele of approximately 0.25. Arngrimsson et al. (1990) did a study through 3 or 4 generations in 94 families in Iceland patterned after the Humphries (1960) study. The families were descended from index women who were delivered in the years 1931-47 and who had either eclampsia or severe preeclampsia. Inheritance was followed through both sons and daughters. They concluded that either a recessive or a dominant model could fit the data. Esplin et al. (2001) found that both men and women who were the product of a pregnancy complicated by preeclampsia were significantly more likely than control men and women to have a child who was the product of a pregnancy complicated by preeclampsia. Their findings were consistent with the suggestion of Liston and Kilpatrick (1991) that the single-gene model of inheritance of preeclampsia that best explains the frequency of preeclampsia in a low-risk population (3 to 6%) is the presence of homozygosity for the same recessive gene in both the mother and the fetus. In accordance with this model, the fetus must have 1 recessive paternally derived allele for preeclampsia to develop. Cnattingius et al. (2004) analyzed pregnancy outcomes from Swedish families joined by full sibs, including information from 244,564 sib pairs who had 701,488 pregnancies. The authors found that 35% of the variance in risk of preeclampsia was attributable to maternal genetic effects, 20% to fetal genetic effects (with equal contribution of maternal and paternal genetic effects), 13% to the couple effect, less than 1% to shared sib environment, and 32% to unmeasured factors. Cnattingius et al. (2004) concluded that genetic factors account for more than half of the risk of preeclampsia, and that maternal genes contribute more than fetal genes. They suggested that the couple effect is due to a genetic interaction between mother and father. Thornton and Macdonald (1999) performed a cohort study of female twins with information on hypertensive diseases of pregnancy obtained by questionnaire screening, and verified the diagnosis from hospital or general practitioner records. Self-reported preeclampsia was found to have a heritability of 0.221 and nonproteinuric hypertension of 0.198. However, none of the pairs who were self-reported as concordant for preeclampsia was confirmed from hospital records. Using hospital records, the heritability of preeclampsia was 0.0 and that for nonproteinuric hypertension was 0.375. Using a model treating preeclampsia as a separate disease from nonproteinuric hypertension, and assuming that the next pair identified was both monozygotic and concordant for preeclampsia, the estimated heritability of preeclampsia remained at 0.0. Using a threshold model in which nonproteinuric hypertension was treated as a mild form of preeclampsia, heritability was estimated at 0.247. They concluded that neither nonproteinuric hypertension nor preeclampsia is inherited in a simple mendelian fashion, and that the genetic contribution to the multifactorial inheritance of these 2 traits is smaller than hitherto believed. Berends et al. (2008) analyzed familial aggregation, consanguinity, and parent-of-origin effects in 106 women from a genetically isolated population in the Netherlands, 50 who had previous preeclampsia and 56 with previous pregnancies complicated by intrauterine growth retardation (IUGR). Eight-six of the women, 39 preeclampsia and 47 IUGR cases, could be linked to 1 common ancestor within 14 generations. The proportion of related women with previous preeclampsia or pregnancies complicated by IUGR was significantly greater than that expected by chance, and the proportion of women born from consanguineous marriages was increased in women with previous preeclampsia and those with IUGR compared to controls (p less than 0.001 for both). Berends et al. (2008) stated that the observed cosegregation of preeclampsia and IUGR supported a common genetic etiology, and that the high proportion of parental consanguineous marriages suggested the possibility of an underlying recessive mutation. No evidence was found for a parent-of-origin effect in either disorder. Population Genetics Preeclampsia complicates 3 to 8% of pregnancies in Western countries and causes 10 to 15% of maternal deaths. Incidence ranges from 3 to 7% for nulliparas and 1 to 3% for multiparas (summary by Uzan et al., 2011). Pathogenesis Napolitano et al. (2000) investigated the interactions between ET1 (131240) and the NO system in the fetoplacental unit. They examined the mRNA expression of ET1, inducible NO synthase (iNOS; 163730), and eNOS in human cultured placental trophoblastic cells obtained from preeclamptic (PE) and normotensive pregnancies. ET1 expression was increased in PE cells, whereas iNOS, which represents the main source of NO synthesis, was decreased; conversely, eNOS expression was increased. ET1 was able to influence its own expression as well as NOS isoform expression in normal and PE trophoblastic cultured cells. The findings suggested the existence of a functional relationship between ET(s) and NOS isoforms that could constitute the biologic mechanism leading to the reduced placental blood flow and increased resistance to flow in the fetomaternal circulation that are characteristic of the pathophysiology of preeclampsia. Cross (2003) reviewed various interpretations of the genetics of preeclampsia and 3 different mouse models suggesting that it can be initiated by 3 independent mechanisms: preexisting borderline maternal hypertension that is exacerbated by pregnancy, elevated levels of the vasoconstrictor angiotensin II (see 106150) in the maternal circulation by placental overproduction of renin (179820), and placental pathology. He stated that the potential contributions of both maternal and fetal genes to the onset of the disorder complicate its genetic analysis in humans. Maynard et al. (2003) found that soluble FMS-related tyrosine kinase-1 (FLT1; 165070) was upregulated in preeclampsia, leading to increased systemic levels of sFLT1 that fell after delivery. Increased sFLT1 in preeclamptic women was associated with decreased circulating levels of free vascular endothelial growth factor (VEGF; 192240) and placental growth factor (PGF; 601121), resulting in endothelial dysfunction in vitro that was rescued by exogenous VEGF and PGF. Administration of sFLT1 to pregnant rats induced hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. Maynard et al. (2003) suggested that excess circulating sFLT1 contributes to the pathogenesis of preeclampsia. In 120 preeclamptic women and 120 matched, normotensive controls, Levine et al. (2004) measured serum levels of the angiogenic factors sFLT1, PGF, and VEGF throughout pregnancy. Beginning at 13 to 16 weeks of gestation, PGF levels were significantly lower in women who later had preeclampsia than in controls (p = 0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with an increase in the sFLT1 level which was also more pronounced in the preeclamptic women. Levine et al. (2004) concluded that increased levels of sFLT1 and reduced levels of PGF predict the subsequent development of preeclampsia. Page et al. (2000) sought vasoactive placental neuropeptides using mRNA fingerprinting and human databases and identified neurokinin B (162330). In female rats, concentrations of NKB several-fold above that of an animal 20 days into pregnancy caused substantial pressor activity. In human pregnancy, the expression of NKB was confined to the outer syncytiotrophoblast of the placenta, significant concentrations of NKB could be detected in plasma as early as week 9, and plasma concentrations of NKB were grossly elevated in pregnancy-induced hypertension and preeclampsia. Page et al. (2000) suggested that elevated levels of NKB in early pregnancy may be an indicator of hypertension and preeclampsia and that treatment with certain neurokinin receptor antagonists may be useful in alleviating symptoms. In a review of the pathogenesis and genetics of preeclampsia, Roberts and Cooper (2001) stated that aberration of the interaction between placental and maternal tissue is probably the primary cause, but the exact nature of the differences from normal pregnancy remained elusive. There are genetic components to susceptibility, but the relative contributions of maternal and fetal genotypes were unclear. Pipkin (2001) reviewed the evidence on risk factors for preeclampsia. Wallukat et al. (1999) reported that patients with preeclampsia develop autoantibodies against the angiotensin II receptor type 1 (AGTR1; 106165), and suggested that these antibodies may participate in the angiotensin II-induced vascular lesions seen in patients with preeclampsia. Zhou et al. (2008) injected pregnant mice with either total IgG or affinity-purified angiotensin AT1 receptor antibodies from women with preeclampsia and observed the development of key features of preeclampsia in the mice, including hypertension, proteinuria, glomerular endotheliosis, placental abnormalities, and small fetus size. These features were prevented by coinjection with the AT1 receptor antagonist losartan or by an antibody-neutralizing 7-amino-acid epitope peptide. Zhou et al. (2008) concluded that preeclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from autoantibody-induced angiotensin receptor activation. Mapping ### PEE1 Unlike most other human disorders, preeclampsia impacts 2 individuals, the mother and her child, both of whom can be severely affected. Although the pathophysiology of the disorder is incompletely understood, familial clustering is apparent. Arngrimsson et al. (1999) reported the results of a genomewide screen of Icelandic families representing 343 affected women. Including those patients with nonproteinuric preeclampsia (gestational hypertension), proteinuric preeclampsia, and eclampsia, they detected a locus on 2p13 with a lod score of 4.70. Moses et al. (2000) reported the results of a medium-density genome scan in 34 families, representing 121 women with preeclampsia, from Australia and New Zealand. Multipoint nonparametric linkage analysis showed suggestive evidence of linkage to chromosome 2 (lod = 2.58), at 144.7 cM, between D2S112 and D2S151. Somewhat weaker linkage to chromosome 11q23-q24 was found. Given the limited precision of estimates of the map location of disease-predisposing loci for complex traits, Moses et al. (2000) concluded that the findings on chromosome 2 were consistent with the findings from the Icelandic study of Arngrimsson et al. (1999), and that their results may represent evidence of the same locus segregating in the population from Australia and New Zealand. They proposed that the chromosome 2 locus should be symbolized PREG1 for preeclampsia, eclampsia gene-1. Oudejans et al. (2015) identified a SNP, rs34174194, in the INO80B gene (616456) as a susceptibility allele for preeclampsia in Icelandic families with linkage to chromosome 2p13. The T-G SNP altered a highly conserved 7-nucleotide sequence in the 3-prime UTR of INO80B. The risk allele (G) of rs34174194 reduced binding of MIR1324 to the 3-prime UTR of the INO80B transcript and was predicted to increase INO80B translation. ### Other Linkage Associations See NOS3 (163729) for a discussion of the possible role of endothelial nitric oxide synthetase, also called eNOS, in the pathogenesis of pregnancy-induced hypertension and a study by Arngrimsson et al. (1997) providing evidence for a preeclampsia susceptibility locus in the region of 7q36 encoding the NOS3 gene. Harrison et al. (1997) reported results of a genomewide linkage search for preeclampsia/eclampsia (PEE) susceptibility genes, using 15 informative pedigrees. The 2.8-cM region between D4S450 and D4S610 on 4q was identified as a strong candidate region for a PEE susceptibility locus. The maximum multipoint lod score within this interval was 2.9. Analysis of markers in the region affected-member method also supported the possibility of a susceptibility locus in this region. Lachmeijer et al. (2001) performed a genome scan including 293 polymorphic markers in 67 Dutch sib-pair families affected by preeclampsia, eclampsia, or HELLP syndrome. A total of 12 regions showed nominal lod score peaks (lod scores between 0.6 and 2.2), with the highest lod score of 1.99 on chromosome 12q at 109.5 cM. Analysis in 38 preeclampsia families showed suggestive evidence for linkage on chromosome 22q at 32.4 cM (lod score of 2.41) and on chromosome 10q at 93.9 cM (lod score of 2.38). In 34 HELLP families, these peaks were absent, but the peak on 12q increased to a lod score of 2.1. The authors suggested that this may indicate that HELLP syndrome has a different genetic background than preeclampsia, which they noted was in contrast to the consensus statement of the Australasian Society on the Study of Hypertension in Pregnancy (Brown et al., 2000), in which HEELP syndrome was classified as a severe form of preeclampsia. A comparison between the Dutch genome scan of Lachmeijer et al. (2001) and the Icelandic scan by Arngrimsson et al. (1999) showed overlapping regions on chromosomes 3p and 15q. Another overlapping area on chromosome 11 was revealed when comparing the Dutch preeclampsia families with the study from Australia/New Zealand (Moses et al., 2000). Lachmeijer et al. (2001) concluded that these overlapping areas may harbor maternal susceptibility genes that increase a woman's risk of preeclampsia. Using additional microsatellite markers, van Dijk et al. (2012) reanalyzed the cohort of 34 families with HELLP syndrome originally studied by Lachmeijer et al. (2001) and found that the lod score for the region on chromosome 12q23 increased from 2.1 to 2.37. Van Dijk et al. (2012) then tested 57 individuals, including 7 families with affected sib pairs, 4 families with affected cousin pairs, and 2 discordant monozygous twin sisters with their partners, of which 36 females were affected, with 26 microsatellite markers in the 23.6-Mb region on 12q23; pedigree analysis narrowed the region to 2 minimal critical intervals: D12S1607 to PAH (612349) and D12S338 to D12S317. No mutations were found in the coding sequences of 38 known or predicted genes within or near those 2 intervals; rather, the HELLP locus was found to reside in a 154-kb intergenic region between C12ORF48 (613687) and IGF1 (147440) (chr12:101,114,674-101,268,434, NCBI36), and this region was confirmed by haplotype association analysis and deep sequencing. Van Dijk et al. (2012) screened the intergenic region and identified a long intergenic noncoding RNA (lincRNA) transcript with expression in the placental extravillous trophoblast (HELLPAR; 614985). ### Associations Pending Confirmation McGinnis et al. (2017) reported the first genomewide association study (GWAS) of offspring from preeclamptic pregnancies and discovery of the first genomewide significant susceptibility locus (rs4769613; p = 5.4 x 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene (165070), encoding Fms-like tyrosine kinase-1, providing biologic support, as a placental isoform of this protein (sFlt1) is implicated in the pathology of preeclampsia (Maynard et al., 2003). The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the 10th centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. Molecular Genetics In 627 families with preeclampsia (including 398 maternal triads and 536 fetal triads), the GOPEC Consortium (2005) analyzed 7 candidate genes previously reported as conferring susceptibility to preeclampsia: angiotensinogen (AGT; 106150), the angiotensin receptors AGTR1 (106165) and AGTR2 (300034), factor V Leiden variant (612309.0001), methylenetetrahydrofolate reductase (MTHFR; 607093), nitric oxide synthase (NOS3; 163729), and tumor necrosis factor-alpha (TNF; 191160). Using the transmission disequilibrium test, no genotype risk ratio achieved the prespecified criteria for statistical significance (posterior probability less than 0.05). The GOPEC Consortium (2005) concluded that none of the genetic variants tested confers a high risk of preeclampsia. Uz et al. (2007) found extremely skewed X-inactivation (greater than or equal to 90:10) in peripheral blood cells of 10 (22%) of 46 Caucasian women with preeclampsia and in 2 (2.33%) of 86 controls, suggesting a role for the X chromosome in the pathogenesis of the disorder in some patients. ### Association with HLA Kilpatrick et al. (1989) studied a group of 56 women who had had proteinuric preeclampsia and who had parous sisters. In the first pregnancy, proteinuric preeclampsia was more common in the sisters than in the maternity hospital population; the relative risk was 6.0. Frequency of HLA-DR4 (see 142860) was higher in sisters with pregnancy-induced hypertension than in sisters with normotensive pregnancies and more of them shared HLA-DR4 with their spouses. Kilpatrick et al. (1989) referred to a study of unrelated women in which they confirmed the association between DR4 and proteinuric preeclampsia. They proposed the hypothesis that preeclampsia occurs when both mother and fetus are homozygous for an HLA-linked recessive gene. Wilton et al. (1990), however, excluded close linkage of an eclampsia susceptibility gene with HLA. Liston and Kilpatrick (1991) examined 6 simple mendelian models of inheritance and rejected all except the one in which both mother and fetus must express the same recessive gene to confer susceptibility. They considered this model to be consistent with the putative association with HLA-DR4. Based on the hypothesis that preeclampsia occurs in women who are homozygous for a relatively common susceptibility gene, Hayward et al. (1992) constructed an exclusion map by using both candidate genes and random DNA markers on a panel of 2-generation families in which preeclampsia was rigorously defined. No evidence was found for linkage to the HLA region or to several genes implicated in the pathogenesis of hypertension, e.g., pronatriodilatin (108780), sodium-hydrogen ion antiporter (107310), mineralocorticoid receptor (600983), or glucocorticoid receptor (138040). Van Meter and Weaver (1993) commented on the study of Hayward et al. (1992). See 106150.0001 for information concerning the association of preeclampsia with a met235-to-thr mutation of the angiotensinogen gene, which maps to 1q. Preeclampsia is a pregnancy complication in which the fetus receives an inadequate blood supply due to failure of trophoblast invasion. Hiby et al. (2004) noted that the only polymorphic histocompatibility antigens on the trophoblast surface are HLA-C molecules (142840), including the paternal allele, which are recognized by members of the highly polymorphic KIR (see KIR2DL1; 604936) family of natural killer cell receptors. There are 2 distinct KIR haplotypes, termed A and B. Haplotype A has 1 activating and 6 inhibitory KIRs, whereas haplotype B has 5 activating and 2 inhibitory KIRs. Hiby et al. (2004) found that mothers with an AA KIR genotype and a fetus with HLA-C2 were at greatly increased risk of preeclampsia. KIR2DL5 (605305), a haplotype B gene encoding an inhibitory receptor, was significantly less frequent in preeclampsia mothers. The KIR-HLA-C2 interaction appeared to be physiologic rather than immunologic, in that maternal HLA-C type was of no consequence. Hiby et al. (2004) found that different human populations have reciprocal relationships between KIR AA frequency and HLA-C2 frequency, suggesting that this combination may be selected against and that reproductive success may have influenced the evolution and maintenance of KIR and HLA-C polymorphisms. ### Association with MTHFR Sohda et al. (1997) studied the 677C-T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR; 607093.0003) in preeclampsia. They found an increased frequency of the 677T allele and the 677T homozygous genotype in patients as compared with controls. The 677T variant of MTHFR had been identified as a risk factor in vascular disease in other studies. Rajkovic et al. (2000) found no statistically significant association between the maternal MTHFR genotype at the 677C-T polymorphism (607093.0003) and risk of preeclampsia. Conversely, Rajkovic et al. (2000) found a strong graded association between maternal plasma folate concentration and risk of preeclampsia. Women with plasma folate concentrations of less than 5.7 nmol/L experienced a 10.4-fold increase in risk of preeclampsia. There was no clear pattern of preeclampsia risk and vitamin B12 concentrations. ### Association with EPHX1 Zusterzeel et al. (2001) studied genetic variability in the EPHX1 gene (132810) in women with a history of preeclampsia. They found that the high activity genotype tyr113/tyr113 (132810.0001) was significantly more common in women with a history of preeclampsia (OR, 2.0, 95% CI, 1.2-3.7) as compared to controls. No difference in the frequency of the polymorphism was found between groups who did or did not develop the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Laasanen et al. (2002) studied 2 single-nucleotide polymorphisms (SNPs) in the EPHX1 gene in 133 Finnish preeclamptic and 115 healthy control women with at least 2 normal pregnancies. The T allele of the exon 3 T-C polymorphism (tyr113 to his; 132810.0001) was overrepresented among the preeclampsia group (0.74) when compared with the control group (0.66), displaying a borderline association (P = 0.05). Haplotype analysis using this polymorphism and the exon 4 A-G polymorphism (his139 to arg; 132810.0002) showed that the high activity haplotype T/A (tyr113/his139) was significantly overrepresented in the preeclampsia group (P = 0.01; odds ratio 1.61, 95% C.I. 1.12-2.32). The authors supported the feasibility of haplotype estimation analysis for detecting association more efficiently than single-point association analysis in terms of detection power. ### Association with GSTP1 Zusterzeel et al. (1999) found that glutathione S-transferase P1 (GSTP1; 134660) is the main GST isoform in normal placental and decidual tissue. In preeclamptic women, they found lower median placental and decidual GSTP1 levels compared to those in controls. Zusterzeel et al. (1999) suggested that reduced levels of GSTP1 in preeclampsia may indicate a decreased capacity of the detoxification system, resulting in a higher susceptibility to preeclampsia. Among 113 preeclampsia trios (mother, father, and baby), Zusterzeel et al. (2002) found an increased frequency of the GSTP1 val105 polymorphism (see 134660.0002) in mothers, fathers, and offspring of preeclamptic pregnancies compared to controls. There was no significant difference of the GSTP1 allele frequencies in preeclamptic mothers, fathers, and offspring. The authors emphasized the paternal contribution to the risk for preeclampsia. ### Association with Coagulation Factor V Brenner et al. (1996) identified the factor V Leiden mutation (R506Q; 612309.0001) in 2 patients with the HELLP syndrome, and Kupferminc et al. (1999) found an association between that mutation and a variety of obstetrical complications, including preeclampsia. Lindqvist et al. (1998), however, found no significant difference in the prevalence of the Leiden mutation between women with preeclampsia and/or intrauterine growth retardation and a control group. In a study of Finnish women, Faisel et al. (2004) found that susceptibility to preeclampsia was associated with a factor V R485K polymorphism but not with the Leiden mutation. ### Association with NOS3 In a study of 150 'coloured' South African patients, 50 with normal pregnancies, 50 with severe preeclampsia, and 50 with abruptio placentae, Hillermann et al. (2005) found that the combined frequency of the GT and TT NOS3 variant genotypes was significantly higher in the abruptio placentae group than in the control group (p = 0.006). Among preeclamptic patients who subsequently developed abruptio placentae, the T allele emerged as a major risk factor for the development of abruptio placentae (p less than 0.0001); the T variant did not seem to affect the risk of preeclampsia itself, however. Animal Model Kanasaki et al. (2008) showed that pregnant mice deficient in catechol-O-methyltransferase (COMT; 116790) showed a preeclampsia-like phenotype resulting from an absence of 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Administration of 2-ME ameliorated all preeclampsia-like features without toxicity in Comt -/- pregnant mice and suppressed placental hypoxia, Hif1a (603348) expression, and soluble Flt1 (165070) elevation. The levels of COMT and 2-ME were significantly lower in women with severe preeclampsia. Kanasaki et al. (2008) suggested that Comt-null mice may provide a model for preeclampsia and that 2-ME may serve as a diagnostic marker as well as a therapeutic agent for preeclampsia. INHERITANCE \- Autosomal dominant GROWTH Other \- Intrauterine growth retardation (in fetus) CARDIOVASCULAR Vascular \- Maternal hypertension (after 20th week gestation, resolved postpartum) ABDOMEN Liver \- Elevated liver enzymes GENITOURINARY Kidneys \- Proteinuria MUSCLE, SOFT TISSUES \- Edema NEUROLOGIC Central Nervous System \- Seizures (eclampsia) HEMATOLOGY \- Thrombocytopenia (HELLP syndrome) PRENATAL MANIFESTATIONS Maternal \- Maternal hypertension (after 20th week gestation, resolved postpartum) LABORATORY ABNORMALITIES \- Proteinuria \- Elevated liver enzymes MISCELLANEOUS \- Occurs in ~3% pregnancies in Western populations \- Clinical manifestation ranges from mild, transient hypertension to HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low platelets) \- Majority of cases are sporadic ▲ 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	PREECLAMPSIA/ECLAMPSIA 1	c0032914	1,548	omim	https://www.omim.org/entry/189800	2019-09-22T16:32:28	{"doid": ["10591"], "mesh": ["D011225"], "omim": ["189800"], "icd-10": ["O13", "O14", "O14.2", "O14.90", "O14.9"], "orphanet": ["275555"], "synonyms": ["Alternative titles", "PREG1", "PEE", "TOXEMIA OF PREGNANCY"]}
Bruise on the pelvis from blunt trauma This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Hip pointer" – news · newspapers · books · scholar · JSTOR (April 2012) Iliac Crest Overview of Ilium as largest bone of the pelvis. Details Identifiers Latinos ilii Anatomical terms of bone [edit on Wikidata] A hip pointer is a contusion on the pelvis caused by a direct blow or a bad fall at an iliac crest and/or hip bone and a bruise of the abdominal muscles (transverse and oblique abdominal muscles). Surrounding structures such as the tensor fasciae latae and the greater trochanter may also be affected. The injury results from the crushing of soft tissue between a hard object and the iliac crest. Contact sports are a common cause of this type of injury, most often in football and hockey in general due to improper equipment and placement. The direct impact can cause an avulsion fracture where a portion of bone is removed by a muscle. The pain is due to the cluneal nerve that runs right along the iliac crest, which makes this a very debilitating injury. This pain can be felt when walking, laughing, coughing or even breathing deeply. A hip pointer bruise usually causes bleeding into the hip abductor muscles, which move legs sideways, away from the midline of the body. This bleeding into muscle tissue creates swelling and makes leg movement painful. The hematoma that occurs can potentially build on the femoral nerve or lateral cutaneous of the femur. This injury usually lasts from one to six weeks, depending on the damage. In most cases, patients recover completely. A full assessment should be undertaken to rule out the possibility of damage to abdominal organs. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Management * 4 References * 5 External links ## Signs and symptoms[edit] Signs and symptoms include immediate pain, bruising and swelling, obvious weakness, spasms and a rapid decline in the hip / leg function, resulting in a decreased range of motion. ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2018) ## Management[edit] Rest, Ice, Compression and Elevation (RICE) are standard treatments in the first 48 hours of an injury to the hip pointer. After 48 hours, patients can begin gently stretching, strengthening exercises, flexibility and coordination. For the first 7–10 days, patients can take anti-inflammatories such as ibuprofen and apply ice. Since this injury is very painful, recovery is usually very slow. When the person is without pain, sports massage and range-of-motion activities may reduce tension and swelling and prevent scar tissue buildup. Furthermore, an injection of corticosteroids into the affected area may reduce symptoms in the short term and accelerate rehabilitation. Operative treatment is rarely indicated and is reserved for patients suffering from significant displacement or fractures of the bones. To prevent hip pointer, the equipment must be adequate in the sport and be well positioned and good size. It should also maintain excellent flexibility, strength and endurance of the hip, pelvis and lower back muscles. ## References[edit] ## External links[edit] * Hip Pointer Homepage * Photo displaying the injury [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hip pointer	None	1,549	wikipedia	https://en.wikipedia.org/wiki/Hip_pointer	2021-01-18T18:33:37	{"wikidata": ["Q17143043"]}
Hereditary antithrombin deficiency, also known as antithrombin III deficiency or AT III deficiency, is a disorder in which individuals are at increased risk for developing blood clots. The type of blood clots seen in individuals with this condition are typically clots that form in the deep veins of the leg (deep vein thrombosis or DVT) and clots that lodge in the lungs (pulmonary embolism or PE). Approximately 50% of individuals with hereditary antithrombin deficiency will develop one or more clots in their lifetime, usually after adolescence. Factors that may increase the likelihood of clotting include pregnancy, the use of oral contraceptives, surgery, increasing age, and a lack of movement. Hereditary antithrombin deficiency is caused by mutations in the SERPINC1 gene and is typically inherited in an autosomal dominant manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hereditary antithrombin deficiency	c0272375	1,550	gard	https://rarediseases.info.nih.gov/diseases/6148/hereditary-antithrombin-deficiency	2021-01-18T18:00:04	{"mesh": ["D020152"], "omim": ["613118"], "orphanet": ["82"], "synonyms": ["Hereditary thrombophilia due to congenital antithrombin deficiency", "Inherited antithrombin deficiency", "Congenital Antithrombin III Deficiency", "Antithrombin III Deficiency", "Hereditary thrombophilia due to congenital antithrombin 3 deficiency", "Thrombophilia due to antithrombin III deficiency", "Congenital AT-III deficiency"]}
For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800). Mapping Working from the hypothesis that coinheritance of low-risk variants contributes to the 2-fold increased risk of glioma in relatives of individuals with primary brain tumors, Shete et al. (2009) conducted a metaanalysis of 2 glioma genomewide association studies by genotyping 550,000 tagged SNPs in a total of 1,878 cases and 3,670 controls, with validation in 3 additional independent series totaling 2,545 cases and 2,953 controls. They observed significant association of a single-nucleotide polymorphism (SNP), rs6010620 (OR = 1.28, 95% CI 1.21-1.35, P = 2.52 x 10(-12)) in intron 12 of the helicase gene RTEL1 (608833) and mapping within a 65-kb region of linkage disequilibrium on chromosome 20q13.33. Amplification of 20q13.33 was seen in approximately 30% of gliomas with copy number change correlating with RTEL1 expression. RTEL1 maintains genomic stability directly by suppressing homologous recombination. Wrensch et al. (2009) conducted a principal component-adjusted genomewide association study of 275,895 autosomal variants among 692 adult high-grade glioma cases, 622 from the San Francisco Adult Glioma Study and 70 from the Cancer Genome Atlas, and 3,992 controls. The replication sample was performed in the 13 SNPs with a P value of less than 10(-6) using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. They found significant association of 2 SNPs in the RTEL1 gene with high-grade glioma: rs6010620 (combined P = 3.4 x 10(-9)) and rs4809324 in intron 17 (combined P = 1.70 x 10(-9)). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	GLIOMA SUSCEPTIBILITY 6	c0017638	1,551	omim	https://www.omim.org/entry/613031	2019-09-22T15:59:55	{"mesh": ["D005910"], "omim": ["613031"], "orphanet": ["182067"]}
Aspartylglucosaminuria is a condition that causes a progressive decline in mental functioning. Infants with aspartylglucosaminuria appear healthy at birth, and development is typically normal throughout early childhood. The first sign of this condition, evident around the age of 2 or 3, is usually delayed speech. Mild intellectual disability then becomes apparent, and learning occurs at a slowed pace. Intellectual disability progressively worsens in adolescence. Most people with this disorder lose much of the speech they have learned, and affected adults usually have only a few words in their vocabulary. Adults with aspartylglucosaminuria may develop seizures or problems with movement. People with this condition may also have bones that become progressively weak and prone to fracture (osteoporosis), an unusually large range of joint movement (hypermobility), and loose skin. Affected individuals tend to have a characteristic facial appearance that includes widely spaced eyes (ocular hypertelorism), small ears, and full lips. The nose is short and broad and the face is usually square-shaped. Children with this condition may be tall for their age, but lack of a growth spurt in puberty typically causes adults to be short. Affected children also tend to have frequent upper respiratory infections. Individuals with aspartylglucosaminuria usually survive into mid-adulthood. ## Frequency Aspartylglucosaminuria is estimated to affect 1 in 18,500 people in Finland. This condition is less common outside of Finland, but the incidence is unknown. ## Causes Mutations in the AGA gene cause aspartylglucosaminuria. The AGA gene provides instructions for producing an enzyme called aspartylglucosaminidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Within lysosomes, the enzyme helps break down complexes of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). AGA gene mutations result in the absence or shortage of the aspartylglucosaminidase enzyme in lysosomes, preventing the normal breakdown of glycoproteins. As a result, glycoproteins can build up within the lysosomes. Excess glycoproteins disrupt the normal functions of the cell and can result in destruction of the cell. A buildup of glycoproteins seems to particularly affect nerve cells in the brain; loss of these cells causes many of the signs and symptoms of aspartylglucosaminuria. ### Learn more about the gene associated with Aspartylglucosaminuria * AGA ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Aspartylglucosaminuria	c0268225	1,552	medlineplus	https://medlineplus.gov/genetics/condition/aspartylglucosaminuria/	2021-01-27T08:25:19	{"gard": ["5854"], "mesh": ["D054880"], "omim": ["208400"], "synonyms": []}
## Clinical Features In a family of Yemenite Jewish extraction, Frydman et al. (1992) described an autosomal recessive syndrome of blepharophimosis and ptosis with weakness of extraocular and frontal muscles. Prognathism, synophrys, and thick eyebrows added to a typical facial appearance. Additional findings included short stature and syndactyly of toes 2 and 3. Borderline mental retardation and anosmia was found in 1 patient. The clinical features and particularly the mode of inheritance distinguished this syndrome from other blepharophimosis-ptosis syndromes (e.g., 110100). Madasseri et al. (2003) described 2 brothers with congenital ptosis and esotropia, 1 of whom also had bilateral accessory nipples. The constellation of clinical features showed significant overlap with the pedigree reported by Frydman et al. (1992), although it lacked the blepharophimosis, short stature, and syndactyly. Madasseri et al. (2003) stated that these 2 brothers might share the same condition reported by Frydman et al. (1992) or might represent a 'new,' possibly X-linked, phenotype of congenital ptosis with esotropia. Inheritance The transmission pattern of blepharophimosis with ptosis, syndactyly, and short stature in the family described by Frydman et al. (1992) was consistent with autosomal recessive inheritance. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Borderline small occipitofrontal head circumference (3rd-25th percentile) Face \- Prognathism Eyes \- Blepharophimosis \- Ptosis \- Weak extraocular muscles \- Synophrys \- Thick eyebrows \- Strabismus (specifically V-type esotropia) \- Hypertropia Nose \- Broad nasal bridge Mouth \- Thick lips SKELETAL Feet \- Cutaneous syndactyly (toes 2-3) SKIN, NAILS, & HAIR Hair \- Synophrys \- Thick eyebrows MUSCLE, SOFT TISSUES \- Weak extraocular muscles \- Weak frontalis muscle NEUROLOGIC Central Nervous System \- Anosmia (1 patient) \- Mental retardation, borderline (1 patient) ▲ 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	BLEPHAROPHIMOSIS WITH PTOSIS, SYNDACTYLY, AND SHORT STATURE	c1859432	1,553	omim	https://www.omim.org/entry/210745	2019-09-22T16:30:22	{"mesh": ["C536235"], "omim": ["210745"], "orphanet": ["2057"]}
A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) is caused by heterozygous mutation in the DNA2 gene (601810) on chromosome 10q. Description PEOA6 is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by Ronchi et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). Clinical Features Ronchi et al. (2013) reported 2 sibs and 2 unrelated patients with PEOA6. One of the sibs reported declining muscle strength since young adulthood. At age 49 years, he was diagnosed with a suspected myopathy. Examination at age 62 showed decreased facial expressions, diffuse muscle atrophy, limb-girdle muscle weakness predominantly affecting the lower limbs, abnormal gait with hyperlordosis, and Gowers sign. He also had exertional dyspnea with obstructive sleep apnea. Laboratory studies showed increased serum creatine kinase. His sister reported exercise intolerance and muscle weakness since childhood. At age 40, she had limb-girdle muscle weakness affecting the upper and lower extremities, myalgia, muscle cramps, external ophthalmoplegia, ptosis, Gowers sign, and difficulty walking on tiptoes. Both had a slender build with decreased muscle bulk. Two additional unrelated women presented with adult-onset mitochondrial disease with ptosis and progressive myopathy. One patient also developed a mild weakness of the upper and lower limb-girdle muscles with occasional exertional dyspnea. Muscle biopsies of all patients showed multiple mtDNA deletions and a few COX-negative fibers. Inheritance The transmission pattern of PEOA6 in the families reported by Ronchi et al. (2013) was consistent with autosomal dominant inheritance. Molecular Genetics In 2 sibs and 2 unrelated women with autosomal dominant progressive external ophthalmoplegia with DNA deletions-6, Ronchi et al. (2013) identified 3 different heterozygous mutations in the DNA2 gene (601810.0001-601810.0003). The first mutation was identified by exome sequencing of the sibs, and the additional patients were ascertained from a larger cohort of 44 patients with mtDNA deletions. In vitro functional expression assays showed that all mutant proteins had impaired nuclease, helicase, and ATPase activities. INHERITANCE \- Autosomal dominant GROWTH Other \- Slender build HEAD & NECK Face \- Facial muscle weakness Eyes \- External ophthalmoplegia \- Ptosis, mild RESPIRATORY \- Exertional dyspnea \- Obstructive sleep apnea (in some patients) MUSCLE, SOFT TISSUES \- Muscle weakness, limb-girdle, mild \- Muscle atrophy, diffuse \- Exercise intolerance \- Gowers sign \- Myalgia \- Muscle cramps \- Abnormal gait \- mtDNA deletions seen on muscle biopsy LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Variable age at onset (range childhood to adulthood) \- Slowly progressive MOLECULAR BASIS \- Caused by mutation in the homolog of the yeast DNA replication helicase 2 gene (DNA2, 601810.0001 ) ▲ 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	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 6	c3554599	1,554	omim	https://www.omim.org/entry/615156	2019-09-22T15:53:01	{"omim": ["615156"], "orphanet": ["352470"], "synonyms": ["Mitochondrial DNA deletion syndrome with limb-girdle weakness", "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 6", "mtDNA deletion syndrome with progressive myopathy", "Mitochondrial DNA deletion syndrome with progressive myopathy", "Alternative titles", "mtDNA deletion syndrome with limb-girdle weakness"], "genereviews": ["NBK487393"]}
A number sign (#) is used with this entry because hereditary persistence of alpha-fetoprotein (HPAFP) is caused by heterozygous mutation in the AFP gene (104150) on chromosome 4q13. Description Hereditary persistence of alpha-fetoprotein (HPAFP) is a clinically benign autosomal dominant condition characterized by continued expression of alpha-fetoprotein in adult life (summary by McVey et al., 1993). Clinical Features Ferguson-Smith et al. (1984) reported an autosomal dominant hereditary persistence of alpha-fetoprotein. The proband was a 38-year-old woman found to have elevated AFP during pregnancy, as part of screening for neural tube defects. The level of AFP in the amniotic fluid was normal; the mother's elevation persisted after delivery. The infant and 2 of 3 other children also had elevated serum AFP. Subsequently, 21 members of her family, including 9 males, were found to have elevated values. Rose et al. (1989) reported a family ascertained through a 42-year-old male who had 2 sibs and a daughter with elevated serum alpha-fetoprotein levels. Such elevated alpha-fetoprotein levels complicate the interpretation of findings in patients being screened for malignancy (e.g., hepatocellular carcinoma or teratoma) or in pregnant women being screened for neural tube defects or Down syndrome in the fetus. Greenberg et al. (1990) reported a family in which a 33-year-old man, 2 of his sibs, and a daughter showed elevated serum AFP levels. Alj et al. (2004) reported 2 unrelated families with HPAFP, 1 of Indian descent and the other of Italian descent. In both cases, elevated serum AFP was found incidentally in the proband, and neither individual had physical abnormalities associated with the trait; liver studies in both individuals were normal. Inheritance The transmission pattern of HPAFP in the families reported by Alj et al. (2004) was consistent with autosomal dominant inheritance. Mapping Although close linkage of HPAFP with group-specific component (GC; 139200) was originally excluded (Ferguson-Smith et al., 1984), repeat GC typing with an improved technique of isoelectric focusing showed several misclassifications in the earlier study, and the new calculations were consistent with linkage (lod, 1.7; theta, 0.0) (Ferguson-Smith et al., 1985). Ferguson-Smith et al. (1985) used a cDNA albumin probe which recognizes RFLPs at the ALB locus. No recombination was found between an ALB polymorphism and HPAFP (lod = 6.02; theta = 0). Molecular Genetics In members of a large Scottish kindred with hereditary persistence of alpha-fetoprotein, McVey et al. (1993) identified a heterozygous mutation in the AFP gene (104150.0001). In affected individuals from 2 unrelated families with HPAFP, Alj et al. (2004) identified 2 different heterozygous mutations in the distal (104150.0001) and proximal (104150.0004) HNF1 (142410) binding regions in the promoter of the AFP gene. Both mutations resulted in increased affinity of the promoters for HNF1, resulting in increased levels of gene transcription. The findings highlighted the importance of HNF1 in AFP gene expression. Alj et al. (2004) suggested that unexplained increased AFP should led to AFP promoter gene sequencing to avoid inappropriate explorations or treatment decisions, as HFAPF is a benign trait. INHERITANCE \- Autosomal dominant LABORATORY ABNORMALITIES \- Elevated serum alpha-fetoprotein MISCELLANEOUS \- Major fetal plasma protein produced by yolk sac and liver \- Benign condition \- Elevated AFP can be seen in other disorders MOLECULAR BASIS \- Caused by mutation in the alpha-fetoprotein gene (AFP, 104150.0001 ) ▲ 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	ALPHA-FETOPROTEIN, HEREDITARY PERSISTENCE OF	c1863080	1,555	omim	https://www.omim.org/entry/615970	2019-09-22T15:50:23	{"omim": ["615970"], "orphanet": ["168615"], "synonyms": []}
Chromosome 2p duplication is a chromosome abnormality that occurs when there is an extra copy of genetic material on the short arm (p) of chromosome 2. 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 2p duplication include developmental delay, intellectual disability, behavioral problems and distinctive facial features. Most cases are not inherited, but people can pass the duplication on to their children. 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 2p duplication	c0795803	1,556	gard	https://rarediseases.info.nih.gov/diseases/5337/chromosome-2p-duplication	2021-01-18T18:01:22	{"mesh": ["C538318"], "umls": ["C0795803"], "synonyms": ["Duplication 2p", "Trisomy 2p", "2p duplication", "2p trisomy", "Partial trisomy 2p"]}
Actinic conjunctivitis Actinic conjunctivitis causes a redness of the eyes, as well as swelling and often grayness around the eyes. Actinic conjunctivitis is an inflammation of the eye contracted from prolonged exposure to actinic (ultraviolet) rays. Symptoms are redness and swelling of the eyes. Most often the condition is caused by prolonged exposure to Klieg lights, therapeutic lamps, or acetylene torches. Other names for the condition include Klieg conjunctivitis, eyeburn, arc-flash, welder's conjunctivitis, flash keratoconjunctivitis, actinic ray ophthalmia, X-ray ophthalmia, and ultraviolet ray ophthalmia.[1] ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Management * 5 See also * 6 References * 7 External links ## Symptoms[edit] Conjunctivitis eye condition contracted from exposure to actinic rays. Symptoms are redness and swelling. [2] ## Causes[edit] Conjunctivitis is prevalent among children of the highlands of Ecuador. The finding supports the hypothesis that prolonged exposure to the sun at altitude—in the less dense atmosphere (with the resultant lower UV absorption)—is the main cause of the injury.[3] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Management[edit] This section is empty. You can help by adding to it. (September 2017) ## See also[edit] * Conjunctivitis * Photokeratitis ## References[edit] 1. ^ "Dorland's Medical Dictionary (confabulation - connexus)". Archived from the original on 2007-08-13. Retrieved 2007-07-27. 2. ^ "Actinic conjunctivitis". 3. ^ Engel, J. Mark; Molinari, Andrea; Ostfeld, Barbara; Deen, Malik; Croxatto, Oscar (Apr 2009). "Actinic conjunctivitis in children: Clinical features, relation to sun exposure, and proposed staging and treatment". J AAPOS. 13 (2): 161–5. doi:10.1016/j.jaapos.2008.10.017. PMID 19393514. ## External links[edit] Classification D * ICD-9-CM: 370.24 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Actinic conjunctivitis	c1504543	1,557	wikipedia	https://en.wikipedia.org/wiki/Actinic_conjunctivitis	2021-01-18T18:35:04	{"icd-9": ["370.24"], "wikidata": ["Q3507879"]}
Pseudohypoparathyroidism type 1B (PHP-1b) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by localized resistance to parathyroid hormone (PTH) mainly in the renal tissues which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels. About 60-70% of patients also present with elevated TSH levels due to TSH resistance. ## Epidemiology The prevalence is unknown. The estimated prevalence of PHP (1a, 1b and PPHP) in Italy is 1/150,000. ## Clinical description PHP1b usually presents in childhood with symptoms of hypocalcemia, including numbness, seizures, tetany, cataracts, and dental problems. Patients may present with skeletal abnormalities, similar to those that occur in patients with hyperparathyroidism, such as reduced bone mineral density and osteitis fibrosa. TSH resistance is usually asymptomatic in PHP1b. Severity of symptoms can vary greatly between patients and even among kindreds. ## Etiology The majority of cases of PHP1b are sporadic, but an autosomal dominant transmission has also been described. About 70% of PHP-Ib patients display methylation defects, sporadic or genetic-based, at GNAS (20q13.2-q13.3) differentially methylated regions (DMRs). PHP-Ib familial form is typically characterized by an isolated loss of methylation at the A/B DMR, secondary to genetic deletions disrupting the upstream imprinting control region in the STX16 gene (20q13.32). Hormonal resistance seen in PHP-1b develops after maternal inheritance of the disease, while paternal inheritance is not associated with any endocrine abnormalities. In sporadic cases, broad methylation alterations at all GNAS DMRs are usually detected and in a subset of such patients, paternal uniparental disomy of chromosome 20 (see this term) may explain this pattern of alteration. ## Diagnostic methods Diagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. Gs-alpha activity in erythrocytes and fibroblasts is usually normal. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). Genetic testing can confirm diagnosis. ## Differential diagnosis Differential diagnoses include primary hypoparathyroidism (which can be ruled out by the absence of hypercalciuria), secondary hyperparathyroidism, autoimmune polyendocrinopathy (see this term), and vitamin D deficiency. It should also be excluded from other forms of PHP (see this term) based on the absence of Albright hereditary osteodystrophy (AHO; see this term) and normal expression of Gs protein. ## Antenatal diagnosis Antenatal diagnosis is possible only in those families with known deletions within GNAS or upstream of this locus. ## Genetic counseling The majority of cases of PHP1b are sporadic but familial transmission, following an autosomal dominant pattern of inheritance, has also been described and genetic counseling is possible in these cases. ## Management and treatment Treatment is based on maintaining normocalcemia and normalizing serum levels of PTH with active vitamin D metabolites (alfacalcidol or calcitriol) and calcium supplementation. Patients should be treated for other associated endocrinopathies when present, particularly hypothyroidism, with levothyroxine. Blood biochemistries and urinary calcium excretion should be monitored annually. Treatment is lifelong but calcium and calcitriol dosages can usually be progressively lowered over time. ## Prognosis With treatment the prognosis is good and life expectancy is predicted to be comparable with the normal population, provided that endocrine disorders are correctly treated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pseudohypoparathyroidism type 1B	c1864100	1,558	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=94089	2021-01-23T16:54:22	{"gard": ["10680"], "mesh": ["C548075", "D011547"], "omim": ["603233"], "umls": ["C1864100", "C2932715"], "icd-10": ["E20.1"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Neuromyotonia" – news · newspapers · books · scholar · JSTOR (August 2019) Neuromyotonia Other namesIsaacs syndrome, Isaacs-Merton syndrome SpecialtyNeurology, neuromuscular medicine Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that causes spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. NMT along with Morvan's syndrome are the most severe types in the Peripheral Nerve Hyperexciteability spectrum. Example of two more common and less severe syndromes in the spectrum are Cramp Fasciculation Syndrome and Benign Fasciculation Syndrome. [1] NMT can have both hereditary and acquired (non- inherited) forms. The prevalence of NMT is unknown.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Types * 3.2 Peripheral nerve hyperexcitability * 4 Treatments * 5 Prognosis * 6 References * 7 External links ## Signs and symptoms[edit] NMT is a diverse disorder. As a result of muscular hyperactivity, patients may present with muscle cramps, stiffness, myotonia-like symptoms (slow relaxation), associated walking difficulties, hyperhidrosis (excessive sweating), myokymia (quivering of a muscle), fasciculations (muscle twitching), fatigue, exercise intolerance, myoclonic jerks and other related symptoms. The symptoms (especially the stiffness and fasciculations) are most prominent in the calves, legs, trunk, and sometimes the face and neck, but can also affect other body parts. NMT symptoms may fluctuate in severity and frequency. Symptoms range from mere inconvenience to debilitating. At least a third of people also experience sensory symptoms. ## Causes[edit] The three causes of NMT are:[citation needed] 1. Acquired 2. Paraneoplastic 3. Hereditary The acquired form is the most common, accounting for up to 80 percent of all cases and is suspected to be autoimmune-mediated, which is usually caused by antibodies against the neuromuscular junction. The exact cause is unknown. However, autoreactive antibodies can be detected in a variety of peripheral (e.g. myasthenia gravis, Lambert-Eaton myasthenic syndrome) and central nervous system (e.g. paraneoplastic cerebellar degeneration, paraneoplastic limbic encephalitis) disorders. Their causative role has been established in some of these diseases but not all. Neuromyotonia is considered to be one of these with accumulating evidence for autoimmune origin over the last few years. Autoimmune neuromyotonia is typically caused by antibodies that bind to potassium channels on the motor nerve resulting in continuous/hyper-excitability. Onset is typically seen between the ages of 15–60, with most experiencing symptoms before the age of 40.[3] Some neuromyotonia cases do not only improve after plasma exchange but they may also have antibodies in their serum samples against voltage-gated potassium channels.[4] Moreover, these antibodies have been demonstrated to reduce potassium channel function in neuronal cell lines. ## Diagnosis[edit] Diagnosis is clinical and initially consists of ruling out more common conditions, disorders, and diseases, and usually begins at the general practitioner level. A doctor may conduct a basic neurological exam, including coordination, strength, reflexes, sensation, etc. A doctor may also run a series of tests that include blood work and MRIs. From there, a patient is likely to be referred to a neurologist or a neuromuscular specialist. The neurologist or specialist may run a series of more specialized tests, including needle electromyography EMG/ and nerve conduction studies (NCS) (these are the most important tests), chest CT (to rule out paraneoplastic) and specific blood work looking for voltage-gated potassium channel antibodies, acetylcholine receptor antibody, and serum immunofixation, TSH, ANA ESR, EEG etc. Neuromyotonia is characterized electromyographically by doublet, triplet or multiplet single unit discharges that have a high, irregular intraburst frequency. Fibrillation potentials and fasciculations are often also present with electromyography.[5] Because the condition is so rare, it can often be years before a correct diagnosis is made. NMT is not fatal and many of the symptoms can be controlled. However, because NMT mimics some symptoms of motor neuron disease (ALS) and other more severe diseases, which may be fatal, there can often be significant anxiety until a diagnosis is made. In some rare cases, acquired neuromyotonia has been misdiagnosed as amyotrophic lateral sclerosis (ALS)[6] particularly if fasciculations may be evident in the absence of other clinical features of ALS. However, fasciculations are rarely the first sign of ALS as the hallmark sign is weakness.[7] Similarly, multiple sclerosis has been the initial misdiagnosis in some NMT patients. In order to get an accurate diagnosis see a trained neuromuscular specialist. People diagnosed with Benign Fasciculation Syndrome or Enhanced Physiological Tremor may experience similar symptoms as NMT, although it is unclear today whether BFS or EPT are weak forms of NMT. ### Types[edit] There are three main types of NMT:[citation needed] * Chronic * Monophasic (symptoms that resolve within several years of onset; postinfection, postallergic) * Relapsing Remitting ### Peripheral nerve hyperexcitability[edit] Neuromyotonia is a type of peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability is an umbrella diagnosis that includes (in order of severity of symptoms from least severe to most severe) benign fasciculation syndrome, cramp fasciculation syndrome, neuromyotonia and morvan's syndrome. Some doctors will only give the diagnosis of peripheral nerve hyperexcitability as the differences between the three are largely a matter of the severity of the symptoms and can be subjective. However, some objective EMG criteria have been established to help distinguish between the three. Moreover, the generic use of the term peripheral nerve hyperexcitability syndromes to describe the aforementioned conditions is recommended and endorsed by several prominent researchers and practitioners in the field.[8] ## Treatments[edit] There is no known cure for neuromyotonia, but the condition is treatable. Anticonvulsants, including phenytoin and carbamazepine, usually provide significant relief from the stiffness, muscle spasms, and pain associated with neuromyotonia. Plasma exchange and IVIg treatment may provide short-term relief for patients with some forms of the acquired disorder.[3] It is speculated that the plasma exchange causes an interference with the function of the voltage-dependent potassium channels, one of the underlying issues of hyper-excitability in autoimmune neuromyotonia.[9] Botox injections also provide short-term relief. Immunosuppressants such as Prednisone may provide long term relief for patients with some forms of the acquired disorder. ## Prognosis[edit] The long-term prognosis is uncertain, and has mostly to do with the underlying cause; i.e. autoimmune, paraneoplastic, etc. However, in recent years increased understanding of the basic mechanisms of NMT and autoimmunity has led to the development of novel treatment strategies. NMT disorders are now amenable to treatment and their prognoses are good. Many patients respond well to treatment, which usually provide significant relief of symptoms. Some cases of spontaneous remission have been noted, including Isaac's original two patients when followed up 14 years later. While NMT symptoms may fluctuate, they generally don't deteriorate into anything more serious, and with the correct treatment the symptoms are manageable. A very small proportion of cases with NMT may develop central nervous system findings in their clinical course, causing a disorder called Morvan's syndrome, and they may also have antibodies against potassium channels in their serum samples. Sleep disorder is only one of a variety of clinical conditions observed in Morvan's syndrome cases ranging from confusion and memory loss to hallucinations and delusions. However, this is a separate disorder. Some studies have linked NMT with certain types of cancers, mostly lung and thymus, suggesting that NMT may be paraneoplastic in some cases. In these cases, the underlying cancer will determine prognosis. However, most examples of NMT are autoimmune and not associated with cancer. ## References[edit] 1. ^ "PNH study". ScienceDirect. 2018. Retrieved 18 June 2020. 2. ^ "Isaac syndrome". OrphaNet. 2013. Retrieved 30 November 2015. 3. ^ a b National Institute of Neurological Disorders and Stroke. (2010). "NINDS Isaac's syndrome information page". Archived from the original on 12 April 2011. Retrieved 8 May 2011. 4. ^ Maddison P (2006). "Neuromyotonia". Clinical Neurophysiology. 117 (10): 2118–27. doi:10.1016/j.clinph.2006.03.008. PMID 16843723. 5. ^ Newsom-Davis J, Mills KR (1993). "Immunological associations of acquired neuromyotonia (Isaacs' syndrome)". Brain. 116 (2): 453–469. doi:10.1093/brain/116.2.453. PMID 8461975. 6. ^ Rowland, Lewis P.; Shneider, Neil A. (31 May 2001). "Amyotrophic Lateral Sclerosis". New England Journal of Medicine. 344 (22): 1688–1700. doi:10.1056/NEJM200105313442207. PMID 11386269. 7. ^ Hirota, Nobuyuki; Eisen, Andrew; Weber, Markus (2000). "Complex fasciculations and their origin in amyotrophic lateral sclerosis and Kennedy's disease". Muscle & Nerve. 23 (12): 1872–1875. doi:10.1002/1097-4598(200012)23:12<1872::AID-MUS12>3.0.CO;2-H. 8. ^ Hart, I. K.; Maddison, P.; Newsom-Davis, J.; Vincent, A.; Mills, K. R. (2002). "Phenotypic variants of autoimmune peripheral nerve hyperexcitability". Brain. 125 (8): 1887–1895. doi:10.1093/brain/awf178. PMID 12135978. 9. ^ Arimura K, Watanabe O, Katajima I, Suehara M, Minato S, Sonoda Y, Higuchi I, Takenaga S, Maruyama I, Osame M (1997). "Antibodies to potassium channels of PC12 in serum of Isaacs' Syndrome: Western blot and immunohistochemical studies". Muscle Nerve. 20 (3): 299–305. doi:10.1002/(SICI)1097-4598(199703)20:3<299::AID-MUS6>3.0.CO;2-6. PMID 9052808. ## External links[edit] Classification D * ICD-10: G71.1 * ICD-9-CM: 333.90 * MeSH: D020386 * DiseasesDB: 31818 External resources * Orphanet: 11619 * v * t * e Diseases of muscle, neuromuscular junction, and neuromuscular disease Neuromuscular- junction disease * autoimmune * Myasthenia gravis * Lambert–Eaton myasthenic syndrome * Neuromyotonia Myopathy Muscular dystrophy (DAPC) AD * Limb-girdle muscular dystrophy 1 * Oculopharyngeal * Facioscapulohumeral * Myotonic * Distal (most) AR * Calpainopathy * Limb-girdle muscular dystrophy 2 * Congenital * Fukuyama * Ullrich * Walker–Warburg XR * dystrophin * Becker's * Duchenne * Emery–Dreifuss Other structural * collagen disease * Bethlem myopathy * PTP disease * X-linked MTM * adaptor protein disease * BIN1-linked centronuclear myopathy * cytoskeleton disease * Nemaline myopathy * Zaspopathy Channelopathy Myotonia * Myotonia congenita * Thomsen disease * Neuromyotonia/Isaacs syndrome * Paramyotonia congenita Periodic paralysis * Hypokalemic * Thyrotoxic * Hyperkalemic Other * Central core disease Mitochondrial myopathy * MELAS * MERRF * KSS * PEO General * Inflammatory myopathy * Congenital myopathy * v * t * e Diseases of ion channels Calcium channel Voltage-gated * CACNA1A * Familial hemiplegic migraine 1 * Episodic ataxia 2 * Spinocerebellar ataxia type-6 * CACNA1C * Timothy syndrome * Brugada syndrome 3 * Long QT syndrome 8 * CACNA1F * Ocular albinism 2 * CSNB2A * CACNA1S * Hypokalemic periodic paralysis 1 * Thyrotoxic periodic paralysis 1 * CACNB2 * Brugada syndrome 4 Ligand gated * RYR1 * Malignant hyperthermia * Central core disease * RYR2 * CPVT1 * ARVD2 Sodium channel Voltage-gated * SCN1A * Familial hemiplegic migraine 3 * GEFS+ 2 * Febrile seizure 3A * SCN1B * Brugada syndrome 6 * GEFS+ 1 * SCN4A * Hypokalemic periodic paralysis 2 * Hyperkalemic periodic paralysis * Paramyotonia congenita * Potassium-aggravated myotonia * SCN4B * Long QT syndrome 10 * SCN5A * Brugada syndrome 1 * Long QT syndrome 3 * SCN9A * Erythromelalgia * Febrile seizure 3B * Paroxysmal extreme pain disorder * Congenital insensitivity to pain Constitutively active * SCNN1B/SCNN1G * Liddle's syndrome * SCNN1A/SCNN1B/SCNN1G * Pseudohypoaldosteronism 1AR Potassium channel Voltage-gated * KCNA1 * Episodic ataxia 1 * KCNA5 * Familial atrial fibrillation 7 * KCNC3 * Spinocerebellar ataxia type-13 * KCNE1 * Jervell and Lange-Nielsen syndrome * Long QT syndrome 5 * KCNE2 * Long QT syndrome 6 * KCNE3 * Brugada syndrome 5 * KCNH2 * Short QT syndrome * KCNQ1 * Jervell and Lange-Nielsen syndrome * Romano–Ward syndrome * Short QT syndrome * Long QT syndrome 1 * Familial atrial fibrillation 3 * KCNQ2 * BFNS1 Inward-rectifier * KCNJ1 * Bartter syndrome 2 * KCNJ2 * Andersen–Tawil syndrome * Long QT syndrome 7 * Short QT syndrome * KCNJ11 * TNDM3 * KCNJ18 * Thyrotoxic periodic paralysis 2 Chloride channel * CFTR * Cystic fibrosis * Congenital absence of the vas deferens * CLCN1 * Thomsen disease * Myotonia congenita * CLCN5 * Dent's disease * CLCN7 * Osteopetrosis A2, B4 * BEST1 * Vitelliform macular dystrophy * CLCNKB * Bartter syndrome 3 TRP channel * TRPC6 * FSGS2 * TRPML1 * Mucolipidosis type IV Connexin * GJA1 * Oculodentodigital dysplasia * Hallermann–Streiff syndrome * Hypoplastic left heart syndrome * GJB1 * Charcot–Marie–Tooth disease X1 * GJB2 * Keratitis–ichthyosis–deafness syndrome * Ichthyosis hystrix * Bart–Pumphrey syndrome * Vohwinkel syndrome) * GJB3/GJB4 * Erythrokeratodermia variabilis * Progressive symmetric erythrokeratodermia * GJB6 * Clouston's hidrotic ectodermal dysplasia Porin * AQP2 * Nephrogenic diabetes insipidus 2 See also: ion channels [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neuromyotonia	c0242287	1,559	wikipedia	https://en.wikipedia.org/wiki/Neuromyotonia	2021-01-18T18:59:20	{"gard": ["6793"], "mesh": ["D020386"], "umls": ["C0751919", "C0242287"], "icd-9": ["333.90"], "icd-10": ["G71.1"], "orphanet": ["84142"], "wikidata": ["Q520797"]}
Limbic encephalitis with caspr2 antibodies is a rare neuroimmunological disorder characterized by the onset of cognitive deficits, psychiatric disturbances (e.g. personality changes), seizures, peripheral nerve hyperexcitability, dysautonomia, neuropathic pain, insomnia and weight loss, in association with detection of caspr2 antibodies in serum or cerebrospinal fluid, with or without underlying malignancies. Other features reported include blepharoclonus, myoclonic status epilepticus, and dyskinesia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Limbic encephalitis with caspr2 antibodies	c4706582	1,560	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=276402	2021-01-23T17:45:19	{"icd-10": ["G13.1"]}
A number sign (#) is used with this entry because of evidence that polycystic kidney disease-5 (PKD5) is caused by homozygous mutation in the DZIP1L gene (617570) on chromosome 3q22. Description PKD5, a form of autosomal recessive polycystic kidney disease (ARPKD), is characterized by early childhood onset of progressive renal dysfunction associated with enlarged hyperechogenic kidneys that often results in end-stage renal disease in the second or third decade of life. Arterial hypertension is apparent in early childhood (summary by Lu et al., 2017). For a discussion of genetic heterogeneity of polycystic kidney disease, see PKD1 (173900). Clinical Features Lu et al. (2017) reported 7 patients from 4 unrelated consanguineous families with PKD5. The patients had childhood onset of progressive renal dysfunction associated with arterial hypertension in the first years of life. Renal ultrasound showed bilaterally enlarged, hyperechogenic kidneys with poor or even absent corticomedullary differentiation and multiple tiny cysts. At least 1 patient had punctate calcifications on imaging. Four patients had progressive disease, resulting in end-stage renal disease in the teenage years and necessitating renal transplant in the teenage years or as young adults. However, 3 patients had essentially normal renal function at ages 9, 13, and 15, respectively; Lu et al. (2017) suggested that these individuals may develop end-stage renal disease later in life. None of the patients had clinical evidence of hepatic fibrosis. Inheritance The transmission pattern of PKD5 in the family reported by Lu et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 7 patients from 4 unrelated consanguineous families with PKD5, Lu et al. (2017) identified homozygous missense or truncating mutations in the DZIP1L gene (617570.0001-617570.0004). Mutations in the first 2 families, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Mutations in the second 2 families were found by direct sequencing of the DZIP1L gene in 218 unrelated subjects with suspected ARPKD or next-generation sequencing of a targeted gene panel in 1,330 individuals with a similar phenotype. Fibroblasts derived from 1 of the patients with a truncating mutation showed no obvious differences in the percentage of ciliated cells, cilia morphology, or localization of several markers of cilia and basal bodies compared to controls. However, the cilia showed decreased accumulation of PKD1 (601313) and PKD2 (173910) along the ciliary membrane compared to controls. These findings suggested that, in the absence of correct DZIP1L function, the ciliary-membrane distribution of PKD1 and PKD2 is compromised, possibly reflecting a defect in the barrier function of the transition zone. Animal Model In a recessive N-ethyl-N-nitrosourea mutagenesis screen, Lu et al. (2017) identified the mouse 'warpy' (wpy) mutant and found that wpy was a nonsense mutation (Q375X) in a region of the Dzip1l gene encoding the coiled-coil domains. Dzip1l wpy/wpy mutants showed widespread dysmorphologies, including highly penetrant polydactyly of all 4 limbs, gross eye abnormalities, and craniofacial defects, including cleft lip/palate. Some of the mouse mutants showed embryonic death. On an outbred genetic background, Dzip1l wpy/wpy mice were obtained at the expected mendelian frequency, although they failed to thrive and were sacrificed by postnatal day 21. These Dzip1l wpy/wpy mice showed early-onset progressive cystic kidney disease, with cysts arising from collecting ducts and proximal tubules. There were also subtle signs of hepatic abnormalities and ductal plate malformations with an excess of bile ducts, but no frank fibrosis. Dzip1l wpy/wpy fibroblasts showed evidence of a defect in Shh (600725) signaling and abnormal ciliary membrane distribution of Pc1 (PKD1; 601313) and Pc2 (PKD2; 173910), possibly reflecting a defect in the barrier function of the transition zone. Inactivation of zebrafish dzip1l also caused phenotypes consistent with ciliary dysfunction. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Vascular \- Arterial hypertension (due to renal disease) GENITOURINARY Kidneys \- Polycystic kidneys \- Multiple tiny cysts \- Enlarged kidneys \- Hyperechogenic kidneys \- Poor cortico-medullary differentiation \- Punctate calcifications \- End-stage renal disease LABORATORY ABNORMALITIES \- Increased urinary creatine \- Impaired creatinine clearance MISCELLANEOUS \- Onset in early childhood \- Slowly progressive \- Most patients require renal transplant in the second or third decades \- Variable severity MOLECULAR BASIS \- Caused by mutation in the DAZ-interacting zinc finger protein 1-like gene (DZIP1L, 617570.0001 ) ▲ 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	POLYCYSTIC KIDNEY DISEASE 5	c0085548	1,561	omim	https://www.omim.org/entry/617610	2019-09-22T15:45:20	{"doid": ["0080273"], "mesh": ["D017044"], "omim": ["617610"], "orphanet": ["731"]}
Trematodiases Eggs of trematodes found in liver cell SpecialtyInfectious disease SymptomsChest pain, Abdominal pain, Fever, digestion issues, Cough, Diarrhea, change in appetite [1][2] CausesTrematoda Diagnostic methodImmunodiagnosis, Parasitological diagnosis [3] PreventionEducation, food safety practices [1] MedicationPraziquantel, Triclabendazole [1] Frequency200000 (2018) [1] Deaths7000 (2018) [1] Trematodiases, also known as trematode infections, are a group of diseases caused by the parasite trematodes.[4] Symptoms can range from mild to severe depending on the species, number and location of trematodes in the infected organism.[1] Symptoms depend on type of trematode present, and include chest and abdominal pain, high temperature, digestion issues, cough and shortness of breath, diarrhoea and change in appetite.[1][2] Trematodiases can be transmitted through food or water that contains larval forms of the parasite.[5][1] Infections can be transmitted through aquatic organisms which act as a host for the maturity of the parasite.[5] Foodborne trematodiases is transmitted when organisms ingest contaminated undercooked food including aquatic plants and organisms.[2][1] Trematodiases can be prevented and controlled through public health programs aimed to educate people about how contaminated water and food can lead to infections.[3] Education programs include raising awareness about the transmission of trematodiases through the consumption of food that is not cooked well such as fish, molluscs, and other aquatic animals and plants.[5] Sanitation and distribution of clean water is also used to control the spread of trematodiases on a larger scale.[6] Foodborne trematodiases that infect the lung, liver and intestines are classified as a neglected tropical disease.[7][6] Cases of trematodiases that can be transmitted through food has affected over 70 countries globally, with the most impacted countries located in Latin America and Asia.[1] In 2018, the World Health Organisation declared that there are approximately 200,000 cases of trematodiases that are caused by four species of trematodes.[1] The majority of cases of foodborne trematodiases are from East and Southeast Asia.[7] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Types of trematodiases * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 References ## Signs and symptoms[edit] Most cases of trematodiases show no symptoms.[1] Infected organisms that show symptoms will range in severity depending on number of parasites.[1] When the number of trematodes are high, signs of infection include severe pain in the abdomen.[1] The signs and symptoms of the disease is also impacted by the location and spread of the parasite in the body.[7] Tissues in organs are damaged when infected by the parasite.[3] This damage can be mechanical as the parasite attaches to the walls of the host, as well as chemical.[5] Symptoms of lung fluke infections (Paragonimus) depend on the parasite’s stage in its life cycle, and how it travels around in the lung.[7][3] Trematodiases that impacts the lungs can cause cough, headache, chest pain, high temperature and change in appetite.[1][5] Intestinal trematodiases infect the gastrointestinal tract.[8] Symptoms of intestinal fluke infections can range from mild to severe symptoms depending on the length of time that the parasite spends in the body. Signs and symptoms that arise in infected organisms include headache, indigestion problems such as diarrhoea, high temperature and pain in the abdomen which can also lead to malnutrition as the infected organism’s appetite is lost.[8][5] In intestinal trematodiases, the walls of the intestine can be damaged, which can lead to ulcers in some infected organisms.[5] Trematodiases caused by liver trematodes infect the host’s liver, gall bladder and bile duct and can cause inflammation within these organs.[5][1] Symptoms vary from case to case and include abdominal pain, loss of appetite, problems with indigestion including diarrhoea and constipation, whereas in some cases, no symptoms are shown.[2][5] O. viverrini damages the bile duct when in the adult stage of the life cycle, forming the cancer cholangiocarcinoma.[1][5] Blood flukes can cause the trematodiases Schistosomiasis which can cause reactions on skin. When infected, the host can also experience symptoms such as nausea, lack of appetite, diarrhoea and abdominal pain.[4][8] ## Causes[edit] Trematodiases are zoonotic infections caused by trematodes.[1] In foodborne trematodiases, these parasites are transferred from animals to humans.[9] Transmission of trematodiases can occur through the consumption of water and food that is contaminated with trematodes in the larval stages of their life cycle.[1] In a host organism, eggs of trematodes can spread through faeces, and sputum if the host is infected by a lung fluke.[7] Once these reach water, they infect aquatic snails which act as intermediate hosts for trematodiases that is transmitted through food.[7][3] A second host will depend on the species of trematode, and are usually aquatic animals[1] Some trematodiases such as Schistosomiasis can also be transmitted when skin comes in contact with water containing the parasite.[8]Trematodes all have different life cycles in which they can reproduce asexually and sexually.[4] When trematodes are at the metacercariae stage in their life cycle, humans and other definitive hosts such as mammals and birds can be infected.[7] In humans, adult trematodes can survive for 25 years.[5] Fasciola hepatica, a species of trematode that causes trematodiases, and infects the liver ### Types of trematodiases[edit] There are different types of trematodiases depending on the species of trematode that has infected the organism as well as their location in humans. There are over 80 different species of trematodes that are transmitted through food that can cause infections in humans.[7] Foodborne trematodiases include intestinal flukes, lung flukes and liver flukes.[7] Liver flukes cause liver disease in humans and are caused by the species Clonorchis, Opisthorchis and Fasciola.[2] Intestinal flukes infect the gastrointestinal tract and can be caused by the species F. buski, Echinostoma, Metagonimus, Heterophyes, Gastrodiscoides.[8][5] Lung flukes, mainly the genus, Paragonimus, infect the lungs of organisms, causing infections that can last for up to 20 years in humans.[5][10] Foodborne trematodiases include Clonorchiasis, Opisthorchiasis, Fascioliasis and Paragonimiasis.[9] ## Diagnosis[edit] Trematodiases can be diagnosed through a variety of methods. One of these is known as parasitological diagnosis, which relies on lab tests that detect the presence of trematode eggs where samples are taken from faeces or sputum.[7][3] Techniques used to measure the number of eggs in samples taken from infected organisms include FLOTAC, Kato-Katz, formalin-ethyl-acetate.[7][3] Different techniques have a different degree in which they can accurately detect eggs of trematodes, and some of these may not be able to detect low amounts.[3] Using a variety of these techniques on different samples can strengthen the accuracy of this method.[3] Another method in which trematodiases can be diagnosed is through antibodies that are produced by the host’s immune response when infected.[3] This is known as immunodiagnosis. These antibody tests can be highly specific, or not specific at all, depending on the technique used.[3] Molecular diagnosis is also used to detect trematodiases. This is specific as it uses the methods of polymerase chain reactions, pyrosequencing and other techniques to detect the parasite’s DNA in samples.[7][3] It is suitable for detecting infections regardless of their number.[3][7] Radiological examinations use imaging such as CT scans, X-rays and ultrasounds to detect certain species of the parasite.[4][3] For liver fluke infections, ultrasounds are commonly used to search for evidence of the infection in the body. It is not very specific in diagnosing the exact trematode which has infected the organism.[5] ## Prevention[edit] Species of trematodes that can cause trematodiases Prevention strategies aim to reduce the number of cases of trematodiases globally and lower infection rates, alongside stopping reinfection of individuals who have been infected before. Public health programs are necessary prevention strategies that aim to raise awareness about the transmission and cause of trematodiases.[1] Food safety and hygiene practices are also implemented to reduce transmission of the parasites through food and water.[3] Most trematodiases is transmitted through eating raw aquatic plants and animals such as fish, crustaceans, crabs, watercress, frogs and snails.[3] Health education programs aim to outline how transmission of disease can be prevented by raising awareness of food safety practices. This includes spreading information about the importance of heating food in eliminating the chance of contracting trematodiases, as well as the importance of cleaning utensils, cutting boards and other equipment to prevent cross-contamination.[5] These education programs are also used to raise awareness to retailers in order to prevent consumers from infections. The Food and Drug Administration recommends that fish which will be consumed undercooked should be placed in low temperatures and frozen under -20 degrees Celsius for at least a week, or under -35 degrees Celsius for a minimum of 15 hours, as freezing removes any chance of transmitting parasites to consumers.[3] Using data from previous years can also be used to create mathematical models that allow for predictions of how the disease is transmitted, and where it can be effectively intervened in order to stop the increase in cases.[7] Improving access to clean water is another method used to prevent the transmission of trematodiases through water. Water sanitation and treatment of sewerage is used to prevent the continuation of the cycle of infections.[1][3] There is no vaccine for foodborne trematodiases that can be used to prevent infections.[5] The World Health Organisation has implemented various methods to control the rates of infection by mapping data in endemic areas and reviewing implemented activities by monitoring infection and incidence rates.[1] ## Treatment[edit] Chemical structure of Paraziquantel, a chemotherapy drug used to treat most forms of trematodiases. Treatment varies depending on the number of cases in an area. Chemotherapy drugs praziquantel and triclabendazole can be used in different amounts depending on the type of trematode infecting the organism, and its location in the body.[1][3] In 2016, 600000 cases globally received treatment for foodborne trematodiases.[1] Praziquantel can act on a broad range of trematodes by disrupting the homeostasis of calcium ions, and is used to treat liver, intestinal and lung fluke infections.[3] It was introduced as a treatment option in 1975 and targets various trematodiases by impacting the trematode’s ability to move in the host.[11] Adverse reactions to this treatment that may occur are mild, and include headache, abdominal pain and dizziness.[11] Although it is very effective and safe in treating most trematodiases, praziquantel can cause hypersensitivity or allergic reactions in rare cases. It also cannot be used to treat the trematodiases fascioliasis.[11] Triclabendazole is a narrow-spectrum treatment of trematodiases and is commonly used to treat fascioliasis.[12] This anthelminthic is effective against the species Fasciola and Paragonimus. Although it was used in domestic livestock from 1983, the treatment was approved for use in humans in 1997 in Egypt.[12] In 2019, it was approved by the US Food and Drug Administration for treating cases of human infections.[12] Common adverse reactions to triclabendazole include dizziness, sweating, pain in abdomen, headaches and biliary colic, which is mainly caused by the removal of dead trematodes from the body’s hepatobiliary system.[12] Preventive chemotherapy is a strategy used in areas where the number of cases and infection rates are very high, as all individuals in the given area are treated with medicine for trematodiases.[1] This is used as an option to prevent further spread of the infection. For clonorchiasis and opisthorchiasis, when the incidence of cases exceeds 20%, all individuals are treated every year.[1] ## Epidemiology[edit] Trematodiases that infects the lung, liver and intestine are classified as neglected tropical diseases by the World Health Organisation.[6] Neglected tropical diseases are made up of bacterial, parasitic and viral infections that negatively impact the development of children, pregnancy and economic outcomes of developing countries.[6] Changes in population numbers, food distribution channels, poverty and health education programs contribute to the fluctuating epidemiological patterns.[3] Social, ecological and economical factors also change distribution patterns globally. Factors such as rainfall, pollution, climate, vegetation, water temperature and quality change the interactions between trematodes and their hosts.[7] The expansion of aquaculture production and irrigation systems has also changed the spread of the disease. In areas where water is not sufficiently sanitised, infection rates have increased.[7] The World Health Organisation declares that there are approximately 200000 cases per year, leading to over 7000 deaths.[1] The highest number of foodborne trematodiases cases and the highest disease burden was recorded in East and Southeast Asia in 2019.[7] In northeast Thailand, O. viverrini which is carcinogenic is present in high numbers, where over 20000 lives are lost a year due to cholangiocarcinoma caused by the trematode.[7] Clonorchis sinesis, a species which causes trematodiases that infects the liver Clonorchis sinensis and Opisthorchis viverrini are two species which can cause trematodiases that infects the liver. These are more prevalent in males than females, and more common in adults than children.[5] F. hepatica, a species of liver flukes, have a higher incidence rate in children and females, with a higher number of cases of lung fluke and intestinal trematodiases in children.[5] Cases of liver and lung fluke trematodiases are high in numbers due to the amount of time the trematode can live in host organisms and increased chances of reinfection.[7] Increase in travel and increase in popularity of traditional dishes such as raw oysters, crab meat, pickled seafood and other undercooked aquatic plants has also contributed to the rise in cases of trematodiases.[7] The Global Burden of Disease Study carried out in 2016 estimated that approximately 75 million people were impacted by trematodiases and that there were around 2 million disability-adjusted life years that were affected and lost to the disease, due to damage that was caused by the infection.[7] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab "Foodborne trematodiases". www.who.int. Retrieved 2020-05-29. 2. ^ a b c d e "CDC - Liver Flukes". www.cdc.gov. 2019-04-18. Retrieved 2020-05-29. 3. ^ a b c d e f g h i j k l m n o p q r s t u Keiser, Jennifer; Utzinger, Jürg (2009). "Food-Borne Trematodiases". Clinical Microbiology Reviews. 22 (3): 466–483. doi:10.1128/CMR.00012-09. PMC 2708390. PMID 19597009. 4. ^ a b c d Liu, Bailu; Li, Li; Shu, Song; Xiao, Yi; Pan, Jiangfeng (2017), LI, Hongjun (ed.), "Trematodiasis", Radiology of Parasitic Diseases: A Practical Approach, Springer Netherlands, pp. 205–243, doi:10.1007/978-94-024-0911-6_10, ISBN 978-94-024-0911-6 5. ^ a b c d e f g h i j k l m n o p q r Khurana, Sumeeta; Malla, Nancy (2013-09-26), "Water- and Food-Borne Trematodiases in Humans", Water and Health, Springer India, pp. 219–227, ISBN 978-81-322-1028-3 6. ^ a b c d Tandon, Veena; Shylla, Jollin A.; Ghatani, Sudeep; Athokpam, Voleentina D.; Sahu, Ranjana (2014-12-05). "Neglected Tropical Diseases: Trematodiases—The Indian Scenario". Proceedings of the National Academy of Sciences, India Section B: Biological Sciences. 85 (4): 901–907. doi:10.1007/s40011-014-0465-x. S2CID 16923049. 7. ^ a b c d e f g h i j k l m n o p q r s t u Fürst, Thomas; Yongvanit, Puangrat; Khuntikeo, Narong; Lun, Zhao-Rong; Haagsma, Juanita A.; Torgerson, Paul R.; Odermatt, Peter; Bürli, Christine; Chitnis, Nakul (2019), Utzinger, Jürg; Yap, Peiling; Bratschi, Martin; Steinmann, Peter (eds.), "Food-borne Trematodiases in East Asia: Epidemiology and Burden", Neglected Tropical Diseases - East Asia, Neglected Tropical Diseases, Springer International Publishing, pp. 13–38, doi:10.1007/978-3-030-12008-5_2, ISBN 978-3-030-12008-5 8. ^ a b c d e Pottinger, Paul S.; Jong, Elaine C. (2017-01-01), Sanford, Christopher A.; Pottinger, Paul S.; Jong, Elaine C. (eds.), "Chapter 48 - Trematodes", The Travel and Tropical Medicine Manual (Fifth Edition), Elsevier, pp. 588–597, doi:10.1016/b978-0-323-37506-1.00048-9, ISBN 978-0-323-37506-1 9. ^ a b "WHO \| Foodborne trematode infections". WHO. Retrieved 2020-05-29. 10. ^ Prevention, CDC-Centers for Disease Control and (2019-04-19). "CDC - Paragonimiasis". www.cdc.gov. Retrieved 2020-05-29. 11. ^ a b c Chai, Jong-Yil (2013). "Praziquantel Treatment in Trematode and Cestode Infections: An Update". Infection & Chemotherapy. 45 (1): 32–43. doi:10.3947/ic.2013.45.1.32. PMC 3780935. PMID 24265948. 12. ^ a b c d Gandhi, Preetam; Schmitt, Esther K; Chen, Chien-Wei; Samantray, Sanjay; Venishetty, Vinay Kumar; Hughes, David (2019). "Triclabendazole in the treatment of human fascioliasis: a review". Transactions of the Royal Society of Tropical Medicine and Hygiene. 113 (12): 797–804. doi:10.1093/trstmh/trz093. PMC 6906998. PMID 31638149. * v * t * e Parasitic disease caused by helminthiases Flatworm/ platyhelminth infection Fluke/trematode (Trematode infection) Blood fluke * Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum * Schistosomiasis * Trichobilharzia regenti * Swimmer's itch Liver fluke * Clonorchis sinensis * Clonorchiasis * Dicrocoelium dendriticum / D. hospes * Dicrocoeliasis * Fasciola hepatica / F. gigantica * Fasciolosis * Opisthorchis viverrini / O. felineus * Opisthorchiasis Lung fluke * Paragonimus westermani / P. kellicotti * Paragonimiasis Intestinal fluke * Fasciolopsis buski * Fasciolopsiasis * Metagonimus yokogawai * Metagonimiasis * Heterophyes heterophyes * Heterophyiasis Cestoda (Tapeworm infection) Cyclophyllidea * Echinococcus granulosus / E. multilocularis * Echinococcosis * Taenia saginata / T. asiatica / T. solium (pork) * Taeniasis / Cysticercosis * Hymenolepis nana / H. diminuta * Hymenolepiasis Pseudophyllidea * Diphyllobothrium latum * Diphyllobothriasis * Spirometra erinaceieuropaei * Sparganosis * Diphyllobothrium mansonoides * Sparganosis Roundworm/ Nematode infection Secernentea Spiruria Camallanida * Dracunculus medinensis * Dracunculiasis Spirurida Filarioidea (Filariasis) * Onchocerca volvulus * Onchocerciasis * Loa loa * Loa loa filariasis * Mansonella * Mansonelliasis * Dirofilaria repens * D. immitis * Dirofilariasis * Wuchereria bancrofti / Brugia malayi / \|B. timori * Lymphatic filariasis Thelazioidea * Gnathostoma spinigerum / G. hispidum * Gnathostomiasis * Thelazia * Thelaziasis Spiruroidea * Gongylonema Strongylida (hookworm) * Hookworm infection * Ancylostoma duodenale / A. braziliense * Ancylostomiasis / Cutaneous larva migrans * Necator americanus * Necatoriasis * Angiostrongylus cantonensis * Angiostrongyliasis * Metastrongylus * Metastrongylosis Ascaridida * Ascaris lumbricoides * Ascariasis * Anisakis * Anisakiasis * Toxocara canis / T. cati * Visceral larva migrans / Toxocariasis * Baylisascaris * Dioctophyme renale * Dioctophymosis * Parascaris equorum Rhabditida * Strongyloides stercoralis * Strongyloidiasis * Trichostrongylus spp. * Trichostrongyliasis * Halicephalobus gingivalis Oxyurida * Enterobius vermicularis * Enterobiasis Adenophorea * Trichinella spiralis * Trichinosis * Trichuris trichiura (Trichuriasis / Whipworm) * Capillaria philippinensis * Intestinal capillariasis * C. hepatica [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Trematodiases	c0040820	1,562	wikipedia	https://en.wikipedia.org/wiki/Trematodiases	2021-01-18T19:10:32	{"gard": ["1891"], "mesh": ["D014201"], "umls": ["C0040820"], "icd-9": ["121.9"], "orphanet": ["1685"], "wikidata": ["Q3030745"]}
Split hand split foot nystagmus is a rare congenital syndrome characterized by split hand and split foot deformity and eye abnormalities, especially nystagmus. It is thought to have an autosomal dominant mode of inheritance. Currently, the underlying genetic defect has not been identified. The outlook for children with this condition is good. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Split hand split foot nystagmus	c1866740	1,563	gard	https://rarediseases.info.nih.gov/diseases/4967/split-hand-split-foot-nystagmus	2021-01-18T17:57:34	{"mesh": ["C537319"], "omim": ["183800"], "umls": ["C1866740"], "orphanet": ["2329"], "synonyms": ["Split hand nystagmus syndrome", "Karsch-Neugebauer syndrome", "KNS"]}
A narrow strip of hardened skin, a constricting ring, forms on the little toe at the level of the digitoplantar fold and progresses to spontaneous amputation of the digit. Familial occurrence has been noted by Maass (1926) and by DaSilva Lima (1880). Simon (1921) reported ainhum in father and 2 sons. Ainhum-like constriction bands occur with neurogenic acroosteolysis (201300) and with mutilating keratoderma (124500, 244850). INHERITANCE \- Autosomal dominant SKELETAL Feet \- Ainhum (spontaneous amputation) of toe (primarily 5th) MISCELLANEOUS \- Occurs most often among black Africans ▲ 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	AINHUM	c0001860	1,564	omim	https://www.omim.org/entry/103400	2019-09-22T15:41:19	{"doid": ["11329"], "mesh": ["D000387"], "omim": ["103400"], "icd-9": ["136.0"], "icd-10": ["L94.6"]}
Feline zoonosis SpecialtyInfectious disease, veterinary medicine A feline zoonosis is a viral, bacterial, fungal, protozoan, nematode or arthropod infection that can be transmitted to humans from the domesticated cat, Felis catus. Some of these are diseases are reemerging and newly emerging infections or infestations caused by zoonotic pathogens transmitted by cats. In some instances, the cat can display symptoms of infection (these may differ from the symptoms in humans) and sometimes the cat remains asymptomatic. There can be serious illnesses and clinical manifestations in people who become infected. This is dependent on the immune status and age of the person. Those who live in close association with cats are more prone to these infections. But those that do not keep cats as pets are also able to acquire these infections because of the transmission can be from cat feces and the parasites that leave their bodies.[1] People can acquire cat-associated infections through bites, scratches or other direct contact of the skin or mucous membranes with the cat. This includes 'kissing' or letting the animal lick the mouth or nose. Mucous membranes are easily infected when the pathogen is in the mouth of the cat. Pathogens can also infect people when there is contact with animal saliva, urine and other body fluids or secretions, When fecal material is unintentionally ingested, infection can occur. A feline zooinosis can be acquired by a person by inhalation of aerosols or droplets coughed up by the cat.[2][3] In the United States, thirty-two percent of homes have at least one cat.[4] Some contagious infections such as campylobacteriosis and salmonellosis cause visible symptoms of the disease in cats. Other infections, such as cat scratch disease and toxoplasmosis, have no visible symptoms and are carried by apparently healthy cats.[5] ## Contents * 1 Cats as vectors * 2 Bites * 3 Viral * 4 Bacterial * 4.1 Pasteurella multocida * 4.2 Capnocytophaga canimorsus * 4.3 Methicillin-resistant Staphylococcus aureus * 4.4 Plague * 4.5 Chagas disease * 4.6 Leishmaniasis * 4.7 Staphylococcus intermedius * 4.8 Leptospirosis * 4.9 Tuberculosis and influenza * 4.10 Kennel cough * 5 Echinococcosis * 6 Arthropods * 7 Fungi * 8 Platyhelminthes * 9 Protozoans * 10 Prevention * 11 See also * 12 References * 13 Bibliography * 14 External links ## Cats as vectors[edit] Some disease-carrying arthropods use cats as a vector, or carrier. Fleas and ticks can carry pathogenic organisms that infect a person with Lyme disease, tick-borne encephalitis, and Rocky mountain spotted fever. [1] ## Bites[edit] Main article: Cat bite Statistics generated by the state of Ohio document that cat bites make up about 20 percent of all animal bites each year. Bites from cats can not only transmit serious diseases such as rabies, but bites can develop bacterial infections. The bite of a cat appears small but it can be deep. As many as 80 percent of cat bites become infected.[5][6] ## Viral[edit] Cowpox infection In 2010, over 400 cases of cowpox infection from cats to human have been described. The symptoms differ between both humans and cats. In people, local exanthema appears on the arms and face. The infection resolves on its own but those who are immunosuppressed can progress to systemic infection that closely resembles smallpox. When the infection has expanded to severe symptoms, it can be lethal. The signs of cowpox infection in cats can be seen as, multiple skin sores on the paws, neck, head and mouth. The cat can also develop a purulent discharge from the eyes. Necrotizing pneumonia has also been observed. Estimates that 50% of human cases of cowpox are due to transmission from cats in the United Kingdom.[1] The avian flu virus H7N2 has been found in cats in New York City.[7] Though transmission to people is possible, it is thought to be rare.[8][9] In Europe, cats were identified as being hosts for West Nile virus.[10] ## Bacterial[edit] ### Pasteurella multocida[edit] The bacterium Pasteurella multocida and its genus can pose a risk of severe diseases in high-risk groups such as the elderly, transplant recipients, cancer patients and immunocompromised individuals. Transmission of the infection to the human from the cat has been attributed to kissing the cat, providing care that exposes the person to the body fluids of the cat and sleeping with the cat.[1][3] ### Capnocytophaga canimorsus[edit] The bacterium Capnocytophaga canimorsus can pose a risk of severe diseases in high-risk groups such as the elderly, transplant recipients, cancer patients and immunocompromised individuals. Transmission of the infection to the human from the cat has been attributed to kissing the cat, providing care that exposes the person to the body fluids of the cat and sleeping with the cat.[1][10][3] Kittens are more likely to transmit the bacterium than adult cats.[10] Exposure to cats with this infection has been associated with meningitis.[11] Capnocytophaga canimorsus sepsis has also been associated with infection in cat owners.[12] ### Methicillin-resistant Staphylococcus aureus[edit] MRSA is a common type of bacteria that is normally found on the skin of people and cats.[1] Methicillin-resistant Staphylococcus aureus (MRSA) is the same bacterium that has become resistant to some antibiotics. Cats and other animals often can carry MRSA without being sick, but MRSA can cause a variety of infections, including of the skin, respiratory tract, and urinary tract of people. MRSA can be transmitted back and forth between people and animals through direct contact. In people, MRSA most often causes skin infections that can range from mild to severe. If left untreated, MRSA can spread to the bloodstream or lungs and cause life-threatening infections.[13][2][3] ### Plague[edit] Cats are known to transmit plague. Plague can take three forms: bubonic plague, primary septicemic plague, and primary pneumonic plague.[12][14] ### Chagas disease[edit] Transmission of Chagas disease has been documented and is associated with sleeping with cats.[12] ### Leishmaniasis[edit] Leishmaniasis is a newly emerging pathogen in Texas.[1] ### Staphylococcus intermedius[edit] The Staphylococcus intermedius bacteria, a common commensal on cats, is associated with infection in humans.[12] ### Leptospirosis[edit] Leptospirosis infection associated with cat urine has been identified as an emerging bacterial pathogen in some European countries. In infected humans, jaundice may or may not be a symptom. If jaundice is a symptom the infection becomes more severe and rapidly progresses.[15] ### Tuberculosis and influenza[edit] Different strains of the tuberculosis bacterium (Mycobacterium bovis, M. tuberculosis and M. microti) have been isolated from cats and associated with infection with the presence of the bacterium in their owners, but a definitive cause has not been established. Neither has one strain of influenza been proven to infect pet owners, though infected cats can infect other cats.[1] ### Kennel cough[edit] Bordetella bronchiseptica has been identified in cats with owners that also are infected with this pathogen. Individuals having this infection have usually been cancer or transplant patients. Those with this infection can develop serious pneumonia.[1] ## Echinococcosis[edit] Echinococcus multilocularis can infect cats and then be transmitted to their owners to cause human alveolar echinococcosis. Foxes have transmitted this pathogen to cats in Germany, Austria, France and Japan.[1] ## Arthropods[edit] Cheyletiellosis (also known as Cheyletiella dermatitis) is a mild, short-term skin inflammation caused by the mite Cheyletiella blakei that feeds on a person's skin cells. It is spread through contact with infested cats. Cheyletiella blakei infection has been associated with sleeping with a cat. Though not a common ectoparasite, it may be an emerging pathogen in California. The infected cat may have no signs of infection. However, affected kittens may have patches of scaly skin with dandruff. The most common symptoms of cheyletiellosis in people include itching, redness, and raised bumps on areas of the skin that touched the infested animal. Cheyletiellosis in people generally resolves on its own.[13][15] ## Fungi[edit] Cats are reservoirs and are able to transmit mycotic infections.[16] Cats, especially kittens can pass on a Ringworm infection to people. Ringworm is a fungal disease and approximately 40 types of fungi can cause ringworm. They are typically of the Trichophyton, Microsporum, or Epidermophyton type.[17] It gets its name from the characteristic ring-like rash on the skin. The disease is spread by touching an infected cat. The rash may be scaly, reddened, and circular. Ringworm on the scalp usually makes a bald patch of scaly skin. Long-haired cats do not always show signs of ringworm infection. Kittens with ringworm have patches that are hairless, circular, or irregularly shaped areas of scaling, crusting, and redness that may or may not be itchy. The area may not be completely hairless, and instead have brittle, broken hairs. If the claws are affected, they may have a whitish, opaque appearance with shredding of the claw's surface.[18] Sporotrichosis is a fungal disease that is transmitted by mostly outdoor cats.[1] ## Platyhelminthes[edit] The lung fluke Paragonimus westermani Paragonimiasis, or lung fluke uses cats as a reservoir and subsequently can transmit the infection to humans. Symptoms in cats have not been observed. There are over nine species of lung flukes that can be transmitted to humans from cats. The disease has been found in Asia, Africa, India, North, South and Central America. It is not uncommon and estimates of those infected are in the millions. Signs symptoms in humans are coughing up blood, migration of the flukes into other body organs including the central nervous system. There it can cause neurological symptoms such as headache, confusion, convulsions, vision problems, and bleeding in the brain. This infection in humans is sometimes mistaken for tuberculosis.[19] Onchocercosis has been associated with pet cats in a few cases.[1] Cats can harbor and transmit hookworms to people.[20] ## Protozoans[edit] Cryptosporidiosis is a parasitic disease that is transmitted through contaminated food or water from an infected person or animal. Cryptosporidiosis in cats is rare, but they can carry the protozoan without showing any signs of illness. Cryptosporidiosis can cause profuse, watery diarrhea with cramping, abdominal pain, and nausea in people. Illness in people is usually self-limiting and lasts only 2–4 days, but can become severe in people with weakened immune systems.[13] Cryptosporidiosis (Cryptosporidium spp.) Cats transmit the protozoan through their feces. The symptoms in people weight loss and chronic diarrhea in high-risk patients. More than one species of this genus can be acquired by people. Dogs can also transmit this parasite.[2][12] Another important protozoan disease associated with cat is Toxoplasma gondii, for which cat acts as definitive reservoir. Infected cats shed oocysts in their faeces, which upon ingestion can infect an individual. Especially pregnant women are at risk who as it is usually associated with abortion and hydrocephalus condition in newborn. ## Prevention[edit] One strategy for the prevention of infection transmission between cats and people is to better educate people on the behaviour that puts them at risk for becoming infected.[3] Those at the highest risk of contracting a disease from a cat are those with behaviors that include: being licked, sharing food, sharing kitchen utensils, kissing, and sleeping with a cat.[1] The very young, the elderly and those who are immunocompromised increase their risk of becoming infected when sleeping with their cats (and dogs). The CDC recommends that cat owners not allow a cat to lick your face because it can result in disease transmission. If someone is licked on their face, mucous membranes or an open wound, the risk for infection is reduced if the area is immediately washed with soap and water. Maintaining the health of the animal by regular inspection for fleas and ticks, scheduling deworming medications along with veterinary exams will also reduce the risk of acquiring a feline zoonosis.[12] Recommendations for the prevention of ringworm transmission to people include: * regularly vacuuming areas of the home that pets commonly visit helps to remove fur or flakes of skin * washing the hands with soap and running water after playing with or petting your pet. * wearing gloves and long sleeves when handling cats infected with. * disinfect areas the pet has spent time in, including surfaces and bedding. * the spores of this fungus can be killed with common disinfectants like chlorine bleach diluted 1:10 (1/4 cup in 1 gallon of water), benzalkonium chloride, or strong detergents. * not handling cats with ringworm by those whose immune system is weak in any way (if you have HIV/AIDS, are undergoing cancer treatment, or are taking medications that suppress the immune system, for example). * taking the cat to the veterinarian if ringworm infection is suspected.[21] ## See also[edit] * Cat bite * Cross-species transmission * Emerging infectious disease * Veterinary medicine ## References[edit] 1. ^ a b c d e f g h i j k l m Chomel, Bruno (2014). "Emerging and Re-Emerging Zoonoses of Dogs and Cats". Animals. 4 (3): 434–445. doi:10.3390/ani4030434. ISSN 2076-2615. PMC 4494318. PMID 26480316. 2. ^ a b c Stull, J. W.; Brophy, J.; Weese, J. S. (2015). "Reducing the risk of pet-associated zoonotic infections". Canadian Medical Association Journal. 187 (10): 736–743. doi:10.1503/cmaj.141020. ISSN 0820-3946. PMC 4500695. PMID 25897046. 3. ^ a b c d e Gurry, Greta A.; Campion, Veronique; Premawardena, Chamath; Woolley, Ian; Shortt, Jake; Bowden, Donald K.; Kaplan, Zane; Dendle, Claire (2017). "High rates of potentially infectious exposures between immunocompromised patients and their companion animals: an unmet need for education". Internal Medicine Journal. 47 (3): 333–335. doi:10.1111/imj.13361. ISSN 1444-0903. PMID 28260250. 4. ^ Adams, Clark E.; Lindsey, Kieran J. (2012-06-15). "Chapter 12. The ecology and management considerations of selected species.". Urban Wildlife Management (2nd ed.). CRC Press. p. 296. ISBN 9781466521278. 5. ^ a b "Cats". Ohio Department of Health. January 21, 2015. Retrieved 2016-11-26. 6. ^ "Zoonoses, Animal diseases that may also affect humans". Victoria State Government, Australia. 2007. Retrieved 2016-11-26. 7. ^ "pr107-16". www1.nyc.gov. Retrieved 22 May 2017. 8. ^ "Avian Flu". www1.nyc.gov. Retrieved 22 May 2017. 9. ^ "pr107-16". www1.nyc.gov. Retrieved 19 June 2017. 10. ^ a b c Rijks, J.M.; Cito, F.; Cunningham, A.A.; Rantsios, A.T.; Giovannini, A. (2016). "Disease Risk Assessments Involving Companion Animals: an Overview for 15 Selected Pathogens Taking a European Perspective" (PDF). Journal of Comparative Pathology. 155 (1): S75–S97. doi:10.1016/j.jcpa.2015.08.003. ISSN 0021-9975. PMID 26422413. 11. ^ Kawashima, Shoji; Matsukawa, Noriyuki; Ueki, Yoshino; Hattori, Manabu; Ojika, Kosei (2009). "Pasteurella multocida meningitis caused by kissing animals: a case report and review of the literature". Journal of Neurology. 257 (4): 653–654. doi:10.1007/s00415-009-5411-0. ISSN 0340-5354. PMID 19997925. 12. ^ a b c d e f Chomel, Bruno B.; Sun, Ben (January 26, 2011). "Zoonoses in the Bedroom" (PDF). Centers for Disease Control and Prevention. Retrieved 2016-11-27. 13. ^ a b c "Cats, Healthy Pets, Healthy People". Centers for Disease Control and Prevention. May 13, 2016. Retrieved 2016-11-25. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 14. ^ Gage, K. L.; Dennis, D. T.; Orloski, K. A.; Ettestad, P.; Brown, T. L.; Reynolds, P. J.; Pape, W. J.; Fritz, C. L.; Carter, L. G.; Stein, J. D. (2000). "Cases of Cat-Associated Human Plague in the Western US, 1977-1998". Clinical Infectious Diseases. 30 (6): 893–900. doi:10.1086/313804. ISSN 1058-4838. PMID 10852811. 15. ^ a b Schuller, S.; Francey, T.; Hartmann, K.; Hugonnard, M.; Kohn, B.; Nally, J. E.; Sykes, J. (2015). "European consensus statement on leptospirosis in dogs and cats". Journal of Small Animal Practice. 56 (3): 159–179. doi:10.1111/jsap.12328. ISSN 0022-4510. PMID 25754092. 16. ^ McPhee, Stephen (2012). Current medical diagnosis & treatment 2012. New York: McGraw-Hill Medical. p. 110. ISBN 9780071763721. 17. ^ "Definition of Ringworm". Centers for Disease Control and Prevention. April 30, 2014. Retrieved 19 June 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 18. ^ "Ringworm - Healthy Pets Healthy People". Centers for Disease Control and Prevention. April 30, 2014. Retrieved 19 June 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 19. ^ Heymann, pp. 443–445. sfn error: no target: CITEREFHeymann (help) 20. ^ "Parasites - Animals (Zoonotic)". Centers for Disease Control and Prevention. Retrieved 19 June 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. 21. ^ "Ringworm (Dermatophytosis Infection)". Centers for Disease Control and Prevention. April 30, 2014. Retrieved June 19, 2017. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. ## Bibliography[edit] * Heymann, David (2015). Control of communicable diseases manual : an official report of the American Public Health Association. Washington, DC: APHA Press, an imprint of the American Public Health Association. ISBN 9780875530185. ## External links[edit] Classification D * ICD-10: A82, W84, B08.0, B66.4 * University of California Davis * v * t * e Zoonotic viral diseases (A80–B34, 042–079) Arthropod -borne Mosquito -borne Bunyavirales * Arbovirus encephalitides: La Crosse encephalitis * LACV * Batai virus * BATV * Bwamba Fever * BWAV * California encephalitis * CEV * Jamestown Canyon encephalitis * Tete virus * Tahyna virus * TAHV * Viral hemorrhagic fevers: Rift Valley fever * RVFV * Bunyamwera fever * BUNV * Ngari virus * NRIV Flaviviridae * Arbovirus encephalitides: Japanese encephalitis * JEV * Australian encephalitis * MVEV * KUNV * Saint Louis encephalitis * SLEV * Usutu virus * West Nile fever * WNV * Viral hemorrhagic fevers: Dengue fever * DENV-1-4 * Yellow fever * YFV * Zika fever * Zika virus Togaviridae * Arbovirus encephalitides: Eastern equine encephalomyelitis * EEEV * Western equine encephalomyelitis * WEEV * Venezuelan equine encephalomyelitis * VEEV * Chikungunya * CHIKV * O'nyong'nyong fever * ONNV * Pogosta disease * Sindbis virus * Ross River fever * RRV * Semliki Forest virus Reoviridae * Banna virus encephalitis Tick -borne Bunyavirales * Viral hemorrhagic fevers: Bhanja virus * Crimean–Congo hemorrhagic fever (CCHFV) * Heartland virus * Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus) * Tete virus Flaviviridae * Arbovirus encephalitides: Tick-borne encephalitis * TBEV * Powassan encephalitis * POWV * Viral hemorrhagic fevers: Omsk hemorrhagic fever * OHFV * Kyasanur Forest disease * KFDV * AHFV * Langat virus * LGTV Orthomyxoviridae * Bourbon virus Reoviridae * Colorado tick fever * CTFV * Kemerovo tickborne viral fever Sandfly -borne Bunyavirales * Adria virus (ADRV) * Oropouche fever * Oropouche virus * Pappataci fever * Toscana virus * Sandfly fever Naples virus Rhabdoviridae * Chandipura virus Mammal -borne Rodent -borne Arenaviridae * Viral hemorrhagic fevers: Lassa fever * LASV * Venezuelan hemorrhagic fever * GTOV * Argentine hemorrhagic fever * JUNV * Brazilian hemorrhagic fever * SABV * Bolivian hemorrhagic fever * MACV * LUJV * CHPV Bunyavirales * Hemorrhagic fever with renal syndrome * DOBV * HTNV * PUUV * SEOV * AMRV * THAIV * Hantavirus pulmonary syndrome * ANDV * SNV Herpesviridae * Murid gammaherpesvirus 4 Bat -borne Filoviridae * BDBV * SUDV * TAFV * Marburg virus disease * MARV * RAVV Rhabdoviridae * Rabies * ABLV * MOKV * DUVV * LBV * CHPV Paramyxoviridae * Henipavirus encephalitis * HeV * NiV Coronaviridae * SARS-related coronavirus * SARS-CoV * MERS-CoV * SARS-CoV-2 Primate -borne Herpesviridae * Macacine alphaherpesvirus 1 Retroviridae * Simian foamy virus * HTLV-1 * HTLV-2 Poxviridae * Tanapox * Yaba monkey tumor virus Multiple vectors Rhabdoviridae * Rabies * RABV * Mokola virus Poxviridae * Monkeypox * v * t * e Tick-borne diseases and infestations Diseases Bacterial infections Rickettsiales * Anaplasmosis * Boutonneuse fever * Ehrlichiosis (Human granulocytic, Human monocytotropic, Human E. ewingii infection) * Scrub typhus * Spotted fever rickettsiosis * Pacific Coast tick fever * American tick bite fever * rickettsialpox * Rocky Mountain spotted fever) Spirochaete * Baggio–Yoshinari syndrome * Lyme disease * Relapsing fever borreliosis Thiotrichales * Tularemia Viral infections * Bhanja virus * Bourbon virus * Colorado tick fever * Crimean–Congo hemorrhagic fever * Heartland bandavirus * Kemerovo tickborne viral fever * Kyasanur Forest disease * Omsk hemorrhagic fever * Powassan encephalitis * Severe fever with thrombocytopenia syndrome * Tete orthobunyavirus * Tick-borne encephalitis Protozoan infections * Babesiosis Other diseases * Tick paralysis * Alpha-gal allergy * Southern tick-associated rash illness Infestations * Tick infestation Species and bites Amblyomma * Amblyomma americanum * Amblyomma cajennense * Amblyomma triguttatum Dermacentor * Dermacentor andersoni * Dermacentor variabilis Ixodes * Ixodes cornuatus * Ixodes holocyclus * Ixodes pacificus * Ixodes ricinus * Ixodes scapularis Ornithodoros * Ornithodoros gurneyi * Ornithodoros hermsi * Ornithodoros moubata Other * Rhipicephalus sanguineus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Feline zoonosis	None	1,565	wikipedia	https://en.wikipedia.org/wiki/Feline_zoonosis	2021-01-18T18:54:55	{"wikidata": ["Q28136278"]}
Palpation thyroiditis refers to the development of thyroid inflammation due to mechanical damage to thyroid follicles.[1] This can occur by vigorous repeated palpation (as with thyroid examination) or surgical manipulation (as can occur with radical neck dissection). It is a type of subacute thyroiditis. Pathology shows multifocal granulomatous folliculitis. T cells predominate compared to B cells. There may be initial transient hyperthyroidism due to leakage of preformed thyroid hormone in blood.[2][3] ## References[edit] 1. ^ Madill, EM; Cooray, SD; Bach, LA (2016). "Palpation thyroiditis following subtotal parathyroidectomy for hyperparathyroidism". Endocrinology, Diabetes & Metabolism Case Reports. 2016. doi:10.1530/EDM-16-0049. PMC 4967109. PMID 27482385. 2. ^ Carney, J.; Moore, S.; Northcutt, R.; Woolner, L.; Stillwell, G. (1975). "Palpation thyroiditis (multifocal granulomatour folliculitis)". American Journal of Clinical Pathology. 64 (5): 639–647. doi:10.1093/ajcp/64.5.639. PMID 1242618. 3. ^ Becker, Kenneth L. (2001), Kenneth L. Becker (ed.), Principles and practice of endocrinology and metabolism, Page 957 (3 ed.), Lippincott Williams & Wilkins, p. 461, ISBN 978-0-7817-1750-2 * v * t * e Thyroid disease Hypothyroidism * Iodine deficiency * Cretinism * Congenital hypothyroidism * Myxedema * Myxedema coma * Euthyroid sick syndrome * Signs and symptoms * Queen Anne's sign * Woltman sign * Thyroid dyshormonogenesis * Pickardt syndrome Hyperthyroidism * Hyperthyroxinemia * Thyroid hormone resistance * Familial dysalbuminemic hyperthyroxinemia * Hashitoxicosis * Thyrotoxicosis factitia * Thyroid storm Graves' disease * Signs and symptoms * Abadie's sign of exophthalmic goiter * Boston's sign * Dalrymple's sign * Stellwag's sign * lid lag * Griffith's sign * Möbius sign * Pretibial myxedema * Graves' ophthalmopathy Thyroiditis * Acute infectious * Subacute * De Quervain's * Subacute lymphocytic * Palpation * Autoimmune/chronic * Hashimoto's * Postpartum * Riedel's Enlargement * Goitre * Endemic goitre * Toxic nodular goitre * Toxic multinodular goiter * Thyroid nodule * Colloid nodule This article about an endocrine, nutritional, or metabolic disease 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	Palpation thyroiditis	c2960048	1,566	wikipedia	https://en.wikipedia.org/wiki/Palpation_thyroiditis	2021-01-18T18:52:45	{"umls": ["C2960048"], "wikidata": ["Q7128690"]}
Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family. There are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine. ## Frequency Waardenburg syndrome affects an estimated 1 in 40,000 people. It accounts for 2 to 5 percent of all cases of congenital hearing loss. Types I and II are the most common forms of Waardenburg syndrome, while types III and IV are rare. ## Causes Mutations in the EDN3, EDNRB, MITF, PAX3, SNAI2, and SOX10 genes can cause Waardenburg syndrome. These genes are involved in the formation and development of several types of cells, including pigment-producing cells called melanocytes. Melanocytes make a pigment called melanin, which contributes to skin, hair, and eye color and plays an essential role in the normal function of the inner ear. Mutations in any of these genes disrupt the normal development of melanocytes, leading to abnormal pigmentation of the skin, hair, and eyes and problems with hearing. Waardenburg syndrome types I and III are caused by mutations in the PAX3 gene. Mutations in the MITF or SNAI2 gene can cause Waardenburg syndrome type II. Mutations in the SOX10, EDN3, or EDNRB gene can cause Waardenburg syndrome type IV. In addition to melanocyte development, these genes are important for the development of nerve cells in the large intestine. Mutations in one of these genes result in hearing loss, changes in pigmentation, and intestinal problems related to Hirschsprung disease. In some cases, the genetic cause of Waardenburg syndrome has not been identified. ### Learn more about the genes associated with Waardenburg syndrome * EDN3 * EDNRB * MITF * PAX3 * SNAI2 * SOX10 ## Inheritance Pattern Waardenburg syndrome is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. A small percentage of cases result from new mutations in the gene; these cases occur in people with no history of the disorder in their family. Some cases of Waardenburg syndrome type II and type IV appear to have an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Waardenburg syndrome	c1847800	1,567	medlineplus	https://medlineplus.gov/genetics/condition/waardenburg-syndrome/	2021-01-27T08:24:40	{"gard": ["5525", "5519", "5520", "5523", "5524"], "mesh": ["D014849"], "omim": ["193500", "193510", "600193", "606662", "608890", "611584", "148820", "277580", "613265", "613266"], "synonyms": []}
A rare developmental defect with connective tissue involvement characterized by joint hyperextensibility and multiple dislocations of large joints, severe myopia, and short stature. Other common features include retinal detachment, iris and chorioretinal coloboma, kyphoscoliosis and other spine deformities, pectus carinatum, talipes equinovarus, and progressive hearing loss. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Severe myopia-generalized joint laxity-short stature syndrome	c4540020	1,568	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=527450	2021-01-23T17:09:57	{"omim": ["617662"]}
Epidermolysis bullosa simplex with mottled pigmentation is a rare form of epidermolysis bullosa (EB). EB is a group of genetic conditions that cause the skin to be very fragile and to blister easily. Erosions and blisters form in response to minor injury or friction, such as rubbing or scratching.[2310] In EB simplex with mottled pigmentation, blistering may begin at birth. People with this condition have a mottled appearance of their skin (ie., darker and lighter colored spots of skin). Their skin may seem to age more quickly and bruise easily. EB simplex with mottled pigmentation is caused by a mutation in the keratin-5 gene (KRT5) and is inherited in an autosomal dominant fashion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Epidermolysis bullosa simplex with mottled pigmentation	c0432316	1,569	gard	https://rarediseases.info.nih.gov/diseases/9737/epidermolysis-bullosa-simplex-with-mottled-pigmentation	2021-01-18T18:00:41	{"mesh": ["C535959"], "omim": ["131960"], "umls": ["C0432316"], "orphanet": ["79397"], "synonyms": ["EBS with mottled pigmentation", "EBS-MP", "Speckled hyperpigmentation, palmo-plantar punctate keratoses and childhood blistering"]}
Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA).[1][2] However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood.[1][2] Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice.[1][3][4] Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma aldosterone concentration (PAC) which differentiates this group of conditions from other forms of secondary hypertension.[1][2] Treatment is tailored to the specific cause and focuses on symptom control, blood pressure management, and avoidance of triggers.[1] ## Contents * 1 Causes * 1.1 Genetic forms * 1.2 Acquired forms * 1.3 Metabolic and dietary forms * 2 Presentation * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Causes[edit] This condition has several known causes including genetic disorders, acquired conditions, metabolic derangements, and dietary imbalances. All causes mimic the effects of elevated aldosterone without raising aldosterone levels but achieve this through varying mechanisms.[1] ### Genetic forms[edit] Genetic disorders that lead to this condition include Liddle's syndrome, Apparent mineralocorticoid excess (AME), and two types of Congenital adrenal hyperplasia (CAH).[1][2] * Liddle's syndrome is autosomal dominant disorder affecting epithelial sodium channels (ENaC) in the distal tubules of the kidneys. In this disorder, a gain of function mutation decreases ENaC degradation leading to increased renal absorption of sodium and water.[4][2] * Apparent mineralocorticoid excess genetic forms include autosomal recessive disorders with mutations lowering the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-β-HSD2).[1] These mutations limit the ability of 11-β-HSD2 to transform active cortisol to the less active cortisone.[2] Excess cortisol is then able to bind and activate mineralocorticoid receptors due to receptor cross-reactivity leading to aldosterone-like effects.[1] * Congenital Adrenal Hyperplasia is an autosomal recessive disorder with multiple types, two of which lead to pseudohyperaldosteronism.[1] Deficiency of 11-beta-hydroxylase blocks the conversion of 11-deoxycorticosterone (DOC) to corticosterone leading to an excess of DOC which acts as a mineralocorticoid similar to aldosterone. Deficiency of 17-alpha-hydroxylase blocks the conversion of pregnenolone and progesterone to their 17-a-hydroxy forms leading to increased mineralocorticoid production.[1] ### Acquired forms[edit] Some causes of pseudohyperaldosteronism can be acquired throughout life with examples including adrenal tumors and Ectopic ACTH syndrome.[5] * Adrenal tumor subtypes include adrenal adenomas that produce 11-deoxycorticosterone (DOC) leading to increased mineralocorticoid activity without elevated aldosterone.[6] * Ectopic ACTH syndrome describes conditions leading to excess production of adrenocorticotropic hormone (ACTH) subsequently leading to mineralocorticoid production.[5] This can arise in ectopic forms of Cushing's syndrome associated with small-cell lung cancers and other ACTH-producing tumors.[5] The excess ACTH can saturate the 11-β-HSD2 enzyme leading to decreased conversion of cortisol to cortisone and increased mineralocorticoid effects.[5] ### Metabolic and dietary forms[edit] Metabolic causes include conditions of glucocorticoid resistance[7] and from mineralocorticoid excess which can occur following high-dose corticosteroid therapy.[1] Dietary causes include overconsumption of licorice-containing products.[3][8] Glycyrrhetinic acid in licorice inhibits the 11-β-HSD2 enzyme resulting in inappropriate stimulation of the mineralocorticoid receptor by cortisol leading to aldosterone-like effects.[3][8] ## Presentation[edit] The presentation of pseudohyperaldosteronism varies depending on the cause. The genetic conditions such as Liddle's syndrome and Congenital adrenal hyperplasia present in childhood or earlier in life than the acquired causes which can present at any age.[1][4][2] Adult patients present with clinical history of resistant hypertension despite typical medical therapy and lifestyle changes.[1][4] Hypertension may be asymptomatic[2] or may lead to symptoms such as headache, dizziness, vision changes, or kidney disease.[4] Symptoms of hypokalemia include fatigue, muscular weakness, and increased urine production.[4][2] ## Diagnosis[edit] In patients with hypertension, diagnostic clues pointing to pseudohyperaldosteronism can be found on routine labwork. These include low serum potassium (hypokalemia), elevated serum sodium (hypernatremia), and elevated serum bicarbonate (metabolic alkalosis).[1] Urine studies may show elevated urine potassium (kaliuresis). To further differentiate between hyperaldosteronism and pseudohyperaldosteronism, studies including plasma renin activity (PRA) and plasma aldosterone concentration (PAC) can be obtained.[1][2] Pseudohyperaldosteronism will exhibit low levels of both PRA and PAC while hyperaldosteronism will demonstrate elevated PAC.[1] Confirmatory tests to diagnose the specific forms of pseudohyperaldosteronism vary depending on the cause. The genetic conditions such as Liddle's syndrome and CAH can be confirmed with genetic tests for the affected genes.[1][4] CAH can also be confirmed by analyzing enzyme levels following ACTH stimulation testing.[1] AME can be diagnosed with a 24 hour urine collection exhibiting an increased ratio of urinary cortisol to urinary cortisone.[1] ## Treatment[edit] Specific treatment of pseudohyperaldosteronism depends on the inciting cause. General management focuses on countering the effects of excess mineralocorticoid activity to achieve adequate blood pressure control and avoid end-organ damage and cardiovascular mortality.[1] In some cases, specific antihypertensive medications may be recommended. In Liddle's syndrome, ENaC-binding potassium-sparing diuretics (e.g. amiloride or triamterene) are used to counter the excess ENaC activity.[4][9][2] In AME, the mineralocorticoid receptor-binding potassium-sparing diuretics (e.g. spironolactone or eplerenone) are used to limit aldosterone receptor activity.[1] Other medications such as glucocorticoids are added in AME and CAH to inhibit ACTH and further cortisol production.[1] Lifestyle changes such as a low sodium diet are also used for managing hypertension,[1][2] and cessation of licorice intake is recommended in cases of licorice overconsumption.[1][3] ## See also[edit] * Apparent mineralocorticoid excess syndrome * Primary aldosteronism * Secondary hypertension ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Raina, Rupesh; Krishnappa, Vinod; Das, Abhijit; Amin, Harshesh; Radhakrishnan, Yeshwanter; Nair, Nikhil R.; Kusumi, Kirsten (2019-07-01). "Overview of Monogenic or Mendelian Forms of Hypertension". Frontiers in Pediatrics. 7: 263. doi:10.3389/fped.2019.00263. ISSN 2296-2360. PMC 6613461. PMID 31312622. 2. ^ a b c d e f g h i j k l Mubarik, Ateeq; Anastasopoulou, Catherine; Riahi, Shayan; Aeddula, Narothama R. (2020), "Liddle Syndrome", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30725596, retrieved 2020-10-21 3. ^ a b c d Sabbadin, Chiara; Bordin, Luciana; Donà, Gabriella; Manso, Jacopo; Avruscio, Giampiero; Armanini, Decio (2019). "Licorice: From Pseudohyperaldosteronism to Therapeutic Uses". Frontiers in Endocrinology. 10: 484. doi:10.3389/fendo.2019.00484. ISSN 1664-2392. PMC 6657287. PMID 31379750. 4. ^ a b c d e f g h Tetti, Martina; Monticone, Silvia; Burrello, Jacopo; Matarazzo, Patrizia; Veglio, Franco; Pasini, Barbara; Jeunemaitre, Xavier; Mulatero, Paolo (2018-03-11). "Liddle Syndrome: Review of the Literature and Description of a New Case". International Journal of Molecular Sciences. 19 (3): 812. doi:10.3390/ijms19030812. ISSN 1422-0067. PMC 5877673. PMID 29534496. 5. ^ a b c d Choi, Kyu Bok (June 2007). "Hypertensive Hypokalemic Disorders". Electrolytes & Blood Pressure : E & BP. 5 (1): 34–41. doi:10.5049/EBP.2007.5.1.34. ISSN 1738-5997. PMC 3894504. PMID 24459498. 6. ^ Wada, N.; Kubo, M.; Kijima, H.; Yamane, Y.; Nishikawa, T.; Sasano, H.; Koike, T. (October 1995). "A case of deoxycorticosterone-producing adrenal adenoma". Endocrine Journal. 42 (5): 637–642. doi:10.1507/endocrj.42.637. ISSN 0918-8959. PMID 8574286. 7. ^ Martinez-Aguayo, Alejandro; Fardella, Carlos (2009). "Genetics of hypertensive syndrome". Hormone Research. 71 (5): 253–259. doi:10.1159/000208798. ISSN 1423-0046. PMID 19339789. S2CID 11267816. 8. ^ a b Makino, Toshiaki (2014). "3-Monoglucuronyl glycyrrhretinic acid is a possible marker compound related to licorice-induced pseudoaldosteronism". Biological & Pharmaceutical Bulletin. 37 (6): 898–902. doi:10.1248/bpb.b13-00997. ISSN 1347-5215. PMID 24882402. 9. ^ Hanukoglu, Israel; Hanukoglu, Aaron (2016-04-01). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. ISSN 0378-1119. PMC 4756657. PMID 26772908. ## External links[edit] Classification D * ICD-10: I15.1 * OMIM: 177200 * MeSH: D056929 * DiseasesDB: 7471 External resources * Orphanet: 526 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pseudohyperaldosteronism	c0221043	1,570	wikipedia	https://en.wikipedia.org/wiki/Pseudohyperaldosteronism	2021-01-18T18:41:00	{"mesh": ["D056929"], "wikidata": ["Q524766"]}
For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500. Mapping Cao et al. (1997) studied 2 independent datasets and reported evidence of a susceptibility locus for schizophrenia on 6q but could not confirm linkage to 6p They used a 2-stage approach and nonparametric linkage analysis: allele sharing identical by descent and multipoint maximum likelihood score (MLS) statistics. In the first dataset, they found excess allele sharing for markers on 6q13-q26; the greatest allele sharing was at 6q21-q22.3 at marker D6S416. The multipoint MLS values had a maximum value of 3.06 near D6S278 and of 3.05 at D6S454/D6S423. A second dataset also showed excess allele sharing for 6q13-q26. Lindholm et al. (2001) performed a genome screen on a 12-generation Swedish family in which, among 210 individuals studied, 43 members were involved in an 'affecteds-only' analysis. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. The pedigree was constructed on the basis of church records, old psychiatric records, national registers, and information from a postdoctoral thesis (Sjogren, 1935). All analyses pointed to the same region, 6q25. D6S264, located at 6q25.2, showed a maximum lod score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum lod score of 2.59 when the pedigree's allele frequencies were used. Lindholm et al. (2001) analyzed additional markers in the 6q25 region and found a maximum lod score of 6.6 with marker D6S253, as well as a 6-cM haplotype that segregated, after 12 generations, with most of the affected individuals. Multipoint analysis with markers in the 6q25 region showed a maximum lod score of 7.7. To evaluate the significance of the genome scan, Lindholm et al. (2001) simulated the complete analysis under the assumption of no linkage. The results showed that a lod score greater than 2.2 should be considered as suggestive of linkage, whereas a lod score greater than 3.7 should be considered as significant. On the whole, these results suggested that a common ancestral region was inherited by the affected individuals in this large pedigree. Lindholm et al. (2001) reviewed other reports of a schizophrenia-susceptibility locus on 6q. They concluded that 'the possibility remains that all the studies of the 6q region describe a single schizophrenia locus.' By genomewide linkage analysis in 155 patients with schizophrenia from 21 Arab-Israeli families, Lerer et al. (2003) identified a 12-cM candidate disease locus at 6q23 between markers D6S1715 and D6S292 (nonparametric lod score of 4.29 for 'core' diagnostic category; parametric lod score of 4.16 under a dominant model). By typing additional microsatellite markers in the same patient sample used by Lerer et al. (2003), Levi et al. (2005) defined a 4.96-cM candidate disease region on 6q23 (maximum multipoint parametric lod score of 4.63 at D6S1626 and D6S292 for 'core' criteria and dominant model). The 'core' diagnostic category was defined as schizophrenia (52 cases), schizoaffective disorder, depressed and/or manic (14 cases total), and unspecified functional psychosis (2 cases). Molecular Genetics Duan et al. (2004) reviewed the accumulated support for the reported linkage of schizophrenia to 6q13-q26 by Cao et al. (1997). They focused on the gene cluster on chromosome 6q23.2 which contains a number of prime candidate genes for schizophrenia and found a significant association with SNPs in the gene encoding trace amine receptor-4 (TRAR4, or TAAR6; 608923). Comparative genomic analyses suggested that the associated polymorphisms could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirmed that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	SCHIZOPHRENIA 5	c1864153	1,571	omim	https://www.omim.org/entry/603175	2019-09-22T16:13:15	{"omim": ["603175"], "synonyms": ["Alternative titles", "SCHIZOPHRENIA 5 WITH OR WITHOUT AN AFFECTIVE DISORDER", "SCHIZOPHRENIA SUSCEPTIBILITY LOCUS, CHROMOSOME 6q-RELATED"]}
A number sign (#) is used with this entry because of evidence that hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is caused by compound heterozygous mutation in the LARS2 gene (604544) on chromosome 3p21. One such patient has been reported. Clinical Features Riley et al. (2016) reported a female infant, born of unrelated Pakistani parents, with a lethal multisystem disorder resulting in death at 5 days of age. The pregnancy was complicated by oligohydramnios, fetal growth restriction, hydrops, and anemia, with antenatal scans showing fetal pericardial effusion, ascites, and scalp edema. The infant was delivered prematurely at 29 weeks by emergency cesarean section, and intubated and ventilated from birth. There were multisystem complications, including severe metabolic acidosis with increased lactate, hyaline membrane disease, mild cardiac defects associated with tachyarrhythmias, pulmonary hypertension, thrombocytopenia, and anemia. Bone marrow aspirate showed ringed sideroblasts, and liver samples showed extramedullary hematopoiesis with dyserythropoiesis. Other features included liver dysfunction with disordered coagulation, refractory seizures, and abnormal EEG consistent with diffuse cerebral dysfunction. Head ultrasound was normal; additional imaging was not performed. Immunoblotting showed decreased complex I protein levels in patient muscle (57% of controls), with even larger decreases in patient liver (25% of controls), although activity levels were not sufficiently decreased to be diagnostic for a mitochondrial respiratory chain disorder. Inheritance The transmission pattern of HLASA in the family reported by Riley et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In a female infant with lethal HLASA, Riley et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene: T522N (604544.0001) and A430V (604544.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the A430V variant resulted in an 18-fold loss of catalytic activity, whereas the T522N variant resulted in a 9-fold reduction compared to wildtype. Immunoblot analysis showed normal levels of LARS2 in patient muscle, but about a 50% decrease in patient liver. Levels of mitochondrial complex proteins, particularly complex I, were decreased in patient liver and less so in patient muscle, but not in patient fibroblasts. There was no defect in mitochondrial protein synthesis in patient fibroblasts or induced myotubes, suggesting that the variants only affect tissue with higher energy demands, such as heart and brain. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth restriction CARDIOVASCULAR Heart \- Ventricular septal defect \- Arrhythmias \- Cardiac dysfunction Vascular \- Patent ductus arteriosus \- Pulmonary hypertension RESPIRATORY \- Respiratory insufficiency Lung \- Hyaline membrane disease ABDOMEN Liver \- Liver dysfunction \- Decreased mitochondrial complex I MUSCLE, SOFT TISSUES \- Mildly decreased mitochondrial complex I NEUROLOGIC Central Nervous System \- Seizures \- Abnormal EEG \- Cerebral dysfunction METABOLIC FEATURES \- Lactic acidosis HEMATOLOGY \- Sideroblastic anemia \- Thrombocytopenia \- Coagulation defects due to liver disease PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios \- Fetal hydrops LABORATORY ABNORMALITIES \- Decreased mitochondrial respiratory complex I in liver and muscle MISCELLANEOUS \- Onset at birth \- Death in early infancy \- One patient has been reported (last curated July 2016) MOLECULAR BASIS \- Caused by mutation in the leucyl-tRNA synthetase-2 gene (LARS2, 604544.0001 ) ▲ 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	HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA	c4310761	1,572	omim	https://www.omim.org/entry/617021	2019-09-22T15:47:13	{"omim": ["617021"], "orphanet": ["528091"], "synonyms": []}
A rare, genetic, slowly progressive neurodegenerative disease resulting from GRID2 deficiency characterized by motor, speech and cognitive delay, hypotonia, truncal and appendicular ataxia, and eye movement abnormalities (tonic upgaze, nystagmus, oculomotor apraxia). Intention tremor may also be associated. Brain imaging reveals progressive cerebellar atrophy with cerebellar flocculus particularly affected. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency	c4015505	1,573	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363432	2021-01-23T17:28:16	{"omim": ["616204"], "icd-10": ["G11.1"], "synonyms": ["Autosomal recessive congenital cerebellar ataxia due to ionotropic glutamate receptor delta-2 subunit deficiency", "SCAR18"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article 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. (September 2014) 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: "Face distortion" – news · newspapers · books · scholar · JSTOR (February 2010) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Face distortion derived from the term "distorting the face," refers to the condition of the human face when it comes into contact with an object moving at high enough speed to distort the face. This could result in anything from a concussion, to a broken jaw, to a fractured skull depending on the force of the object while it's moving to when it comes into contact with the face. Most face distortions are shown to be visible only in slow motion, as seen in popular showings of the event. ## Uses in popular culture[edit] Several movies, as well as some anime, involving boxing, martial arts, or other styles of fighting have scenes involving face distortion. Movies like Cinderella Man, which involves American boxing, has a few of these moments. Anime like Bleach and Naruto contain moments of face distortion as well. ## Medical[edit] The medical aspect of a face distortion is usually the case involving the skull, neck, or brain. whatever treatment for the aftermath of a face distortion depends on the condition of the receiver after the event occurs. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Face distortion	c4072832	1,574	wikipedia	https://en.wikipedia.org/wiki/Face_distortion	2021-01-18T19:03:17	{"umls": ["C4072832"], "wikidata": ["Q5428354"]}
A number sign (#) is used with this entry because congenital disorder of glycosylation type If (CDG1F) is caused by homozygous or compound heterozygous mutation in the MPDU1 gene (604041) on chromosome 17p13. Description Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579). Clinical Features Schenk et al. (2001) described 3 unrelated patients with clinical features consistent with a congenital disorder of glycosylation. Patient 'S' had intractable seizures from birth, severe feeding difficulties, no psychomotor development, and patchy desquamation over his entire body. His seizures worsened, accompanied by recurrent apnea leading to his death at age 10 months. Patient 'L' had hypertonia, an ichthyosis-like skin disorder, and psychomotor and growth retardation. At age 16 years, she had severe dwarfism, a developmental level of 1 year, and unchanged skin disease. Patient 'A' had severe psychomotor retardation but no growth or skin problems; he had seizures that responded well to valproate. At the age of 10 years his developmental age was about 2.5 years. Isoelectric focusing of serum transferrin from the 3 patients revealed hypoglycosylation in a type I-like pattern. The patients' fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation, and transfer of incomplete oligosaccharides to protein was detected. Kranz et al. (2001) reported a patient with CDG If who had severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision. Molecular Genetics In 3 unrelated patients with type I CDG, Schenk et al. (2001) identified mutations in the MPDU1 gene: 2 patients ('S' and 'A') of consanguineous parents were homozygotes (604041.0001 and 604041.0002, respectively) and the other (patient 'L') was a compound heterozygote (604041.0003 and 604041.0004). Defects in MPDU1 defined a new glycosylation disorder, CDG If. In a patient with CDG If, Kranz et al. (2001) identified a homozygous point mutation in the MPDU1 gene (604041.0005). The parents were not known to be consanguineous, but both families had lived in the same village for generations. Kranz et al. (2001) stated that this was the first glycosylation disorder to affect the use, rather than the biosynthesis, of donor substrates for lipid-linked oligosaccharides. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive \- Poor overall growth HEAD & NECK Head \- Microcephaly Eyes \- Lack of visual fixation \- Amaurosis \- Nystagmus \- Strabismus \- Absent electroretinogram response (2 patients) \- Optic atrophy \- Pale papillae RESPIRATORY \- Apnea, recurrent (1 patient) ABDOMEN Gastrointestinal \- Poor feeding (in some patients) SKELETAL \- Contractures SKIN, NAILS, & HAIR Skin \- Dry skin \- Scaly skin \- Hyperkeratosis \- Erythroderma \- Patchy desquamation MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Lack of development (1 patient) \- Hypertonia (1 patient) \- Inability to stand or walk alone \- Ataxia \- Lack of speech \- Seizures \- Cerebral atrophy HEMATOLOGY \- Coagulopathy, mild (in some patients) LABORATORY ABNORMALITIES \- Type 1 hypoglycosylation pattern of serum transferrin \- Accumulation of truncated oligosaccharides Man(5)GlcNAc2 and Man(9)GlcNAc(2) MISCELLANEOUS \- Onset at birth \- Variable disease course \- Four unrelated patients have been reported (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the mannose-P-dolichol utilization defect 1 gene (MPDU1, 604041.0001 ) ▲ 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	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE If	c1836669	1,575	omim	https://www.omim.org/entry/609180	2019-09-22T16:06:33	{"doid": ["0080558"], "mesh": ["C535744"], "omim": ["609180"], "orphanet": ["79323"], "synonyms": ["Alternative titles", "CDG If"]}
## Summary ### Clinical characteristics. Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are the presence of HGA in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Oxidation of the HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark on standing. Ochronosis occurs only after age 30 years; arthritis often begins in the third decade. Other manifestations include pigment deposition, aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation, renal stones, and prostate stones. ### Diagnosis/testing. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between one and eight grams. Identification of biallelic pathogenic variants in HGD on molecular genetic testing confirms the diagnosis and allows family studies. ### Management. Treatment of manifestations: Management of joint pain tailored to the individual; physical and occupational therapy to help maintain muscle strength and flexibility; knee, hip, and shoulder replacements when needed; surgical intervention for prostate stones and renal stones as needed; aortic stenosis may necessitate valve replacement. Surveillance: In individuals older than age 40 years, echocardiography to detect aortic dilation, aortic or mitral valve calcification, and stenosis; CT to detect coronary artery calcification. Agents/circumstances to avoid: Physical stress to the spine and large joints, including heavy manual labor or high-impact sports, to try to reduce progression of severe arthritis. Evaluation of relatives at risk: Testing for the presence of elevated urinary HGA in sibs of affected individuals allows for early diagnosis and intervention to prevent secondary complications. ### Genetic counseling. Alkaptonuria 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. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if both HGD pathogenic variants in the family are known. ## Diagnosis ### Suggestive Findings Alkaptonuria should be suspected in individuals with any of the following major features: * Dark urine or urine that turns dark on standing. Oxidation of homogentisic acid (HGA) excreted in the urine produces a melanin-like product and causes the urine to turn dark on standing. Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent. However, darkening may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine. * Ochronosis (bluish-black pigmentation of connective tissue). Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis (Figure 1). * Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision [Chévez Barrios & Font 2004]. * Ear cartilage pigmentation is seen in the concha and antihelix. The cartilage is slate blue or gray and feels irregular or thickened. Calcification of the ear cartilage may be observed on radiographs. * Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. * A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. * Arthritis, often beginning in the spine and resembling ankylosing spondylitis in its large-joint distribution. Radiographs of the spine showing flattened and calcified intervertebral disks are pathognomonic (Figure 1). Findings include degeneration of the intervertebral disks followed by disk calcification and eventually fusion of the vertebral bodies. Osteophyte formation and calcification of the intervertebral ligaments also occur. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and osteophyte formation. Enthesopathy can be seen at the muscle insertions [Mannoni et al 2004]. #### Figure 1 A. Ochronosis of the sclera of the eye B. Ochronosis of the antihelix and concha ### Establishing the Diagnosis The diagnosis of alkaptonuria is established in a proband with the following: #### Biochemical Findings Elevated homogentisic acid (HGA) in the urine. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in a urine sample by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between one and eight grams. A normal 24-hour urine sample contains 20-30 mg of HGA. Notes: (1) Elevated HGA can be detected on a random urine sample. (2) Biochemical testing cannot detect the carrier state. #### Molecular Genetic Findings Identification of biallelic pathogenic variants in HGD on molecular genetic testing (see Table 1) is not required to establish the diagnosis in a proband. However, molecular genetic testing is needed in order to provide carrier testing and prenatal test result interpretation for at-risk family members. Molecular testing approaches can include single-gene testing and genome sequencing. * Single-gene testing. Sequence analysis of HGD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Note: Targeted analysis for pathogenic variants may be performed first in individuals of Slovak ancestry. Pathogenic variants included in a panel may vary by laboratory. * Comprehensive genome sequencing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of alkaptonuria. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Alkaptonuria View in own window Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method HGDSequence analysis 390% Gene-targeted deletion/duplication analysis 42 individuals 5 Targeted analysis for pathogenic variants>80% 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. 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. 5\. To date, only two individuals with deletions involving HGD have been reported [Zouheir Habbal et al 2014, Nemethova et al 2016]. 6\. Four pathogenic variants (c.481G>A, c.457dup, c.808G>A, and c.1111dup) represent Slovak founder variants, accounting for 80% of all pathogenic variants found in the Slovak population. Six pathogenic variants c.688C>T, c.899T>G, c.174delA, c.16-1G>A, c.342+1G>A, and c.140C>T are common in other populations, but rare in the Slovak population. ## Clinical Characteristics ### Clinical Description The clinical findings of alkaptonuria include darkening of urine on standing as a result of the presence of homogentisic acid (HGA) and its oxidation products, connective tissue ochronosis, and arthritis of the spine and larger joints. HGA excretion and disease severity can vary significantly within the same family. In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. Alkaptonuria does not cause developmental delay or cognitive impairment and does not generally reduce the life span of affected individuals. Urinary changes. Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent. However, darkening may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine. Connective tissue. In general, pigmentary changes are observed after age 30 years. Tendon-related findings, including a thickened Achilles tendon, tendonitis, and rupture, have also been observed clinically [Phornphutkul et al 2002] and are demonstrable by MRI. Joints. Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Joint symptoms involving the spine usually appear in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [Phornphutkul et al 2002]. Lumbar and thoracic spine symptoms precede cervical spine symptoms. The sacroiliac region is usually spared. Limitation of spine flexion directly correlates with degree of disability. Individuals with decreased forward flexion demonstrate impaired function and increased fatigue [Perry et al 2006]. Joint disease appears to start earlier and progress more rapidly in males than in females. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years [Phornphutkul et al 2002]. Small joint involvement is not significant. Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction [Introne et al 2002]. Other organ involvement * Heart. Pigment deposition in the heart valves and blood vessels leads to aortic or mitral valve calcification with stenosis or regurgitation and occasionally aortic dilatation. Aortic valve stenosis occurs at a high frequency in the sixth and seventh decades of life. Unlike cardiac valve disease that occurs in the general population, there is no correlation with standard cardiovascular risk factors. Aortic stenosis may necessitate aortic valve replacement. Coronary artery calcification has been demonstrated on chest CT [Hannoush et al 2012]. * Renal stones. By age 64 years, 50% of individuals with alkaptonuria have a history of renal stones. * Prostate stones. Black prostate stones occur relatively frequently in individuals with alkaptonuria. In one series, eight of 27 men age 31-60 years had prostate stones. Prostate stones may contribute to recurrent infection or urinary obstruction and require surgical removal. ### Genotype-Phenotype Correlations No correlation is observed between the type of HGD pathogenic variant and amount of HGA excreted or disease severity. ### Penetrance Elevated urinary HGA and ochronotic arthritis occur in all individuals who are homozygous or compound heterozygous for pathogenic variants in HGD. ### Nomenclature Occasionally alkaptonuria is referred to collectively (and incorrectly) as ochronosis. ### Prevalence At least 1000 affected individuals have been described in the literature; this is likely an underestimate. The incidence of alkaptonuria in the US is estimated at 1:250,000 to 1:1,000,000 live births. Alkaptonuria occurs worldwide; a high prevalence has been observed in the Dominican Republic and in northwestern Slovakia, likely as the result of a founder effect. The prevalence of alkaptonuria in Slovakia is estimated at 1:19,000 [Zatkova et al 2003]. ## Differential Diagnosis Ochronosis. Ochronosis resulting from alkaptonuria may be confused with acquired, reversible pigmentary changes following prolonged use of carbolic acid dressings for chronic cutaneous ulcers [La Du 2001]. Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrine® [Ludwig et al 1963], the skin-lightening agent hydroquinone, or the antibiotic minocycline [Suwannarat et al 2004]. In one individual with alkaptonuria, the ochronotic pigment in the eye was misdiagnosed as melanosarcoma, resulting in enucleation of the eye [Skinsnes 1948]. A thorough history combined with lack of excessive HGA excretion in the urine should eliminate false positive diagnoses. Arthritis. The arthritis of alkaptonuria resembles ankylosing spondylitis in its damage to the spine and large joints, although it differs in sparing the sacroiliac joint and in its radiographic appearance. Radiographic findings of the spine also differentiate alkaptonuria from rheumatoid arthritis and osteoarthritis. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the following evaluations are recommended: * Complete history and physical examination with particular attention to range of motion in the spine and large joints * Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs * Electrocardiogram and echocardiogram in individuals older than age 40 years * Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Joint pain is substantial in individuals with alkaptonuria, and close attention to pain control is necessary. Optimal pain management should be tailored to the individual with close follow up and long-term management. Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Knee, hip, and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis [Spencer et al 2004]. Aortic stenosis may necessitate valve replacement. Treatment of prostate stones and renal stones may include surgical intervention. ### Prevention of Primary Manifestations Although several therapeutic modalities have been investigated, no preventive or curative treatment is available. See Therapies Under Investigation. ### Prevention of Secondary Manifestations Maintaining joint range of motion through moderate non-weight-bearing exercise such as swimming may have beneficial effects. Younger individuals with alkaptonuria should be directed toward non-contact and lower-impact sports. ### Surveillance Cardiac. Surveillance for cardiac complications every one to two years is advisable after age 40 years and should include: * Echocardiography to detect aortic dilation and aortic or mitral valve calcification and stenosis; * Surveillance CT scans (according to the recommendation of a cardiologist) in affected individuals with coronary artery calcification. Urology. Urologic complications become more prevalent after age 40 years: * Routine surveillance is not recommended, but awareness of this potential complication is advised. * Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT. ### Agents/Circumstances to Avoid Avoidance of physical stress to the spine and large joints, including heavy manual labor or high-impact sports, may reduce the progression of severe arthritis. ### Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from preventive measures. Those found to have alkaptonuria should be counseled to avoid high-impact and contact sports. Career considerations include avoidance of occupations involving heavy physical labor. Instruction on joint strengthening and flexibility exercises, in conjunction with appropriate physical activity, can help preserve overall joint mobility and function. Evaluations can include: * Biochemical testing for the presence of elevated urinary homogentisic acid (HGA). * Molecular genetic testing if the pathogenic variants in the family are known. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Pharmacologic treatment of alkaptonuria with oral administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) or nitisinone has been proposed [Anikster et al 1998]. Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone is approved for the treatment of tyrosinemia type I. Nitisinone reduced urinary HGA excretion by at least 69% in two individuals, but at the expense of an elevated plasma tyrosine concentration [Phornphutkul et al 2002], resulting in photophobia. The only other known side effect is (rarely) corneal crystals. Theoretically, neurologic complications associated with tyrosinemia type III may develop. In a pilot study, low-dose nitisinone reduced urinary HGA by up to 95% in nine individuals with alkaptonuria. In the same study, seven individuals were treated for up to 15 weeks with nitisinone while receiving normal protein intake; all had elevated plasma tyrosine concentrations. No ophthalmic, neurologic, or severe dermatologic complications were observed. Two individuals had transient elevations in liver transaminase levels that returned to normal after stopping nitisinone [Suwannarat et al 2005]. In a three-year therapeutic trial, 2 mg of nitisinone daily reduced urine and plasma HGA by 95% throughout the study duration [Introne et al 2011]. Plasma tyrosine averaged 800μM without dietary restriction. Side effects were minimal. One affected individual developed corneal crystals that required discontinuation of nitisinone, and one affected individual had elevated liver transaminases. Statistically significant improvement in hip range of motion and measurements of musculoskeletal function were not observed in the treatment group compared to the control group; however there was a positive trend showing slowing of aortic stenosis. Additional trials are currently underway to establish clinical benefit. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. ### Other No therapy is proven to prevent or correct the pigmentary changes of ochronosis. * Dietary restriction of phenylalanine and tyrosine has been proposed to reduce the production of HGA, but severe restriction of these amino acids is not practical in the long term and may be dangerous. * High-dose vitamin C decreases urinary benzoquinone acetic acid, a derivative of HGA, but has no effect on HGA excretion [Wolff et al 1989]. It has been hypothesized that high-dose ascorbic acid may prevent the deposition of ochronotic pigment, although it does not alter the basic metabolic defect [Wolff et al 1989]. No credible studies have demonstrated the clinical efficacy of ascorbic acid [La Du 2001]. * Oral bisphosphonate therapy has been suggested to halt the progressive bone loss; however, a prospective study of four affected individuals failed to demonstrate benefit [Aliberti et al 2007]. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Alkaptonuria	c0002066	1,576	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1454/	2021-01-18T20:46:50	{"mesh": ["D000474"], "synonyms": ["Alcaptonuria"]}
Post-traumatic epilepsy SpecialtyNeurology Post-traumatic epilepsy (PTE) is a form of acquired epilepsy that results from brain damage caused by physical trauma to the brain (traumatic brain injury, abbreviated TBI).[1] A person with PTE suffers repeated post-traumatic seizures (PTS, seizures that result from TBI) more than a week after the initial injury.[2] PTE is estimated to constitute 5% of all cases of epilepsy and over 20% of cases of acquired epilepsy[3][4][1] (in which seizures are caused by an identifiable organic brain condition).[5] It is not known how to predict who will develop epilepsy after TBI and who will not.[6] However, the likelihood that a person will develop PTE is influenced by the severity and type of injury; for example penetrating injuries and those that involve bleeding within the brain confer a higher risk. The onset of PTE can occur within a short time of the physical trauma that causes it, or months or years after.[3] People with head trauma may remain at a higher risk for post-traumatic seizures than the general population even decades after the injury.[7] PTE may be caused by several biochemical processes that occur in the brain after trauma, including overexcitation of brain cells and damage to brain tissues by free radicals.[8] Diagnostic measures include electroencephalography (EEG) and brain imaging techniques such as magnetic resonance imaging, but these are not totally reliable. Antiepileptic drugs do not prevent the development of PTE after head injury, but may be used to treat the condition if it does occur. When medication does not work to control the seizures, surgery may be needed.[9] Modern surgical techniques for PTE have their roots in the 19th century, but trepanation (cutting a hole in the skull) may have been used for the condition in ancient cultures.[10] ## Contents * 1 Classification * 2 Causes * 2.1 Genetics * 2.2 Severity of trauma * 2.3 Nature of trauma * 2.4 Post-traumatic seizures * 3 Pathophysiology * 4 Diagnosis * 5 Prevention * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 History * 10 Research * 11 See also * 12 References * 13 External links ## Classification[edit] Seizures may occur after traumatic brain injury; these are known as post-traumatic seizures (PTS). However, not everyone who has post-traumatic seizures will continue to have post-traumatic epilepsy, because the latter is a chronic condition. However, the terms PTS and PTE are used interchangeably in medical literature.[11][12] Seizures due to post-traumatic epilepsy are differentiated from non-epileptic post-traumatic seizures based on their cause and timing after the trauma. A person with PTE suffers late seizures, those occurring more than a week after the initial trauma.[13] Late seizures are considered to be unprovoked, while early seizures (those occurring within a week of trauma) are thought to result from direct effects of the injury. A provoked seizure is one that results from an exceptional, nonrecurring cause such as the immediate effects of trauma rather than a defect in the brain; it is not an indication of epilepsy.[14] Thus for a diagnosis of PTE, seizures must be unprovoked. Disagreement exists about whether to define PTE as the occurrence of one or more late, unprovoked seizures, or whether the condition should only be diagnosed in people with two or more.[15] Medical sources usually consider PTE to be present if even one unprovoked seizure occurs, but more recently it has become accepted to restrict the definition of all types of epilepsy to include only conditions in which more than one occur.[11] Requiring more than one seizure for a diagnosis of PTE is more in line with the modern definition of epilepsy, but it eliminates people for whom seizures are controlled by medication after the first seizure.[11] As with other forms of epilepsy, seizure types in PTE may be partial (affecting only part of one hemisphere of the brain) or generalized (affecting both hemispheres and associated with loss of consciousness).[16] In about a third of cases, people with PTE have partial seizures; these may be simple or complex.[17] In simple partial seizures, level of consciousness is not altered, while in complex partial seizures consciousness is impaired.[14] When generalized seizures occur, they may start out as partial seizures and then spread to become generalized.[17] ## Causes[edit] Cumulative incidence after 30 years of PTE in head injured individuals[18] It is not clear why some patients develop PTE while others with very similar injuries do not.[11] However, possible risk factors have been identified, including severity and type of injury, presence of early seizures, and genetic factors. ### Genetics[edit] Genetics may play a role in the risk that a person will develop PTE; people with the ApoE-ε4 allele may be at higher risk for PTE.[7] The haptoglobin Hp2-2 allele may be another genetic risk factor, possibly because it binds hemoglobin poorly and thus allows more iron to escape and damage tissues.[7] However, most studies have found that having family members with epilepsy does not significantly increase the risk of PTS,[11] suggesting that genetics are not a strong risk factor. ### Severity of trauma[edit] The more severe the brain trauma is, the more likely a person is to suffer late PTE.[19] Evidence suggests that mild head injuries do not confer an increased risk of developing PTE, while more severe types do.[20] In simple mild TBI, the risk for PTE is about 1.5 times that of the uninjured population.[18] By some estimates, as many as half of sufferers of severe brain trauma experience PTE;[19] other estimates place the risk at 5% for all TBI patients and 15–20% for severe TBI.[21] One study found that the 30-year risk of developing PTE was 2.1% for mild TBI, 4.2% for moderate, and 16.7% for severe injuries, as shown in the chart at right.[18][22] ### Nature of trauma[edit] The nature of the head trauma also influences the risk of PTE. People who suffer depressed skull fractures, penetrating head trauma, early PTS, and intracerebral and subdural haematomas due to the TBI are especially likely to suffer PTE, which occurs in more than 30% of people with any one of these findings.[19] About 50% of patients with penetrating head trauma develop PTE,[8][20] and missile injuries and loss of brain volume are associated with an especially high likelihood of developing the condition.[23] Injuries that occur in military settings carry higher-than-usual risk for PTE, probably because they more commonly involve penetrating brain injury and brain damage over a more widespread area.[7] Intracranial hematomas, in which blood accumulates inside the skull, are one of the most important risk factors for PTE.[24] Subdural hematoma confers a higher risk of PTE than does epidural hematoma, possibly because it causes more damage to brain tissue.[8] Repeated intracranial surgery confers a high risk for late PTE, possibly because people who need more surgery are more likely to have factors associated with worse brain trauma such as large hematomas or cerebral swelling.[8] In addition, the chances of developing PTE differ by the location of the brain lesion: brain contusion that occurs on in one or the other of the frontal lobes has been found to carry a 20% PTE risk, while a contusion in one of the parietal lobes carries a 19% risk and one in a temporal lobe carries a 16% chance.[22] When contusions occur in both hemispheres, the risk is 26% for the frontal lobes, 66% for the parietal, and 31% for the temporal.[22] ### Post-traumatic seizures[edit] The risk that a person will develop PTE is heightened but not 100% if PTS occur.[20] Because many of the risk factors for both PTE and early PTS are the same, it is unknown whether the occurrence of PTS is a risk factor in and of itself.[7] However, even independent of other common risk factors, early PTS have been found to increase the risk of PTE to over 25% in most studies.[4] A person who has one late seizure is at even greater risk for having another than one who has early PTS; epilepsy occurs in 80% of people who have a late seizure.[25] Status epilepticus, a continuous seizure or multiple seizures in rapid succession, is especially strongly correlated with the development of PTE; status seizures occur in 6% of all TBIs but are associated with PTE 42% of the time, and quickly halting a status seizure reduces chances of PTE development.[22] ## Pathophysiology[edit] For unknown reasons, trauma can cause changes in the brain that lead to epilepsy.[3][26] There are a number of proposed mechanisms by which TBI causes PTE, more than one of which may be present in a given person.[8] In the period between a brain injury and onset of epilepsy, brain cells may form new synapses and axons, undergo apoptosis or necrosis, and experience altered gene expression.[25] In addition, damage to particularly vulnerable areas of the cortex such as the hippocampus may give rise to PTE.[4] Blood that gathers in the brain after an injury may damage brain tissue and thereby cause epilepsy.[8] Products that result from the breakdown of hemoglobin from blood may be toxic to brain tissue.[8] The "iron hypothesis" holds that PTE is due to damage by oxygen free radicals, the formation of which is catalyzed by iron from blood.[19] Animal experiments using rats have shown that epileptic seizures can be produced by injecting iron into the brain.[8] Iron catalyzes the formation of hydroxyl radicals by the Haber-Weiss reaction;[8] such free radicals damage brain cells by peroxidizing lipids in their membranes.[27] The iron from blood also reduces the activity of an enzyme called nitric oxide synthase, another factor thought to contribute to PTE.[19] After TBI, abnormalities exist in the release of neurotransmitters, chemicals used by brain cells to communicate with each other; these abnormalities may play a role in the development of PTE.[8] TBI may lead to the excessive release of glutamate and other excitatory neurotransmitters (those that stimulate brain cells and increase the likelihood that they will fire). This excessive glutamate release can lead to excitotoxicity, damage to brain cells through overactivation of the biochemical receptors that bind and respond to excitatory neurotransmitters. Overactivation of glutamate receptors damages neurons; for example it leads to the formation of free radicals.[8] Excitotoxicity is a possible factor in the development of PTE;[13] it may lead to the formation of a chronic epileptogenic focus.[8] An epileptic focus is the part of the brain from which epileptic discharges originate.[28] In addition to chemical changes in cells, structural changes that lead to epilepsy may occur in the brain.[3] Seizures that occur shortly after TBI can reorganize neural networks and cause seizures to occur repeatedly and spontaneously later on.[4] The kindling hypothesis suggests that new neural connections are formed in the brain and cause an increase in excitability.[19] The word kindling is a metaphor: the way the brain's response to stimuli increases over repeated exposures is similar to the way small burning twigs can produce a large fire.[29] This reorganization of neural networks may make them more excitable.[4] Neurons that are in a hyperexcitable state due to trauma may create an epileptic focus in the brain that leads to seizures.[12] In addition, an increase in neurons' excitability may accompany loss of inhibitory neurons that normally serve to reduce the likelihood that other neurons will fire; these changes may also produce PTE.[4] ## Diagnosis[edit] EEG shows abnormal activity in some types of seizure disorder, but may or may not display abnormal findings in PTE. To be diagnosed with PTE, a person must have a history of head trauma and no history of seizures prior to the injury.[30] Witnessing a seizure is the most effective way to diagnose PTE.[12] Electroencephalography (EEG) is a tool used to diagnose a seizure disorder, but a large portion of people with PTE may not have the abnormal "epileptiform" EEG findings indicative of epilepsy.[12] In one study, about a fifth of people who had normal EEGs three months after an injury later developed PTE. However, while EEG is not useful for predicting who will develop PTE, it can be useful to localize the epileptic focus, to determine severity, and to predict whether a person will suffer more seizures if they stop taking antiepileptic medications.[8] Magnetic resonance imaging (MRI) is performed in people with PTE, and CT scanning can be used to detect brain lesions if MRI is unavailable.[8] However, it is frequently not possible to detect the epileptic focus using neuroimaging.[31] For a diagnosis of PTE, seizures must not be attributable to another obvious cause.[4] Seizures that occur after head injury are not necessarily due to epilepsy or even to the head trauma.[11] Like anyone else, TBI survivors may suffer seizures due to factors including imbalances of fluid or electrolytes, epilepsy from other causes, hypoxia (insufficient oxygen), and ischemia (insufficient blood flow to the brain).[11] Withdrawal from alcohol is another potential cause of seizures.[32] Thus these factors must be ruled out as causes of seizures in people with head injury before a diagnosis of PTE can be made. ## Prevention[edit] Prevention of PTE involves preventing brain trauma in general; protective measures include bicycle helmets and child safety seats.[8] No specific treatment exists to prevent the development of epilepsy after TBI occurs.[3] In the past, antiepileptic drugs were used with the intent of preventing the development of PTE.[3] However, while antiepileptic drugs can prevent early PTS, clinical studies have failed to show that prophylactic use of antiepileptic drugs prevents the development of PTE.[2][3][7][33] Why antiepileptic drugs in clinical trials have failed to stop PTE from developing is not clear, but several explanations have been offered.[7] The drugs may simply not be capable of preventing epilepsy, or the drug trials may have been set up in a way that did not allow a benefit of the drugs to be found (e.g. drugs may have been given too late or in inadequate doses).[7] Animal studies have similarly failed to show much protective effect of the most commonly used seizure medications in PTE trials, such as phenytoin and carbamazepine.[7] Antiepileptic drugs are recommended to prevent late seizures only for people in whom PTE has already been diagnosed, not as a preventative measure.[34] On the basis of the aforementioned studies, no treatment is widely accepted to prevent the development of epilepsy.[19] However, it has been proposed that a narrow window of about one hour after TBI may exist during which administration of antiepileptics could prevent epileptogenesis (the development of epilepsy).[9] Corticosteroids have also been investigated for the prevention of PTE, but clinical trials revealed that the drugs did not reduce late PTS and were actually linked to an increase in the number of early PTS.[3] ## Treatment[edit] Carbamazepine, commonly used to treat PTE Antiepileptic drugs may be given to prevent further seizures; these drugs completely eliminate seizures for about 35% of people with PTE.[22] However, antiepileptics only prevent seizures while they are being taken; they do not reduce the occurrence once the patient stops taking the drugs.[2] Medication may be stopped after seizures have been controlled for two years.[4] PTE is commonly difficult to treat with drug therapy,[3][35] and antiepileptic drugs may be associated with side effects.[34] The antiepileptics carbamazepine and valproate are the most common drugs used to treat PTE; phenytoin may also be used but may increase risk of cognitive side effects such as impaired thinking.[9] Other drugs commonly used to treat PTE include clonazepam, phenobarbitol, primidone, gabapentin, and ethosuximide.[12] Among antiepileptic drugs tested for seizure prevention after TBI (phenytoin, sodium valproate, carbamazepine, phenobarbital), no evidence from randomized controlled trials has shown superiority of one over another.[8] People whose PTE does not respond to medication may undergo surgery to remove the epileptogenic focus, the part of the brain that is causing the seizures.[9] However surgery for PTE may be more difficult than it is for epilepsy due to other causes,[9] and is less likely to be helpful in PTE than in other forms of epilepsy.[8] It can be particularly difficult in PTE to localize the epileptic focus, in part because TBI may affect diffuse areas of the brain.[31] Difficulty locating the seizure focus is seen as a deterrent to surgery.[4] However, for people with sclerosis in the mesial temporal lobe (in the inner aspect of the temporal lobe), who comprise about one third of people with intractable PTE, surgery is likely to have good outcome.[4] When there are multiple epileptic foci or the focus cannot be localized, and drug therapy is not effective, vagus nerve stimulation is another option for treating PTE.[31] People with PTE have follow-up visits, in which health care providers monitor neurological and neuropsychological function and assess the efficacy and side effects of medications.[8] As with sufferers of other types of epilepsy, PTE sufferers are advised to exercise caution when performing activities for which seizures could be particularly risky, such as rock climbing.[9] ## Prognosis[edit] The prognosis for epilepsy due to trauma is worse than that for epilepsy of undetermined cause.[20] People with PTE are thought to have shorter life expectancies than people with brain injury who do not suffer from seizures.[12] Compared to people with similar structural brain injuries but without PTE, people with PTE take longer to recover from the injury, have more cognitive and motor problems, and perform worse at everyday tasks.[12] This finding may suggest that PTE is an indicator of a more severe brain injury, rather than a complication that itself worsens outcome.[12] PTE has also been found to be associated with worse social and functional outcomes but not to worsen patients' rehabilitation or ability to return to work.[8] However, people with PTE may have trouble finding employment if they admit to having seizures, especially if their work involves operating heavy machinery.[36] The period of time between an injury and development of epilepsy varies, and it is not uncommon for an injury to be followed by a latent period with no recurrent seizures.[25] The longer a person goes without developing seizures, the lower the chances are that epilepsy will develop.[4] At least 80–90% of people with PTE have their first seizure within two years of the TBI.[8] People with no seizures within three years of the injury have only a 5% chance of developing epilepsy.[37] However, one study found that head trauma survivors are at an increased risk for PTE as many as 10 years after moderate TBI and over 20 years after severe TBI.[7] Since head trauma is fairly common and epilepsy can occur late after the injury, it can be difficult to determine whether a case of epilepsy resulted from head trauma in the past or whether the trauma was incidental.[31] The question of how long a person with PTE remains at higher risk for seizures than the general population is controversial.[7] About half of PTE cases go into remission, but cases that occur later may have a smaller chance of doing so.[20] ## Epidemiology[edit] Studies have found that the incidence of PTE ranges between 1.9 and more than 30% of TBI sufferers, varying by severity of injury and by the amount of time after TBI for which the studies followed subjects.[7] Brain trauma is one of the strongest predisposing factors for epilepsy development, and is an especially important factor in young adults.[22] Young adults, who are at the highest risk for head injury, also have the highest rate of PTE,[8] which is the largest cause of new-onset epilepsy cases in young people.[38] Children have a lower risk for developing epilepsy; 10% of children with severe TBI and 16–20% of similarly injured adults develop PTE.[22] Being older than 65 is also a predictive factor in the development of epilepsy after brain trauma.[25] One study found PTE to be more common in male TBI survivors than in females.[12] ## History[edit] Benjamin Winslow Dudley performed trepanation for PTE before antisepsis was available. Records of PTE exist from as early as 3000 BC.[36] Trepanation, in which a hole is cut in the skull, may have been used to treat PTE in ancient cultures.[10] In the early 19th century, the surgeons Baron Larrey and WC Wells each reported having performed the operation for PTE.[10] The French-educated American surgeon Benjamin Winslow Dudley (1785–1870) performed six trepanations for PTE between the years of 1819 and 1832 in Kentucky and had good results despite the unavailability of antisepsis.[39] The surgery involved opening the skull at the site of injury, debriding injured tissue, and sometimes draining blood or fluid from under the dura mater.[39] Dudley's work was the largest series of its kind that had been done up to that point, and it encouraged other surgeons to use trepanation for post-traumatic seizures.[39] His reports on the operations came before it was accepted that surgery to relieve excess pressure within the skull was effective in treating epilepsy, but it helped set the stage for trepanation for PTE to become common practice.[39] The procedure became more accepted in the late 19th century once antisepsis was available and cerebral localization was a familiar concept.[39] However, in 1890, the prominent German physician Ernest von Bergmann criticized the procedure; he questioned its efficacy (except in particular circumstances) and suggested that operations had been declared successful too soon after the procedures to know whether they would confer a long-term benefit.[10] The late 19th century saw the advent of intracranial surgery, operating on brain lesions believed to be causing seizures, a step beyond cranial surgery which involved just the skull and meninges.[10] By 1893, at least 42 intracranial operations had been performed for PTE in the US, with limited success.[10] Surgery was the standard treatment for PTE until the years following World War II, when the condition received more attention as soldiers who had survived head trauma developed it.[19] The increased need for drugs to treat PTE led to trials with antiepileptics; these early trials suggested that the drugs could prevent epileptogenesis (the development of epilepsy).[19] It was still thought that antiepileptic drugs could prevent epileptogeneis in the 1970s;[27] in 1973, 60% of physicians surveyed used them to prevent PTE.[33] However, the clinical trials which had supported a protective effect of antiepileptics were uncontrolled; in later, controlled trials the drugs failed to demonstrate an antiepileptogenic effect.[40] Studies did show that antiepileptics prevented seizures occurring within a week after injury, and in 1995 the task force of the Brain Trauma Foundation published a recommendation suggesting their use to protect against seizures early after trauma.[33] However, recommendations were published against the prophylactic use of antiepileptic drugs more than a week after injury by the Brain Injury Special Interest group of the American Academy of Physical Medicine and Rehabilitation in 1998 and by the American Association of Neurological Surgeons in 2000.[12] ## Research[edit] How epilepsy develops after an injury to the brain is not fully understood, and gaining such understanding may help researchers find ways to prevent it, or make it less severe or easier to treat.[22] Researchers hope to identify biomarkers, biological indications that epileptogenesis is occurring, as a means to find drugs that can target pathways by which epilepsy develops.[25] For example, drugs could be developed to interfere with secondary brain injury (injury that does not occur at the moment of trauma but results from processes initiated by it), by blocking pathways such as free radical damage to brain tissue.[31] An increase in understanding of age differences in epilepsy development after trauma may also help researchers find biomarkers of epileptogenesis.[25] There is also interest in finding more antiepileptic drugs, with the potential to interfere with epileptogenesis.[41] Some new antiepileptic drugs such as topiramate, gabapentin, and lamotrigine have already been developed and have shown promise in treatment of PTE.[8] No animal model has all the characteristics of epileptogenesis in humans, so research efforts aim to identify one.[22][25] Such a model may help researchers find new treatments and identify the processes involved in epileptogenesis.[7] However, the most common mechanical models of traumatic brain injury such as fluid percussion injury, controlled cortical impact, and weight-drop injury models exhibit epileptogenesis at chronic time points with documented remote electroencephalographic and behavioral seizures, and increased seizure susceptibility.[42] It has been reported that PTE can also occur in zebrafish, resulting in similar pathophysiological responses to human TBI.[43] ## See also[edit] * Complications of traumatic brain injury ## References[edit] 1. ^ a b Brady, Rhys D.; Casillas-Espinosa, Pablo M.; Agoston, Denes V.; Bertram, Edward H.; Kamnaksh, Alaa; Semple, Bridgette D.; Shultz, Sandy R. (March 2019). "Modelling traumatic brain injury and posttraumatic epilepsy in rodents". Neurobiology of Disease. 123: 8–19. doi:10.1016/j.nbd.2018.08.007. PMC 6348144. PMID 30121231. 2. ^ a b c Pagni CA, Zenga F (2005). "Posttraumatic epilepsy with special emphasis on prophylaxis and prevention". Acta Neurochirurgica. Acta Neurochirurgica Supplementum. 93: 27–34. doi:10.1007/3-211-27577-0_3. ISBN 978-3-211-24150-9. PMID 15986723. 3. ^ a b c d e f g h i Garga N, Lowenstein DH (2006). "Posttraumatic Epilepsy: A Major Problem in Desperate Need of Major Advances". Epilepsy Currents. 6 (1): 1–5. doi:10.1111/j.1535-7511.2005.00083.x. PMC 1363374. PMID 16477313. 4. ^ a b c d e f g h i j k Mani J, Barry E (2006). "Posttraumatic epilepsy". In Wyllie E, Gupta A, Lachhwani DK (eds.). The Treatment of Epilepsy: Principles and Practice. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 521–524. ISBN 0-7817-4995-6. 5. ^ Scheffer, Ingrid E.; Berkovic, Samuel; Capovilla, Giuseppe; Connolly, Mary B.; French, Jacqueline; Guilhoto, Laura; Hirsch, Edouard; Jain, Satish; Mathern, Gary W. (April 2017). "ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology". Epilepsia. 58 (4): 512–521. doi:10.1111/epi.13709. PMC 5386840. PMID 28276062. 6. ^ Pitkänen A, Kharatishvili I, Karhunen H, et al. (2007). "Epileptogenesis in experimental models". Epilepsia. 48 (Supplement 2): 13–20. doi:10.1111/j.1528-1167.2007.01063.x. PMID 17571349. S2CID 23523719. 7. ^ a b c d e f g h i j k l m D'Ambrosio R, Perucca E (2004). "Epilepsy after head injury". Current Opinion in Neurology. 17 (6): 731–735. doi:10.1097/00019052-200412000-00014. PMC 2672045. PMID 15542983. 8. ^ a b c d e f g h i j k l m n o p q r s t u v Agrawal A, Timothy J, Pandit L, Manju M (2006). "Post-traumatic epilepsy: An overview". Clinical Neurology and Neurosurgery. 108 (5): 433–439. doi:10.1016/j.clineuro.2005.09.001. PMID 16225987. S2CID 2650670. 9. ^ a b c d e f Posner E, Lorenzo N (October 11, 2006). "Posttraumatic epilepsy". Emedicine.com. Retrieved on 2008-07-30. 10. ^ a b c d e f Eadie MJ, Bladin PF (2001). A Disease Once Sacred: A History of the Medical Understanding of Epilepsy. London: John Libbey. pp. 215–216. ISBN 0-86196-607-4. 11. ^ a b c d e f g Frey LC (2003). "Epidemiology of posttraumatic epilepsy: A critical review". Epilepsia. 44 (Supplement 10): 11–17. doi:10.1046/j.1528-1157.44.s10.4.x. PMID 14511389. S2CID 34749005. Archived from the original on 2012-12-16. 12. ^ a b c d e f g h i j Tucker GJ (2005). "Seizures". In Silver JM, McAllister TW, Yudofsky SC (eds.). Textbook Of Traumatic Brain Injury. American Psychiatric Pub., Inc. pp. 309–321. ISBN 1-58562-105-6. 13. ^ a b Gupta YK, Gupta M (2006). "Post traumatic epilepsy: A review of scientific evidence" (PDF). Indian Journal of Physiology and Pharmacology. 50 (1): 7–16. PMID 16850898. Archived from the original (PDF) on 2011-07-13. Retrieved 2008-07-31. 14. ^ a b Ayd FJ (2000). Lexicon of Psychiatry, Neurology, and the Neurosciences. Philadelphia, Pa: Lippincott-Williams & Wilkins. pp. 888–890. ISBN 0-7817-2468-6. 15. ^ Statler KD (2006). "Pediatric posttraumatic seizures: Epidemiology, putative mechanisms of epileptogenesis and promising investigational progress". Dev. Neurosci. 28 (4–5): 354–363. doi:10.1159/000094162. PMID 16943659. S2CID 24833791. 16. ^ Cuccurullo S (2004). Physical Medicine and Rehabilitation Board Review. Demos Medical Publishing. pp. 68–71. ISBN 1-888799-45-5. 17. ^ a b Parent JM, Aminoff MJ (2004). "Treatment of epilepsy in general medical conditions". In Dodson WE, Avanzini G, Shorvon SD, Fish DR, Perucca E (eds.). The Treatment of Epilepsy. Oxford: Blackwell Science. p. 244. ISBN 0-632-06046-8. 18. ^ a b c Annegers JF, Hauser WA, Coan SP, Rocca WA (January 1998). "A population-based study of seizures after traumatic brain injuries". New England Journal of Medicine. 338 (1): 20–4. doi:10.1056/NEJM199801013380104. PMID 9414327. 19. ^ a b c d e f g h i Iudice A, Murri L (2000). "Pharmacological prophylaxis of post-traumatic epilepsy". Drugs. 59 (5): 1091–9. doi:10.2165/00003495-200059050-00005. PMID 10852641. S2CID 28616181. 20. ^ a b c d e JW Sander, MC Walker and JE Smalls (editors) (2007). "Chapter 12: Adult onset epilepsies, DW Chadwick" (PDF). Epilepsy: From Cell to Community – A Practical Guide to Epilepsy (PDF). National Society for Epilepsy. pp. 127–132. ISBN 978-0-9519552-4-6. Retrieved 2008-07-26.CS1 maint: extra text: authors list (link) 21. ^ Oliveros-Juste A, Bertol V, Oliveros-Cid A (2002). "Preventive prophylactic treatment in posttraumatic epilepsy". Revista de Neurología (in Spanish). 34 (5): 448–459. doi:10.33588/rn.3405.2001439. PMID 12040514. 22. ^ a b c d e f g h i Pitkänen A, McIntosh TK (2006). "Animal models of post-traumatic epilepsy". Journal of Neurotrauma. 23 (2): 241–261. doi:10.1089/neu.2006.23.241. PMID 16503807. 23. ^ Beghi E (2004). "Aetiology of epilepsy". In Dodson WE, Avanzini G, Shorvon SD, Fish DR, Perucca E (eds.). The Treatment of Epilepsy. Oxford: Blackwell Science. p. 61. ISBN 0-632-06046-8. 24. ^ de la Peña P, Porta-Etessam J (1998). "Post-traumatic epilepsy". Revista de Neurología (in Spanish). 26 (150): 256–261. doi:10.33588/rn.26150.981066. PMID 9580443. 25. ^ a b c d e f g Herman ST (2002). "Epilepsy after brain insult: Targeting epileptogenesis". Neurology. 59 (9 Suppl 5): S21–S26. doi:10.1212/wnl.59.9_suppl_5.s21. PMID 12428028. S2CID 6978609. 26. ^ Mazarati A (2006). "Is Posttraumatic Epilepsy the Best Model of Posttraumatic Epilepsy?". Epilepsy Currents. 6 (6): 213–214. doi:10.1111/j.1535-7511.2006.00149.x. PMC 1783489. PMID 17260063. 27. ^ a b Willmore LJ (1990). "Post-traumatic epilepsy: Cellular mechanisms and implications for treatment". Epilepsia. 31 (Supplement 3): S67–73. doi:10.1111/j.1528-1157.1990.tb05861.x. PMID 2226373. S2CID 34342615. 28. ^ Morimoto K, Fahnestock M, Racine RJ (May 2004). "Kindling and status epilepticus models of epilepsy: Rewiring the brain". Prog. Neurobiol. 73 (1): 1–60. doi:10.1016/j.pneurobio.2004.03.009. PMID 15193778. S2CID 36849482. 29. ^ Abel MS, McCandless DW (1992). "The kindling model of epilepsy". In Adams RN, Baker GB, Baker JM, Bateson AN, Boisvert DP, Boulton AA, et al. (eds.). Neuromethods: Animal Models of Neurological Disease. Totowa, NJ: Humana Press. pp. 153–155. ISBN 0-89603-211-6. 30. ^ Menkes JH, Sarnat HB, Maria BL (2005). Child Neurology. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 683–684. ISBN 0-7817-5104-7. 31. ^ a b c d e Firlik KS, Spencer DD (2004). "Surgery of post-traumatic epilepsy". In Dodson WE, Avanzini G, Shorvon SD, Fish DR, Perucca E (eds.). The Treatment of Epilepsy. Oxford: Blackwell Science. pp. 775–778. ISBN 0-632-06046-8. 32. ^ Barry E, Bergey GK, Krumholz A, et al. (1997). "Posttraumatic seizure types vary with the interval after head injury". Epilepsia. 38 (Supplement 8): 49S–50S. doi:10.1111/j.1528-1157.1997.tb01495.x. S2CID 221735326. 33. ^ a b c Schierhout G, Roberts I (2001 (Unchanged in 2008)). Schierhout, Gillian (ed.). "Anti-epileptic drugs for preventing seizures following acute traumatic brain injury". Cochrane Database of Systematic Reviews (4): CD000173. doi:10.1002/14651858.CD000173. PMID 11687070. Check date values in: `\|date=` (help) (Retracted, see doi:10.1002/14651858.cd000173.pub2. If this is an intentional citation to a retracted paper, please replace `{{Retracted}}` with `{{Retracted\|intentional=yes}}`.) 34. ^ a b Beghi E (2003). "Overview of studies to prevent posttraumatic epilepsy". Epilepsia. 44 (Supplement 10): 21–26. doi:10.1046/j.1528-1157.44.s10.1.x. PMID 14511391. S2CID 25635858. 35. ^ Aroniadou-Anderjaska V, Fritsch B, Qashu F, Braga MF (February 2008). "Pathology and Pathophysiology of the Amygdala in Epileptogenesis and Epilepsy". Epilepsy Res. 78 (2–3): 102–16. doi:10.1016/j.eplepsyres.2007.11.011. PMC 2272535. PMID 18226499. 36. ^ a b Young B (1992). "Post-traumatic epilepsy". In Barrow DL (ed.). Complications and Sequelae of Head Injury. Park Ridge, Ill: American Association of Neurological Surgeons. pp. 127–132. ISBN 1-879284-00-6. 37. ^ Swash M (1998). Outcomes in Neurological and Neurosurgical Disorders. Cambridge, UK: Cambridge University Press. pp. 172–173. ISBN 0-521-44327-X. 38. ^ Diaz-Arrastia R, Agostini MA, Frol AB, et al. (November 2000). "Neurophysiologic and neuroradiologic features of intractable epilepsy after traumatic brain injury in adults". Archives of Neurology. 57 (11): 1611–1616. doi:10.1001/archneur.57.11.1611. PMID 11074793. 39. ^ a b c d e Jensen RL, Stone JL (1997). "Benjamin Winslow Dudley and early American trephination for posttraumatic epilepsy". Neurosurgery. 41 (1): 263–268. doi:10.1097/00006123-199707000-00045. PMID 9218316. 40. ^ Willmore LJ (December 2005). "Antiepileptic drugs and neuroprotection: Current status and future roles". Epilepsy & Behavior. 7 (Supplement 3): S25–S28. doi:10.1016/j.yebeh.2005.08.006. PMID 16239127. S2CID 40670766. 41. ^ Chang BS, Lowenstein DH (2003). "Practice parameter: Antiepileptic drug prophylaxis in severe traumatic brain injury: Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 60 (1): 10–16. doi:10.1212/01.wnl.0000031432.05543.14. PMID 12525711. 42. ^ Glushakov, Alexander V.; Glushakova, Olena Y.; Doré, Sylvain; Carney, Paul R.; Hayes, Ronald L. (2016). "Animal Models of Posttraumatic Seizures and Epilepsy". Methods in Molecular Biology. 1462: 481–519. doi:10.1007/978-1-4939-3816-2_27. ISBN 978-1-4939-3814-8. ISSN 1940-6029. PMC 6036905. PMID 27604735. 43. ^ Cho, Sung‐Joon; Park, Eugene; Telliyan, Tamar; Baker, Andrew; Reid, Aylin Y. (August 2020). "Zebrafish model of posttraumatic epilepsy". Epilepsia. 61 (8): 1774–1785. doi:10.1111/epi.16589. ISSN 0013-9580. ## External links[edit] Classification D * MeSH: D004834 External resources * eMedicine: NEURO/318 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Post-traumatic epilepsy	c0014557	1,577	wikipedia	https://en.wikipedia.org/wiki/Post-traumatic_epilepsy	2021-01-18T18:46:06	{"gard": ["7437"], "mesh": ["D004834"], "wikidata": ["Q7233592"]}
Glycogen storage disease Fanconi–Bickel syndrome is a form of glycogen storage disease. It is also known for Guido Fanconi and Horst Bickel,[1][2] who first described it in 1949. It is associated with GLUT2,[3][4] a glucose transport protein which, when functioning normally, allows glucose to exit several tissues, including the liver, nephrons, and enterocytes of the intestines, and enter the blood. The syndrome results in hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature.[5] ## References[edit] 1. ^ synd/65 at Who Named It? 2. ^ FANCONI G, BICKEL H (November 1949). "Not Available". Helv Paediatr Acta. 4 (5): 359–96. PMID 15397919. 3. ^ Santer R, Steinmann B, Schaub J (March 2002). "Fanconi–Bickel syndrome--a congenital defect of facilitative glucose transport". Curr. Mol. Med. 2 (2): 213–27. doi:10.2174/1566524024605743. PMID 11949937. Archived from the original on 2009-08-23. Retrieved 2019-12-30. 4. ^ Santer R, Groth S, Kinner M, et al. (January 2002). "The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi–Bickel syndrome". Hum. Genet. 110 (1): 21–9. doi:10.1007/s00439-001-0638-6. PMID 11810292. 5. ^ Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B (October 1998). "Fanconi–Bickel syndrome--the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature". Eur. J. Pediatr. 157 (10): 783–97. doi:10.1007/s004310050937. PMID 9809815. Archived from the original on 2001-11-22. Retrieved 2008-08-20. ## External links[edit] Classification D * ICD-10: E74.0 * OMIM: 227810 * DiseasesDB: 31709 External resources * Orphanet: 2088 * v * t * e Genetic disorder, membrane: Solute carrier disorders 1-10 * SLC1A3 * Episodic ataxia 6 * SLC2A1 * De Vivo disease * SLC2A5 * Fructose malabsorption * SLC2A10 * Arterial tortuosity syndrome * SLC3A1 * Cystinuria * SLC4A1 * Hereditary spherocytosis 4/Hereditary elliptocytosis 4 * SLC4A11 * Congenital endothelial dystrophy type 2 * Fuchs' dystrophy 4 * SLC5A1 * Glucose-galactose malabsorption * SLC5A2 * Renal glycosuria * SLC5A5 * Thyroid dyshormonogenesis type 1 * SLC6A19 * Hartnup disease * SLC7A7 * Lysinuric protein intolerance * SLC7A9 * Cystinuria 11-20 * SLC11A1 * Crohn's disease * SLC12A3 * Gitelman syndrome * SLC16A1 * HHF7 * SLC16A2 * Allan–Herndon–Dudley syndrome * SLC17A5 * Salla disease * SLC17A8 * DFNA25 21-40 * SLC26A2 * Multiple epiphyseal dysplasia 4 * Achondrogenesis type 1B * Recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia * SLC26A4 * Pendred syndrome * SLC35C1 * CDOG 2C * SLC39A4 * Acrodermatitis enteropathica * SLC40A1 * African iron overload see also solute carrier family This article about an endocrine, nutritional, or metabolic disease 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	Fanconi–Bickel syndrome	c3495427	1,578	wikipedia	https://en.wikipedia.org/wiki/Fanconi%E2%80%93Bickel_syndrome	2021-01-18T18:48:28	{"gard": ["2268"], "mesh": ["D005198"], "umls": ["C3495427"], "orphanet": ["2088"], "wikidata": ["Q5572613"]}
Redness of the skin or mucous membranes Not to be confused with Arrythmia. 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: "Erythema" – news · newspapers · books · scholar · JSTOR (December 2009) (Learn how and when to remove this template message) Erythema Characteristic "bull's eye" rash (erythema migrans) of early Lyme disease SpecialtyDermatology Erythema (from the Greek erythros, meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries.[1] It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology include nervous blushes.[2] ## Contents * 1 Causes * 2 Diagnosis * 3 Types * 4 See also * 5 References * 6 External links ## Causes[edit] It can be caused by infection, massage, electrical treatment, acne medication, allergies, exercise, solar radiation (sunburn), photosensitization,[3] acute radiation syndrome, mercury toxicity, blister agents,[4] niacin administration,[5] or waxing and tweezing of the hairs—any of which can cause the capillaries to dilate, resulting in redness. Erythema is a common side effect of radiotherapy treatment due to patient exposure to ionizing radiation. ## Diagnosis[edit] Erythema disappears on finger pressure (blanching), while purpura or bleeding in the skin and pigmentation do not. There is no temperature elevation, unless it is associated with the dilation of arteries in the deeper layer of the skin.[citation needed] ## Types[edit] * Erythema ab igne * Erythema chronicum migrans * Erythema induratum * Erythema infectiosum (or fifth disease) * Erythema marginatum * Erythema migrans * Erythema multiforme (EM) * Erythema nodosum * Erythema toxicum * Erythema elevatum diutinum * Erythema gyratum repens * Keratolytic winter erythema * Palmar erythema ## See also[edit] * Flushing (physiology) * List of cutaneous conditions ## References[edit] 1. ^ Mosby's Medical Dictionary (9th ed.). St. Louis, Missouri: Elsevier. 2013. ISBN 978-0-323-08541-0. 2. ^ erythema, Mosby's Medical, Nursing & Allied Health Dictionary, Fourth Edition, Mosby-Year Book 1994, p. 570 3. ^ Jane C. Quinn; Yuchi Chen; Belinda Hackney; Muhammad Shoaib Tufail; Leslie A. Weston; Panayiotis Loukopoulos (2018), "Acute-onset high-morbidity primary photosensitisation in sheep associated with consumption of the Casbah and Mauro cultivars of the pasture legume biserrula", BMC Veterinary Research, 14 (1): 11, doi:10.1186/s12917-017-1318-7, PMC 5765607, PMID 29325550 4. ^ https://fas.org/nuke/guide/usa/doctrine/army/mmcch/Vesicant.htm#CLINICAL Archived 2017-12-12 at the Wayback Machine EFFECTS 5. ^ Weterle R, Rybakowski J (Mar–Apr 1990). "Test niacynowy w schizofrenii" [The niacin test in schizophrenia]. Psychiatr Pol. 24 (2): 116–20. PMID 2084715. ## External links[edit] Classification D * ICD-10: L51-L54 * ICD-9-CM: 695 * ICD-O: l * MeSH: D004890 * DiseasesDB: 4466 Look up erythema in Wiktionary, the free dictionary. Wikimedia Commons has media related to Erythemas. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Erythema	c0332575	1,579	wikipedia	https://en.wikipedia.org/wiki/Erythema	2021-01-18T18:50:00	{"mesh": ["D004890"], "umls": ["C0332575"], "icd-9": ["695"], "icd-10": ["L51", "L54"], "wikidata": ["Q1166142"]}
A number sign (#) is used with this entry because of evidence that microtia, hearing impairment, and cleft palate is caused by homozygous mutation in the HOXA2 gene (604685) on chromosome 7p15. One such family has been reported. There is also evidence that microtia with or without hearing impairment is caused by heterozygous mutation in the HOXA2 gene. Clinical Features Alasti et al. (2008) examined 3 of 4 affected members of a consanguineous Iranian family who had bilateral microtia, mixed symmetric severe to profound hearing impairment, and partial cleft palate. The helix, tragus, and antitragus were seen in all patients. On otoscopy, the external auditory canal was short and severely narrowed bilaterally, appearing almost stenotic; the disease was categorized as microtia grade II. A partial cleft palate was found in all 3 patients, 1 of whom also had right-sided facial paresis. High-resolution CT scan of the ears confirmed severe narrowing in the cartilaginous part of the auditory canal and showed near-atresia in the bony portion, and in all 3 patients, the malformed ossicular chain appeared to be fixed by an incomplete atretic plate. The inner ear structures were normal in 2 patients, but the third had no inner ear structures on the left. MRI confirmed the left inner ear agenesis in that patient; the brain MRI of the patient with facial paresis was normal and hypoplasia of the right seventh cranial nerve was suspected, based on clinical examination. All 4 patients had prelingual onset of hearing impairment; audiometry revealed bilateral symmetric severe to profound mixed hearing impairment affecting all frequencies and leading to a flat audiometric shape. ### Microtia with or without Hearing Impairment Brown et al. (2013) studied a 3-generation family segregating autosomal dominant microtia with or without hearing loss. Five of the 7 affected family members were examined, all of whom exhibited small, malformed ears with a thickened helix and superficial postauricular sulcus. The external auditory canals were normally formed, and the palate was intact in all. Renal anatomy was normal in the 3 individuals who underwent imaging. Audiometry was performed in 3 of the 4 affected family members with hearing loss and showed mild to severe bilateral mixed hearing loss. Middle ear explorations previously performed on 2 affected individuals revealed abnormalities of the ossicular chain, with a thickened posterior crus and absent anterior crus and stapedial tendon in 1 patient, and a rigid ossicular chain in the other. Piceci et al. (2017) reported a 5-generation nonconsanguineous Italian family segregating autosomal dominant nonsyndromic bilateral microtia. The male proband had overtly dysplastic ears showing decreased median longitudinal length in the presence of mildly sharp pointed superior portion of the helix, absent superior crus and triangular fossa of the antihelix, overfolded helix with an underdeveloped inferior crus, underdeveloped antitragus, serpiginous antihelix stem, deep incisura between tragus and antitragus with a laterally dislocated hypoplastic lobe. Other outer ear structures and canals were average. Otoacoustic emissions were bilaterally regular. No additional anomalies were found. The patient's mother and maternal grandfather had similar ear anomalies, and audiometric testing had unremarkable results. Extended family history disclosed dysplastic ears in a maternal second-degree aunt and the maternal great- and great-great-grandfathers. Mapping Alasti et al. (2008) performed genomewide linkage analysis in a consanguineous Iranian family segregating autosomal recessive microtia, hearing impairment, and cleft palate, and obtained a maximum multipoint lod score of 3.15 with markers D7S503, D7S629, and D7S2444 on chromosome 7p15.3-p14.3. Fine mapping revealed an identical homozygous haplotype in all 4 affected individuals, with a maximum multipoint lod score of 4.17 for all markers across the 13.7-cM interval delimited by D7S503 and D7S435. Molecular Genetics In a consanguineous Iranian family with microtia, hearing impairment, and cleft palate, Alasti et al. (2008) identified homozygosity for a missense mutation in the HOXA2 gene (604685.0001). The unaffected parents were heterozygous for the mutation, which was not found in 231 Iranian or 109 Belgian controls. ### Microtia with or without Hearing Impairment In a 3-generation family in which 7 members had microtia with or without hearing loss, Brown et al. (2013) identified a heterozygous nonsense mutation in HOXA2 (Q235X; 604685.0002) that segregated with disease and was not found in controls. Analysis of HOXA2 in 119 patients with unilateral or bilateral microtia from Colombia and Ecuador revealed 2 patients with unilateral microtia and a potentially pathogenic variant, but each variant was also present in 1 control. In affected members of a 5-generation Italian family segregating isolated bilateral microtia without hearing loss, Piceci et al. (2017) identified a heterozygous nonsense mutation (E224X; 604685.0003) in the HOXA2 gene that segregated with the trait in the family. The mutation, which was found by sequencing the HOXA2 gene and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases. INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Ears \- Microtia \- Severe narrowing of cartilaginous auditory canal \- Near-stenosis of bony portion of auditory canal \- Malformed ossicular chain \- Incomplete atretic plate \- Hearing loss, prelingual, severe to profound (affecting all frequencies) \- Severe narrowing of cartilaginous auditory canal (in homozygotes) \- Near-stenosis of bony portion of auditory canal (in homozygotes) \- Hearing loss, mixed, mild to severe (in heterozygotes) Mouth \- Cleft palate, partial (in homozygotes) MOLECULAR BASIS \- Caused by mutation in the homeobox A2 gene (HOXA2, 604685.0001 ) ▲ 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	MICROTIA, HEARING IMPAIRMENT, AND CLEFT PALATE	c2676772	1,580	omim	https://www.omim.org/entry/612290	2019-09-22T16:02:01	{"mesh": ["C567359"], "omim": ["612290"], "orphanet": ["140963"]}
A number sign (#) is used with this entry because posterior column ataxia with retinitis pigmentosa (AXPC1) is caused by homozygous mutation in the FLVCR1 gene (609144) on chromosome 1q32. Description Posterior column ataxia with retinitis pigmentosa is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by Ishiura et al., 2011). Clinical Features Higgins et al. (1997) reported a large kindred in which 6 members had an autosomal recessive form of ataxia. Onset was in childhood with concentric contraction of the visual fields and proprioceptive loss. By the third decade, affected individuals became blind, had severe sensory ataxia, achalasia, scoliosis, and inanition (weakness and wasting). Sensory nerve conduction velocities were absent. MRI showed hyperintense signals in the spinal cord. The original founder of the family was born in 1765 and immigrated to colonial America from a territory along the German-Swiss border. Eleven generations could be traced. Higgins et al. (1997) noted that a similar phenotype with autosomal dominant inheritance, Biemond ataxia (176250), had been described. Berciano and Polo (1998) reported a consanguineous Spanish family with a phenotype identical to that described by Higgins et al. (1997). The Spanish family had previously been characterized as having early-onset cerebellar ataxia. Rajadhyaksha et al. (2010) provided more clinical details of the Spanish family reported by Berciano and Polo (1998). All affected individuals had visual disturbances due to retinitis pigmentosa during the first decade of life. Gait abnormalities became noticeable by the second decade, and slowly progressed thereafter. One patient, who had onset of ataxia at age 14 years, had a sural nerve biopsy at age 35 that showed a loss of large myelinated fibers. Rajadhyaksha et al. (2010) reported another family, of French Canadian origin, with the disorder. Affected individuals had a childhood-onset hereditary sensory neuropathy with retinitis pigmentosa and ataxia. Initial presentations included delayed walking, orthopedic deformities, scoliosis, and mild distal weakness of intrinsic hand and foot muscles. Neuropathy was characterized by decreased fine touch and vibration with proprioceptive loss in the feet and areflexia. All lost the ability to walk. Upper limb ataxia was mild. Other features included recurrent urinary tract infections and incontinence. Ishiura et al. (2011) reported 2 sibs, born of consanguineous Japanese parents, with autosomal recessive PCARP. The index patient developed night-blindness at age 5 years and later developed ataxic gait. On examination at age 31 years, she had retinitis pigmentosa with optic atrophy. She also had mild mental retardation and showed ataxic gait and truncal titubation; Romberg sign was positive. There was decreased muscle tone in the limbs with normal strength. Deep tendon reflexes were decreased in the arms and absent in the legs, and vibratory and position sense were lost in the toes. Peripheral blood smear showed no acanthocytes. Axial MRI showed a hyperintense signal in the posterior half of the cervical spinal cord. Her brother was similarly affected. Ishiura et al. (2011) noted that mental retardation had not previously been described in this disorder and speculated that it may have an alternative cause in this family. Mapping By linkage analysis of the affected family reported by Higgins et al. (1997), Higgins et al. (1999) mapped the disease locus, termed AXPC1, to an 8.3-cM region on chromosome 1q31-q32 between markers D1S2692 and D1S414 (maximum lod score of 8.94 at D1S2692). Higgins et al. (2000) found that the family reported by Berciano and Polo (1998) showed linkage to the AXPC1 locus, with a maximum lod score of 3.56 at D1S414. By further genetic mapping of the families reported by Higgins et al. (1999) and Berciano and Polo (1998), Rajadhyaksha et al. (2010) narrowed the AXPC1 locus to a 4.2-Mb region between rs10494961 and rs9309430. Molecular Genetics In affected members of the German-Swiss family reported by Higgins et al. (1997), Rajadhyaksha et al. (2010) identified a homozygous mutation in the FLVCR1 gene (N121D; 609144.0001). The mutation was found by targeted DNA capture and high-throughput sequencing of the 4.2-Mb AXPC1 locus, followed by bioinformatics analysis and filtering. Further analysis of a Spanish and a French Canadian family with the disorder identified 2 additional homozygous mutations in the FLVCR1 gene (A241T, 609144.0002 and C192R, 609144.0003, respectively). Based on the function of FLVCR1, Rajadhyaksha et al. (2010) hypothesized that a defect in heme regulation or processing in the central nervous system may result in neurodegeneration. In a Pennsylvania Mennonite patient with posterior column ataxia and retinitis pigmentosa, Puffenberger et al. (2012) identified homozygosity for the N121D mutation in the FLVCR1 gene (609144.0001), previously found in the German-Swiss family originally reported by Higgins et al. (1997). The variant was detected in heterozygosity in 5 of 406 Mennonite control chromosomes, for a population-specific allele frequency of 1.23%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) By linkage analysis followed by candidate gene sequencing in 2 Japanese sibs, born of consanguineous parents, with PCARP and mild mental retardation, Ishiura et al. (2011) identified a homozygous mutation in the FLVCR1 gene (G493R; 609144.0004). Each unaffected parent and an unaffected sib was heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Ring scotoma (early) \- Retinitis pigmentosa \- Night blindness (infancy and early childhood) \- Blindness by third decade \- Fundus with peripheral 'bony spicules' \- Optic atrophy \- No light-evoked response on electroretinogram (ERG) ABDOMEN Gastrointestinal \- Achalasia \- Gastrointestinal dysmotility GENITOURINARY Bladder \- Urinary incontinence \- Recurrent urinary tract infections SKELETAL Spine \- Scoliosis Hands \- Camptodactyly MUSCLE, SOFT TISSUES \- Neurogenic muscle atrophy \- Distal muscle weakness NEUROLOGIC Central Nervous System \- Delayed walking (1 family) \- Mental retardation (1 family) Peripheral Nervous System \- Sensory ataxia \- Broad-based gait \- Positive Romberg sign \- Areflexia \- Loss of proprioception \- Decreased fine touch in the lower extremities \- Decreased vibratory sense in the lower extremities \- Mild upper limb ataxia \- Immobility by the third decade \- Absence of sensory nerve conduction velocities \- Atrophic sural nerve \- Loss of large myelinated fibers seen on sural nerve biopsy \- Hyperintense signaling of dorsal aspect of spinal cord seen on MRI (inversion recovery images) MISCELLANEOUS \- Onset in childhood \- Slowly progressive disorder MOLECULAR BASIS \- Caused by mutation in the feline leukemia virus subgroup C receptor 1 gene (FLVCR1, 609144.0001 ) ▲ 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	POSTERIOR COLUMN ATAXIA WITH RETINITIS PIGMENTOSA	c1836916	1,581	omim	https://www.omim.org/entry/609033	2019-09-22T16:06:48	{"mesh": ["C536343"], "omim": ["609033"], "orphanet": ["88628"], "synonyms": ["Alternative titles", "PCARP"]}
Xq27.3q28 duplication syndrome is a recently described syndrome characterized by short stature, hypogonadism, developmental delay and facial dysmorphism. ## Epidemiology It has been clinically and molecularly characterized in 3 male members from the same family. ## Clinical description Facial features include deep-set eyes, bulbous nasal tip and thin lips. Hypogonadism is due to primary gonadal failure. Patients also had some features which are probably caused by testosterone deficiency such as a high-pitched voice, sparse body hair and small hands and feet. Carrier females present with a short stature and early menopause. ## Etiology This syndrome is caused by an Xq27.3q28 interstitial duplication encompassing the FMR1 and AFF2 genes but not the MECP2 gene. This duplication was characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). ## Genetic counseling Transmission is X-linked. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Xq27.3q28 duplication syndrome	c3275521	1,582	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=261483	2021-01-23T17:45:25	{"omim": ["300869"], "icd-10": ["Q99.8"], "synonyms": ["Dup(X)(q27.3q28)", "Trisomy Xq27.3-q28", "Trisomy Xq27.3q28", "Xq27.3-q28 microduplication syndrome"]}
Pontine tegmental cap dysplasia is a rare, central nervous system malformation characterized by specific pattern of congenital anomalies affecting the pons, medulla, and cerebellum. Clinical manifestations of multiple cranial nerves deficits, pyramidal and cerebellar signs include neonatal hypotonia, ataxia, sensorineural deafness, reduced vision, language and speech disorders, feeding and swallowing difficulties, facial paralysis and intellectual disability. Various cardiac, gastrointestinal, genitourinary and skeletal defects have been sometimes 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	Pontine tegmental cap dysplasia	c3541340	1,583	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=269229	2021-01-23T17:03:10	{"gard": ["10919"], "omim": ["614688"], "icd-10": ["Q04.8"], "synonyms": ["PTCD"]}
A rare genetic interstitial lung disease characterized by diffuse lung disease of variable phenotype ranging from severe respiratory insufficiency in infancy to asymptomatic adults, due to surfactant protein C deficiency. Typical presentation in infancy includes dyspnea, cough, wheezing, and gradual cyanosis, with or without failure to thrive. Radiological findings include diffuse ground-glass opacities in neonates, later interstitial thickening associated with lung hyperinflation, intraparenchymal/subpleural cysts, honeycombing, subpleural nodules, or bronchiectasis. Infiltrates and air leaks are frequent complications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Interstitial lung disease due to SP-C deficiency	c1970470	1,584	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=440392	2021-01-23T17:34:06	{"mesh": ["C567048"], "omim": ["610913"], "icd-10": ["J84.8"], "synonyms": ["Interstitial lung disease due to surfactant protein C deficiency"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Chauffeur's fracture" – news · newspapers · books · scholar · JSTOR (February 2009) (Learn how and when to remove this template message) This article needs attention from an expert in medicine. The specific problem is: The fracture is fairly obscure with limited scientific literature available.. WikiProject Medicine may be able to help recruit an expert. (March 2009) Chauffeur's fracture Other namesHutchinson fracture, backfire fracture X-ray of a displaced intra-articular distal radius fracture in an external fixator. The articular surface is widely displaced and irregular. This is a Chauffeur's fracture. Frykman class 3. SpecialtyOrthopedic Chauffeur's fracture, also known as Hutchinson fracture, is a type of oblique fracture of the radial styloid process in the forearm.[1] The injury is typically caused by compression of the scaphoid bone of the hand against the styloid process of the distal radius. It can be caused by falling onto an outstretched hand. Treatment is often open reduction and internal fixation, which is surgical realignment of the bone fragments and fixation with pins, screws, or plates. ## History[edit] Jonathan Hutchinson first described Chauffeur's fracture in 1866.[1] The term "Chauffeur's fracture" originated from Just Lucas-Championnière in 1904.[1] The name originates from early chauffeurs, who sustained these injuries when the car back-fired while the chauffeur was hand-cranking to start the car.[1][2] The back-fire forced the crank backward into the chauffeur's palm and produced the characteristic styloid fracture.[2][3] ## References[edit] 1. ^ a b c d Andreotti, Mattia; Tonon, Francesco; Caruso, Gaetano; Massari, Leo; Riva, Michele A. (March 2020). "The "Chauffeur Fracture": Historical Origins of an Often-Forgotten Eponym". HAND. 15 (2): 252–254. doi:10.1177/1558944718792650. ISSN 1558-9447. PMC 7076623. PMID 30079762. 2. ^ a b Lund, F. B. (1904-11-03). "Fractures of the Radius in Starting Automobiles". The Boston Medical and Surgical Journal. 151 (18): 481–483. doi:10.1056/NEJM190411031511802. ISSN 0096-6762. 3. ^ Greenspan, Adam. (2004). Orthopedic imaging : a practical approach. Greenspan, Adam. (4th ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-7817-5006-7. OCLC 54455663. ## External links[edit] Classification D * ICD-10: S52.5 External resources * AO Foundation: 23-B1.1 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Chauffeur's fracture	c1961067	1,585	wikipedia	https://en.wikipedia.org/wiki/Chauffeur%27s_fracture	2021-01-18T19:05:27	{"umls": ["C1961067"], "wikidata": ["Q3572829"]}
A rare, benign tumor of the pancreas characterized by variable number and size of the cysts lined with glycogen rich epithelial cells. Clinical manifestation may include epigastric or abdominal pain, weight loss, diabetes, jaundice and palpable abdominal mass. Some patients have no symptoms and the tumor is discovered incidentally. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Adenoma of pancreas	c1142432	1,586	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93292	2021-01-23T18:21:49	{"gard": ["4204"], "mesh": ["C538110"], "umls": ["C1142432"], "icd-10": ["D13.6"], "synonyms": ["Pancreatic adenoma"]}
A number sign (#) is used with this entry because antigens of the Ss blood group result from variation in the gene encoding glycophorin B (GYPB; 617923) on chromosome 4q31. Description Ss blood group antigens reside on the red-cell glycoprotein GYPB. The S and s antigens result from a polymorphism at amino acid 29 of GYPB, where S has met29 and s has thr29. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. GYPB, glycophorin A (GYPA; 617922), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. Antigens of the MN blood group (111300) reside on GYPA. The M and N antigens differ at amino acids 1 and 5 of GYPA, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs blood group system (see 111300). Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015). Molecular Genetics Blumenfeld and Adamany (1978) found that the MM blood group polypeptide differs from the NN polypeptide in 2 amino acids, these being serine and glycine in MM and leucine and glutamic acid in NN. The MN individual shows all 4 amino acids. The 2 major sialoglycoproteins of the human red cell membrane, alpha and delta (glycophorins A and B, respectively), carry the MNSs antigenic specificities. They have identical amino acid sequences for the first 26 residues from the N terminus. Alpha expresses M or N blood group activity; delta carries only blood group N activity. Furthermore, the asparagine at position 26 of the alpha carries an oligosaccharide chain that is absent from the same position of delta. The 2 sialoglycoproteins differ in their remaining amino acid sequence, and delta expresses Ss activity. Ss and MN are closely linked but separate gene loci on chromosome 4q28-q31. Several instances of recombination between Ss and MN loci have been observed (see review by Race and Sanger, 1975). Close linkage of the genes for the 2 sialoglycoproteins that carry the MN and Ss specificities, respectively, was also indicated by the identification of hybrid molecules that appear to have arisen by a Lepore-type mechanism (Mawby et al., 1981). The erythrocyte glycophorins, which lie partly within the cell membrane and partly exposed to the exterior, contain 203 amino acids. The amino-terminal half is exposed and is the one that bears the oligosaccharide complexes that determine blood-group antigen specificities and serve as receptors for viruses and plant agglutinins. As indicated in 111300, the Ss blood group antigens are located on glycophorin B. The structural difference between SS and ss specificities is a methionine-to-threonine polymorphism at position 29. Ferrari and Pavia (1986) synthesized 2 peptides, each 8 amino acids long, carrying the Ss specificities: SS, asn-gly-glu-met-gly-gln-leu-val; ss, asn-gly-glu-thr-gly-gln-leu-val. Glycophorin C (GYPC; 110750) is the site of the Gerbich blood group antigen specificity (616089). Huang et al. (1987) presented evidence derived from protein and genomic DNA analyses that erythrocytes of 2 unrelated persons homozygous for the S-s-U- blood group phenotype lack delta-glycophorin as a result of a delta-glycophorin gene deletion. Dantu and Stones are 2 variant antigens carried by hybrid glycoproteins that appear to be products of delta and alpha glycophorin fusion genes. In Stones, symbolized St(a), the junction is from amino acid residue 26 or 28 of delta to residue 59 or 61 of alpha, whereas in Dantu, residue 38 or 39 of delta is joined to residue 71 or 72 of alpha. Huang and Blumenfeld (1988) delineated the structure of the alpha and delta glycophorins at the genomic level in the DNA from a 3-generation black family in which both the presence of Dantu and Mi-III (another rare MNs antigen) and the absence of delta-glycophorin were seen. Red cells with the rare En(a-) variant are resistant to falciparum malaria (see 611162) (Pasvol et al., 1982). Such cells lack glycophorin A (Siebert and Fukuda, 1986). The rare U(-) variant of the Ss system, which lacks the other major sialoglycoprotein, glycophorin B, is relatively resistant to invasion. Wr(b)-negative cells are also resistant to invasion by P. falciparum despite the fact that they have normal amounts of glycophorins A and B on their surface. All of these observations, as well as experiments using antibodies to glycophorins and certain sugars, particularly N-acetylglucosamine, have led to a tentative model of the role of glycophorin in the red cell invasion of P. falciparum (Pasvol and Wilson, 1982). By analyzing genome sequence data from human populations, Leffler et al. (2017) identified a diverse array of large copy-number variants affecting GYPA and GYPB. They found that a complex structural rearrangement involving loss of GYPB and gain of 2 GYPB-GYPA hybrid genes encoding the Dantu antigen of the MNSs blood group system explained the association of a nearby region with protection from severe malaria. The protective haplotype had 5 GYP genes, including 2 copies of GYPE, 2 copies of the Dantu hybrid genes, and 1 copy of GYPA, compared with the reference haplotype of 3 genes (GYPE, GYPB, and GYPA). The protective haplotype reduced the risk of severe malaria by 40% in regions of Kenya, but it had not yet been found in west Africa. Evolution Glycophorin A (GYPA; 111300) and B, which determine the MN and Ss blood types, respectively, are 2 major receptors that are expressed on erythrocyte surfaces and interact with Plasmodium falciparum ligands. Ko et al. (2011) analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. Ko et al. (2011) identified a haplotype causing 3 amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in 5 populations with high exposure to malaria. Ko et al. (2011) observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. By contrast, Ko et al. (2011) observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion was correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	BLOOD GROUP, Ss	None	1,587	omim	https://www.omim.org/entry/111740	2019-09-22T16:44:12	{"omim": ["111740"], "synonyms": ["Alternative titles", "Ss BLOOD GROUP"]}
Niemann-Pick disease is an inherited condition involving lipid metabolism, which is the breakdown, transport, and use of fats and cholesterol in the body. In people with this condition, abnormal lipid metabolism causes harmful amounts of lipids to accumulate in the spleen, liver, lungs, bone marrow, and brain. Niemann-Pick disease type A appears during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to gain weight and grow at the expected rate (failure to thrive), and progressive deterioration of the nervous system. Due to the involvement of the nervous system, Niemann-Pick disease type A is also known as the neurological type. There is currently no effective treatment for this condition and those who are affected generally do not survive past early childhood. Niemann-Pick disease type A is caused by mutations in the SMPD1 gene. It is inherited in an autosomal recessive pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Niemann-Pick disease type A	c0268242	1,588	gard	https://rarediseases.info.nih.gov/diseases/7206/niemann-pick-disease-type-a	2021-01-18T17:58:41	{"mesh": ["D052536"], "omim": ["257200"], "orphanet": ["77292"], "synonyms": ["Sphingomyelin lipidosis", "Sphingomyelinase deficiency"]}
## Description Congenital dysplasia of the hip (CDH) is an abnormality of the seating of the femoral head in the acetabulum. Its severity ranges from mild instability of the femoral head with slight capsular laxity, through moderate lateral displacement of the femoral head, without loss of contact of the head with the acetabulum, up to complete dislocation of the femoral head from the acetabulum. It is one of the most common skeletal congenital anomalies (summary by Sollazzo et al., 2000). Acetabular dysplasia is an idiopathic, localized developmental dysplasia of the hip that is characterized by a shallow hip socket and decreased coverage of the femoral head. Its radiologic criteria include the center-edge angle of Wiberg, the Sharp angle, and the acetabular roof obliquity. Most patients with acetabular dysplasia develop osteoarthritis (165720) after midlife, and even mild acetabular dysplasia can cause hip osteoarthritis (summary by Mabuchi et al., 2006). CDH occurs as an isolated anomaly or with more general disorders represented by several syndromes and with chromosomal abnormalities such as trisomy 18 (Wynne-Davies, 1970). ### Genetic Heterogeneity of Developmental Dysplasia of the Hip Developmental dysplasia of the hip-1 (DDH1) maps to chromosome 13q22; DDH2 (615612) maps to chromosome 3p21. Clinical Features Mabuchi et al. (2006) described a large Japanese family in which acetabular dysplasia inherited as an autosomal dominant was the basis of osteoarthritis of the hip joint. Eight individuals in 4 generations had acetabular dysplasia manifested as pain in the hip joint during adolescence and progressing to severely crippling hip osteoarthritis before age 60 years. The patients were in general good health, height was not reduced, and there was no skeletal involvement suggestive of chondrodysplasia. Hip osteoarthritis was indistinguishable from that of idiopathic nonfamilial osteoarthritis associated with acetabular dysplasia. The family's phenotype resembled that of Beukes familial hip dysplasia (142669) in that both exhibited shallow acetabula and eventual osteoarthritis. However, the later onset of symptoms, lack of deformity in the femoral head and/or greater trochanter, and absence of broadening of the femoral neck distinguished the phenotype of the Japanese family from that of Beukes familial hip dysplasia. Mapping Mabuchi et al. (2006) performed genomewide screening in a Japanese family with acetabular dysplasia and osteoarthritis and observed linkage to chromosome 13q22. Haplotype analysis narrowed the locus to a 6.0-cM interval, with a maximum multipoint lod score of 3.57. Population Genetics There is a great discrepancy in the frequency of CDH according to geographic and ethnic differences. In general, CDH is more frequent in whites than in blacks and Chinese (Weinstein, 1987; Wilkinson, 1992). For Caucasian populations, an incidence of 1 per 1,000 live births can be assumed (Warkany, 1985). Record and Edwards (1958) estimated the risk of recurrence in subsequently born sibs to be about 5%. CDH, often bilateral, is more frequent in females than in males, with a 5:1 ratio (Weinstein, 1987). Joint laxity, normally greater in females than in males, probably accounts for the preponderance of affected females over males. Feldman et al. (2013) stated that there are well-defined areas of high prevalence of DDH in Japan as well as in Italy and other Mediterranean countries. Inheritance The Japanese family of Mabuchi et al. (2006) with acetabular dysplasia exhibited transmission consistent with autosomal dominant inheritance. Autosomal dominant inheritance was favored by Bornfors et al. (1964). Horton et al. (1979) observed a kindred in which 16 males and 16 females in 6 generations were affected. There were several examples of male-to-male transmission. In 27 family members, hip dislocation was associated with joint laxity. Five had joint laxity only. Six obligate heterozygotes showed no abnormality. In Ferrara, Italy, CDH has an usually high frequency, for which reason there has been keen awareness of the problem and need for early diagnosis and treatment. For that purpose a special center for the study of CDH was established in the 1930s. Sollazzo et al. (2000) performed a complex segregation analysis in a sample of 171 pedigrees collected through probands affected by nonsyndromic dysplasia of the hip treated in the Ferrara CDH Centre between 1991 and 1996. Analysis favored a 2-locus model, in which the accepted segregation model at the major locus was compatible with recessive transmission, with a gene frequency of the deleterious allele of approximately 0.20. For the other locus, among the mendelian hypotheses tested, the recessive model turned out to be the most parsimonious. History A classic article by Perkins (1928) on signs by which to diagnose congenital dislocation of the hip was excerpted by Peltier (1992). Carter and Wilkinson (1964) postulated the existence of 2 genetic systems responsible for the etiology of CDH: the former, polygenic, related to dysplasia of the acetabulum; the latter, probably dominant, controlling the capsule around the hip joint. Wynne-Davies (1970), in accordance with this hypothesis, suggested that 2 etiologic groups with congenital dislocation of the hip can be observed: one group with acetabular dysplasia, inherited through a multiple gene system (and responsible for a high proportion of cases diagnosed late), and another group with joint laxity (responsible for a high proportion of neonatal cases), revealing a genetic predisposition in which the action of unknown environmental factors appeared to be important. Animal Model Hip dysplasia with dislocation occurs in high frequency in the German shepherd dog (Bornfors et al., 1964). INHERITANCE \- Multifactorial SKELETAL Pelvis \- Congenital hip dislocation \- Positive Ortolani sign MISCELLANEOUS \- Preponderance of affected females (80%) to males \- Positive family history in 12-33% patients \- Incidence 1-1.5/1,000 live births ▲ 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	DEVELOPMENTAL DYSPLASIA OF THE HIP 1	c4551649	1,589	omim	https://www.omim.org/entry/142700	2019-09-22T16:40:11	{"mesh": ["D006618"], "omim": ["142700"], "synonyms": ["Alternative titles", "HIP DYSPLASIA, DEVELOPMENTAL", "HIP DYSPLASIA, CONGENITAL", "ACETABULAR DYSPLASIA"]}
A number sign (#) is used with this entry because of the demonstration that the disorder is caused by mutations in the human homolog of the mouse 'hairless' gene (HR; 602302); see 203655. Clinical Features Papillary lesions over most of the body and almost complete absence of hair are features. The patients are born with hair that falls out and is not replaced. Histologic studies show malformation of the hair follicles. Damste and Prakken (1954) described a kindred in which 3 sisters and 2 sons of their mother's first cousin were affected. Loewenthal and Prakken (1961) described another case, the daughter of third cousins. Cystic malformation of hair follicles was observed. Ahmad et al. (1998) suggested that the human counterpart of the mouse 'hairless' mutation should be called atrichia with papular lesions. They pictured the characteristic cystic papules on the elbows and knees of their patients. Sprecher et al. (2000) assessed the pattern of androgenetic alopecia in 31 healthy male second-degree relatives of patients affected with APL belonging to a large consanguineous kindred. No difference in age at onset or extent of androgenetic alopecia was observed between healthy homozygotes and heterozygous carriers of the mutation. Sprecher et al. (2000) concluded that the presence of a deleterious mutation in one allele of the 'hairless' gene does not affect the pattern of androgenetic hair loss. Ahmad et al. (1998), who referred to this condition as congenital atrichia, reported the identification of a missense mutation in the zinc finger domain of the hairless gene in a large inbred family of Irish Travellers. The gypsies known as Irish Travellers had existed as a distinct indigenous ethnic minority within Ireland for centuries. Hairs were typically absent from the scalp, with shedding of the natal hair shortly after birth, and patients were completely devoid of eyebrows, eyelashes, and axillary and pubic hair. A biopsy of the scalp skin from one of the affected individuals showed absence of hair follicles, with sparsely distributed sebaceous glands. There was no histologic evidence of an inflammatory process. All affected individuals had grouped cystic and papular lesions on the knees and elbows, which had the clinical and histopathologic appearance of milia. Affected individuals showed no growth or developmental delay, normal hearing, teeth, and nails, and no abnormalities of sweating. Heterozygous individuals had normal hair and were clinically indistinguishable from genotypically normal persons. Published estimates of the prevalence of APL remain surprisingly low considering pathogenetic mutations in HR have been found in distinct populations around the world. Zlotogorski et al. (2002) and Henn et al. (2002) asserted that APL is more common than previously thought and is often mistaken for the putative autoimmune form of alopecia universalis (see 104000). Zlotogorski et al. (2002) proposed revised clinical criteria for APL based on their personal observation of 9 Arab families and retrospective analysis of other families described in the literature. These features include family history with autosomal recessive inheritance and possible consanguinity; atrichia at birth or shedding of normal scalp hair several months after birth with failure to regrow; appearance of skin papules (most commonly on the face, under the midline of the eye, and on the extremities) within the first year of life; sparse eyebrows and eyelashes; lack of secondary axillary, pubic, or body hair; whitish hypopigmented streaks on the scalp; normal nails, teeth, and sweating; normal growth and development; and failure of any treatment modality to restore hair growth. Miller et al. (2001) reported a patient with vitamin D-resistant rickets type IIA (277440), a compound heterozygote for mutations in the VDR gene (601769.0013, 601769.0014), in which the phenotype of atrichia with papular lesions was identical to that seen in patients carrying mutations in the HR gene. The authors suggested that VDR and HR, which are both zinc finger proteins, may be in the same genetic pathway that controls postnatal cycling of the hair follicle. Mapping Sprecher et al. (1998) described the largest consanguineous kindred of APL reported to that time and provided strong evidence for autosomal recessive inheritance. They mapped the APL locus to 8p12 in a 5-cM interval between marker D8S560 and marker D8S1739. A maximum lod score of 3.7 was obtained with marker D8S1786, at a recombination fraction of 0.0 Molecular Genetics Although Ahmad et al. (1998) detected a mutation in the HR gene (arg620 to gln) in a family of Irish Travellers with atrichia with papular lesions, Hillmer et al. (2001) concluded that, in fact, this mutation is not a disease-causing mutation but a polymorphism without consequences for hair development. In Germany they found a gln620 allele frequency of 2.7%, which would predict that almost 60,000 individuals in Germany are affected with autosomal recessive papular atrichia; however, no German has been reported with this disorder. They identified an individual homozygous for gln620 who was unambiguously not affected with papular atrichia. He had, however, male-pattern loss of scalp hair beginning at the age of 18 to 20 years and by the age of 26 years had developed severe androgenetic alopecia (109200). The rest of the scalp hair, eyebrows, and beard hair, as well as pubic, axillary, and body hair, developed normally and remained completely normal. There were no signs of a papular rash. By RT-PCR, Sprecher et al. (1999) compared the coding sequence of the HR gene in fibroblast cell lines derived from a patient with APL and an unrelated individual. They identified a 1-bp deletion (3434delC; 602302.0006) in the HR gene that cosegregated with the disease phenotype in the large family reported by Sprecher et al. (1998). This deletion was predicted to cause a frameshift mutation in the highly conserved C-terminal part of the HR protein, a region putatively involved in the transcription factor activity of the HR gene product. These results indicated phenotypic heterogeneity in inherited atrichias caused by mutations in the HR gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development. Henn et al. (2002) reported a small German kindred in which 2 sibs were compound heterozygous for different HR mutations (602302.0010, 602302.0011). They were both born with normal hair that was lost within the first few months of life and did not grow back. Both had undergone several unsuccessful invasive treatments for autoimmune alopecia universalis before the diagnosis of APL was made and confirmed by DNA analysis. Paller et al. (2003) identified 3 small nonconsanguineous families having 1 offspring affected by early-onset hair loss that never regrew with an associated papular eruption and/or failed response to treatment for alopecia universalis. The clinical findings in all 3 families were consistent with APL. Paller et al. (2003) identified compound heterozygous mutations in the HR gene in all 3 affected individuals. Their 3 additional compound heterozygous patients from families without consanguinity further supported the hypothesis that isolated cases of APL may be more common than previously thought and suggested that infants with presumed autoimmune alopecia universalis in small nonconsanguineous families may warrant testing for HR gene mutations, particularly before embarking on therapeutic modalities that will fail in APL. In affected individuals from 5 unrelated consanguineous Pakistani families with generalized scalp and body alopecia, sparse eyebrows and lashes, and papules, Kim et al. (2007) identified homozygosity for 1 of 3 nonsense mutations in the HR gene. Microsatellite marker analysis showed that each of 2 sets of families carrying the same nonsense mutation had an identical homozygous haplotype, suggesting that the mutations did not arise independently but were propagated in the population. All affected individuals presented with the same clinical manifestations. Kim et al. (2007) noted that, in keeping with previous reports, they did not observe any genotype/phenotype correlations. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Papillary lesions, generalized Hair \- Hypotrichosis \- Hair follicles cystic MOLECULAR BASIS \- Caused by mutation in the HR lysine demethylase and nuclear receptor corepressor gene (HR, 602302.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	ATRICHIA WITH PAPULAR LESIONS	c1859592	1,590	omim	https://www.omim.org/entry/209500	2019-09-22T16:30:37	{"doid": ["0060689"], "mesh": ["C565924"], "omim": ["209500"], "orphanet": ["86819"], "synonyms": ["Alternative titles", "PAPULAR ATRICHIA"]}
Giant-cell reticulohistiocytoma SpecialtyDermatology Giant-cell reticulohistiocytoma (also known as Solitary reticulohistiocytoma and Solitary reticulohistiocytosis)[1] is a cutaneous condition characterized by a solitary skin lesion.[1] ## See also[edit] * Indeterminate cell histiocytosis * List of cutaneous conditions ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 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	Giant-cell reticulohistiocytoma	None	1,591	wikipedia	https://en.wikipedia.org/wiki/Giant-cell_reticulohistiocytoma	2021-01-18T18:32:54	{"wikidata": ["Q5558340"]}
Multisystemic smooth muscle dysfunction syndrome is a disease in which the activity of smooth muscle throughout the body is impaired. This leads to widespread problems including blood vessel abnormalities, a decreased response of the pupils to light, a weak bladder, and weakened contractions of the muscles used for the digestion of food (hypoperistalsis). A certain mutation in the ACTA2 gene has been shown to cause this condition in some individuals. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Multisystemic smooth muscle dysfunction syndrome	c3151201	1,592	gard	https://rarediseases.info.nih.gov/diseases/12811/multisystemic-smooth-muscle-dysfunction-syndrome	2021-01-18T17:58:53	{"omim": ["613834"], "orphanet": ["404463"], "synonyms": ["Congenital mydriasis, patent ductus arteriosus, thoracic aortic aneurysm, and vasculopathy"]}
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-29 (SCA29), also known as congenital nonprogressive cerebellar ataxia (CNPCA), is caused by heterozygous mutation in the ITPR1 gene (147265) on chromosome 3p26. Description Spinocerebellar ataxia-29 is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012). Heterozygous mutation in the ITPR1 gene also causes SCA15 (606658), which is distinguished by later age at onset and normal cognition. For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Tomiwa et al. (1987) reported affected mother and daughter with nonprogressive congenital cerebellar ataxia and normal intelligence. Computed tomography revealed localized atrophy of the cerebellar vermis. Kattah et al. (1983) described a family in which 5 members had primary position vertical nystagmus. Fenichel and Phillips (1989) described a family in which 4 persons in 3 generations had nonprogressive ataxia from birth. Magnetic resonance imaging in 1 child showed hypoplasia or partial aplasia of the cerebellar vermis. Patients had delayed motor development, truncal ataxia, nystagmus, and normal intelligence. Fenichel and Phillips (1989) were impressed with the fact that 12 of 14 reported persons were female and that 2 affected males were more severely affected than were their female relatives. This led them to suggest both X-linked dominant and autosomal dominant inheritance as possibilities. Rivier and Echenne (1992) described a mother and her 2 daughters with congenital, nonprogressive cerebellar ataxia and atrophy of the cerebellar vermis. Slowly progressive improvement of motor abilities in all 3 patients was an unusual feature. Imamura et al. (1993) described a mother and daughter with early-onset nonprogressive cerebellar ataxia. The mother had a broad-based unsteady gait with frequent falling dating from the first years of life. She had cerebellar signs, including bilateral horizontal nystagmus. MRI at the age of 29 demonstrated increased sulcation of the cerebellar hemispheres and atrophic vermian lobules and hemispheric folia, especially in the anterior part. The basal cistern was enlarged. One of her 2 children, a daughter, was floppy from birth and at 8 months also demonstrated delayed development and truncal ataxia. Cerebellar atrophy, which could not be detected by CT at the age of 12 months, was clearly discernible by MRI at the age of 3. Male-to-male transmission was reported by Kornberg and Shield (1991). A preponderance of female patients seems to have been observed. Dudding et al. (2004) reported a 4-generation Australian kindred of Caucasian ancestry in which at least 20 members had congenital nonprogressive ataxia inherited in an autosomal dominant pattern. All affected individuals had congenital onset of ataxia or delayed walking and wide-based gait as a young child. In addition, all affected members had cognitive impairment of varying degrees, which was more disabling than the ataxia. Although dysarthria was common, nystagmus and dysdiadochokinesis were only observed in 1 and 2 patients, respectively. Five family members reported a slight improvement in coordination with increasing age. Three of 7 patients who agreed to testing had atrophy of the cerebellar vermis on MRI, and there was no association between cerebellar hypoplasia and the degree of either ataxia or cognitive impairment. Linkage analysis excluded the major loci for spinocerebellar ataxia. Titomanlio et al. (2005) reported a father and son with a mild form of isolated cerebellar vermis aplasia, confirming an autosomal dominant mode of inheritance of the disease. Both patients showed progressive improvement of their motor abilities; neurologic examination of the father at age 35 was normal except for mild mental retardation. Huang et al. (2012) reported a 3-generation Canadian family in which 4 individuals had early-onset nonprogressive spinocerebellar ataxia. The proband, in the third generation, was noted to have delayed psychomotor development at age 8 months. Physical examination at age 28 months showed language delay, gaze-evoked nystagmus, hypotonia, truncal titubation, appendicular dysmetria, poor speech, and lack of independent ambulation. Brain MRI showed mild atrophy of the cerebellar vermis, which progressed on reassessment several years later. At age 5 years, she developed complex partial seizures that responded to medication. Her 45-year-old father had delayed motor development and reported academic difficulties, although he completed high school and some college courses. Physical examination of the father showed saccadic eye movements, end-range nystagmus, dysarthria, gait and limb ataxia, and intention tremor. Brain MRI showed diffuse cerebellar atrophy. The proband's paternal aunt showed delayed ambulation and learning difficulties, and the paternal grandmother was similarly affected. Sensation was not affected in this family. Parolin Schnekenberg et al. (2015) reported 2 unrelated children with a clinical diagnosis of ataxic cerebral palsy who were found to carry 2 different de novo heterozygous mutations in the ITPR1 gene (see, e.g., 147265.0004). Both patients showed delayed motor development, ataxic gait, and moderate intellectual disability. Other more variable features included nystagmus and hyperreflexia. Brain imaging was normal in both patients. Functional studies of the variants were not performed. Inheritance The transmission pattern of congenital ataxia in the family reported by Dudding et al. (2004) was consistent with autosomal dominant inheritance. Mapping By genomewide analysis of a large kindred with congenital nonprogressive cerebellar ataxia, Dudding et al. (2004) identified linkage to an 18.9-cM region on chromosome 3p (maximum 2-point lod score of 4.26 at marker D3S3630). The disease locus lies distal to D3S1304 in the pter region of chromosome 3. Approximately 8 cM of the candidate region overlaps with the locus defined for SCA15 (606658). In a review of the literature, Dudding et al. (2004) noted the phenotypic variability of autosomal dominant congenital nonprogressive cerebellar ataxia and suggested that it may be a genetically heterogeneous condition. ### Genetic Heterogeneity Furman et al. (1985) reported a family in which a mother and 2 daughters had an early-onset nonprogressive form of ataxia. The mother presented with oscillopsia and visual blurring at the age of 32 years. She had been clumsy all her life, without progression of symptoms. She had normal intelligence, truncal ataxia, mild limb dysmetria, upbeating nystagmus, and gaze-provoked horizontal nystagmus. All 3 affected members had localized atrophy of the cerebellar vermis on brain MRI. Jen et al. (2006) provided follow-up of the family reported by Furman et al. (1985); 2 additional affected children were identified. The disorder was found to be nonprogressive: older family members showed no change in cerebellar atrophy on MRI. The initial presentation of primary position upbeat nystagmus resolved to only gaze-evoked nystagmus. Older individuals developed episodes of vertigo and ataxia with vertical oscillopsia, similar to an episodic ataxia syndrome. Of all 5 affected family members, 2 showed developmental delay and learning difficulties. Using genomewide microarray analysis, Jen et al. (2006) excluded linkage of the family reported by Furman et al. (1985) to chromosome 3p, as well as other loci reported for dominantly inherited SCA syndromes. Jen et al. (2006) found suggestive linkage (lod scores near 1.8) to chromosomes 1q44, 5q35, 7q36, and 9q31-q32. The findings indicated genetic heterogeneity for autosomal dominant nonprogressive congenital ataxia. Molecular Genetics By exome sequencing of a member of the family with SCA29 reported by Dudding et al. (2004), Huang et al. (2012) identified a heterozygous mutation in the ITPR1 gene (V1553M; 147265.0003). The mutation was confirmed by Sanger sequencing and segregated with the disorder in this family. Direct sequencing of the ITPR1 gene in a Canadian family with a similar disorder identified a different heterozygous missense mutation (N602D; 147265.0004). Both mutations occurred at highly conserved residues in the coupling/regulatory domain that modulates channel function, possibly resulting in dysregulation of intracellular calcium signaling. Animal Model Ogura et al. (2001) found that heterozygous Itpr1 knockout mice (Itpr1 +/-) demonstrated impaired motor coordination compared to wildtype mice as shown on the rotarod test. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus \- Saccadic eye movements NEUROLOGIC Central Nervous System \- Cerebellar ataxia, nonprogressive \- Delayed motor development \- Broad-based gait \- Limb ataxia \- Dysarthria \- Dysdiadochokinesis \- Intention tremor \- Dysmetria \- Nystagmus \- Cognitive impairment, mild \- Atrophy of the cerebellar vermis seen on MRI MISCELLANEOUS \- Onset at birth \- Slow or nonprogressive MOLECULAR BASIS \- Caused by mutation in the inositol 1,4,5-triphosphate receptor 1 gene (ITPR1, 147265.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	SPINOCEREBELLAR ATAXIA 29	c1861732	1,593	omim	https://www.omim.org/entry/117360	2019-09-22T16:43:31	{"doid": ["0050978"], "mesh": ["C537206"], "omim": ["117360"], "orphanet": ["208513"], "synonyms": ["Alternative titles", "CEREBELLAR ATAXIA, CONGENITAL NONPROGRESSIVE, AUTOSOMAL DOMINANT", "CEREBELLAR VERMIS APLASIA", "APLASIA OF CEREBELLAR VERMIS"]}
A rare, non-syndromic, posterior fossa malformation characterized by a cisterna magna that measures above 15 mm in length, 5 mm in height and 20 mm in width (or greater than 10 mm in fetuses) associated with a normal cerebellar vermis and absence of hydrocephalus. The majority of patients are asymptomatic; however, variable neurodevelopmental outcomes, including delayed speech and language development, motor development delay, visiospatial perception difficulties, and attention problems, has been observed in some 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	Mega-cisterna magna	c3164501	1,594	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97252	2021-01-23T17:48:27	{"umls": ["C3164501"], "icd-10": ["Q07.8"]}
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: "Dieterich's disease" – news · newspapers · books · scholar · JSTOR (December 2018) (Learn how and when to remove this template message) This article possibly contains inappropriate or misinterpreted citations that do not verify the text. Please help improve this article by checking for citation inaccuracies. (December 2018) (Learn how and when to remove this template message) Dieterich's disease, also known as avascular necrosis of the metacarpal head,[1] is an extremely rare condition characterized by temporary or permanent loss of blood supply to the metacarpal head of the metacarpal bone, resulting in loss of bone tissue. The five metacarpal bones are long bones located between the carpals of the wrist and phalanges of the fingers. Collectively, the metacarpals are referred to as the "metacarpus." In the case of Dieterich's disease, some but not all metacarpal heads are affected. Onset of this disease can be attributed to steroid usage, systemic lupus erythematosus, or trauma. In some cases, it is randomly-occurring.[2] Dieterich's disease can be diagnosed through medical screening or blood testing. Physicians may also diagnose Dieterich's disease by taking a history of the patient's symptoms. Some treatment options include medication, surgery, or therapy.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 History * 6 Cases * 6.1 Unnamed 54-year old female * 6.2 Unnamed 37-year old male * 6.3 Unnamed 16-year old male * 6.4 Unnamed 36-year old male * 6.5 Unnamed 68-year old woman * 7 See also * 8 References ## Signs and symptoms[edit] Early on, symptoms may not be noticeable. Patients may either be asymptomatic or may experience progressive joint collapse with increased pain and increasingly restricted range of motion.[3] ## Cause[edit] The cause of Dieterich’s disease is still not fully understood. The disease can afflict patients of any age, but typically affects patients in their 30s. Though rare, it can also occur in children.[4] Statistics show that generally more men are affected by Dieterich's than women in an estimated ratio of 3:2.[3][5] The third (middle finger) metacarpal head has been reported to be the most common site of necrosis.[6] Though osteonecrosis is a fairly common condition, many cases of avascular necrosis of the metacarpal head go without being diagnosed. This is because presentation of symptoms is variable depending on the patient. Sometimes, the patient may even choose to ignore their symptoms.[5] Onset of Dieterich's disease can possibly be attributed to steroid usage, trauma, systemic lupus erythematosus, renal transplant, or scleroderma. It can also afflict patients living with congenital short digits or atypical anatomical epiphyseal blood supply. In some cases, however, Dieterich's disease can occur spontaneously.[3][7] ## Diagnosis[edit] Scans showing bone tissue will typically display flattening or collapse of the metacarpal head, or deterioration of cartilage in the joint.[8] In some cases, a physician may take a patient history and make a diagnosis based on a combination of medical imaging and symptom history.[9] Dieterich's disease can be characterized by swelling, which can be indicated by C-reactive protein (CRP) and normal erythrocyte sedimentation rates (ESR), both of which can be shown in a blood investigation.[6] ## Treatment[edit] No single method of treatment has been determined as the optimal treatment yet, as each case is extremely variable.[3] ## History[edit] This condition was first described by German doctor H. Dieterich in 1932 in his journal entitled "Die subchondrale Herderkrankung am Metacarpale iii," translating to mean "The subchondral focal disease on metacarpal III," in English.[3] ## Cases[edit] ### Unnamed 54-year old female[edit] An unnamed female was seen by Belgian doctors for a swollen, painful third metacarpophalangeal joint. According to the patient, these symptoms had persisted for 3 months with no previous recorded trauma. She had been taking large doses of cortisone to treat lung disease due to smoking. Though the patient could fully extend the joint, flexion was limited. Radiographs revealed deterioration of cartilage and collapse of the metacarpal head. The patient was unsuccessfully treated with anti-inflammatory drugs, then treated with removal of necrotic bone and bone grafting surgery with fair success.[8] ### Unnamed 37-year old male[edit] A 37-year old male was seen by Chinese hand-surgery specialists for chronic dull pain in his right hand. Physical examination showed swelling in his third and fourth metacarpophalangeal joints, and there was significantly limited range of motion on the third metacarpophalangeal joint. Patient had no history of trauma, but may have been affected by his work as a mechanical laborer. He had been seen one year previously and magnetic resonance imaging revealed flattening of the fourth metacarpal head. The patient returned because of continued pain. The third metacarpal head was then treated through bone grafting. In a follow up, it was noted that pain and swelling had diminished and there was a noted improvement in range of motion of the third metacarpophalangeal joint.[5] ### Unnamed 16-year old male[edit] A 16-year old teenage male was seen for sudden pain in his right metacarpophalangeal joints. Though there was no history of trauma, the patient was a manual laborer. Range of motion was slightly limited and joint was mildly swollen and tender when palpated. Patient was originally treated with splinting and ibuprofen, but this further worsened his condition. Patient was then treated with physical therapy, but symptoms persisted. Finally, patient was treated with bone grafting surgery and splinted for three weeks. After surgery followed by physical therapy, full range of motion was restored within eight weeks.[3] ### Unnamed 36-year old male[edit] A 36-year old male electrician with no past history of trauma presented with a painful right middle finger metacarpophalangeal joint. Range of motion was not limited. The afflicted joint did not have any particular outwardly visible indicators of Dieterich's disease besides some crackling noises with movement. Patient would stretch his finger for temporary relief. In this case, though blood work and plain-film imaging did not show any abnormalities, an MRI showed avascular necrosis in the middle finger. The patient was successfully treated with physical therapy.[6] ### Unnamed 68-year old woman[edit] A 68-year old woman was first seen with pain attributed to either inflammatory or septic arthritis. She had been receiving orthopedic treatment previously due to increasing pain. The afflicted metacarpal head of the ring finger showed limited range of movement and chronic swelling. Through laboratory testing and based on the evolution of the pain, it was determined to be Dieterich's disease. The patient was initially suggested surgical treatment, but she rejected surgery due to acceptable functional status of the joint.[9] ## See also[edit] * Aseptic necrosis * Avascular necrosis ## References[edit] 1. ^ "Dieterich's disease". Genetic and Rare Diseases Information Center. 2. ^ Dixon A. "Dietrich disease". Radiology Reference Article. Radiopaedia.org. Retrieved 2018-10-24. 3. ^ a b c d e f g Fette AM (March 2010). "Case report: Dieterich's disease in a teenage boy". Journal of Pediatric Orthopedics. Part B. 19 (2): 191–4. doi:10.1097/BPB.0b013e32832fef16. PMID 19907347. 4. ^ Sagar P, Shailam R, Nimkin K (December 2010). "Avascular necrosis of the metacarpal head: a report of two cases and review of literature". Pediatric Radiology. 40 (12): 1895–901. doi:10.1007/s00247-010-1763-y. PMID 20614113. S2CID 6816522. 5. ^ a b c Li W, Liu B, Song J, Liu Y, Liu H, Pei S, Wei Z, Zhang J, Dong M (September 2016). "Bilateral Multiple Metacarpal Head Avascular Necrosis: A Case Report". International Surgery. 101 (9–10): 473–477. doi:10.9738/intsurg-d-16-00010.1. 6. ^ a b c McGoldrick NP, McGoldrick FJ (January 2015). "Avascular necrosis of the metacarpal head: a case of Dietrich's disease and review of the literature". The American Journal of Case Reports. 16: 12–5. doi:10.12659/AJCR.892389. PMC 4296845. PMID 25594915. 7. ^ Karlakki SL, Bindra RR (January 2003). "Idiopathic avascular necrosis of the metacarpal head". Clinical Orthopaedics and Related Research (406): 103–8. doi:10.1097/01.blo.0000030168.56585.cb (inactive 2021-01-17). PMID 12579007.CS1 maint: DOI inactive as of January 2021 (link) 8. ^ a b Thienpont E, Vandesande W, De Smet L (April 2001). "Dieterich's disease: avascular necrosis of the metacarpal head: a case report". Acta Orthopaedica Belgica. 67 (2): 182–4. PMID 11383299. S2CID 32622032. 9. ^ a b Ares O, Seijas R, Conesa X, Pedemonte J (October 2008). "Avascular necrosis of the metacarpal head: Dieterich's disease". Acta Orthopaedica Belgica. 74 (5): 693–6. PMID 19058708. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Dieterich's disease	c2931124	1,595	wikipedia	https://en.wikipedia.org/wiki/Dieterich%27s_disease	2021-01-18T19:00:24	{"gard": ["204"], "mesh": ["C536172"], "umls": ["C2931124"], "wikidata": ["Q55790152"]}
A number sign (#) is used with this entry because of evidence that GPI biosynthesis defect-1 (GPIBD1) is caused by homozygous mutation in the PIGM gene (610273) on chromosome 1q23. Description Glycosylphosphatidylinositol is a glycolipid that anchors more than 150 proteins to the cell surface, and these proteins, termed GPI-anchored proteins (GPI-APs), perform a variety of functions as enzymes, adhesion molecules, complement regulators, and coreceptors in signal transduction pathways. Reduced surface levels of GPI-APs or abnormal GPI-AP structure can therefore result in variable manifestations. Glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1) is characterized predominantly by portal hypertension due to portal vein thrombosis. Most patients have absence seizures, cerebral thrombosis, and macrocephaly. Some patients have mildly to moderately impaired intellectual development (summary by Makrythanasis et al., 2016; Pode-Shakked et al., 2019). ### Genetic Heterogeneity of Glycosylphosphatidylinositol Biosynthesis Defects Also see GPIBD2 (239300), caused by mutation in the PIGV gene (610274); GPIBD3 (614080), caused by mutation in the PIGN gene (606097); GPIBD4 (300868), caused by mutation in the PIGA gene (311770); GPIBD5 (280000), caused by mutation in the PIGL gene (605947); GPIBD6 (614749), caused by mutation in the PIGO gene (614730); GPIBD7 (615398), caused by mutation in the PIGT gene (610272); GPIBD8 (614207), caused by mutation in the PGAP2 gene (615187); GPIBD9 (615802), caused by mutation in the PGAP1 gene (611655); GPIBD10 (615716), caused by mutation in the PGAP3 gene (611801); GPIBD11 (616025), caused by mutation in the PIGW gene (610275); GPIBD12 (616809), caused by mutation in the PIGY gene (610662); GPIBD13 (616917), caused by mutation in the PIGG gene (616918); GPIBD14 (617599), caused by mutation in the PIGP gene (605938); GPIBD15 (617810), caused by mutation in the GPAA1 gene (603048); GPIBD16 (617816), caused by mutation in the PIGC gene (601730); GPIBD17 (618010), caused by mutation in the PIGH gene (600154); GPIBD18 (618143), caused by mutation in the PIGS gene (610271); GPIBD19 (618548), caused by mutation in the PIGQ gene (605754); GPIBD20 (618580), caused by mutation in the PIGB gene (604122); and GPIBD21 (618590), caused by mutation in the PIGU gene (608528). Clinical Features Almeida et al. (2006) reported 3 affected children from 2 unrelated consanguineous families, of Middle Eastern and Turkish origin, respectively, with a newly described inherited deficiency of GPI. The probands from each family developed portal vein thrombosis and portal hypertension by age 2 years. One developed absence seizures at age 4 years, and the other developed atonic seizures at age 3 years. The younger sib in the Turkish family was treated with prophylactic oral anticoagulants and did not develop thrombosis, but still developed absence seizures at age 5 years. None of the patients had central venous thrombosis or vascular anomalies and none showed hemolysis or bone marrow failure. Detailed laboratory studies showed variably decreased expression of GPI-linked proteins, including CD59 (107271) and CD24 (600074), on hematopoietic cells. Almeida et al. (2006) noted that paroxysmal nocturnal hemoglobinuria (PNH; 300818), an acquired clonal disorder caused by mutation in the PIGA gene (311770), is also characterized by a GPI defect. Pode-Shakked et al. (2019) reported 4 patients from 2 unrelated Arab families with glycosylphosphatidylinositol deficiency and mutations in the PIGM gene. Three sibs in family A had cerebral and portal vein thrombosis, macrocephaly, prominent superfical facial/abdominal veins, and hepato- or splenomegaly. The 2 oldest sibs, a brother and sister, had persistent atypical absence seizures beginning at age 3 to 4 years. The brother died at age 7 due to complications of cirrhosis. Another sister, who was diagnosed prenatally, had portal and cerebral vein thromboses beginning at age 7 months. She had an acute episode of left-sided hemiplegia at age 16 months, with residual left-sided hemiplegia and inability to speak. Both sisters had mildly to moderately impaired intellectual development. The 4-year-old boy in family B had cerebral and portal vein thrombosis, macrocephaly, dilated superficial facial and abdominal veins, and hepatosplenomegaly. Molecular Genetics Almeida et al. (2006) identified a homozygous mutation in the promoter region of the PIGM gene (610273.0001) in 3 patients from 2 unrelated consanguineous families with glycosylphosphatidylinositol deficiency. The mutation occurred in a conserved region in the promoter region of the gene and disrupted binding of the transcription factor SP1 (189906). PIGM mRNA levels were severely reduced. The findings confirmed that the disorder is caused by a defect in the biosynthetic pathway crucial for anchoring proteins to the cell surface. In 4 affected members from 2 unrelated Arab families with GPIBD1, Pode-Shakked et al. (2019) identified homozygosity for the same promoter mutation in the PIGM gene that had been identified by Almeida et al. (2006). The mutation segregated with the disorder in both families. Clinical Management Almeida et al. (2007) reported follow-up of 1 of the patients with GPI deficiency reported by Almeida et al. (2006). This 14-year-old girl had severe refractory seizures occurring several times a day, which resulted in her being wheelchair-bound, poorly responsive, and unable to feed herself. Treatment with sodium phenylbutyrate, a histone deacetylase inhibitor, resulted in significant clinical improvement and remission of seizures. In vitro studies of patient cells showed no evidence of histone acetylation at the mutated PIGM promoter, suggesting that the SP1-binding site is crucial for histone acetylation. PIGM transcription and mRNA levels were increased in the presence of sodium butyrate even in the presence of the mutation. Patient cells in vitro and in vivo showed restoration of GPI biosynthesis and expression after treatment. Three patients in the families with GPIBD1 reported by Pode-Shakked et al. (2019) were treated with sodium phenylbutyrate. The 2 sisters in family A had modest clinical improvement, but the authors noted difficulty with treatment adherence in the family. The boy in family B began treatment at age 15 months; at follow-up at age 4 years, he remained clinically neurologically intact and without seizures. In both families, no significant changes were demonstrated using serial measurements of GPI surface markers (CD59, CD24, FLAER) after initiation of treatment. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Vascular \- Venous thrombosis \- Portal hypertension ABDOMEN Liver \- Hepatic venous thrombosis \- Portal vein thrombosis \- Portal hypertension \- Hepatomegaly Spleen \- Splenomegaly NEUROLOGIC Central Nervous System \- Seizures, absence \- Seizures, atonic HEMATOLOGY \- No hemolysis \- No bone marrow abnormalities LABORATORY ABNORMALITIES \- Decreased expression of glycosylphosphatidylinositol-linked proteins (e.g., CD59 107271 and CD24 600274 ) on hematopoietic cells MISCELLANEOUS \- Two unrelated families have been reported (last curated May 2014) \- Onset of thrombosis by age 2 years MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol glycan, class M gene (PIGM, 610273.0001 ) ▲ 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	GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 1	c1853205	1,596	omim	https://www.omim.org/entry/610293	2019-09-22T16:04:44	{"mesh": ["C537277"], "omim": ["610293"], "orphanet": ["83639"], "synonyms": ["Alternative titles", "PORTAL HYPERTENSION WITH SEIZURES AND/OR MACROCEPHALY", "GLYCOSYLPHOSPHATIDYLINOSITOL DEFICIENCY"]}
Acholia SpecialtyGastroenteritis Acholia is the lack or absence of bile secretion.[1] It can also be referred to as hypocholia.[2] Acholia is a sign, meaning lack of the normal brown color in feces, pale feces, suggesting interference with liver function.[3] ## Contents * 1 Etymology * 2 Cause * 3 See too * 4 References * 5 External links ## Etymology[edit] Ancient Greek: a \+ chole (without bile). ## Cause[edit] A condition in which little or no bile is secreted or the flow of bile into the digestive tract is obstructed. The acholia is a sign of many diseases, such as hepatitis. Acholia causes the color of feces to fade.[3] ## See too[edit] * Choluria ## References[edit] 1. ^ Dorland's Medical Dictionary for Health Consumers. Saunders; 2007. 2. ^ Dieulafoy, Georges (1912). A Text-book of Medicine. D. Appleton. p. 953. Retrieved 7 November 2017. "Acholia." 3. ^ a b La médecine de A à Z. Hachette; 1973. ## External links[edit] Classification D Classification D * ICD-10: K82.8 * ICD-9-CM: 575.8 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acholia	c0948198	1,597	wikipedia	https://en.wikipedia.org/wiki/Acholia	2021-01-18T18:42:26	{"umls": ["C0948198"], "icd-9": ["575.8"], "icd-10": ["K82.8"], "wikidata": ["Q8187550"]}
In 95% of cases worldwide, Leber hereditary optic atrophy (LHON) is due to 1 of 3 point mutations of mitochondrial DNA in genes that code for complex I of the respiratory chain: 3460G-A in MTND1 (516000.0001), 11778G-A in MTND4 (516003.0001), and 14484T-C in MTND6 (516006.0001). That only approximately 50% of male and 10% of female mutation carriers develop symptoms (Newman, 2002) indicates a requirement for additional genetic or environmental factors for phenotypic expression of LHON. Epidemiologic studies failed to substantiate anecdotal reports of a link with excess alcohol and tobacco (Kerrison et al., 2000). Bu and Rotter (1991) concluded that available pedigree data on LHON are most consistent with a 2-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. They demonstrated that a proportion of affected females are probably heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female was 0.11 +/- 0.02. The calculated frequency of the X chromosome-linked gene for LHON was 0.08. Among affected females, 60% are expected to be heterozygous and the remainder are expected to be homozygous at the responsible X chromosome-linked locus. Sweeney et al. (1992) presented evidence against an X-linked susceptibility locus near DXS7: linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately, excluded the presence of such a locus from an interval of about 30 cM around DXS7, with a total lod score of -26.51 at a recombination fraction of 0.0. Assuming that the optic tissue is the primary site of action of the mutant gene(s), Bu and Rotter (1992) further proposed that there should be no fewer than 6 embryonic precursor cells for the involved optic tissue at the stage in early development when X-chromosome inactivation occurs. They also estimated that the disease threshold (i.e., proportion of cells with abnormal X chromosome active in the responsible tissue at the time of X-chromosome inactivation) for a heterozygous female is in the range of 0.60 to 0.83. On the basis of families with Leber optic atrophy observed in Australia, Mackey (1993) analyzed the frequency of blindness in the offspring of affected blind women. The frequency of blindness in women was much too high if the susceptibility gene on the X chromosome is dominant. Furthermore, since most of the blind females would be heterozygous, half of their sons and half of their daughters should be blind, also far from the observed figures. If recessive, blindness in women would be predicted to be almost exactly what is observed to be the case in LHON families. However, recessive inheritance of susceptibility would predict that all sons and no daughters of blind females would be affected, also far from the observed figures. On the basis of this analysis, Mackey (1993) concluded that it is unlikely that an X-linked factor is involved in the expression of LHON; some other sex-variable factor must be involved. Nakamura et al. (1993) pursued the 2-locus mitochondrial and X-linked nuclear gene model for Leber optic atrophy, which proposes that an affected female is either a homozygote at the X-linked locus or a heterozygote with biased inactivation of a normal allele on an X chromosome. In Japanese families, Nakamura et al. (1993) found an excellent fit for the predicted 1:1 segregation of a putative X-linked gene. When male sibship data with a presumed heterozygous mother from maternal lines was investigated, the calculated frequency of the X-linked gene was 0.10, which may not be different from that estimated in Caucasians, 0.08. On the other hand, the estimated penetrance for a heterozygous female was about twice as high in the Japanese (0.196) as in Caucasians (0.111). In Japanese LHON pedigrees, more females are affected than in Caucasian pedigrees. The mtDNA 11778 mutation (516003.0001) accounts for about 92% of Japanese cases but perhaps only 50 to 70% of Caucasian cases. If a nuclear X-linked modifier gene influences the expression of the mitochondrial mutant gene responsible for LHON, then the affected females should be homozygous for the nuclear determinant or, if heterozygous, lyonization should favor the mutant X. With this in mind, Pegoraro et al. (1996) studied X-inactivation patterns in 35 females with known mitochondrial DNA mutations from 10 LHON pedigrees. The results did not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. Chalmers et al. (1996) presented evidence from linkage analysis in British and Italian families with genetically proven LHON that excluded the presence of an X-linked visual loss susceptibility locus (VLSL) involved in the pathogenesis of LHON. VLSL was excluded over 169 cM of the X chromosome when all families were analyzed together and when only families with the nucleotide 11778 mutation in the MTND4 gene (516003.0001) were studied. Furthermore, there was no excess skewing of X inactivation in affected females, a finding supported also by Oostra et al. (1996). Chalmers et al. (1996) found no evidence for close linkage to 3 markers in the pseudoautosomal region of the sex chromosomes. The authors concluded that the mechanism of incomplete penetrance and male predominance in LHON remained unclear. According to the 2-locus model for LHON, females would be affected only if they were homozygous for the X-linked recessive susceptibility gene or had skewed X inactivation. Pegoraro et al. (2003) noted that previous attempts to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X inactivation in affected females had been unsuccessful, although the inactivation pattern had been studied only in DNA isolated from blood cells. They analyzed a wide range of tissues, including the optic nerves and the retina, at autopsy in 2 female LHON patients. They found no evidence of skewed X inactivation in the affected tissues, thus further weakening the hypothesized involvement of a specific X chromosome locus in the pathophysiologic expression of LHON. One patient was from an Italian pedigree and carried the MTND1 3460 mutation (516000.0001). The onset of optic neuropathy and an extrapyramidal syndrome occurred at 22 years of age, and she died at 75 years of age of heart failure after a 10-year course of progressive dementia. All tissues showed homoplasmic mutant mtDNA. The second patient was heteroplasmic for the MTND4 11778 mutation (516003.0001). This woman was affected with optic neuropathy at 38 years of age and died at 68 years of age of chronic obstructive pulmonary disease. Large multigenerational pedigrees with LHON are well recognized, with affected individuals present in as many as 10 generations. It is therefore unlikely that a nuclear modifier locus would be strictly coinherited with the primary mtDNA mutation throughout the whole pedigree. Given the relative rarity of the primary mtDNA mutation, it is far more likely that the nuclear modifier is common in the general population and moves in and out of the maternal pedigree through random mating between mothers who transmit the LHON mtDNA mutation (who largely remain unaffected) and unrelated male partners not harboring the LHON mtDNA mutation. The nuclear modifier, as reasoned by Hudson et al. (2005) is likely to be 1 or more ancient genetic variants that may be present at a high frequency in the population. Following this reasoning, they used a nonparametric complex disease mapping strategy to identify the modifier locus. They collected a total of 389 DNA samples from affected and unaffected individuals from 100 families with LHON in 6 different countries. The percentage with heteroplasmy was determined, and only samples with more than 70% mutated mtDNA were included in the linkage study because this level of mutated mtDNA is associated with the same penetrance as homoplasmic mutated mtDNA (Chinnery et al., 2001). They initially performed nonparametric linkage (NPL) analysis in 6 Finnish families, since linkage disequilibrium blocks in young, geographically isolated populations are generally larger than average, facilitating low density linkage mapping of complex traits (Wright et al., 1999). They then turned to independent European cohorts with LHON. Thus they defined an X-chromosomal haplotype bounded by markers in the proximal half of the short arm of the X chromosome at DXS8090 and DXS1068, located in Xp11. The effect of the modulating haplotype was independent of the mtDNA genetic background and appeared to explain the incomplete penetrance and sex bias that characterizes LHON. History Using 15 X-chromosome markers for linkage analysis of Leber disease families, Chen et al. (1989) excluded the involvement of a gene located almost anywhere on the X chromosome. Although the strong male bias for Leber optic atrophy might suggest an interaction between an X-linked gene and a mitochondrial DNA defect, the experience of this study made this unlikely. Findings from genealogic data suggest that more males than females in the maternal lineages have optic atrophy, thus raising the possibility of an X-chromosomal gene that renders susceptible to optic atrophy those individuals who have mtDNA mutations for Leber hereditary optic neuropathy (LHON; see 535000). Vilkki et al. (1991) presented data suggesting linkage of a susceptibility locus to DXS7 in several Finnish LHON families; maximum lod = 2.32 at theta = 0.0. Chen and Denton (1991) questioned this conclusion on the basis of their data. Hudson et al. (2005) remarked that early attempts to map a susceptibility locus were inconclusive because the studies used widely spaced, often noninformative markers and failed to account for mtDNA heteroplasmy. Later studies were more comprehensive, but exclusion mapping was based on an X-linked recessive model, which cannot explain the segregation pattern in all pedigrees (Mackey, 1993), and study size limited the power to exclude a substantial portion of the X chromosome (Juvonen et al., 1993; Chalmers et al., 1996). Eyes \- Susceptibility to optic atrophy Inheritance \- X-linked ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	LEBER OPTIC ATROPHY, SUSCEPTIBILITY TO	c0917796	1,598	omim	https://www.omim.org/entry/308905	2019-09-22T16:17:56	{"mesh": ["D029242"], "omim": ["308905"], "orphanet": ["104"], "synonyms": ["Alternative titles", "LOAS", "LEBER HEREDITARY OPTIC NEUROPATHY, MODIFIER OF", "LHON, MODIFIER OF"]}
A rare variant of Guillain-Barré syndrome characterized by acute onset monophasic sensory neuropathy with diminished or absent tendon reflexes, loss of proprioception, positive Romberg sign and nerve conduction features of demyelination. It presents several weeks after acute infection with paresthesias, ataxia and neuropathic pain. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acute sensory ataxic neuropathy	c4707661	1,599	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231466	2021-01-23T18:32:33	{"icd-10": ["G61.0"], "synonyms": ["ASAN", "Acute sensory ataxic GBS", "Acute sensory ataxic Guillain-Barré syndrome"]}

Subsets and Splits

No community queries yet

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