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Tin poisoning Tin SpecialtyToxicology Tin poisoning refers to the toxic effects of tin and its compounds. Cases of poisoning from tin metal, its oxides, and its salts are "almost unknown"; on the other hand, certain organotin compounds are almost as toxic as cyanide.[1] ## Contents * 1 Biology and toxicology * 2 References * 3 Further reading * 4 External links ## Biology and toxicology[edit] Tin has no known natural biological role in living organisms. It is not easily absorbed by animals and humans. The low toxicity is relevant to the widespread use of tin in dinnerware and canned food.[1] Nausea, vomiting and diarrhea have been reported after ingesting canned food containing 200 mg/kg of tin.[2] This observation led, for example, the Food Standards Agency in the UK to propose upper limits of 200 mg/kg.[3] A study showed that 99.5% of the controlled food cans contain tin in an amount below that level.[4] However, un-lacquered tin cans with food of a low pH, such as fruits and pickled vegetables, can contain elevated concentrations of tin.[2] The toxic effects of tin compounds is based on the interference with the iron and copper metabolism. For example, it affects heme and cytochrome P450, and decreases their effectiveness.[5] Organotin compounds can be very toxic. "Tri-n-alkyltins" are phytotoxic and, depending on the organic groups, can be powerful bactericides and fungicides. Other triorganotins are used as miticides and acaricides.[1] Tributyltin (TBT) was extensively used in marine antifouling paints, until discontinued for leisure craft due to concerns over longer-term marine toxicity in high-traffic areas such as marinas with large numbers of static boats. ## References[edit] 1. ^ a b c G. G. Graf "Tin, Tin Alloys, and Tin Compounds" in Ullmann's Encyclopedia of Industrial Chemistry, 2005 Wiley-VCH, Weinheim doi:10.1002/14356007.a27_049 2. ^ a b Blunden, Steve; Wallace, Tony (2003). "Tin in canned food: a review and understanding of occurrence and effect". Food and Chemical Toxicology. 41 (12): 1651–1662. doi:10.1016/S0278-6915(03)00217-5. PMID 14563390. 3. ^ "Eat well, be well — Tin". Food Standards Agency. Archived from the original on 2010-10-07. Retrieved 2009-04-16. 4. ^ "Tin in canned fruit and vegetables (Number 29/02)" (PDF). Food Standards Agency. 2002-08-22. Retrieved 2009-04-16. 5. ^ Westrum, Bente; Thomassen, Yngvar (2002). The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals and the Dutch Expert Committee on Occupational Standards : 130. Tin and inorganic tin compounds. Arbete och Hälsa 2002:10. Arbetslivsinstitutet. hdl:2077/4283. ISBN 91-7045-646-1. ## Further reading[edit] * Howe, Paul; Watts, Peter (2005-01-01). Tin and Inorganic Tin Compounds. ISBN 9789241530651. * Coles, Richard; Kirwan, Mark J. (2011-02-25). Food and Beverage Packaging Technology. ISBN 9781444392173. * Blunden, Steve; Wallace, Tony (2003). "Tin in canned food: A review and understanding of occurrence and effect". Food and Chemical Toxicology. 41 (12): 1651–62. doi:10.1016/S0278-6915(03)00217-5. PMID 14563390. ## External links[edit] Classification D * ICD-10: T56.6 * ICD-9-CM: 985.8 * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tin poisoning	None	3,300	wikipedia	https://en.wikipedia.org/wiki/Tin_poisoning	2021-01-18T18:32:13	{"icd-9": ["985.8"], "icd-10": ["T56.6"], "wikidata": ["Q7807844"]}
Embryonal carcinoma is a type of testicular cancer, which is cancer that starts in the testicles, the male reproductive glands located in the scrotum. It most often develops in young and middle-aged men. It tends to grow rapidly and spread outside the testicle. Embryonal carcinomas are classified as nonseminoma germ cell tumors. Most testicular cancers grow from germ cells, the cells that make sperm. Germ cell tumors are broadly divided into seminomas and nonseminomas because each type has a different prognosis and treatment regimen. Nonseminomas, which are more common, tend to grow more quickly than seminomas. Nonseminoma tumors are often made up of more than one type of cell, and are identified according to the different cell types. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Embryonal carcinoma	c0206659	3,301	gard	https://rarediseases.info.nih.gov/diseases/5140/embryonal-carcinoma	2021-01-18T18:00:43	{"mesh": ["D018236"], "umls": ["C0206659"], "orphanet": ["180226"], "synonyms": []}
A rare, genetic, immune deficiency with skin involvement characterized by clinical triad of non-scarring alopecia affecting mainly the scalp, well-demarcated mucosal erythema and psoriasiform erythematous intertriginous plaques. Follicular keratosis, keratoconjuctivitis, cataracts, angular cheilitis, fissured tongue, and recurrent infections are additional clinical features. Histopathology of mucosal lesions show characteristic findings of dyskeratotic keratinocytes, vacuolated basal cells, lack of epithelial maturation and decreased number of desmosomes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hereditary mucoepithelial dysplasia	c1274795	3,302	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1839	2021-01-23T17:53:02	{"gard": ["5427"], "mesh": ["C536476"], "omim": ["158310"], "umls": ["C1274795"], "synonyms": ["Urban-Schosser-Spohn syndrome"]}
A rare, acquired peripheral neuropathy disease characterized by chronic neuropathic pain involving the sensory territory of the pudendal nerve (from clitoris to anus or from penis to anus), aggravated by sitting and for which no organic cause can be found by imaging studies or laboratory tests. It is often associated with pelvic dysfunction. ## Epidemiology The prevalence of Pudendal neuralgia (PN) is unknown. A female predominance is reported, with a female/male ratio of 6:4. ## Clinical description PN usually presents between the ages of 50-70 years. and manifests with neuropathic pain of varying intensity in the perineal region. The pain is described as an intense, sharp, burning sensation, and sometimes as numbness. Rectal or vaginal foreign body sensations (sympathalgia) are commonly reported. Pain is unilateral or often medial, and is more intense during the day, when sitting or when wearing tight clothing. The pain is often associated with pelvic sensitization, which explains the urinary (pollakiuria, dysuria), anorectal (dyschezia, increased pain after bowl movement) and sexual (dyspareunia, intolerance of vulval contact, post-coital exacerbation of pain, persistent genital arousal, erectile dysfunction) problems as well as myofascial pain in the buttocks. The co-occurrence of truncal sciatica is common. Several forms of PN exist: benign, regressive, evolutive with flares, stable, and very debilitating forms with progressive symptom aggravation. ## Etiology The pudendal nerve can be compressed or entrapped by posterior pelvis ligaments (comprised of the sacrotuberous and sacrospinalis ligaments), or in the Alcock's canal (due to splitting of the obturator muscle aponeurosis). There is also the possibility of proximal entrapment at the level of the sub-piriformis canal and distal entrapment of the dorsal nerve of the clitoris/penis at the level of the sub-pubic canal. Other causes of pudendal neuralgia may include birth-related difficulties (due to excessive stretching), trauma, surgical, radiation sequalae, intense bicycling, spinal deviation, pelvic skeletal fractures or a tumor. In these cases, the pain is likely to be permanent and sitting position has little or no effect on it. ## Diagnostic methods The diagnostic criteria (Nantes criteria) for PN includes the presence of pain in the distribution of the pudendal nerve that is worsened by sitting, with no objective sensory impairment, which does not provoke awakening in the night, and that is relieved with anesthesia by pudendal nerve block. MRI allows for PN to be classified, based on the entrapment site: type I, in the sciatic notch; type II, the ischial spine and sacrosciatic ligament; type IIIa, the obturator internus muscle; type IIIb, the obturator internus and piriformis muscles, and type IV, the distal branches of the pudendal nerve. The diagnosis is strictly clinical and no additional examination can validate the diagnosis with certainty. Imaging tests may be necessary to rule out other diagnoses (pelvic and lumbosacral MRI, endoscopy, infection check-up, etc.). Normal imaging findings do not exclude a diagnosis of PN. ## Differential diagnosis Differential diagnoses include neuropathies of the neighboring nerves (ilio-inguinal, genitofemoral, lower cluneal), coccygodynia (given the location of pain projecting into the anus and rectum, aggravated by sitting position) and myofascial syndromes of the deep gluteus muscles (piriformes, obturator internus muscle, levator ani). Dermatological inflammatory pathologies (psoriasis, vulvar sclerotrophic lichen) should be systematically eliminated. When the pain is not triggered by sitting position, but rather by sexual intercourse, vestibulodynia should be considered. Isolated chronic urethralgia or bladder pain syndrome may be considered when perineal pain varies with urination. ## Management and treatment Management includes the treatment of neuropathic pain with antidepressant therapy (amitriptyline at low dose or duloxetine) or antiepileptic (pregabalin, gabapentin) and percutaneous posterior tibial nerve stimulation. Physiotherapy, osteopathy and short-term psychotherapy are also proposed as first-line solutions. The effect of anesthetic infiltration of the pudendal nerve is limited and its therapeutic effects in the medium and long term have not been demonstrated. In refractory forms, surgical decompression of the pudendal nerve has been effective (the trans-gluteal pathway being the only surgery whose efficacy has been proved). In those where surgery has been ineffective, an implanted neurostimulator can be proposed at the conus medullaris level or on sacral roots and pudendal nerve level. ## Prognosis PN greatly affects quality of life, but has no effect on life expectancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pudendal neuralgia	c1997249	3,303	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=60039	2021-01-23T18:00:48	{"gard": ["10713"], "mesh": ["D060545"], "umls": ["C1997249", "C3178970"], "icd-10": ["G57.8"], "synonyms": ["Alcock syndrome", "Pudendal algia", "Pudendal nerve entrapment syndrome", "Pudendal neuralgia by pudendal nerve entrapment", "Pudendalgia"]}
Pneumoconiosis caused by inhalation of silica, quartz or slate particles 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: "Silicosis" – news · newspapers · books · scholar · JSTOR (February 2018) (Learn how and when to remove this template message) Silicosis Other namesMiner's phthisis, Grinder's asthma, Potter's rot[1] pneumonoultramicroscopicsilicovolcanoconiosis[2][3] Fine silica dust SpecialtyPulmonology Silicosis is a form of occupational lung disease caused by inhalation of crystalline silica dust. It is marked by inflammation and scarring in the form of nodular lesions in the upper lobes of the lungs. It is a type of pneumoconiosis.[4] Silicosis (particularly the acute form) is characterized by shortness of breath, cough, fever, and cyanosis (bluish skin). It may often be misdiagnosed as pulmonary edema (fluid in the lungs), pneumonia, or tuberculosis. Silicosis resulted in at least 43,000 deaths globally in 2013, down from at least 50,000 deaths in 1990.[5] The name silicosis (from the Latin silex, or flint) was originally used in 1870 by Achille Visconti (1836–1911), prosector in the Ospedale Maggiore of Milan.[6] The recognition of respiratory problems from breathing in dust dates to ancient Greeks and Romans.[7] Agricola, in the mid-16th century, wrote about lung problems from dust inhalation in miners. In 1713, Bernardino Ramazzini noted asthmatic symptoms and sand-like substances in the lungs of stone cutters. With industrialization, as opposed to hand tools, came increased production of dust. The pneumatic hammer drill was introduced in 1897 and sandblasting was introduced in about 1904,[8] both significantly contributing to the increased prevalence of silicosis. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 2.1 Silica * 3 Diagnosis * 3.1 Classification * 4 Prevention * 5 Treatment * 6 Epidemiology * 6.1 Occupational silicosis * 6.2 Desert lung disease * 7 Regulation * 7.1 Key provisions * 7.2 Compliance schedule * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Miner's lung with silicosis and tuberculosis. (Basque Museum of the History of Medicine and Science, Spain) Because chronic silicosis is slow to develop, signs and symptoms may not appear until years after exposure.[9] Signs and symptoms include: * Dyspnea (shortness of breath) exacerbated by exertion * Cough, often persistent and sometimes severe * Fatigue * Tachypnea (rapid breathing) which is often labored, * Loss of appetite and weight loss * Chest pain * Fever * Gradual darkening of skin (blue skin) * Gradual dark shallow rifts in nails eventually leading to cracks as protein fibers within nail beds are destroyed. In advanced cases, the following may also occur: * Cyanosis, pallor along upper parts of body (blue skin) * Cor pulmonale (right ventricle heart disease) * Respiratory insufficiency Patients with silicosis are particularly susceptible to tuberculosis (TB) infection—known as silicotuberculosis. The reason for the increased risk—3 fold increased incidence—is not well understood. It is thought that silica damages pulmonary macrophages, inhibiting their ability to kill mycobacteria. Even workers with prolonged silica exposure, but without silicosis, are at a similarly increased risk for TB.[10] Pulmonary complications of silicosis also include chronic bronchitis and airflow limitation (indistinguishable from that caused by smoking), non-tuberculous Mycobacterium infection, fungal lung infection, compensatory emphysema, and pneumothorax. There are some data revealing an association between silicosis and certain autoimmune diseases, including nephritis, scleroderma, and systemic lupus erythematosus, especially in acute or accelerated silicosis. In 1996, the International Agency for Research on Cancer (IARC) reviewed the medical data and classified crystalline silica as "carcinogenic to humans." The risk was best seen in cases with underlying silicosis, with relative risks for lung cancer of 2–4. Numerous subsequent studies have been published confirming this risk. In 2006, Pelucchi et al. concluded, "The silicosis-cancer association is now established, in agreement with other studies and meta-analysis."[11] ## Pathophysiology[edit] Slice of a lung affected by silicosis When small silica dust particles are inhaled, they can embed themselves deeply into the tiny alveolar sacs and ducts in the lungs, where oxygen and carbon dioxide gases are exchanged. There, the lungs cannot clear out the dust by mucous or coughing. When fine particles of crystalline silica dust are deposited in the lungs, macrophages that ingest the dust particles will set off an inflammatory response by releasing tumor necrosis factors, interleukin-1, leukotriene B4 and other cytokines. In turn, these stimulate fibroblasts to proliferate and produce collagen around the silica particle, thus resulting in fibrosis and the formation of the nodular lesions. The inflammatory effects of crystalline silica are apparently mediated by the NALP3 inflammasome.[12] Characteristic lung tissue pathology in nodular silicosis consists of fibrotic nodules with concentric "onion-skinned" arrangement of collagen fibers, central hyalinization, and a cellular peripheral zone, with lightly birefringent particles seen under polarized light. The silicotic nodule represents a specific tissue response to crystalline silica.[8] In acute silicosis, microscopic pathology shows a periodic acid-Schiff positive alveolar exudate (alveolar lipoproteinosis) and a cellular infiltrate of the alveolar walls.[13] ### Silica[edit] Main article: Silicon dioxide Silicon (Si) is the second most common element in the Earth's crust (oxygen is the most common). The compound silica, also known as silicon dioxide (SiO2), is formed from silicon and oxygen atoms. Since oxygen and silicon make up about 75% of the Earth's crust, the compound silica is quite common. It is found in many rocks, such as granite, sandstone, gneiss and slate, and in some metallic ores. Silica can be a main component of sand. It can also be in soil, mortar, plaster, and shingles. The cutting, breaking, crushing, drilling, grinding, or abrasive blasting of these materials may produce fine to ultra fine airborne silica dust. Silica occurs in 3 forms: crystalline, microcrystalline (or cryptocrystalline) and amorphous (non-crystalline). "Free" silica is composed of pure silicon dioxide, not combined with other elements, whereas silicates (e.g., talc, asbestos, and mica) are SiO2 combined with an appreciable portion of cations. * Crystalline silica exists in 7 different forms (polymorphs), depending upon the temperature of formation. The main 3 polymorphs are quartz, cristobalite, and tridymite. Quartz is the second most common mineral in the world (next to feldspar).[14] * Microcrystalline silica consists of minute quartz crystals bonded together with amorphous silica. Examples include flint and chert. * Amorphous silica consists of kieselgur (diatomite), from the skeletons of diatoms, and vitreous silica, produced by heating and then rapid cooling of crystalline silica. Amorphous silica is less toxic than crystalline, but not biologically inert, and diatomite, when heated, can convert to tridymite or cristobalite. Silica flour is nearly pure SiO2 finely ground. Silica flour has been used as a polisher or buffer, as well as paint extender, abrasive, and filler for cosmetics. Silica flour has been associated with all types of silicosis, including acute silicosis. Silicosis is due to deposition of fine respirable dust (less than 10 micrometers in diameter) containing crystalline silicon dioxide in the form of alpha-quartz, cristobalite, or tridymite. ## Diagnosis[edit] There are three key elements to the diagnosis of silicosis. First, the patient history should reveal exposure to sufficient silica dust to cause this illness. Second, chest imaging (usually chest x-ray) that reveals findings consistent with silicosis. Third, there are no underlying illnesses that are more likely to be causing the abnormalities. Physical examination is usually unremarkable unless there is complicated disease. Also, the examination findings are not specific for silicosis. Pulmonary function testing may reveal airflow limitation, restrictive defects, reduced diffusion capacity, mixed defects, or may be normal (especially without complicated disease). Most cases of silicosis do not require tissue biopsy for diagnosis, but this may be necessary in some cases, primarily to exclude other conditions. For uncomplicated silicosis, chest x-ray will confirm the presence of small (< 10 mm) nodules in the lungs, especially in the upper lung zones. Using the ILO classification system, these are of profusion 1/0 or greater and shape/size "p", "q", or "r". Lung zone involvement and profusion increases with disease progression. In advanced cases of silicosis, large opacity (> 1 cm) occurs from coalescence of small opacities, particularly in the upper lung zones. With retraction of the lung tissue, there is compensatory emphysema. Enlargement of the hilum is common with chronic and accelerated silicosis. In about 5–10% of cases, the nodes will calcify circumferentially, producing so-called "eggshell" calcification. This finding is not pathognomonic (diagnostic) of silicosis. In some cases, the pulmonary nodules may also become calcified. A computed tomography or CT scan can also provide a mode detailed analysis of the lungs, and can reveal cavitation due to concomitant mycobacterial infection. * Chest X-ray showing uncomplicated silicosis * Complicated silicosis * Silicosis ILO Classification 2-2 R-R * Fibrothorax and pleural effusion caused by silicosis ### Classification[edit] Classification of silicosis is made according to the disease's severity (including radiographic pattern), onset, and rapidity of progression.[15] These include: Chronic simple silicosis Usually resulting from long-term exposure (10 years or more) to relatively low concentrations of silica dust and usually appearing 10–30 years after first exposure.[16] This is the most common type of silicosis. Patients with this type of silicosis, especially early on, may not have obvious signs or symptoms of disease, but abnormalities may be detected by x-ray. Chronic cough and exertional dyspnea (shortness of breath) are common findings. Radiographically, chronic simple silicosis reveals a profusion of small (<10 mm in diameter) opacities, typically rounded, and predominating in the upper lung zones. Accelerated silicosis Silicosis that develops 5–10 years after first exposure to higher concentrations of silica dust. Symptoms and x-ray findings are similar to chronic simple silicosis, but occur earlier and tend to progress more rapidly. Patients with accelerated silicosis are at greater risk for complicated disease, including progressive massive fibrosis (PMF). Complicated silicosis Silicosis can become "complicated" by the development of severe scarring (progressive massive fibrosis, or also known as conglomerate silicosis), where the small nodules gradually become confluent, reaching a size of 1 cm or greater. PMF is associated with more severe symptoms and respiratory impairment than simple disease. Silicosis can also be complicated by other lung disease, such as tuberculosis, non-tuberculous mycobacterial infection, and fungal infection, certain autoimmune diseases, and lung cancer. Complicated silicosis is more common with accelerated silicosis than with the chronic variety. Acute silicosis Silicosis that develops a few weeks to 5 years after exposure to high concentrations of respirable silica dust. This is also known as silicoproteinosis. Symptoms of acute silicosis include more rapid onset of severe disabling shortness of breath, cough, weakness, and weight loss, often leading to death. The x-ray usually reveals a diffuse alveolar filling with air bronchograms, described as a ground-glass appearance, and similar to pneumonia, pulmonary edema, alveolar hemorrhage, and alveolar cell lung cancer. ## Prevention[edit] Play media A video discussing a field-based approach to silica monitoring. Monitoring could help reduce exposure to silica. The best way to prevent silicosis is to avoid worker exposure to dust.[17] The next best preventive measure is to control the dust. Water spray is often used where dust emanates to control the kick up of silica dust. To avoid dust accumulating on clothing and skin, place clothes in a seal-able bag and, if possible, shower once returning home. When dust starts accumulating around a workplace, utilize an industrial vacuum to contain and transport dust to a safe location.[18] Dust can also be controlled through personal dry air filtering.[19] Preventing silicosis may require specific measures. One example is during tunnel construction where purpose-designed cabins are used in addition to air scrubbers to filter the air during construction.[20] Items to be considered when selecting respiratory protection include whether it provides the correct level of protection, if facial fit testing has been provided, if the wearer is absent of facial hair, and how filters will be replaced.[20] ## Treatment[edit] Silicosis is a permanent disease with no cure.[13] Treatment options currently available focus on alleviating the symptoms and preventing any further progress of the condition. These include: * Stopping further exposure to airborne silica, silica dust and other lung irritants, including tobacco smoking. * Cough suppressants. * Antibiotics for bacterial lung infection. * Tuberculosis (TB) prophylaxis for those with positive tuberculin skin test or IGRA blood test. * Prolonged anti-tuberculosis (multi-drug regimen) for those with active TB. * Chest physiotherapy to help the bronchial drainage of mucus. * Oxygen administration to treat hypoxemia, if present. * Bronchodilators to facilitate breathing. * Lung transplantation to replace the damaged lung tissue is the most effective treatment, but is associated with severe risks of its own from the lung transplant surgery as well as from consequences of long-term immunosuppression (e.g., opportunistic infections). * For acute silicosis, bronchoalveolar lavage may alleviate symptoms, but does not decrease overall mortality. ## Epidemiology[edit] Silicosis resulted in 46,000 deaths in 2013 down from 55,000 deaths in 1990.[5] ### Occupational silicosis[edit] Silicosis is the most common occupational lung disease worldwide. It occurs everywhere, but is especially common in developing countries.[21] From 1991 to 1995, China reported more than 24,000 deaths due to silicosis each year.[9] It also affects developed nations. In the United States, it is estimated that between one and two million workers have had occupational exposure to crystalline silica dust and 59,000 of these workers will develop silicosis sometime in the course of their lives.[9][22] According to CDC data,[23] silicosis in the United States is relatively rare. The incidence of deaths due to silicosis declined by 84% between 1968 and 1999, and only 187 deaths in 1999 had silicosis as the underlying or contributing cause.[24] Additionally, cases of silicosis in Michigan, New Jersey, and Ohio are highly correlated to industry and occupation.[25] Although silicosis has been known for centuries, the industrialization of mining has led to an increase in silicosis cases. Pneumatic drilling in mines and less commonly, mining using explosives, would raise fine-ultra fine crystalline silica dust (rock dust). In the United States, a 1930 epidemic of silicosis due to the construction of the Hawk's Nest Tunnel near Gauley Bridge, West Virginia caused the death of at least 400 workers. Other accounts place the mortality figure at well over 1000 workers, primarily African American transient workers from the southern United States.[26] Workers who became ill were fired and left the region, making an exact mortality account difficult.[27] The Hawks Nest Tunnel Disaster is known as "America's worst industrial disaster.[28] The prevalence of silicosis led some men to grow what is called a miner's mustache, in an attempt to intercept as much dust as possible. Chronic simple silicosis has been reported to occur from environmental exposures to silica in regions with high silica soil content and frequent dust storms.[29] Also, the mining establishment of Delamar Ghost Town, Nevada was ruined by a dry-mining process that produced a silicosis-causing dust. After hundreds of deaths from silicosis, the town was nicknamed The Widowmaker. The problem in those days was somewhat resolved with an addition of a nozzle to the drill which sprayed a mist of water, turning dust raised by drilling into mud, but this inhibited mining work. Because of work-exposure to silica dust, silicosis is an occupational hazard to construction, demolition, mining, sandblasting, quarry, tunnelling,[30] ceramics and foundry workers, as well as grinders, stone cutters, stone countertops, refractory brick workers, tombstone workers, workers in the oil and gas industry,[31] pottery workers, fiberglass manufacturing, glass manufacturing, flint knappers and others. Brief or casual exposure to low levels of crystalline silica dust are said to not produce clinically significant lung disease.[32] In less developed countries where work conditions are poor and respiratory equipment is seldom used, the life expectancy is low (e.g. for silver miners in Potosí, Bolivia is around 40 years due to silicosis). Recently, silicosis in Turkish denim sandblasters was detected as a new cause of silicosis due to recurring, poor working conditions.[33] Silicosis is seen in horses associated with inhalation of dust from certain cristobalite-containing soils in California. Social realist artist Noel Counihan depicted men who worked in industrial mines in Australia in the 1940s dying of silicosis in his series of six prints, 'The miners' (1947 linocuts).[34] While it has been long-thought that cases of silicosis in Australia were no longer possible, the recent reported epidemic in 2018 demonstrated that additional protections for workers were needed. Some have spoken publicly on the need to re-learn lessons from past experiences to prevent further disease.[35] and 2019[36][37] The Australian Government Department of Health established a National Dust Disease Taskforce in response to the number of reported cases of silicosis in 2018.[38] ### Desert lung disease[edit] Main article: Dust pneumonia A non-occupational form of silicosis has been described that is caused by long-term exposure to sand dust in desert areas, with cases reported from the Sahara, Libyan desert and the Negev.[39] The disease is caused by deposition of this dust in the lung.[40] Desert lung disease may be related to Al Eskan disease, a lung disorder thought to be caused by exposure to sand dust containing organic antigens, which was first diagnosed after the 1990 Gulf war.[41] The relative importance of the silica particles themselves and the microorganisms that they carry in these health effects remains unclear.[42] ## Regulation[edit] In March 2016, OSHA officially mandated that companies must provide certain safety measures for employees who work with or around silica, in order to prevent silicosis, lung cancer, and other silica-related diseases.[43] ### Key provisions[edit] * Reduce the permissible exposure limit (PEL) for respirable crystalline silica to 50 micrograms per cubic meter of air, averaged over an 8-hour shift. * Use engineering controls (such as water or ventilation) to limit worker exposure to silica dust; provide respirators when engineering controls cannot adequately limit exposure; limit worker access to high exposure areas; develop a written exposure control plan, offer medical exams to highly exposed workers, and train workers on silica risks and how to limit exposures. However, recent studies have found workers who grind granite counters and use water controls to eliminate dust are becoming ill from exposure to dust after water has evaporated the next day.[44] * Provide medical exams to monitor highly exposed workers and gives them information about their lung health. An additional provision exists for small business who are provided flexibility.[45] ### Compliance schedule[edit] Both standards contained in the final rule take effect on June 23, 2016, after which industries have one to five years to comply with most requirements, based on the following schedule: * Construction – June 23, 2017, one year after the effective date. * General Industry and Maritime – June 23, 2018, two years after the effective date. * Hydraulic Fracturing – June 23, 2018, two years after the effective date for all provisions except Engineering Controls, which have a compliance date of June 23, 2021.[45] ## See also[edit] * Pneumoconiosis * Asbestosis – Pneumoconiosis caused by inhalation and retention of asbestos fibers * Health effects arising from the September 11 attacks * Hawks Nest Tunnel disaster – Tunnel in West Virginia where hundreds of workers contracted silicosis * Dust pneumonia ## References[edit] 1. ^ Jane A. Plant; Nick Voulvoulis; K. Vala Ragnarsdottir (13 March 2012). Pollutants, Human Health and the Environment: A Risk Based Approach. John Wiley & Sons. p. 273. ISBN 978-0-470-74261-7. Archived from the original on 31 December 2013. Retrieved 24 August 2012. 2. ^ "Pneumonoultramicroscopicsilicovolcanoconiosis". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 2017-10-10. 3. ^ "Pneumonoultramicroscopicsilicovolcanoconiosis". Merriam-Webster Dictionary. 4. ^ Derived from Gr. πνεῦμα pneúm\|a (lung) + buffer vowel -o- \+ κόνις kóni\|s (dust) + Eng. scient. suff. -osis (like in asbest"osis" and silic"osis", see ref. 10). 5. ^ a b GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. 6. ^ United States Bureau of Mines, "Bulletin: Volumes 476–478", U.S. G.P.O., (1995), p 63. 7. ^ Rosen G: The History of Miners' Diseases: A Medical and Social Interpretation. New York, Schuman, 1943, pp.459–476. 8. ^ a b "Diseases associated with exposure to silica and nonfibrous silicate minerals. Silicosis and Silicate Disease Committee". Arch. Pathol. Lab. Med. 112 (7): 673–720. July 1988. PMID 2838005. 9. ^ a b c "Silicosis Fact Sheet". World Health Organization. May 2000. Archived from the original on 2007-05-10. Retrieved 2007-05-29. 10. ^ Cowie RL (November 1994). "The epidemiology of tuberculosis in gold miners with silicosis". Am. J. Respir. Crit. Care Med. 150 (5 Pt 1): 1460–2. doi:10.1164/ajrccm.150.5.7952577. PMID 7952577. 11. ^ Pelucchi C, Pira E, Piolatto G, Coggiola M, Carta P, La Vecchia C (July 2006). "Occupational silica exposure and lung cancer risk: a review of epidemiological studies 1996–2005". Ann. Oncol. 17 (7): 1039–50. doi:10.1093/annonc/mdj125. PMID 16403810. Archived from the original on 2012-07-01. 12. ^ Cassel SL, Eisenbarth SC, Iyer SS, et al. (June 2008). "The Nalp3 inflammasome is essential for the development of silicosis". Proc. Natl. Acad. Sci. U.S.A. 105 (26): 9035–40. Bibcode:2008PNAS..105.9035C. doi:10.1073/pnas.0803933105. PMC 2449360. PMID 18577586. 13. ^ a b Wagner, GR (May 1997). "Asbestosis and silicosis". Lancet. 349 (9061): 1311–1315. doi:10.1016/S0140-6736(96)07336-9. PMID 9142077. S2CID 26302715. 14. ^ Crystalline Silica Primer, US Dept of the Interior and US Bureau of Mines, 1992. 15. ^ NIOSH Hazard Review. Health Effects of Occupational Exposure to Respirable Crystalline Silica. DHHS 2002-129. pp. 23. 16. ^ Weisman DN and Banks DE. Silicosis. In: Interstitial Lung Disease. 4th ed. London: BC Decker Inc. 2003, pp391. 17. ^ World Health Organization (2007). "Elimination of Silicosis" (PDF). GOHNET NEWSLETTER (12). Retrieved 2019-11-27. 18. ^ "Guide to Training Your Staff for OSHA Compliance \| Industrial Vacuum". www.industrialvacuum.com. Retrieved 2018-10-23. 19. ^ CPWR-The Center for Construction Research and Training. "Work Safely with Silica: methods to control silica exposure". Archived from the original on 2012-12-20. 20. ^ a b ATS (7 January 2019). "NSW Air Quality Working Group". Australian Tunnelling Society. Retrieved 7 January 2019. 21. ^ Steenland K, Goldsmith DF (November 1995). "Silica exposure and autoimmune diseases". Am. J. Ind. Med. 28 (5): 603–8. doi:10.1002/ajim.4700280505. PMID 8561170. 22. ^ "Safety and Health Topics Silica, Crystalline". Occupational Safety and Health Administration. March 2007. Archived from the original on 2007-05-18. Retrieved 2007-05-29. 23. ^ "Ch. 2: Fatal and Nonfatal Injuries, and Selected Illnesses: Respiratory Diseases: Pneumoconioses: Silicosis". Worker Health Chartbook 2004. National Institute for Occupational Safety and Health (NIOSH). 2004. doi:10.26616/NIOSHPUB2004146. 2004-146. Archived from the original on 2017-11-23. 24. ^ NIOSH & 2004-146, Fig2-192 25. ^ NIOSH & 2004-146, Fig2-190 26. ^ "The Hawks Nest Tunnel," Patricia Spangler, 2008 27. ^ Keenan, Steve (2008-04-02). "Book explores Hawks Nest tunnel history » Local News » The Fayette Tribune, Oak Hill, W.Va". Fayettetribune.com. Archived from the original on 2008-04-07. Retrieved 2012-02-16. 28. ^ "The Hawk’s Nest Incident: America’s Worst Industrial Disaster," Dr. Martin Cherniack 1986 29. ^ Norboo T, Angchuk PT, Yahya M, et al. (May 1991). "Silicosis in a Himalayan village population: role of environmental dust". Thorax. 46 (5): 341–3. doi:10.1136/thx.46.5.341. PMC 463131. PMID 2068689. 30. ^ Cole, Kate (7 January 2020). "Investigating best practice to prevent illness and disease in tunnel construction workers". Winston Churchill Trust Australia. Retrieved 7 January 2020. 31. ^ "NIOSHTIC-2 Publications Search - 20040975 - OSHA/NIOSH hazard alert: worker exposure to silica during hydraulic fracturing". www.cdc.gov. Archived from the original on 2018-03-17. Retrieved 2018-03-16. 32. ^ "Adverse effects of crystalline silica exposure. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health". Am. J. Respir. Crit. Care Med. 155 (2): 761–8. February 1997. doi:10.1164/ajrccm.155.2.9032226. PMID 9032226. 33. ^ Denim sandblasters contract fatal silicosis in illegal workshops Archived 2009-10-19 at the Wayback Machine 34. ^ Art Gallery of NSW: Noel Couniham Collection Archived 2014-09-03 at the Wayback Machine 35. ^ Atkin, Michael (7 January 2020). "The biggest lung disease crisis since asbestos: Our love of stone kitchen benchtops is killing workers". ABC News. Retrieved 7 January 2020. 36. ^ Atkin, Michael (7 January 2020). "Silicosis-causing silica significantly 'more potent' than asbestos". ABC News. Retrieved 7 January 2020. 37. ^ Cole, Kate (7 January 2020). "Silicosis is not the new Asbestosis". ABC Radio National. Retrieved 7 January 2020. 38. ^ DoH (2019-11-21). "The Department of Health National Dust Disease Taskforce". Department of Health. Retrieved 7 January 2020. 39. ^ Hawass ND (September 1987). "An association between 'desert lung' and cataract—a new syndrome". Br J Ophthalmol. 71 (9): 694–7. doi:10.1136/bjo.71.9.694. PMC 1041277. PMID 3663563. 40. ^ Nouh MS (1989). "Is the desert lung syndrome (nonoccupational dust pneumoconiosis) a variant of pulmonary alveolar microlithiasis? Report of 4 cases with review of the literature". Respiration. 55 (2): 122–6. doi:10.1159/000195715. PMID 2549601. 41. ^ Korényi-Both AL, Korényi-Both AL, Molnár AC, Fidelus-Gort R (September 1992). "Al Eskan disease: Desert Storm pneumonitis". Mil Med. 157 (9): 452–62. doi:10.1093/milmed/157.9.452. PMID 1333577. 42. ^ Griffin DW (July 2007). "Atmospheric movement of microorganisms in clouds of desert dust and implications for human health". Clin. Microbiol. Rev. 20 (3): 459–77, table of contents. doi:10.1128/CMR.00039-06. PMC 1932751. PMID 17630335. 43. ^ "OSHA publishes final rule on silica". Archived from the original on 2016-08-18. Retrieved 2016-08-18. 44. ^ Greenfieldboyce, Nell (2019-10-02). "Workers Are Falling Ill, Even Dying, After Making Kitchen Countertops". National Public Radio. Retrieved 2019-11-27. 45. ^ a b "OSHA's Final Rule to Protect Workers from Exposure to Respirable Crystalline Silica". www.osha.gov. Archived from the original on 2016-08-20. Retrieved 2016-07-22. ## External links[edit] Classification D * ICD-10: J62 * ICD-9-CM: 502 * MeSH: D012829 * DiseasesDB: 12117 External resources * MedlinePlus: 000134 * eMedicine: med/2127 Wikimedia Commons has media related to Silicosis. * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * 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Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Silicosis	c0037116	3,304	wikipedia	https://en.wikipedia.org/wiki/Silicosis	2021-01-18T18:57:46	{"gard": ["7647"], "mesh": ["D012829"], "umls": ["C0037116"], "wikidata": ["Q653318"]}
Oculodentodigital dysplasia is a condition that affects many parts of the body, particularly the eyes (oculo-), teeth (dento-), and fingers (digital). Common features in people with this condition are small eyes (microphthalmia) and other eye abnormalities that can lead to vision loss. Affected individuals also frequently have tooth abnormalities, such as small or missing teeth, weak enamel, multiple cavities, and early tooth loss. Other common features of this condition include a thin nose and webbing of the skin (syndactyly) between the fourth and fifth fingers. Less common features of oculodentodigital dysplasia include sparse hair growth (hypotrichosis), brittle nails, an unusual curvature of the fingers (camptodactyly), syndactyly of the toes, small head size (microcephaly), and an opening in the roof of the mouth (cleft palate). Some affected individuals experience neurological problems such as a lack of bladder or bowel control, difficulty coordinating movements (ataxia), abnormal muscle stiffness (spasticity), hearing loss, and impaired speech (dysarthria). A few people with oculodentodigital dysplasia also have a skin condition called palmoplantar keratoderma. Palmoplantar keratoderma causes the skin on the palms and the soles of the feet to become thick, scaly, and calloused. Some features of oculodentodigital dysplasia are evident at birth, while others become apparent with age. ## Frequency The exact incidence of oculodentodigital dysplasia is unknown. It has been diagnosed in fewer than 1,000 people worldwide. More cases are likely undiagnosed. ## Causes Mutations in the GJA1 gene cause oculodentodigital dysplasia. The GJA1 gene provides instructions for making a protein called connexin 43. This protein forms one part (a subunit) of channels called gap junctions, which allow direct communication between cells. Gap junctions formed by connexin 43 proteins are found in many tissues throughout the body. GJA1 gene mutations result in abnormal connexin 43 proteins. Channels formed with abnormal proteins are often permanently closed. Some mutations prevent connexin 43 proteins from traveling to the cell surface where they are needed to form channels between cells. Impaired functioning of these channels disrupts cell-to-cell communication, which likely interferes with normal cell growth and cell specialization, processes that determine the shape and function of many different parts of the body. These developmental problems cause the signs and symptoms of oculodentodigital dysplasia. ### Learn more about the gene associated with Oculodentodigital dysplasia * GJA1 ## Inheritance Pattern Most cases of oculodentodigital dysplasia are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Less commonly, oculodentodigital dysplasia can be 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. Fewer than ten cases of autosomal recessive oculodentodigital dysplasia have been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Oculodentodigital dysplasia	c0812437	3,305	medlineplus	https://medlineplus.gov/genetics/condition/oculodentodigital-dysplasia/	2021-01-27T08:25:19	{"gard": ["7239"], "mesh": ["C563160"], "omim": ["164200"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that acromicric dysplasia (ACMICD) is caused by heterozygous mutation in exon 41 or 42 of the FBN1 gene (134797) on chromosome 15q21. Description Acromicric dysplasia is an autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal (summary by Le Goff et al., 2011). Allelic disorders with overlapping skeletal and joint features include geleophysic dysplasia-2 (GPHYSD2; 614185) and the autosomal dominant form of Weill-Marchesani syndrome (608328). Clinical Features Maroteaux et al. (1986) described and named a 'new' entity on the basis of 6 patients. Features were mild facial anomalies, markedly shortened hands and feet, and growth retardation that was severe in most. The metacarpals and phalanges were short and stubby; the proximal portion of the second metacarpal showed a notch on its radial side and the fifth metacarpal had a notch on its ulnar side. Similar histologic changes were found in biopsy of the proximal tibial growth cartilage in 2 cases: disorganization of the growth zone with islands of cells and abnormal arrangement of collagen. Both sexes were affected. All 6 cases were sporadic (with normal parental age and no parental consanguinity). In an addendum, Maroteaux et al. (1986) stated that they had observed acromicric dysplasia in mother and son. Faivre et al. (2001) reported a series of 22 patients, 10 male and 12 female, with acromicric dysplasia. Length at birth was normal, but height fell progressively off the centiles postnatally; mean adult height was 130 cm. Intelligence was normal. Mild dysmorphic features were noted and became less obvious in adults. Other occasional features included well developed muscles, hoarse voice, generalized joint limitation in some patients, frequent ear, tracheal, and respiratory complications, and spine abnormalities. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x-ray abnormalities. The condition appeared to be sporadic in 16 cases, but vertical transmission was seen in 3 families, consistent with an autosomal dominant mode of inheritance. Inheritance Le Goff et al. (2011) demonstrated that acromicric dysplasia is an autosomal dominant disorder. Molecular Genetics In 10 patients with acromicric dysplasia, Le Goff et al. (2011) performed exome sequencing followed by candidate gene analysis and identified heterozygosity for 9 different mutations in the FBN1 gene (see, e.g., 134797.0055, 134797.0057, and 134797.0059-134797.0061). Two of the mutations were also found in heterozygosity in patients with geleophysic dysplasia-2 (GPHYSD2), a disorder with similar skeletal, joint, and skin features but with cardiac involvement often leading to early death. Le Goff et al. (2011) concluded that geleophysic dysplasia and acromicric dysplasia are clinically distinct but allelic conditions. Passarge et al. (2016) stated that all FBN1 mutations resulting in ACMICD or GPHYSD2 have been found in exon 41 or 42. These exons encode the TGF-beta-binding protein-like domain-5 (TB5) (Le Goff et al., 2011). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature, severe Other \- Pseudomuscular build HEAD & NECK Face \- Round face \- Long philtrum \- Prominent philtrum \- Mild facial anomalies Eyes \- Long eyelashes \- Well-defined eyebrows Nose \- Bulbous nose \- Anteverted nostrils Mouth \- Small mouth \- Thick lips SKELETAL \- Delayed bone age Spine \- Ovoid vertebral bodies Limbs \- Cone-shaped epiphyses \- Internal notch of femoral head \- Shortened long tubular bones Hands \- Short hands \- Short, stubby metacarpals \- Short, stubby phalanges \- Second metacarpal notched proximally on radial side \- Fifth metacarpal notched on ulnar side Feet \- Short feet SKIN, NAILS, & HAIR Skin \- Thick skin Hair \- Long eyelashes \- Well-defined eyebrows VOICE \- Hoarse voice LABORATORY ABNORMALITIES \- Growth cartilage disorganized, with islands of cells and abnormal collagen arrangement MOLECULAR BASIS \- Caused by mutation in the fibrillin 1 gene (FBN1, 134797.0055 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ACROMICRIC DYSPLASIA	c0265287	3,306	omim	https://www.omim.org/entry/102370	2019-09-22T16:45:25	{"doid": ["0111243"], "mesh": ["C535662"], "omim": ["102370"], "orphanet": ["969"]}
Worth type autosomal dominant osteosclerosis is a sclerozing bone disorder characterized by generalized skeletal densification, particularly of the cranial vault and tubular long bones, which is not associated to an increased risk of fracture. ## Epidemiology The syndrome has been described in less than 10 families. ## Clinical description Craniofacial anomalies develop during adolescence and include a prominent forehead, wide and deep mandibles, wide nasal root, taurus palatinus and increased gonial angle. ## Etiology The syndrome is due to a mutation in the LRP5 gene that leads to increased bone formation. ## Genetic counseling Transmission is autosomal dominant. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Endosteal hyperostosis, Worth type	c0432273	3,307	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2790	2021-01-23T18:47:14	{"gard": ["390"], "mesh": ["C536748"], "omim": ["144750"], "umls": ["C0432273", "C2931308"], "icd-10": ["Q78.2"], "synonyms": ["Autosomal dominant osteosclerosis, Worth type", "Worth syndrome"]}
Contagious equine metritis (CEM) is a type of metritis (uterine inflammation) in horses that is caused by a sexually transmitted infection. It is thus an equine venereal disease of the genital tract of horses, brought on by the Taylorella equigenitalis bacteria and spread through sexual contact. The disease was first reported in 1977, and has since been reported worldwide.[1] ## Contents * 1 Signs * 2 Diagnosis * 3 Treatment * 4 History * 5 References * 6 External links ## Signs[edit] Signs in mares appear ten to fourteen days after breeding to an infected or carrier stallion. A gray to creamy vulvar discharge mats the hair of the buttocks and tail, although in many cases, the discharge is absent and the infection is not apparent. Most mares recover spontaneously, although many become carriers. Infected mares are usually infertile during the acute illness. However, the infertility only lasts a few weeks, after which pregnancy is possible. Stallions do not show signs of infection. The first indication of the carrier state is lack of pregnancy in the mares covered by the stallion. ## Diagnosis[edit] Diagnosis is made by taking samples for bacterial culture from all accessible sites. In mares, this includes the endometrium, cervix, clitoral fossa and sinuses. In stallions, samples are taken from the skin folds of the prepuce, urethral fossa, urethra, and the pre-ejaculatory fluid. Samples are refrigerated and transported to an approved testing laboratory within 48 hours of collection. Blood tests for mares are available for detecting antibodies to Taylorella equigenitalis. Blood tests are not possible for stallions. These tests become positive 10 or more days after infection. If positive, they only indicate that the mare has had the disease in the past, and do not indicate whether the mare is a carrier now. ## Treatment[edit] Taylorella equigenitalis is susceptible to most antibiotics, although the carrier state in mares is difficult to eliminate. Most mares with acute endometritis recover spontaneously. Recommended therapy is to infuse the uterus with an antibiotic such as penicillin, cleansing the clitoral area with 2% chlorhexidine solution and then applying chlorhexidine or nitrofurazone ointment to the clitoral fossa and sinuses. The entire treatment is repeated daily for five days. It is relatively easy to eliminate the carrier state in stallions using local disinfectant. With the stallion's penis dropped and the glans extended from the foreskin, the shaft of the penis, including the folds of the prepuce and the urethral fossa, should be cleansed daily for five days with a 2% chlorhexidine solution. After drying, nitrofurazone cream is applied to these areas. ## History[edit] The disease was first reported in 1977 on horse breeding farms in England, when an unusually high proportion of mares were not becoming pregnant.[2] CEM was also officially confirmed in Ireland and Australia in 1977.[2] It was found in United States in 1978 in horses imported to Kentucky from Europe.[3] A second American outbreak occurred a year later in Missouri but in both cases, the diseases were quickly eradicated.[4] In 2008, a Quarter Horse stallion standing at stud in Kentucky was found to be carrying Taylorella equigenitalis; an investigation of this case revealed infections in eight other US states, in eleven different breeds of horse.[5] ## References[edit] 1. ^ Snider, TA (August 2015). "Reproductive disorders in horses". The Veterinary Clinics of North America. Equine Practice. 31 (2): 389–405. doi:10.1016/j.cveq.2015.04.011. PMID 26210954. 2. ^ a b Eaglesome, MD; Garcia, MM (August 1979). "Contagious equine metritis: a review". The Canadian Veterinary Journal. 20 (8): 201–6. PMC 1789568. PMID 389400. 3. ^ Sugimoto, Chihiro; Isayama, Yasuro; Sakazaki, Riichi; Kuramochi, Shigehiko (May 1983). "Transfer of Haemophilus equigenitalis Taylor et al. 1978 to the genus Taylorella gen. nov. as Taylorella equigenitalis comb. nov". Current Microbiology. 9 (3): 155–162. doi:10.1007/BF01567289. 4. ^ "Contagious equine metritis". Horsetalk.co.nz. 7 March 2012. 5. ^ Timoney, PJ (May 2011). "Horse species symposium: contagious equine metritis: an insidious threat to the horse breeding industry in the United States". Journal of Animal Science. 89 (5): 1552–60. doi:10.2527/jas.2010-3368. PMID 20889687. ## External links[edit] * CEM article at Equine-Reproduction.com * Contagious Equine Metritis article at the Veterinary Laboratories Agency, an Executive Agency of the United Kingdom Department for Environment, Food and Rural Affairs * Contagious Equine Metritis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Contagious equine metritis	c0276037	3,308	wikipedia	https://en.wikipedia.org/wiki/Contagious_equine_metritis	2021-01-18T18:29:19	{"wikidata": ["Q473340"]}
GM2-gangliosidosis, AB variant is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. Signs and symptoms of the AB variant become apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with the AB variant experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with the AB variant usually live only into early childhood. ## Frequency The AB variant is extremely rare; only a few cases have been reported worldwide. ## Causes Mutations in the GM2A gene cause GM2-gangliosidosis, AB variant. The GM2A gene provides instructions for making a protein called the GM2 ganglioside activator. This protein is required for the normal function of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord. Beta-hexosaminidase A and the GM2 ganglioside activator protein work together in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, the activator protein binds to a fatty substance called GM2 ganglioside and presents it to beta-hexosaminidase A to be broken down. Mutations in the GM2A gene disrupt the activity of the GM2 ganglioside activator, which prevents beta-hexosaminidase A from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms of the AB variant. Because the AB variant impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis. ### Learn more about the gene associated with GM2-gangliosidosis, AB variant * GM2A ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GM2-gangliosidosis, AB variant	c0268275	3,309	medlineplus	https://medlineplus.gov/genetics/condition/gm2-gangliosidosis-ab-variant/	2021-01-27T08:25:19	{"gard": ["2522"], "mesh": ["D049290"], "omim": ["272750"], "synonyms": []}
Atypical pulmonary carcinoid tumour Atypical pulmonary carcinoid. H&E stain. SpecialtyOncology 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: "Atypical pulmonary carcinoid tumour" – news · newspapers · books · scholar · JSTOR (April 2014) (Learn how and when to remove this template message) Atypical pulmonary carcinoid tumour is a subtype of pulmonary carcinoid tumor. It is an uncommon low-grade malignant lung mass that is most often in the central airways of the lung. It is also known as "atypical lung carcinoid tumour", " atypical lung carcinoid" or "moderately differentiated neuroendocrine carcinoma". It is a more aggressive than typical carcinoid tumors: nodal metastases in 70% vs. 5%. The 5 year survival is 49-69%. Atypical carcinoid tumors have increased mitotic activity (2-10 per 10 HPF), nuclear pleomorphism or foci of necrosis. ## Morphological differential diagnosis[edit] Atypical carcinoid of the lung exhibiting endobronchial growth, increased mitotic activity was seen (2-10 per 10 HPF). H&E stain. * Typical pulmonary carcinoid tumor * Typical pulmonary carcinoid lacks comedo-like necrosis, and has < 0.2 mitotic figures/HPF. ## References[edit] This oncology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Atypical pulmonary carcinoid tumour	c4072942	3,310	wikipedia	https://en.wikipedia.org/wiki/Atypical_pulmonary_carcinoid_tumour	2021-01-18T18:52:10	{"umls": ["C4072942", "C1708766"], "wikidata": ["Q3658375"]}
Familial acute myeloid leukemia with mutated CEBPA is one form of a cancer of the blood-forming tissue (bone marrow) called acute myeloid leukemia. In normal bone marrow, early blood cells called hematopoietic stem cells develop into several types of blood cells: white blood cells (leukocytes) that protect the body from infection; red blood cells (erythrocytes) that carry oxygen; and platelets (thrombocytes), which are involved in blood clotting. In acute myeloid leukemia, the bone marrow makes large numbers of abnormal, immature white blood cells called myeloid blasts. Instead of developing into normal white blood cells, the myeloid blasts develop into cancerous leukemia cells. The large number of abnormal cells in the bone marrow interferes with the production of functional white blood cells, red blood cells, and platelets. People with familial acute myeloid leukemia with mutated CEBPA have a shortage of white blood cells (leukopenia), leading to increased susceptibility to infections. A low number of red blood cells (anemia) also occurs in this disorder, resulting in fatigue and weakness. Affected individuals also have a reduction in the amount of platelets (thrombocytopenia), which can result in easy bruising and abnormal bleeding. Other symptoms of familial acute myeloid leukemia with mutated CEBPA may include fever and weight loss. While acute myeloid leukemia is generally a disease of older adults, familial acute myeloid leukemia with mutated CEBPA often begins earlier in life, and it has been reported to occur as early as age 4. Between 50 and 65 percent of affected individuals survive their disease, compared with 25 to 40 percent of those with other forms of acute myeloid leukemia. However, people with familial acute myeloid leukemia with mutated CEBPA have a higher risk of having a new primary occurrence of this disorder after successful treatment of the initial occurrence. ## Frequency Acute myeloid leukemia occurs in approximately 3.5 in 100,000 individuals per year. Familial acute myeloid leukemia with mutated CEBPA is a very rare form of acute myeloid leukemia; only a few affected families have been identified. ## Causes As its name suggests, familial acute myeloid leukemia with mutated CEBPA is caused by mutations in the CEBPA gene that are passed down within families. These inherited mutations are present throughout a person's life in virtually every cell in the body. The CEBPA gene provides instructions for making a protein called CCAAT enhancer-binding protein alpha. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of certain genes. It is believed to act as a tumor suppressor, helping to prevent cells from growing and dividing too rapidly or in an uncontrolled way. CEBPA gene mutations that cause familial acute myeloid leukemia with mutated CEBPA result in a shorter version of CCAAT enhancer-binding protein alpha. This shorter version is produced from one copy of the CEBPA gene in each cell, and it is believed to interfere with the tumor suppressor function of the normal protein produced from the second copy of the gene. Absence of the tumor suppressor function of CCAAT enhancer-binding protein alpha is believed to disrupt the regulation of blood cell production in the bone marrow, leading to the uncontrolled production of abnormal cells that occurs in acute myeloid leukemia. In addition to the inherited mutation in one copy of the CEBPA gene in each cell, most individuals with familial acute myeloid leukemia with mutated CEBPA also acquire a mutation in the second copy of the CEBPA gene. The additional mutation, which is called a somatic mutation, is found only in the leukemia cells and is not inherited. The somatic CEBPA gene mutations identified in leukemia cells generally decrease the DNA-binding ability of CCAAT enhancer-binding protein alpha. The effect of this second mutation on the development of acute myeloid leukemia is unclear. ### Learn more about the gene associated with Familial acute myeloid leukemia with mutated CEBPA * CEBPA ## Inheritance Pattern Familial acute myeloid leukemia with mutated CEBPA is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that one copy of the altered CEBPA gene in each cell is sufficient to cause the disorder. Most affected individuals also acquire a second, somatic CEBPA gene mutation in their leukemia cells. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Familial acute myeloid leukemia with mutated CEBPA	c0023467	3,311	medlineplus	https://medlineplus.gov/genetics/condition/familial-acute-myeloid-leukemia-with-mutated-cebpa/	2021-01-27T08:25:33	{"mesh": ["D015470"], "omim": ["601626"], "synonyms": []}
Collagenous gastritis (CG) is a rare condition that primarily affects the digestive system. People with CG have increased buildup of collagen in the subepithelial layer of the stomach. This condition typically affects children and young adults up to 22 years, or older adults over 35 years of age. Signs and symptoms appear to vary depending on the age group. Initial symptoms in children and young adults often include anemia and abdominal pain, whereas older adults often have chronic watery diarrhea associated with collagenous colitis, celiac disease or both. Adult collagenous gastritis is also associated with autoimmune diseases such as Sjögren syndrome, lymphocytic gastritis, lymphocytic colitis, and ulcerative colitis. Other signs and symptoms of CG may include nausea and vomiting, weight loss, abdominal distention, and gastrointestinal bleeding. The cause of the condition is unclear. Because of the small number of cases, no standard therapy for CG has been established based on randomized, controlled clinical trials. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Collagenous gastritis	c4040043	3,312	gard	https://rarediseases.info.nih.gov/diseases/10961/collagenous-gastritis	2021-01-18T18:01:13	{"synonyms": []}
Inflammatory myofibroblastic tumour Other namesInflammatory fibrosarcoma[1] Micrograph of an inflammatory myofibroblastic tumour of the kidney. Kidney biopsy. H&E stain. Inflammatory myofibroblastic tumour is a lesional pattern of inflammatory pseudotumour, as plasma cell granuloma.[2] It is abbreviated IMT. ## Contents * 1 Symptoms * 2 Pathology * 3 Diagnosis * 3.1 Localization * 4 Treatment * 5 See also * 6 References * 7 External links ## Symptoms[edit] The symptoms depend on the specific location of the tumour, which can be anywhere in the body.[3] ## Pathology[edit] Inflammatory myofibroblastic tumours are characterized by a mix of inflammatory cells, e.g. plasma cells, lymphocytes and eosinophils, and bland spindle cells without nuclear atypia. These tumours may have necrosis, hemorrhage, focal calcification and mitotic activity. The histologic differential diagnosis includes: * calcifying fibrous pseudotumour * inflammatory fibroid tumour * nodular fasciitis. Approximately half of IMTs have a rearrangement of the ALK gene.[4] ## Diagnosis[edit] Inflammatory myofibroblastic tumours are diagnosed based on their appearance under the microscope, by pathologists.[5] Medical imaging findings are non-specific. ### Localization[edit] * Lung[6] or Bronchus[7] * Liver[8] * Urinary bladder[9] * Parotid[10] ## Treatment[edit] Main modality for treatment is surgical only.[citation needed] ## See also[edit] * Nodular fasciitis * Inflammatory fibroid polyp ## References[edit] 1. ^ "Inflammatory myofibroblastic tumor \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 28 June 2019. 2. ^ Manohar, B.; Bhuvaneshwari, S. (Jan 2011). "Plasma cell granuloma of gingiva". J Indian Soc Periodontol. 15 (1): 64–6. doi:10.4103/0972-124X.82275. PMC 3134051. PMID 21772725. 3. ^ Singhal, M.; Ramanathan, S.; Das, A.; Singh, G.; Bagga, R.; Khandelwal, N. (2011). "Omental inflammatory myofibroblastic tumour mimicking peritoneal carcinomatosis". Cancer Imaging. 11: 19–22. doi:10.1102/1470-7330.2011.0005 (inactive 2021-01-10). PMC 3080123. PMID 21435987.CS1 maint: DOI inactive as of January 2021 (link) 4. ^ Gleason, BC.; Hornick, JL. (Apr 2008). "Inflammatory myofibroblastic tumours: where are we now?". J Clin Pathol. 61 (4): 428–37. doi:10.1136/jcp.2007.049387. PMID 17938159. 5. ^ Soga, H.; Yao, A.; Matsushita, K.; Shimogaki, H.; Kawabata, G. (2011). "Inflammatory pseudotumor of the retroperitoneum removed via a retroperitoneoscopic approach". JSLS. 15 (2): 272–4. doi:10.4293/108680811X13071180406871. PMC 3148889. PMID 21902993. 6. ^ Kaitoukov, Y; Rakovich, G; Trahan, S; Grégoire, J (2011). "Inflammatory pseudotumour of the lung". Canadian Respiratory Journal. 18 (6): 315–7. doi:10.1155/2011/702646. PMC 3267618. PMID 22187684. 7. ^ Sanchez, P. G.; Madke, G. R.; Pilla, E. S.; Foergnes, R; Felicetti, J. C.; Valle, Ed; Geyer, G (2007). "Endobronchial inflammatory pseudotumor: A case report". Jornal Brasileiro de Pneumologia. 33 (4): 484–6. doi:10.1590/S1806-37132007000400020. PMID 17982543. 8. ^ Sari, A; Tunakan, M; Ünsal, B; Ekıncı, N; Rezanko, T; Elçın, F; Aydoğdu, Z (2010). "Inflammatory pseudotumor of the liver diagnosed by needle biopsy: Report of three cases (one with neuroendocrine tumor of the rectum and lung)". The Turkish Journal of Gastroenterology. 21 (3): 308–12. doi:10.4318/tjg.2010.0107. PMID 20931439. S2CID 27068239. 9. ^ Yaghi MD. A case report of inflammatory myofibroblastic tumor of urinary bladder. Urol Ann [serial online] 2016 [cited 2016 Jul 18];8:366-8. Available from: http://www.urologyannals.com/text.asp?2016/8/3/366/184880 10. ^ Dhua, Anjan Kumar; Garg, Mohit; Sen, Amita; Chauhan, Devender S. (May 2013). "Inflammatory myofibroblastic tumor of parotid in infancy—A new entity". International Journal of Pediatric Otorhinolaryngology. 77 (5): 866–868. doi:10.1016/j.ijporl.2013.02.020. PMID 23562234. ## External links[edit] Classification D * ICD-O: M8825/1 External resources * Orphanet: 178342 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Inflammatory myofibroblastic tumour	c0334121	3,313	wikipedia	https://en.wikipedia.org/wiki/Inflammatory_myofibroblastic_tumour	2021-01-18T18:35:31	{"gard": ["7146"], "mesh": ["D006104"], "umls": ["C0334121"], "orphanet": ["178342"], "wikidata": ["Q6030100"]}
A number sign (#) is used with this entry because X-linked thrombocytopenia with or without dyserythropoietic anemia (XLTDA) is caused by mutation in the GATA1 gene (305371) on chromosome Xp11. Description XLTDA is an X-linked recessive hematologic disorder characterized by thrombocytopenia and abnormal platelet morphology and function due to defective platelet maturation. Some patients have a variable severity of dyserythropoietic anemia (summary by Millikan et al., 2011). Clinical Features Nichols et al. (2000) described a woman with mild chronic thrombocytopenia who had 2 pregnancies complicated by severe fetal anemia requiring in utero red blood cell transfusions. The offspring were male half-sibs who were anemic and severely thrombocytopenic from birth. Each ultimately required a bone marrow transplant. Before transplant, peripheral blood showed a paucity of platelets and abnormal erythrocyte size and shape (poikilocytosis and anisocytosis). Bone marrow biopsy showed dyserythropoiesis and numerous small, dysplastic megakaryocytes. Electron microscopy revealed abnormal megakaryocytes with an abundance of smooth endoplasmic reticulum, eccentric nucleus, and a paucity of granules. Platelets also had a paucity of granules, abundant smooth endoplasmic reticulum, and abnormal membranous complexes. White blood cells were unaffected. Both boys had cryptorchidism. There were 3 asymptomatic female sibs. Mehaffey et al. (2001) described a family in which 4 males in 2 generations related through female carriers had thrombocytopenia characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis with no measurable anemia. Freson et al. (2001) described a family with isolated X-linked macrothrombocytopenia without anemia (but with some dyserythropoietic features) in 13 males in 9 sibships of 3 generations connected through carrier females. Electron microscopy of the patients' platelets showed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes. Patient platelets also showed functional defects and low expression of certain membrane glycoproteins. Freson et al. (2002) reported a family with X-linked thrombocytopenia and dyserythropoietic anemia in which 6 boys died of the disorder before age 2 years. One surviving boy and his mother were available for study. Peripheral blood smear from the boy showed decreased numbers of normal to giant platelets and abnormal erythrocytes, with anisocytes and poikilocytes. Electron microscopy of the platelets showed paucity of alpha-granules and clusters of smooth endoplasmic reticulum. Bone marrow biopsy showed dyserythropoiesis, dysmorphic erythroblasts, and dysplastic megakaryocytes. The mother had only a small number of enlarged platelets, but no anemia and no thrombocytopenia. Inheritance The transmission pattern of XLTDA in the family reported by Nichols et al. (2000) was consistent with X-linked recessive inheritance. The mother had mild features of the disorder, which may have resulted from skewed X inactivation. Molecular Genetics In 2 male half-sibs with X-linked congenital thrombocytopenia with dyserythropoietic anemia, Nichols et al. (2000) identified a hemizygous mutation in the GATA1 gene (V205M; 305371.0001). The mother, who had mild chronic thrombocytopenia and mild anemia, was heterozygous for the mutation. The findings indicated an important role for GATA1 in erythropoiesis, megakaryocyte development, and platelet formation. In affected members of a family with X-linked macrothrombocytopenia without anemia, Mehaffey et al. (2001) identified a mutation in the GATA1 gene (G208S; 305371.0003). In affected members of a family with X-linked macrothrombocytopenia without anemia, Freson et al. (2001) identified a mutation in the GATA1 gene (D218G; 305371.0002). In a family with XLT with anemia, Freson et al. (2002) identified a mutation in the GATA1 gene (D218Y; 305371.0005). Genotype/Phenotype Correlations Compared to XLT individuals with the D218G mutation who did not have anemia (Freson et al., 2001), Freson et al. (2002) found that those with the D218Y mutation who had anemia had more disturbed platelet and erythrocyte morphology and disturbed expression levels of the platelet GATA1-target gene products. The more severe D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of an unaffected female carrier, and her leukocytes showed a skewed X-inactivation pattern. The authors concluded that the nature of the amino acid substitution at position 218 of GATA1 may be of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients, and possibly also in inducing skewed X inactivation. INHERITANCE \- X-linked recessive HEAD & NECK Nose \- Epistaxis SKIN, NAILS, & HAIR Skin \- Easy bruisability \- Petechiae HEMATOLOGY \- Thrombocytopenia \- Macrothrombocytes \- Platelets have paucity of granules \- Platelets had abnormal membrane complexes \- Platelets have increased smooth endoplasmic reticulum \- Abnormal platelet maturation \- Impaired platelet function \- Elevated thrombopoietin (TPO) \- Increased number of abnormal megakaryocytes seen on bone marrow biopsy \- Anemia, dyserythropoietic (in some patients) \- Abnormal RBC morphology (anisocytosis, poikilocytes, acanthocytes) (in some patients) \- Macrothrombocytes occasionally noted in carrier female peripheral blood smear MISCELLANEOUS \- Onset in infancy \- Variable severity \- Persistent bleeding after injury or surgery MOLECULAR BASIS \- Caused by mutation in the GATA-binding protein-1 gene (GATA1, 305371.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	THROMBOCYTOPENIA, X-LINKED, WITH OR WITHOUT DYSERYTHROPOIETIC ANEMIA	c1845837	3,314	omim	https://www.omim.org/entry/300367	2019-09-22T16:20:24	{"doid": ["1588"], "mesh": ["C564525"], "omim": ["300367"], "orphanet": ["67044"], "genereviews": ["NBK1364"]}
Factor XIII deficiency is an extremely rare inherited blood disorder characterized by abnormal blood clotting that may result in abnormal bleeding. Signs and symptoms occur as the result of a deficiency in the blood clotting factor 13, which is responsible for stabilizing the formation of a blood clot. In affected individuals, the blood fails to clot appropriately, resulting in poor wound healing. Blood may seep into surrounding soft tissues, resulting in local pain and swelling. Internal bleeding may occur; about 25 percent of affected individuals experience bleeding in the brain. FXIII deficiency is usually caused by mutations in the F13A1 gene, but mutations have also been found in the F13B gene. It is usually inherited in an autosomal recessive fashion. Acquired forms have also been reported in association with liver failure, inflammatory bowel disease, and myeloid leukemia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Factor XIII deficiency	c0015530	3,315	gard	https://rarediseases.info.nih.gov/diseases/10766/factor-xiii-deficiency	2021-01-18T18:00:37	{"mesh": ["D005177"], "omim": ["613225", "613235"], "orphanet": ["331"], "synonyms": ["Congenital Factor XIII deficiency", "Fibrin stabilizing factor deficiency"]}
Stranger anxiety is a form of distress that children feel when exposed to strangers. Crying is a common sign of anxiety in children Stranger anxiety is a form of distress that children experience when exposed to strangers. Stranger anxiety and stranger fear are two interchangeable terms. Stranger anxiety is a typical part of the developmental sequence that most children experience. It can occur even if the child is with a caregiver or another person they trust.[1] It peaks from six to 12 months[2] [3] but may recur afterwards until the age of 24 months.[4] As a child gets older, stranger anxiety can be a problem as they begin to socialize. Children may become hesitant to play with unfamiliar children.[1] Foster children are especially at risk, particularly if they experienced neglect early in their life.[1] The anxiety children experience when meeting a stranger is based on the sensation of fear they develop when introduced to an unfamiliar factor in their life that elicits the feeling of fear. They are not born with the awareness that meeting a stranger for the first time will cause them to be fearful. The child discovers this feeling when facing the stimulus, in this case a stranger, for the first time. Experiencing fear causes toddlers to sense they are in a potentially threatened position and therefore, they go towards their caregiver in order to seek protection from the stranger. This reaction enables children to develop instincts to guide them when they feel endangered and seek the protection of a familiar and trusted individual to ensure their safety and survival. The stimuli which provoke a child's anxiety in the presence of a stranger are influenced by the individual's age, gender and his or her distance from the toddler. When a child is in the company of an unknown child, they are less frightened than if they were with an unknown adult. This is due to the height of the individual. The taller the person, the more frightening they seem. In addition, children are more fearful of a stranger when they are standing in close proximity to them, while their caregiver is farther away or completely out of their sight. The gender of the stranger contributes to the level of anxiety a child experiences. When in the presence of a male, the child feels more anxious than in front of a female.[5] The anxiety a child feels when facing a stranger is based on various fears that arise in them. A few of these are based on the actions the stranger could unexpectedly take. For example, the child worries they can be taken away from their caregiver or harmed. The fear of the unknown elicits the anxiety. Although anxiety can go away in few minutes, it could also last a long time.[6] As children reach the age of two, their feelings of anxiety in the presence of strangers are nearly gone. However, some children can still experience apprehension up until the age of four.[7] It is less probable for toddlers to experience anxiety in the presence of a stranger if a figure they trust, such as their caregivers, perform positive interactions with this person. For example, they employ a calm tone of voice, they smile and hug the stranger. This enables the child to feel a certain reassurance seeing that their caregiver does not show any sign of fear in the presence of this individual.[8] ## Contents * 1 Onset * 1.1 Signs of stranger anxiety[1] * 1.2 Modeling and stranger anxiety * 1.2.1 Infancy * 1.2.1.1 Implications * 1.2.2 Childhood * 1.2.2.1 Implications * 2 Dealing with stranger anxiety * 3 Stranger anxiety and autism spectrum disorder * 3.1 Modelling in stranger anxiety in ASD * 3.2 Strategies * 4 Stranger terror * 4.1 Strange situation * 4.2 Some signs of stranger terror * 5 See also * 6 References * 7 External links ## Onset[edit] Stranger anxiety develops slowly; it does not just appear suddenly. It typically first starts to appear around four months of age with infants behaving differently with caregivers than with strangers. In fact, there is a difference between their interactions with their caregiver and the stranger. They become cautious when strangers are around; therefore, preferring to be with their caregiver instead of the stranger. Around 7–8 months, stranger anxiety becomes more present; therefore, it occurs more frequently at this point. Infants start to be aware of their environment and they are aware of their relationships with people; so, stranger anxiety is clearly displayed. Around this time, children choose and prefer to be with their primary caregiver. As a child's cognitive skills develop and improve, typically around 12 months, their stranger anxiety can become more intense. They display behaviors like running to their caregiver, grabbing at the caregiver's legs, or demanding to be picked up.[1] Children seem also to respond more positively to a person who gives positive reinforcements and more negatively to a person who gives negative reinforcements.[9] Fearfulness within the sight of outsiders is thought to be developed around 6 months of age. In fact, that fear of strangers increases throughout their first year of life. The beginning of stranger fear is accepted to be adaptive, offering balance to infants’ tendencies toward approach and exploration and adding to the developing attachment system. However, in extreme cases of stranger fear, this can be a warning sign to the emergence of social anxiety.[10] According to the University of Pittsburgh, stranger anxiety tends to be seen before separation anxiety.[11] Play media Infants may be afraid of strangers ### Signs of stranger anxiety[1][edit] According to the University of Pittsburgh based on the child, signs of stranger anxiety can differ from one to child the other. For example; 1. In the presence of a stranger, some infants can abruptly go quiet and look at the stranger with fear. 2. Certain emotions will increase in other children while in the presence of a stranger such as loud crying and fussiness. 3. And others will have the tendency to bury themselves in their caregiver's arms or even place themselves away from the stranger by placing the caregiver between themselves and the stranger. ### Modeling and stranger anxiety[edit] #### Infancy[edit] Parental attitudes also have an effect on a child's fear acquisition.[12] In their early months and years, infants acquire most of their behavioral information for their direct family and often, their primary caregivers.[13] Young infants are more selective and preferentially learn about new threats for their mother's responses.[13] High risk mothers can easily influence their child's responses since are more likely to mimic their actions.[13][12] For example, a child who sees their mother demonstrating negative reactions towards a specific person, then the child is more likely to have a negative response towards that same person. While most studies have researched the effect of mothers' behaviors on their children, it is important to note that the effect of parental modeling is not unique to mothers, but the phenomenon occurs for both mothers and fathers.[14] ##### Implications[edit] Fear beliefs that occur vicariously can be reversed using the same form of acquisition through a vicarious counter-conditioning procedure. For example, a parent can show a stranger's angry face with happy face or a scared-paired animal with happy faces as well and vice versa.[13] Also, feared responses seem to decrease with time if infants are provided with opportunities to have physical contact with the stimuli which helps alleviate the stimuli's fearful properties.[12] #### Childhood[edit] Stranger fear is less likely in older children (i.e. at least six years old) since there is a greater readiness for them to accept behavioral information from outside the family.[13] However, studies show that older children do exhibit increased anxiety to new threats and avoidant responses following discussion with parents.[14] The effect of parental modeling of anxiety on children may go beyond influencing anxious behaviors in children, but also affect their subjective feelings and cognition during middle childhood.[14] ##### Implications[edit] This has important implications for parents and those working with school-age children because it suggests that they can potentially prevent or reverse fear developing if they recognize a child is involved in a fear-related vicarious learning event.[13] In cases where infants become fearful of strangers or unknown entities (such as foreign objects), parents should respond positively towards the stranger, only after the child has a phobic response to it.[13] ## Dealing with stranger anxiety[edit] Since stranger anxiety can manifest itself suddenly or happen gradually throughout the development of the toddler, dealing with it can be hard sometimes because people are often not prepared to react to it or they don't even know what stranger anxiety is. Stranger anxiety should be viewed as a normal, common part of a child's development. Since it is often characterized by negative emotions and fear, multiple steps were created to induct a feeling of trust and safety between the child and the strangers. The child's feelings should always be valued * Addressing the issue with the stranger ahead of time, so that they can learn to approach the child slowly, giving them time to warm up. The stranger should be informed of the child's fear, so they are not hurt when the child reacts negatively to them. * Holding child's hand when they are introduced to new people has been found to be a good way to create a feeling of trust between them and the stranger. * Frequently introducing children to new people. Taking them to places where they might interact with strangers. * Being patient when a fearful situation shows up will be crucial. If rushed, child can become even more sensitive. * Gradually bringing new babysitters or child-care workers into the child's life. * Showing understanding of the fears of children should be priority number one. Ignoring or dismissing these feelings will only aggravate the problem. * Above all, the child's feelings should always be valued more than the strangers'. Patience and respect are very important when dealing with stranger anxiety. A child should never be labeled or ridiculed for being frightened.[1] Extreme anxiety can affect development, especially if a child is so terrified that they will not explore new environments and hinder themselves from learning. Also, research shows that exposure to circumstances that produce persistent fear and chronic anxiety can have a lifelong effect on a child's brain by disrupting its developing architecture. While stranger anxiety is a normal part of child development, if it becomes so severe that it restricts normal life professional help might be necessary. Seeking the help of a pediatrician is recommended if the situation doesn't improve, or even regresses in time. Often, pediatricians will be able to find the origin of the anxiety suffered by the child and create a plan of action in order to rectify the situation.[1] ## Stranger anxiety and autism spectrum disorder[edit] According to the American Psychiatric Association, autism spectrum disorder (ASD) is defined as “a developmental disorder characterized by troubles with social interaction and communication, and by restricted and repetitive behavior”.[15] There is a significant overlap between the behaviors that characterize ASD and those observed in stranger anxiety, which makes diagnoses and research more difficult.[15] However, individuals with ASD often have a rigid understanding of the world and behave in a very rule-based and compartmentalized manner, depending on their placement on the spectrum. Thus, the social interactions and stranger approaches seen in children are often modeled from their caretakers and are based on the rules they are told. ### Modelling in stranger anxiety in ASD[edit] Children with developmentally appropriate behavior also model their parents’ behavior and can exhibit stranger anxiety until about they are six years old, but children with ASD have difficulty accepting behavioral information and understanding how to behave with certain people and strangers.[16] Thus, if caretakers/parents demonstrate negative behavior, like facial expressions, verbal communications, or physical retractions, towards strangers, children with autism will often imitate this behavior. Although children with ASD often have difficulty with imitation, children are often taught that strangers are “dangerous”. Moreover, if caretakers teach children with autism that strangers are unsafe, they will demonstrate stranger anxiety and have difficulty understanding otherwise as they grow.[17] For example, caretakers may teach children to never speak to strangers, but children with ASD will understand this literally and may fear and be anxious around all strangers. ### Strategies[edit] Therefore, it is crucial to appropriately teach children with autism who they may expect to meet in a given location and situation and what those people look like, in order for them to be self-sufficient and not anxious wherever they are. Individuals with ASD need to understand not only who they should be interacting with in the community, but also what the expected behaviors are during these interactions.[18] Moreover, caretakers/parents are cautioned to not reinforce negative reactions when strangers are seen and to teach “stranger danger” precariously. Thus, children with autism should be taught strategies that slightly differ than a developmentally appropriate child. One example of a strategy is the Circles Program, which color coordinates individuals that a child may encounter by titling them in different colored circles and outlining the expected social boundaries with these people. Another strategy used for children with ASD and stranger anxiety is to use social stories, this includes pictures and audio tapes which makes understanding possible changes they may encounter with strangers.[18] ## Stranger terror[edit] Play media Child afraid of new women in classroom Stranger terror is extremely severe stranger anxiety that inhibits the child's normal functioning. The DSM- V describes stranger terror as infants with a reactive attachment disorder, inhibited type and do not respond to or initiate contact with others, but rather show extreme trepidation and ambivalence about unknown adults.[19] Anxiety and fear around strangers usually appears around six months of age and it slowly increases throughout the first year of life. This increase in stranger anxiety correlates with the same time as when the child starts crawling, walking and exploring its surroundings. The age of the child seems to play an important role in the development of stranger terror in infants.[20] Older infants (i.e. at least 12 months) seem to be more affected than younger infants because their cognitive development to know and remember has matured more than younger infants and their attachment to caregivers is stronger than younger infants. Stranger anxiety and stranger terror is associated to the Attachment Theory, to the attachment to caregiver. Seen across different species, attachment increases the chances of the infant's survival in the world. In a research conducted by Tyrrell and Dozier (1997),[21] they found that infants in foster care show more attachment-related difficulties than control infants in their families. Those foster children were sometimes unsoothable after the contact or even just the presence of a stranger. There have been hypotheses that for these infants the appearance of the stranger represented a potential loss of the new attachment figure and it was the fear of re-experiencing this loss that prompted their behavior.[20] Those children with stranger anxiety will rarely go beyond their caregiver to explore their surroundings. Stranger terror elicits strong reactions from children as described below, most likely due to the degree of traumatic event which causes their strong reactions such as the loss of a mother.[20] In order to cope with attachment-related traumas, children suffering from stranger terror develop abnormal means of coping with these events by viewing all adults as threatening and avoiding contact with everyone, for example.[20] ### Strange situation[edit] In a Strange Situation experiment, a child of the age of 20 months was in a room with their mother and a stranger would enter. The child would go hide behind the legs of the mother. The mother was then asked to leave the room and leave the child with the stranger. After the first separation, the child began to scream and was extremely upset. He refused all contact with the stranger and when the adult tried to pick up the child he would scream louder until put back down. Any attempts by the stranger to sooth the child was unsuccessful. When the mother came back in the room for the first reunion, the child somewhat calmed down, but he was still very upset and distressed. For the second part of the experiment, the child was left alone in the room for a couple of minutes before the stranger entered again. The second the stranger entered the room the child began crying loudly again even if no contact was made.[citation needed] To conclude, although resistance to a stranger is common for children, the extreme reactions was far more urgent and depicted terror. In addition, most babies in the experiment show some evidence of settling when the stranger enters the room the second time. In contrast, children with stranger terror showed an increase in distress upon the stranger's entry. Children go and hide when a stranger enters their home ### Some signs of stranger terror[edit] * Fleeing when a person they don't know enters their home, even if they aren’t interacting with the child. * Worried facial expressions that are typically seen on an older child. * Being very upset by a stranger's presence, even in the child's own home. * Loud screaming or arching of the back when an unfamiliar person tries to comfort or hold the child. * Being silent or wary for longer than normal periods with fearful facial expressions.[1] ## See also[edit] * Psychology portal * Separation anxiety disorder * Social phobia * Social anxiety ## References[edit] 1. ^ a b c d e f g h Stranger anxiety 2. ^ Deterding, Robin R.; William Winn Hay; Myron J. Levin; Judith M. Sondheimer (2006). Current Diagnosis and Treatment in Pediatrics. New York: McGraw-Hill Medical. p. 200. ISBN 978-0-07-146300-3. 3. ^ Williams, Sears (August 2011). "bye-bye BABY". Baby Talk. 76 (6): 22–24. Retrieved October 2, 2011. 4. ^ What to Expect. Toddler Stranger Anxiety. 5. ^ Lampinen, James Michael; Sexton-Radek, Kathy (2010-09-13). Protecting Children from Violence: Evidence-Based Interventions. Psychology Press. ISBN 9781136980046. 6. ^ Pantley, Elizabeth (2010-03-26). The No-Cry Separation Anxiety Solution: Gentle Ways to Make Good-bye Easy from Six Months to Six Years. McGraw Hill Professional. ISBN 9780071747073. 7. ^ Martin, Carol Lynn; Fabes, Richard (2008-01-25). Discovering Child Development. Cengage Learning. ISBN 9781111808112. 8. ^ Shaffer, David (2008-09-19). Social and Personality Development. Cengage Learning. ISBN 9781111807269. 9. ^ Greenberg, David (1973). "Infant and Stranger Variables Related to Stranger Anxiety in the First Year of Life". Developmental Psychology. 9 (2): 207–212. doi:10.1037/h0035084. 10. ^ Brooker, R. J., Buss, K. A., Lemery-Chalfant, K., Aksan, N., Davidson, R. J., & Goldsmith, H. H. (2013). (2013). "The Development of Stranger Fear in Infancy and Toddlerhood: Normative Development, Individual Differences, Antecedents, and Outcomes". Developmental Science. 16 (6): 864–78. doi:10.1111/desc.12058. PMC 4129944. PMID 24118713.CS1 maint: multiple names: authors list (link) 11. ^ "Stranger Anxiety" (PDF). 12. ^ a b c Dubi, Kathrin; Rapee, Ronald M.; Emerton, Jane L.; Schniering, Carolyn A. (2008-05-01). "Maternal Modeling and the Acquisition of Fear and Avoidance in Toddlers: Influence of Stimulus Preparedness and Child Temperament" (PDF). Journal of Abnormal Child Psychology. 36 (4): 499–512. doi:10.1007/s10802-007-9195-3. ISSN 0091-0627. PMID 18080181. 13. ^ a b c d e f g Dunne, Güler; Askew, Chris (2013). "Vicarious learning and unlearning of fear in childhood via mother and stranger models". Emotion. 13 (5): 974–980. doi:10.1037/a0032994. PMID 23795591. 14. ^ a b c Burstein, Marcy; Ginsburg, Golda S. (2010). "The effect of parental modeling of anxious behaviors and cognitions in school-aged children: An experimental pilot study". Behaviour Research and Therapy. 48 (6): 506–515. doi:10.1016/j.brat.2010.02.006. PMC 2871979. PMID 20299004. 15. ^ a b Tuchman, R (2003). "Autism". Neurologic Clinics. 21 (4): 915–932. doi:10.1016/S0733-8619(03)00011-2. PMID 14743656. 16. ^ Dunne, G. (2013). "Vicarious learning and unlearning of fear in childhood via mother and stranger models". Emotion. 13 (5): 974–980. doi:10.1037/a0032994. PMID 23795591. 17. ^ Dubi, K (2008). "Maternal modeling and the acquisition of fear and avoidance in toddlers: influence of stimulus preparedness and child temperament" (PDF). Abnormal Child Psychology. 36 (4): 499–512. doi:10.1007/s10802-007-9195-3. PMID 18080181. 18. ^ a b Wood, J. J. (2009). "Cognitive behavioral therapy for anxiety in children with autism spectrum disorders: a randomized, controlled trial". Journal of Child Psychology and Psychiatry. 50 (3): 224–234. doi:10.1111/j.1469-7610.2008.01948.x. PMC 4231198. PMID 19309326. 19. ^ Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association. 2013. ISBN 978-0-89042-554-1. 20. ^ a b c d Albus, Kathleen E.; Dozier, Mary (1999). "Indiscriminate friendliness and terror of strangers in infancy: Contributions from the study of infants in foster care". Infant Mental Health Journal. 20: 30–41. doi:10.1002/(SICI)1097-0355(199921)20:1<30::AID-IMHJ3>3.0.CO;2-J. 21. ^ Tizard, B. (1977). Adoption: A second chance. New York: The Free Press. ## External links[edit] * Stranger anxiety at American Academy of Pediatrics * Stranger anxiety at Arkansas Center for Effective Parenting * Separation Anxiety in Young Children [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Stranger anxiety	None	3,316	wikipedia	https://en.wikipedia.org/wiki/Stranger_anxiety	2021-01-18T18:30:43	{"wikidata": ["Q511454"]}
This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (March 2012) (Learn how and when to remove this template message) Smooth muscle tumor of uncertain malignant potential, abbreviated STUMP, is an uncommon tumor of the uterine smooth muscle that may behave like a benign tumor or a cancerous tumor. This tumor should not be confused with the prostatic stromal tumor of uncertain malignant potential which may be abbreviated the same way (STUMP). The Bell criteria were developed to help categorize them and differentiate them from their main differential diagnoses, leiomyosarcoma and uterine leiomyoma. ## Contents * 1 Bell criteria * 1.1 Atypia * 1.2 Mitotic figures * 1.3 Necrosis * 1.4 Algorithm * 2 See also * 3 References * 4 External links ## Bell criteria[edit] ### Atypia[edit] * none * minimal: smooth nuclei, smooth contours, minimal variation in nuclear size, shape, and evenly distributed chromatin * moderate: many large, plump, irregular nuclei, 1-2 mitotic figures * severe: obvious pleomorphism, enlarged bizarre nuclei with dense chromatin, giant cells, often multinucleated, enlarged, atypical nucleoli ### Mitotic figures[edit] Evaluation of the mitotic figures in a STUMP requires evaluation of 3 specific criteria 1. Hairy extensions of chromatin must be present, extending from a central clot-like dense mass of chromosomes. Hairy extensions from an empty center favor a non-mitosis. Count 4 sets of 10 fields in the area of highest mitotic activity and use the highest count 2. No nuclear membrane 3. Rule out lymphocytes, mast cells, stripped nuclei, degenerated cells, and precipitated hematoxylin. ### Necrosis[edit] Coagulative tumor cell necrosis is common in clinically malignant smooth muscle cell tumors. It consists of an abrupt transition between necrotic cells and preserved cells. Ghost nuclei from necrotic cells are often seen, but inflammatory cells are uncommon. Hyalinizing necrosis is more common in leiomyomas. It consists of a zone of hyalinized collagen between dead cells and preserved cells, commonly eosinophilic. If dead nuclei present, they are uniform and the chromatin is often. Necrosis secondary to ulceration in submucous leiomyomas features acute inflammatory cells and a peripheral reparative process, whereas ghost outlines of nuclei are usually inconspicuous or absent. ### Algorithm[edit] * Bell's criteria do not apply to extrauterine tumors * No or mild atypia, no tumor cell necrosis ⇒ leiomyoma. If 5 or more mitotic figures are present in 10 high powered fields but the behavior still appears benign, may append “with significant mitotic activity”. * Moderate to severe atypia without tumor cell necrosis * atypical leiomyoma if < 10 mitotic figures per high power field or * leiomyosarcoma if ≥ 10 mitotic figures per high power field * Moderate to severe atypia and tumor cell necrosis ⇒ leiomyosarcoma (mitotic figures don’t matter). ## See also[edit] * Prostatic stromal tumor of uncertain malignant potential ## References[edit] * Guntupalli SR, Ramirez PT, Anderson ML, Milam MR, Bodurka DC, Malpica A (June 2009). "Uterine smooth muscle tumor of uncertain malignant potential: a retrospective analysis". Gynecol. Oncol. 113 (3): 324–6. doi:10.1016/j.ygyno.2009.02.020. PMID 19342083. * Ng JS, Han A, Chew SH, Low J (August 2010). "A clinicopathologic study of uterine smooth muscle tumours of uncertain malignant potential (STUMP)" (PDF). Ann. Acad. Med. Singap. 39 (8): 625–8. PMID 20838704. * Ip PP, Cheung AN, Clement PB (July 2009). "Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases". Am. J. Surg. Pathol. 33 (7): 992–1005. doi:10.1097/PAS.0b013e3181a02d1c. PMID 19417585. * Chen WY, Yang AH, Liu HC (April 1991). "Spindle cell stromal tumors of gastrointestinal tract: a histological and immunohistochemical study". Zhonghua Yi Xue Za Zhi (Taipei). 47 (4): 219–27. PMID 1710946. * Pernick, Nat (August 11, 2020). "Smooth muscle tumors of uncertain malignant potential". www.pathologyoutlines.com. Retrieved November 18, 2020. ## External links[edit] Classification D * ICD-10: D39.0 * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Smooth muscle tumor of uncertain malignant potential	c0206658	3,317	wikipedia	https://en.wikipedia.org/wiki/Smooth_muscle_tumor_of_uncertain_malignant_potential	2021-01-18T19:08:17	{"mesh": ["D018235"], "wikidata": ["Q7394858"]}
A disorder that is the most common form of congenital adrenal hyperplasia (CAH), characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females and with adrenal insufficiency (in both sexes), and that presents with dehydration, hypoglycemia in the neonatal period (that can be lethal if untreated), and hyperandrogenia. ## Epidemiology The prevalence is about 1/14,000. ## Clinical description Classic 21-OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting (see these terms). Clinical signs of classic 21-OHD CAH are observed prenatally or at birth. Girls present with ambiguous genitalia (clitoromegaly, partially fused labia majora with rugae, common urogenital sinus) and the extent of virilization can vary from a nearly male appearance to minimal clitoromegaly. A normal uterus and various degrees of abnormal vaginal development are seen. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration and hypotension in the first few weeks of life due to aldosterone deficiency. They can develop failure to thrive, hyponatremia, hyperkalemia, acidosis and hypoglycemia which can be life threatening if not treated immediately. Hyperandrogenia manifests with accelerated growth velocity and accelerated skeletal maturation (leading to short stature in adulthood), advanced bone age, premature pubarche and precocious puberty during childhood, acne and hirsutism, menstrual problems, subfertility, and metabolic disturbances and obesity during adulthood. ## Etiology The disease is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which controls cortisol and aldosterone production. ## Diagnostic methods Diagnosis of girls with classic 21-OHD CAH is usually at birth when ambiguous genitalia are present. Fetuses can be diagnosed for CAH prenatally by measuring 17-hydroxy-progesterone (17-OHP) levels found in amniotic fluid. National systematic screening programs in most European countries diagnose cases of CAH at birth. ## Differential diagnosis Differential diagnoses include other forms of CAH, polycystic ovary syndrome (PCOS, see these terms) or any diseases with androgen excess. ## Antenatal diagnosis Prenatal testing is available by either chorionic villus sampling (CVS) during the 10th -12th week of gestation or by amniocentesis during the 15th -18th week by measuring the enzyme activity of 17-OHP. ## Genetic counseling As classic 21-OHD CAH follows an autosomal recessive pattern of inheritance, genetic counseling is possible. ## Management and treatment Prenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital ambiguity in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls in the first year of life. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal growth and puberty. Hydrocortisone is usually given to children as glucocorticoid (GC) replacement therapy (10-15mg/m2/day divided into 2 or 3 doses) and 9alpha-fludrocortisone for mineralocorticoid (MC) replacement. Dosage is monitored and modified during times of stress. There is a risk of developing acute adrenal insufficiency (see this term) and other complications due to chronic hyperandrogenemia. Excessive treatment with GC causes cushingoid features, and excess MC causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, psychologists, is important. ## Prognosis With proper treatment patients have a normal life expectancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	c2936858	3,318	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90794	2021-01-23T17:39:37	{"gard": ["12665"], "mesh": ["C535979"], "omim": ["201910"], "umls": ["C2936858"], "icd-10": ["E25.0"], "synonyms": ["Classic 21-OHD CAH"]}
Rain scald (also known as dermatophilosis, tufailosis, rain rot or streptothricosis[1]) is a dermatological disease affecting cattle and horses. Once in the skin, the bacterium Dermatophilus congolensis causes inflammation of the skin as well as the appearance of scabs and lesions. ## Contents * 1 Symptoms * 2 Diagnosis * 3 Treatment * 4 Prevention * 5 References ## Symptoms[edit] There are two different manifestations of rain scald: the winter form, which is more severe due to the longer coat of the horse, and the summer form, which is less severe.[2] Horses are usually affected on the back, head, and neck where insects commonly bite, and the legs, which are commonly infected if the horse is kept in moist footing.[3] Initially, the horse will display a matted coat and bumps which will progress to crusty scabs and lesions.[4] The animal may also be pruritic and display signs of discomfort. ## Diagnosis[edit] Diagnosis is most commonly done with the identification of bacteria in the lesions by microscopic evaluation.[5] A positive diagnosis of rain scald can be confirmed if filamentous bacteria are observed, as well as chains of small, spherical bacteria (cocci).[4] If a diagnosis cannot be confirmed with a microscope, blood agar cultures can be grown to confirm the presence of D. congolensis.[5] The resulting colonies have filaments and are yellow in colour. ## Treatment[edit] Rain scald normally heals on its own; however, the condition can spread, so prompt treatment is recommended. Although some cases can be severe, most rain scald is minor and can be treated at home naturally. Treatment involves cleaning affected areas with antiseptic scrub and applying a solution of 1% potash alum.[6] Affected areas should be gently washed with a mild disinfectant shampoo or solution like chlorhexidine or povidone iodine. A broad-spectrum antibiotic powder, spray or ointment is applied. Severely affected horses may need systemic antibiotic treatment by injection or by mouth.[7] Typically the condition is not life-threatening, nor does it impact the welfare of the horse, so treatments are more for the owner's peace of mind and cosmetic appeal of the animal.[4] ## Prevention[edit] In addition to wet conditions, exposure to ticks, biting flies, and contact with other infected animals can also cause the spread of rain scald.[3] Tick and insect control is an effective way to stop the spread of the bacteria from one animal to another.[5] Separating infected animals will help to isolate bacterial colonies.[3] Keeping the animal in a dry, well-ventilated area out of the rain and wet conditions will stop the bacteria from growing.[4] As the bacteria multiplies best in warm, wet conditions, keeping the horse stabled, sheltered, or rugged with a waterproof rug during wet weather, protects the skin from prolonged wetting and helps to prevent infection.[7] ## References[edit] 1. ^ Macadam, I. (September 1, 1970). "Some observations on bovine cutaneous streptothricosis in Northern Nigeri ds/tahm/2.04.10_DERMATOPHIL.pdf". OIE. 2. ^ Szczepanik, Marcin; Marcin Golynski; Dorota Pomorska; Piotr Wilkolek; Iwona Taszkun; Marcel Kovalik (2006). "Dermatophilosis in a horse - a case report" (PDF). Bulletin of the Veterinary Institute in Pulawy. 50: 619–622. Retrieved 10 November 2011. 3. ^ a b c "Fast Facts: Dermatophilosis" (PDF). The Center for Food Security & Public Health Iowa State University. January 2006. Retrieved 10 November 2011. 4. ^ a b c d "Dermatophilosis: Introduction". The Merck Veterinary Manual. Merck SHarp & Dohme Corp. Retrieved 10 November 2011. 5. ^ a b c "Dermatophilosis" (PDF). OIE. 2008. Retrieved 7 November 2011. 6. ^ Horse & Hound (2018-02-06). "Struggling with rain scald? Find out how to beat it..." Horse & Hound. Retrieved 2019-12-28. 7. ^ a b "Rain Scald in Horses". vca_corporate. Retrieved 2019-12-28. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Rain scald	c0275572	3,319	wikipedia	https://en.wikipedia.org/wiki/Rain_scald	2021-01-18T18:39:31	{"umls": ["C0275572"], "wikidata": ["Q4564484"]}
For a phenotypic description and a discussion of genetic heterogeneity of noninsulin-dependent diabetes mellitus (NIDDM), see 125853. Mapping Ghosh et al. (1999) conducted a genome scan at an average resolution of 10 cM for type II diabetes (125853) susceptibility genes in 716 affected sib pairs from 477 Finnish families. At the time of report, their best evidence for linkage was on chromosome 20, with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum lod (MLS) was 3.08 on 20p under an additive model, whereas the weighted MLS was 2.06 on 20q. They interpreted the evidence from this and other studies as suggesting at least 2 diabetes-susceptibility genes located on chromosome 20. Ghosh et al. (1999) also screened the HNF4A gene (600281), which is responsible for type I maturity-onset diabetes of the young (125850), in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. They found no evidence that sequence changes in the HNF4A gene accounted for the linkage results they observed. Linkage to a 20-cM region of 20q12-q13.1 was found by Bowden et al. (1997), Ji et al. (1997), and Zouali et al. (1997). Since few mutations were found in the HNF4A gene, which is mutant in MODY1 (125850), one or more other genes within 20q12-q13.1 were thought to be responsible for the observed genetic linkage to type II diabetes. Price et al. (1999) constructed a radiation hybrid map and YAC/BAC physical map for precise mapping of newly identified transcribed sequences and polymorphic markers. They suggested that this map would aid in linkage and linkage disequilibrium studies and facilitate identification and cloning of candidate type II diabetes susceptibility genes in this region of the genome. Molecular Genetics Familial genetic studies of noninsulin-dependent diabetes mellitus (NIDDM; 125853) of different human populations, including French Caucasians, suggested evidence for linkage of NIDDM and chromosome 20q13, where the MC3R gene maps. Hani et al. (2001) assessed the MC3R gene for variations in a large cohort of French families with NIDDM. In these patients they identified 2 missense mutations in the MC3R gene. These 2 variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium test results, the authors stated that these MC3R gene-coding variants were not associated with diabetes or obesity. They concluded that these variants were marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DIABETES MELLITUS, NONINSULIN-DEPENDENT, 3	c1863594	3,320	omim	https://www.omim.org/entry/603694	2019-09-22T16:12:43	{"mesh": ["C566342"], "omim": ["603694"], "synonyms": ["Alternative titles", "NIDDM3", "NONINSULIN-DEPENDENT DIABETES MELLITUS 3"]}
Beta-thalassemias with other manifestations are a group of beta-thalassemias (see this term) associated with another disorder. ## Etiology These forms of beta-thalassemia are not related to defects in the beta-globin gene cluster but to mutations either in the gene encoding the transcription factor TFIIH (beta-thalassemia - trichothiodystrophy) or in the X-linked transcription factor GATA-1 (beta-thalassemia - X-linked thrombocytopenia; see these terms). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Beta-thalassemia with other manifestations	None	3,321	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231386	2021-01-23T18:57:07	{"icd-10": ["D58.2"]}
Diffuse large B-cell lymphoma (DLBCL), a form of non-Hodgkin lymphoma, is the most common blood cancer. Lymphomas occur when cells of the immune system, known as B lymphocytes, grow and multiply uncontrollably. DLBCL occurs mostly in adults and is a fast-growing (aggressive) lymphoma. It can start in the lymph nodes or outside of the lymphatic system in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Often, the first sign of DLBCL is a painless rapid swelling in the neck, armpit, abdomen, or groin caused by enlarged lymph nodes. For some people, the swelling may be painful. Other symptoms include night sweats, unexplained fevers, and weight loss. Treatment may differ depending on the location of the tumor and the subtype of lymphoma. For those who have advanced DCBCL and have not been treated previously, a combination of chemotherapy and the monoclonal antibody rituximab (Rituxan) (R-CHOP) may be tried.. In addition, as of October 2017, axicabtagene ciloleucel (brand name: Yescarta), a type of gene therapy, has been approved by the United States FDA to treat DCBCL that is not responding to at least two treatment attempts or has returned after being treated before. A stem cell transplant may also be an option if DLBCL returns or relapses. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Diffuse Large B-Cell Lymphoma	c0079744	3,322	gard	https://rarediseases.info.nih.gov/diseases/3178/diffuse-large-b-cell-lymphoma	2021-01-18T18:00:52	{"mesh": ["D016403"], "umls": ["C0079744"], "orphanet": ["544"], "synonyms": ["DLBCL"]}
Isolated distichiasis is a rare congenital eyelid anomaly characterized by an accessory row of eyelashes (that may be partial or complete) posterior to the normal row of cilia, at or close to the meibomian gland orifices, that is not associated with any other condition, and that may lead to ocular irritation and corneal damage 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Isolated distichiasis	c0423848	3,323	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99177	2021-01-23T17:24:16	{"omim": ["126300"], "umls": ["C0423848"], "icd-10": ["Q10.3"]}
Luzzatto et al. (1979) concluded that an X-chromosomal gene affects growth of hemopoietic cells. The conclusion was based on study of a Nigerian family segregating for a G6PD variant called Ilesha. In heterozygous females one or the other allele was almost exclusively expressed. The data were consistent with random inactivation of one X chromosome followed by selection for one of the two resulting cell types on the basis of an unlinked X-borne gene that affects the rate of proliferation of hemopoietic cells. Deviation from 1:1 ratio of cell types in females heterozygous for X-linked mutations has been observed for HGPRT (where almost all erythroid cells are wildtype). X-chromosome structural aberrations also deviate from the 1:1 ratio; no chromosome abnormality was found in the family of Luzzatto et al. (1979). Inheritance \- X-linked Heme \- Hemopoietic proliferation ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HEMOPOIETIC PROLIFERATION	c1844026	3,324	omim	https://www.omim.org/entry/306930	2019-09-22T16:18:14	{"omim": ["306930"]}
A number sign (#) is used with this entry because of evidence that MASP2 deficiency is caused by homozygous mutation in the MASP2 gene (605102) on chromosome 1p36. Description MASP2 deficiency, classically defined as MASP2 protein level of less than 100 ng/ml, occurs in about 4% of Caucasians and up to 18% of some African populations. Some MASP2-deficient individuals have increased risk of infection or autoimmune disease, but most are asymptomatic. MASP2 plays a role in activation of the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Thiel et al., 2007 and Sokolowska et al., 2015). For a discussion of genetic heterogeneity of lectin complement activation pathway defects, see LCAPD1 (614372). Clinical Features Stengaard-Pedersen et al. (2003) described a patient with inherited deficiency of MASP2. Born in 1967, the man was healthy until the age of 13 years, when the diagnosis of ulcerative colitis (see 266600) was made. He was successfully treated with topical prednisolone. At the age of 29 years, erythema multiforme bullosum developed. Systemic lupus erythematosus was suspected because of joint symptoms and myalgia in combination with weakly positive tests for antinuclear antibody. The patient had a favorable response to treatment with prednisolone, and other immunosuppressive drugs were subsequently added to the regimen. Severe pneumococcal pneumonia was documented on at least 3 occasions, with 1 episode of sepsis requiring prolonged intensive care. At the age of 30 years, progressive lung fibrosis without vasculitis, alveolitis, or granulomas was found. Stengaard-Pedersen et al. (2003) found that the functional activity of the mannan-binding lectin (MBL; 154545)-MASP (see MASP1, 600521) complex in the patient was less than 10 mU of MBL activity per microgram, indicating severe deficiency. The MBL-MASP complex from the patient contained MASP1 and the MASP1 isoform MASP3, but not MASP2 or the MASP2 isoform MAP19. St. Swierzko et al. (2009) investigated cord blood MASP2 concentrations in a large cohort of 1,788 neonates of Caucasian origin: the median value was 93 ng/ml. Serum MASP2 concentrations correlated with gestational age and birthweight and were significantly lower in premature babies and other preterm babies compared with term babies. Neonates with MASP2 concentrations below 42 ng/ml were considered to be MASP2-deficient and had a shorter mean gestational age and a higher incidence of prematurity and low birthweight. However, they did not have increased perinatal infections compared to the others. Among 362 samples tested for the D120G polymorphism (605102.0001) in the MASP2 gene, none were homozygous. Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity (MBL-MASP2 complex activity). There was no association between this SNP and prematurity, low birthweight, or perinatal infections. Sokolowska et al. (2015) reported 2 unrelated individuals with pulmonary tuberculosis who were homozygous for the MASP2 D120G polymorphism. One was a 72-year-old man with chronic obstructive pulmonary disease, whereas the other was a 36-year-old woman with no other comorbidities. In addition, 1 of 276 healthy controls was homozygous for the D120G variant. All 3 individuals had low MASP2 serum concentrations and low MBL-MASP2 complex activities. One of the tuberculosis patients also had an MBL2 (154545) mutation (154545.0001) that affected both MBL serum concentration and activity. In a review of published cases including their 2 cases, Sokolowska et al. (2015) noted that 10 patients with MASP2 deficiency and serious diseases, mainly affecting the respiratory tract, had been reported. However, 7 healthy controls homozygous for MASP2 deficiency had also been reported. Thus, the clinical impact of MASP2 deficiency remained uncertain. Molecular Genetics In a patient with MASP2 deficiency, Stengaard-Pedersen et al. (2003) identified homozygosity for a mutation in exon 3 of the MASP2 gene, resulting in an asp120-to-gly (D120G; 605102.0001) substitution. Population Genetics Sokolowska et al. (2015) noted that early reports estimated the frequency of total MASP2 deficiency due to the D120G SNP at 6 in 10,000 (0.0006), but subsequent reports indicated that it may be higher, up to 0.0036 or 0.0061. Thiel et al. (2007) examined several different human populations for MASP2 levels and variation in the MASP2 gene. The MASP2 levels were lowest in Africans from Zambia (median of 196 ng/ml) followed by Hong Kong Chinese (262 ng/ml), Brazilian Amerindians (290 ng/ml), and Danish Caucasians (416 ng/ml). The frequencies of several polymorphisms that influenced serum levels were determined: a 4-residue tandem duplication was found only in Chinese (gene frequency 0.26%) and the D120G variant was found only in Caucasians and Inuits from West-Greenland (frequency of 3.7 to 3.9%). The P126L and R99Q variants were present in Africans and Amerindians only, except for R99Q in 1 Caucasian. The MASP2 present in individuals homozygous for V377A or R99Q had a normal enzyme activity, whereas MASP2 in individuals homozygous for P126L was nonfunctional. INHERITANCE \- Autosomal recessive IMMUNOLOGY \- Increased susceptibility to infection (in some patients) \- Defective activation of the complement system LABORATORY ABNORMALITIES \- Decreased levels of circulating MASP2 MISCELLANEOUS \- Up to 5 or 18% % of healthy individuals may have MASP2 deficiency and be asymptomatic depending on the population MOLECULAR BASIS \- Caused by variation in the mannan-binding lectin serine protease 2 gene (MASP2, 605102.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MASP2 DEFICIENCY	c3151085	3,325	omim	https://www.omim.org/entry/613791	2019-09-22T15:57:31	{"mesh": ["C565360"], "omim": ["613791"], "orphanet": ["331187"], "synonyms": ["Alternative titles", "LECTIN COMPLEMENT ACTIVATION PATHWAY, DEFECT IN, 2"]}
A congenital optic disc anomaly characterized by a funnel shaped excavation of the posterior fundus that incorporates the optic disc. Clinically, the optic disc malformation resembles the morning glory flower. Morning glory disc anomaly (MGDA) is usually unilateral and often results in a decrease in best-corrected visual acuity (BCVA). MGDA can be isolated or associated with other ocular or non-ocular anomalies. ## Epidemiology The overall prevalence of MGDA is unknown, but it is estimated at 1/38,500 among subjects between 2 and 19 years old in Sweden. More than 100 cases have been reported in the medical literature. The disease is thought to be more common in women than in men. ## Clinical description MGDA often manifests early in childhood with strabismus of the affected eye. When the child is older and BCVA can be assessed, a substantial visual loss is noted (BCVA usually ranging between counting fingers and 20/200 in the affected eye). However, visual acuity is not always severely impaired, and can be close to normal. MGDA can be isolated or associated with other ocular anomalies in the same or contralateral eye (nystagmus, cataract, microphthalmia, glaucoma, coloboma of the crystalline lens, optic nerve drusen, aniridia, lid haemangioma, preretinal gliosis, peripheral retinal non-perfusion, serous retinal detachment, lenticonus, glioma or cyst of any optic pathway, acute retrobulbar optic neuritis, etc.). In younger patients, MGDA combined with persistent hyperplastic primary vitreous may indicate higher incidence of, and more severe associated complications. Associated facial dysmorphism (hypertelorism, dysplastic ears, cleft lip and palate, etc.), intracranial anomalies (basal encephalocele, other types of encephalocele, affected pituitary gland, corpus callosum agenesis, cerebral midline lipomas, etc.) and renal abnormalities (renal hypoplasia, chronic glomerulonephritis, hydronephrosis, etc.) have been reported, as well as several neurovascular and cardiac defects. MGDA can be associated with Moyamoya disease, PHACES syndrome, Aicardi syndrome, neurofibromatosis type 2, Arnold-Chiari malformation type I, CHARGE syndrome, Poland syndrome, among others. Bilateral cases are rare and might be correlated with a more severe systemic involvement. ## Etiology The exact etiology is not fully understood, but the syndrome is related to poor development of the posterior sclera and lamina cribrosa during gestation. The PAX6 gene could be linked to the anomaly. ## Diagnostic methods The diagnosis is based on clinical examination and relies on fundoscopy findings, showing an enlarged optic disc with peripapillary pigmentations, funnel shaped deep excavation, a radiating pattern of retinal blood vessels and a pale fluffy tuft of hyperplastic glial tissue overlying the optic disc. Optical coherence tomography, OCT may show a serous retinal detachment. Other MGDA-associated ocular anomalies, disorders elsewhere, e.g. cerebral malformations, systemic involvement and diseases, etc. should be ruled out. ## Differential diagnosis The differential diagnoses include optic disc colobomas, staphylomas and amblyopia. ## Management and treatment There is no curative treatment for the anomaly. However, associated amblyopia is usually treated by occlusion of the contralateral eye with good possibilities of some visual improvement. Strabismus can be corrected with surgery. Serous retinal detachment seems common, usually not requiring treatment but needing follow up. Vitrectomy with peripapillary photocoagulation and silicone oil tamponade may be required if a proliferative retinal detachment is associated with macular hole in children with MGDA. Associated somatic disorders/conditions, especially cranial malformations, cerebrovascular anomalies, cardiovascular anomalies, renal anomalies, endocrine and other systemic disease, etc. should be diagnosed and, if possible, treated accordingly. ## Prognosis The visual loss is usually non-progressive but MGDA increases the risk of serous retinal detachment (30% of patients in some studies). Other reported complications include choroidal neovascularization. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Morning glory disc anomaly	c0549307	3,326	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35737	2021-01-23T18:57:45	{"omim": ["120430"], "umls": ["C0549307"], "icd-10": ["Q14.2"], "synonyms": ["Ectasic coloboma", "Morning glory syndrome"]}
Idiopathic CD4 positive T-lymphocytopenia (ICL) is a rare disorder of the immune system. People with ICL have low levels of a type of white blood cell, called a CD4+ T cell. These low levels can not be explained by other causes of immunodeficiency, including HIV infection. T cells have many jobs in our immune system, such as attacking bacteria and viruses. CD4 is a protein found on the surface of many different cells within your immune system. It lets the different cells of your immune system work with each other. When CD4+ T cells are decreased, your body becomes more prone to infection. Signs and Symptoms of ICL vary. Some people have no symptoms, however most have illnesses suggestive of a lowered immune system, including infections (varicella-zoster virus, human papilloma virus), autoimmune disorders (autoimmune hemolytic anemia, lupus), and certain types of cancer (non-Hodgkin lymphoma). A few people with ICL are found to carry specific gene mutations; however, for most cases of ICL the underlying cause is not known. Currently, there is no cure for ICL, but treatments are available to help manage individual symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Idiopathic CD4 positive T-lymphocytopenia	c3809768	3,327	gard	https://rarediseases.info.nih.gov/diseases/12375/idiopathic-cd4-positive-t-lymphocytopenia	2021-01-18T17:59:50	{"omim": ["615518"], "orphanet": ["228000"], "synonyms": ["IMMUNODEFICIENCY 13", "IMD13", "ICL", "Idiopathic CD4 lymphocytopenia", "IDIOPATHIC CD4 LYMPHOPENIA"]}
A number sign (#) is used with this entry because of evidence that osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is caused by homozygous mutation in the CHST11 gene (610128) on chromosome 12q23. One such family has been reported. Description Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum (Shabbir et al., 2018). Clinical Features Chopra et al. (2015) described 2 sisters, born of parents from the same region of Ireland, who had congenital digital malformations of the hands and feet and also developed a lymphoproliferative disorder. Both sisters were shorter than other family members (10th centile on growth charts). Examination of the proband revealed bilateral brachydactyly with disproportionately short index fingers and either valgus or varus deformity at many of the interphalangeal joints; similar findings were present in her toes. Her similarly affected older sister had died at age 20 due to complications of an unnamed lymphoproliferative disorder; the proband was still alive at 46 years of age and had been treated for a pulmonary malignancy most consistent with a diagnosis of peripheral T-cell lymphoma. The sisters had 5 unaffected sibs, and no other family members were known to have congenital abnormalities of the hands or feet. Apart from their father, who was diagnosed with chronic lymphocytic leukemia at age 59 and died at age 64, no other family members had developed lymphoproliferative disorders. Shabbir et al. (2018) reported a consanguineous Pakistani pedigree in which 10 patients over 3 generations showed highly variable skeletal defects in vertebrae and leg bones, as well as hand and foot malformations, predominantly brachydactyly. Limb defects were generally bilateral and symmetric, and shortened lower leg bones resulted in mild short stature. Digital anomalies included adducted thumbs, overriding fingers (most often third over fourth), ulnar curvature of the index fingers, and camptoclinodactyly of fingers 3 to 5, as well as short and broad halluces with valgus inclinations (referred to by the authors as varus), second toes overriding the third, short fifth toes, and postaxial polydactyly of the feet. There was no restriction in movement in wrists or ankles despite the crowding of carpals and tarsals. Five patients exhibited scoliosis; other skeletal defects included dislocated patellae and fibulae, and pectus excavatum. Two of the adult patients (50 and 20 years of age) reported joint pain, but x-rays did not show any degenerative changes characteristic of osteoarthritis. There was no history of cancer in this family. Mapping In a consanguineous Pakistani family with skeletal defects and brachydactyly with overlapping malformed digits, Shabbir et al. (2018) performed homozygosity mapping using SNP genotype data and identified a 1.6-Mb region of shared homozygosity at chromosome 12q23.3, between rs1922261 and rs6539247. Cytogenetics In a 46-year-old woman of Irish descent with malformations of the hands and feet and a lymphoproliferative disorder, Chopra et al. (2015) performed whole-genome sequencing and identified homozygosity for a 55-kb deletion on chromosome 12 (chr12:104,948,000-105,003,000, GRCh37) that included exon 2 of the CHST11 gene (610128) as well as the embedded microRNA MIR3922. The deletion was not found in 3 unaffected sibs or in the 1000 Genomes Project database; DNA was unavailable from the proband's deceased affected sister. The parents were born in the same part of Ireland, and an 180-kb potential identity-by-descent region (chr12:104,920,000-105,100,000, GRCh37) overlapped the entire deletion. The authors suggested that the CHST11 deletion alone could account for the proband's bony malformation, but stated that the contribution of the deletion to her T-cell lymphoproliferative disorder was less clear. Molecular Genetics In a consanguineous Pakistani family with skeletal defects and brachydactyly with overlapping malformed digits, negative for variants in 12 known brachydactyly-associated genes, Shabbir et al. (2018) performed exome sequencing and identified homozygosity for a 15-bp in-frame deletion in the CHST11 gene (610128.0001) that segregated with disease and was not found in public variant databases. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, mild CHEST External Features \- Pectus excavatum (in some patients) Ribs Sternum Clavicles & Scapulae \- Prominent clavicles (in some patients) SKELETAL Spine \- Scoliosis Limbs \- Short distal long bones of lower limbs \- Short radii and ulnae \- Dislocated patellae \- Thinning of tibiae and fibulae \- Lateroventral displacement of fibulae Hands \- Brachydactyly \- Overlapping fingers (primarily third and fourth fingers) \- Short thumb \- Adducted thumb \- Ulnar-curved index finger \- Curved middle finger, ulnar or radial \- Camptoclinodactyly of ring finger \- Camptoclinodactyly of fifth finger \- Extra osseous elements in fingers \- Short proximal phalanges in second through fourth fingers \- Hypoplastic distal phalanges \- Symphalangism in fingers \- Fifth finger with 2 phalanges \- Missing or extra flexion creases on fingers Feet \- Brachydactyly \- Short halluces \- Broad halluces \- Hallux valgus \- Second toe overlapping third \- Postaxial polydactyly (in some patients) \- Hypertrophic first digital rays \- Dysmorphic and short proximal and distal phalanges \- Laterally displaced calcanei MISCELLANEOUS \- Based on report of a large consanguineous Pakistani pedigree (last curated October 2018) \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the carbohydrate sulfotransferase-11 gene (CHST11, 610128.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	OSTEOCHONDRODYSPLASIA, BRACHYDACTYLY, AND OVERLAPPING MALFORMED DIGITS	None	3,328	omim	https://www.omim.org/entry/618167	2019-09-22T15:43:18	{"omim": ["618167"]}
A number sign (#) is used with this entry because of evidence that open angle glaucoma-1F (GLC1F) is caused by heterozygous mutation in the ASB10 gene (615054) on chromosome 7q36. Clinical Features Wirtz et al. (1999) reported a family in which 10 members in 4 generations showed evidence of primary open angle glaucoma (POAG) including intraocular pressures of 22 mm Hg or more, and/or optic cup-disc rations of 0.6 or more, and/or visual field defects consistent with glaucomatous damage. Mapping In a family in which 10 members in 4 generations had adult-onset primary open angle glaucoma, Wirtz et al. (1999) found that the disorder segregated as an autosomal dominant trait, with the disease locus mapping to 7q35-q36 between markers D7S2442 and D7S483 with a multipoint lod score of 4.06. Molecular Genetics In a large Oregon family with adult-onset primary open angle glaucoma mapping to chromosome 7q35-q36, originally reported by Wirtz et al. (1999), Pasutto et al. (2012) refined the GLC1F region by recombination events and sequenced 42 candidate genes located within the critical interval. Heterozygosity for a synonymous variant in the ASB10 gene (T255T; 615054.0001) segregated with disease in the family, and the variant was not found in the HapMap or dbSNP databases, the 1000 Genomes Project database, or in 85 controls. Analysis of the complete ASB10 coding region in 195 POAG cases from a US data set and a cohort of 977 German glaucoma patients, including 440 with high tension POAG, 485 with normal tension glaucoma (NTG; see 606657), and 52 with juvenile-onset primary open angle glaucoma (JOAG), identified 26 amino acid changes in 70 patients and 9 amino acid changes in 13 controls (p = 0.008; see, e.g., 615054.0002-615054.0004). The frequency of potentially detrimental mutations was similar between the phenotype groups, taking into account the small number of JOAG patients analyzed: 6.2% in high intraocular pressure (IOP) POAG, 5.2% in NTG, and 3.8% in JOAG. These missense variants were almost equally distributed between patients with high IOP (6%, combined POAG and JOAG) and patients with normal IOP values (5.2%, NTG). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GLAUCOMA 1, OPEN ANGLE, F	c1863926	3,329	omim	https://www.omim.org/entry/603383	2019-09-22T16:13:05	{"mesh": ["C566383"], "omim": ["603383"], "synonyms": ["Alternative titles", "GLAUCOMA, PRIMARY OPEN ANGLE, ADULT-ONSET"]}
Collapse or closure of a lung resulting in reduced or absent gas exchange 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: "Atelectasis" – news · newspapers · books · scholar · JSTOR (May 2008) (Learn how and when to remove this template message) Atelectasis Other namesCollapsed lung[1] Atelectasis of a person's right lung Pronunciation * /ˌætɪˈlɛktəsɪs/ SpecialtyPulmonology Atelectasis is the collapse or closure of a lung resulting in reduced or absent gas exchange. It is usually unilateral, affecting part or all of one lung.[2] It is a condition where the alveoli are deflated down to little or no volume, as distinct from pulmonary consolidation, in which they are filled with liquid. It is often called a collapsed lung, although that term may also refer to pneumothorax.[1] It is a very common finding in chest x-rays and other radiological studies, and may be caused by normal exhalation or by various medical conditions. Although frequently described as a collapse of lung tissue, atelectasis is not synonymous with a pneumothorax, which is a more specific condition that features atelectasis. Acute atelectasis may occur as a post-operative complication or as a result of surfactant deficiency. In premature babies, this leads to infant respiratory distress syndrome. The term uses combining forms of atel- \+ ectasis, from Greek: ἀτελής, "incomplete" + ἔκτασις, "extension". ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Classification * 3.1.1 Absorption (resorption) atelectasis * 3.1.2 Compression (relaxation) atelectasis * 3.1.3 Cicatrization (contraction) atelectasis * 3.1.4 Chronic atelectasis * 3.1.4.1 Right middle lobe syndrome * 3.1.4.2 Patchy atelectasis * 3.1.4.3 Rounded atelectasis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Atelectasis. May have no signs and symptoms or they may include:[3] * cough, but not prominent; * chest pain (not common); * breathing difficulty (fast and shallow); * low oxygen saturation; * pleural effusion (transudate type); * cyanosis (late sign); * increased heart rate. It is a common misconception and pure speculation that atelectasis causes fever. A study of 100 post-op patients followed with serial chest X-rays and temperature measurements showed that the incidence of fever decreased as the incidence of atelectasis increased.[4] A recent review article summarizing the available published evidence on the association between atelectasis and post-op fever concluded that there is no clinical evidence supporting this speculation.[5] ## Causes[edit] The most common cause is post-surgical atelectasis, characterized by splinting, i.e. restricted breathing after abdominal surgery. Another common cause is pulmonary tuberculosis. Smokers and the elderly are also at an increased risk. Outside of this context, atelectasis implies some blockage of a bronchiole or bronchus, which can be within the airway (foreign body, mucus plug), from the wall (tumor, usually squamous cell carcinoma) or compressing from the outside (tumor, lymph node, tubercle). Another cause is poor surfactant spreading during inspiration, causing the surface tension to be at its highest which tends to collapse smaller alveoli. Atelectasis may also occur during suction, as along with sputum, air is withdrawn from the lungs. There are several types of atelectasis according to their underlying mechanisms or the distribution of alveolar collapse; resorption, compression, microatelectasis and contraction atelectasis. Relaxation atelectasis (also called passive atelectasis) is when a pleural effusion or a pneumothorax disrupts the contact between the parietal and visceral pleurae.[6] Risk factors associated with increased likelihood of the development of atelectasis include: type of surgery (thoracic, cardiopulmonary surgeries), use of muscle relaxation, obesity, high oxygen, the lower lung segments. Factors not associated with the development of atelectasis include: age, presence of chronic obstructive pulmonary disease (COPD) or asthma, and type of anesthetic. In the early 1950s, in UK aviation medicine, the condition "acceleration atelectasis" was given the name "Hunter Lung" due to its prevalence in pilots of the transonic fighter jet, the Hawker Hunter, which used a 100% oxygen supply.[7][8] ## Diagnosis[edit] Atelectasis of the right lower lobe seen on chest X-ray. Clinically significant atelectasis is generally visible on chest X-ray; findings can include lung opacification and/or loss of lung volume. Post-surgical atelectasis will be bibasal in pattern. Chest CT or bronchoscopy may be necessary if the cause of atelectasis is not clinically apparent. Direct signs of atelectasis include displacement of interlobar fissures and mobile structures within the thorax, overinflation of the unaffected ipsilateral lobe or contralateral lung, and opacification of the collapsed lobe.In addition to clinically significant findings on chest X-rays, patients may present with indirect signs and symptoms such as elevation of the diaphragm, shifting of the trachea, heart and mediastinum; displacement of the hilus and shifting granulomas.[9] ### Classification[edit] Atelectasis of the middle lobe on a sagittal CT reconstruction. Atelectasis may be an acute or chronic condition. In acute atelectasis, the lung has recently collapsed and is primarily notable only for airlessness. In chronic atelectasis, the affected area is often characterized by a complex mixture of airlessness, infection, widening of the bronchi (bronchiectasis), destruction, and scarring (fibrosis). #### Absorption (resorption) atelectasis[edit] The Earth's atmosphere is mainly composed of 78 vol. % nitrogen and 21 vol. % oxygen (+ 1 vol. % argon and traces of other gases). Since oxygen is exchanged at the alveoli-capillary membrane, nitrogen is a major component for the alveoli's state of inflation. If a large volume of nitrogen in the lungs is replaced with oxygen, the oxygen may subsequently be absorbed into the blood, reducing the volume of the alveoli, resulting in a form of alveolar collapse known as absorption atelectasis.[10] #### Compression (relaxation) atelectasis[edit] It is usually associated with accumulation of blood, fluid, or air within the pleural cavity, which mechanically collapses the lung. This is a frequent occurrence with pleural effusion, caused by congestive heart failure (CHF). Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis.[11] #### Cicatrization (contraction) atelectasis[edit] It occurs when either local or generalized fibrotic changes in the lung or pleura hamper expansion and increase elastic recoil during expiration.[11] Causes include granulomatous disease, necrotising pneumonia and radiation fibrosis.[12] #### Chronic atelectasis[edit] Chronic atelectasis may take one of two forms—middle lobe syndrome or rounded atelectasis. ##### Right middle lobe syndrome[edit] In right middle lobe syndrome, the middle lobe of the right lung contracts, usually because of pressure on the bronchus from enlarged lymph glands and occasionally a tumor. The blocked, contracted lung may develop pneumonia that fails to resolve completely and leads to chronic inflammation, scarring, and bronchiectasis. ##### Patchy atelectasis[edit] Is due to lack of surfactant, as occurs in hyaline membrane disease of newborn or acute (adult) respiratory distress syndrome (ARDS).[13] ##### Rounded atelectasis[edit] In rounded atelectasis (folded lung or Blesovsky syndrome[14]), an outer portion of the lung slowly collapses as a result of scarring and shrinkage of the membrane layers covering the lungs (pleura), which would show as visceral pleural thickening and entrapment of lung tissue. This produces a rounded appearance on x-ray that doctors may mistake for a tumor. Rounded atelectasis is usually a complication of asbestos-induced disease of the pleura, but it may also result from other types of chronic scarring and thickening of the pleura. ## Treatment[edit] Treatment is directed at correcting the underlying cause. In atelectasis manifestations that result from the mucus plugging of the airways as seen in patients with cystic fibrosis and pneumonia, mucolytic agents such as acetylcysteine (NAC) is used. This nebulized treatment works by reducing mucous viscosity and elasticity by breaking disulfide bonds in mucoproteins within the mucus complex, thus facilitating mucus clearance.[15] Post-surgical atelectasis is treated by physiotherapy, focusing on deep breathing and encouraging coughing. An incentive spirometer is often used as part of the breathing exercises. Walking is also highly encouraged to improve lung inflation. People with chest deformities or neurologic conditions that cause shallow breathing for long periods may benefit from mechanical devices that assist their breathing. One method is continuous positive airway pressure, which delivers pressurized air or oxygen through a nose or face mask to help ensure that the alveoli do not collapse, even at the end of a breath. This is helpful, as partially inflated alveoli can be expanded more easily than collapsed alveoli. Sometimes additional respiratory support is needed with a mechanical ventilator. The primary treatment for acute massive atelectasis is correction of the underlying cause. A blockage that cannot be removed by coughing or by suctioning the airways often can be removed by bronchoscopy. Antibiotics are given for an infection. Chronic atelectasis is often treated with antibiotics because infection is almost inevitable. In certain cases, the affected part of the lung may be surgically removed when recurring or chronic infections become disabling or bleeding is significant. If a tumor is blocking the airway, relieving the obstruction by surgery, radiation therapy, chemotherapy, or laser therapy may prevent atelectasis from progressing and recurrent obstructive pneumonia from developing. ## See also[edit] * Alveolar capillary dysplasia, a very rare type of diffuse congenital disorder of the lung * Flat-chested kitten syndrome or FCKS: atelectasis in neo-natal kittens * Tympanic membrane atelectasis: Retraction of the ear drum into the middle ear can also be referred to as atelectasis. * William Pasteur, pioneer pulmonologist ## References[edit] 1. ^ a b Orenstein, David M. (2004). Cystic Fibrosis: A Guide for Patient and Family. Lippincott Williams & Wilkins. p. 62. ISBN 9780781741521. 2. ^ Wedding, Mary Ellen; Gylys, Barbara A. (2005). Medical Terminology Systems: A Body Systems Approach: A Body Systems Approach. Philadelphia, Pa: F. A. Davis Company. ISBN 0-8036-1289-3.[page needed] 3. ^ "Atelectasis". MayoClinic. Retrieved 20 February 2017. 4. ^ Engoren, Milo (January 1995). "Lack of Association Between Atelectasis and Fever". Chest. 107 (1): 81–84. doi:10.1378/chest.107.1.81. PMID 7813318. 5. ^ Mavros, Michael N.; Velmahos, George C.; Falagas, Matthew E. (August 2011). "Atelectasis as a Cause of Postoperative Fever". Chest. 140 (2): 418–424. doi:10.1378/chest.11-0127. PMID 21527508. 6. ^ Tarun Madappa. "Atelectasis". Medscape. Retrieved 2018-02-02. Updated: Nov 28, 2017 7. ^ Air Vice-Marshal John Ernsting (2008). "The RAF institute of aviation medicine 1945-1994 contributions to aviation and flight safety" (PDF). Royal Air Force Historical Society Journal (43): 18–53. ISSN 1361-4231. 8. ^ Lt Col Rob “Mongo” Monberg. "Review of acceleration atelectasis: An old problem in new settings" (PDF). IAMFSP. 9. ^ Woodring, John H., and James C. Reed. "Types and mechanisms of pulmonary atelectasis." Journal of thoracic imaging 11.2 (1996): 92-108. 10. ^ White, Gary C. (2002). Basic Clinical Lab Competencies for Respiratory Care, 4th ed. Delmar Cengage Learning. p. 230. ISBN 978-0-7668-2532-1. 11. ^ a b Robbins (2013). Basic Pathology. Elsevier. p. 460. ISBN 978-1-4377-1781-5. 12. ^ Sheikh, Zishan; Weerakkody, Yuranga. "Lung atelectasis". Radiopaedia. Retrieved 20 February 2017. 13. ^ Kaplan medical pathology lecture notes book (2019). p.118 14. ^ Payne, C. R; Jaques, P; Kerr, I. H (1980). "Lung folding simulating peripheral pulmonary neoplasm (Blesovsky's syndrome)". Thorax. 35 (12): 936–940. doi:10.1136/thx.35.12.936. PMC 471419. PMID 7268670. 15. ^ http://www.ncbi.nlm.nih.gov/books/NBK545316/. ## External links[edit] Classification D * ICD-10: J98.1 * ICD-9-CM: 518.0 * MeSH: D001261 * DiseasesDB: 10940 External resources * MedlinePlus: 000065 * eMedicine: med/180 * 04-048a. at Merck Manual of Diagnosis and Therapy Home Edition * Atelectasis at Merck Manual of Diagnosis and Therapy Professional Edition * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Atelectasis	c0004144	3,330	wikipedia	https://en.wikipedia.org/wiki/Atelectasis	2021-01-18T18:42:42	{"mesh": ["D001261"], "umls": ["C0004144"], "icd-9": ["518.0"], "icd-10": ["J98.1"], "wikidata": ["Q754031"]}
A rare condition of variable severity associated with vertebral and rib segmentation defects and characterised by a short neck with limited mobility, winged scapulae, a short trunk, and short stature with multiple vertebral anomalies at all levels of the spine. ## Epidemiology The incidence and prevalence are unknown. The disease seems to be more frequent in the Puerto Rican population. ## Clinical description Autosomal recessive spondylocostal dysostosis (ARSD) is usually diagnosed in the neonatal period. The main skeletal malformations include fusion of the vertebrae, hemivertebrae, and rib fusion with other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of these malformations and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections. Anomalies of the central nervous system, genitourinary tract and heart (spina bifida, meningocele, renal and ureteral abnormalities, hypospadias, complex congenital heart disease, atrial septal defect, anomalous pulmonary venous return etc.) have been reported but are not common. Facial dysmorphism and intellectual deficit are occasional features. ## Etiology So far, four genes, all involved in the Notch signalling pathway - DLL3 (19q13.2), MESP2 (15q26.1), LFNG (7p22.3) and HES7 (17p13.1) - have been identified but mutations in these genes do not account for all of the cases. ## Diagnostic methods Diagnosis is clinical and may be supported by ultrasonography and spine radiographs. ## Antenatal diagnosis Prenatal diagnosis is possible using fetal ultrasound. ## Genetic counseling The disease is inherited as an autosomal recessive trait. ## Management and treatment Management includes intensive medical care, bone surgery, and orthopedic treatment. ## Prognosis ARSD may cause respiratory insufficiency that may lead to life-threatening complications in the first year of life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal recessive spondylocostal dysostosis	c0265343	3,331	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2311	2021-01-23T18:34:10	{"gard": ["6798"], "mesh": ["C537565", "C535781"], "omim": ["277300", "608681", "609813", "613686", "616566"], "umls": ["C0265343", "C2931020"], "icd-10": ["Q76.8"], "synonyms": ["Jarcho-Levin syndrome"]}
Posterior urethral valve Vesiculæ seminales and ampullæ of ductus deferentes, seen from the front. Posterior urethral valves are at the dorsal aspect (back) of the prostatic urethra. SpecialtyUrology Posterior urethral valve (PUV) disorder is an obstructive developmental anomaly in the urethra and genitourinary system of male newborns.[1] A posterior urethral valve is an obstructing membrane in the posterior male urethra as a result of abnormal in utero development. It is the most common cause of bladder outlet obstruction in male newborns. The disorder varies in degree, with mild cases presenting late due to milder symptoms. More severe cases can have renal and respiratory failure from lung underdevelopment as result of low amniotic fluid volumes, requiring intensive care and close monitoring.[2] It occurs in about one in 8000 babies.[3] ==Presentation== PUV. Can be diagnosed antenatally or even at birth when the US showing that the male baby having a hydronephrosis. While the late presentation can be as UTI , Diurnal enuresis , voiding pain ## Contents * 1 Complications * 2 Diagnosis * 2.1 Classification * 3 Treatment * 4 Female homolog * 5 References * 6 External links ## Complications[edit] * Incontinence * Urinary tract infection * Renal failure * Vesicoureteral reflux * Chronic kidney disease ## Diagnosis[edit] Postvesicular obstruction due to urethral valves. Abdominal ultrasound is of some benefit, but not diagnostic. Features that suggest posterior urethral valves are bilateral hydronephrosis, a thickened bladder wall with thickened smooth muscle trabeculations, and bladder diverticula.[citation needed] Voiding cystourethrogram (VCUG) is more specific for the diagnosis. Normal plicae circularis are variable in appearance and often not seen on normal VCUGs. PUV on voiding cystourethrogram is characterized by an abrupt tapering of urethral caliber near the verumontanum, with the specific level depending on the developmental variant. Vesicoureteral reflux is also seen in over 50% of cases. Very often the posterior urethra maybe dilated thus making the abrupt narrowing more obvious. the bladder wall may show trabeculations or sacculations or even diverticuli.[citation needed] Diagnosis can also be made by cystoscopy, where a small camera is inserted into the urethra for direct visualization of the posteriorly positioned valve. A limitation of this technique is that posterior valve tissue is translucent and can be pushed against the wall of the urethra by inflowing irrigation fluid, making it difficult to visualize. Cystoscopy may also demonstrate the bladder changes.[citation needed] Centers in Europe and Japan have also had excellent results with cystosonography, although it has not been approved for use in the United States yet.[4] ### Classification[edit] The male urethra laid open on its anterior (upper) surface. Posterior valves are usually fusion of the plicae colliculi between the entrance of the seminal vesicles at the veromontanum, and extend to the membranous urethra. Posterior urethral obstruction was first classified by H. H. Young in 1919. The verumontanum, or mountain ridge, is a distinctive landmark in the prostatic urethra, important in the systemic division of posterior valve disorders:[citation needed] * Type I - Most common type; due to anterior fusing of the plicae colliculi, mucosal fins extending from the bottom of the verumontanum distally along the prostatic and membranous urethra[5] * Type II - Least common variant; vertical or longitudinal folds between the verumontanum and proximal prostatic urethra and bladder neck * Type III - Less common variant; a disc of tissue distal to verumontanum, also theorized to be a developmental anomaly of congenital urogenital remnants in the bulbar urethra Dewan has suggested that obstruction in the posterior urethra is more appropriately termed congenital obstructions of the posterior urethral membrane (COPUMs), a concept that has come from an in-depth analysis of the historical papers, and evaluation of patients with a prenatal diagnosis that has facilitated video recording of the uninstrumented obstructed urethra.[6] The congenital obstructive lesions in the bulbar urethra, named Type III Valves by Young in 1919, have been eponymously referred to as Cobb's collar or Moorman's ring.[7] For each of the COPUM (Posterior Urethra) and Cobb's (Bulbar Urethra) lesions, the degree of obstruction can be variable, consistent with a variable expression of the embryopathy.[8] The now nearly one hundred year old nomenclature of posterior urethral valves was based on limited radiology and primitive endoscopy, thus a change COPUM or Cobb's has been appropriate.[citation needed] ## Treatment[edit] If suspected antenatally, a consultation with a paediatric surgeon/ paediatric urologist maybe indicated to evaluate the risk and consider treatment options. Treatment is by endoscopic valve ablation. Fetal surgery is a high risk procedure reserved for cases with severe oligohydramnios, to try to limit the associated lung underdevelopment, or pulmonary hypoplasia, that is seen at birth in these patients. The risks of fetal surgery are significant and include limb entrapment, abdominal injury, and fetal or maternal death. Specific procedures for in utero intervention include infusions of amniotic fluid, serial bladder aspiration, and creating a connection between the amniotic sac and the fetal bladder, or vesicoamniotic shunt.[4] There are three specific endoscopic treatments of posterior urethral valves: * Vesicostomy followed by valve ablation - a stoma, or hole, is made in the urinary bladder, also known as low diversion, after which the valve is ablated and the stoma is closed. * Pyelostomy followed by valve ablation - stoma is made in the pelvis of the kidney as a slightly high diversion, after which the valve is ablated and the stoma is closed * Primary (transurethral) valve ablation - the valve is removed through the urethra without creation of a stoma The standard treatment is primary (transurethral) ablation of the valves.[9] Urinary diversion is used in selected cases,[9] and its benefit is disputed.[10][11] Following surgery, the follow-up in patients with posterior urethral valve syndrome is long term, and often requires a multidisciplinary effort between paediatric surgeons/ paediatric urologists, paediatric nephrologists, pulmonologists, neonatologists, radiologists and the family of the patient. Care must be taken to promote proper bladder compliance and renal function, as well as to monitor and treat the significant lung underdevelopment that can accompany the disorder. Definitive treatment may also be indicated for the vesico-ureteral reflux. ## Female homolog[edit] Vector diagram of posterior urethral obstruction causing severe bilateral hydronephrosis and bladder trabeculation The female homolog to the male verumontanum from which the valves originate is the hymen. ## References[edit] 1. ^ Manzoni C, Valentini A (2002). "Posterior urethral valves". Rays. 27 (2): 131–4. PMID 12696266. 2. ^ "Emedicine - Posterior urethral valves - overview and treatment". Emedicine. Retrieved July 26, 2010. 3. ^ "Posterior urethral valves - Disease Information". Children's hospital, Boston. Archived from the original on May 19, 2011. Retrieved January 31, 2011. 4. ^ a b "Emedicine - Posterior Urethral Valves - Diagnosis and Treatment". Emedicine. Archived from the original on July 8, 2012. Retrieved July 18, 2010. 5. ^ "Nationwide Children's Hospital, Radiology - Posterior urethral valves". Nationwide Children's Hospital. Retrieved July 26, 2010. 6. ^ Dewan, Paddy (2014-07-19). "Posterior Urethral Obstruction: COPUM". Bangladesh Journal of Endosurgery. 2 (1): 29–32. doi:10.3329/bje.v2i1.19590. ISSN 2306-4390. 7. ^ "Nationwide Children's Hospital, Radiology - Cobb's Collar". Nationwide Children's Hospital. Retrieved July 26, 2010. 8. ^ Dewan, PA; Goh, DW (1995). "Variable expression of the congenital membrane of the posterior urethra". Urology. 45 (3): 507–509 1995. doi:10.1016/s0090-4295(99)80024-7. PMID 7879340. 9. ^ a b Warren J, Pike JG, Leonard MP (April 2004). "Posterior urethral valves in Eastern Ontario - a 30 year perspective". Can J Urol. 11 (2): 2210–5. PMID 15182412.CS1 maint: multiple names: authors list (link) 10. ^ Kim YH, Horowitz M, Combs A, Nitti VW, Libretti D, Glassberg KI (August 1996). "Comparative urodynamic findings after primary valve ablation, vesicostomy or proximal diversion". J. Urol. 156 (2 Pt 2): 673–6. doi:10.1097/00005392-199608001-00028. PMID 8683757.CS1 maint: multiple names: authors list (link) 11. ^ Smith GH, Canning DA, Schulman SL, Snyder HM, Duckett JW (May 1996). "The long-term outcome of posterior urethral valves treated with primary valve ablation and observation". J Urol. 155 (5): 1730–4. doi:10.1016/S0022-5347(01)66186-X. PMID 8627873.CS1 maint: multiple names: authors list (link) ## External links[edit] Classification D * ICD-10: Q64.2 * DiseasesDB: 34137 External resources * eMedicine: ped/2357 radio/572 * v * t * e Congenital malformations and deformations of urinary system Abdominal Kidney * Renal agenesis/Potter sequence, Papillorenal syndrome * cystic * Polycystic kidney disease * Meckel syndrome * Multicystic dysplastic kidney * Medullary sponge kidney * Horseshoe kidney * Renal ectopia * Nephronophthisis * Supernumerary kidney * Pelvic kidney * Dent's disease * Alport syndrome Ureter * Ectopic ureter * Megaureter * Duplicated ureter Pelvic Bladder * Bladder exstrophy Urethra * Epispadias * Hypospadias * Posterior urethral valves * Penoscrotal transposition Vestigial Urachus * Urachal cyst * Urachal fistula * Urachal sinus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Posterior urethral valve	c0238506	3,332	wikipedia	https://en.wikipedia.org/wiki/Posterior_urethral_valve	2021-01-18T18:39:56	{"gard": ["7439"], "umls": ["C0238506", "C0542520"], "orphanet": ["93110"], "wikidata": ["Q2500550"]}
A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-4 (PPNAD4) is caused by a duplication on chromosome 19p13 that includes the PRKACA gene (601639). A recurrent somatic mutation in the PRKACA gene has been found in up to 70% of cortisol-secreting adrenocortical adenomas. For a general phenotypic description and a discussion of genetic heterogeneity of primary pigmented nodular adrenocortical disease, see PPNAD1 (610489). Description Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014). Clinical Features Beuschlein et al. (2014) reported 5 patients, including a mother and son, with bilateral ACTH-independent adrenal hyperplasia resulting in clinical Cushing syndrome symptoms. The other 3 patients were boys between 3 and 9 years of age. Four patients were diagnosed with primary pigmented nodular adrenocortical disease (PPNAD) and 1 with ACTH-independent macronodular adrenal hyperplasia (AIMAH). The diagnosis of ACTH-independent Cushing syndrome was based on biochemical hallmarks of hypercortisolism, suppressed plasma corticotropin levels, and nonsuppressible serum cortisol levels after dexamethasone administration. Catabolic features included muscle weakness, skin fragility, and osteoporosis. Goh et al. (2014) reported 13 unrelated patients with Cushing syndrome due to a cortisol-producing adrenocortical adenoma. Clinical symptoms were variable, but included Cushingoid appearance with recent weight gain, 'moon facies,' hirsutism, thinning of hair, acne, dordocervical fat pad, proximal muscle weakness, ecchymoses, osteopenia, diabetes mellitus, hypertension, and emotional lability or depression. Sato et al. (2014) found that patients with adrenocortical adenomas associated with the somatic L206R mutation in the PRKACA gene had clinical symptoms of Cushing syndrome and tended to have significantly smaller adenoma sizes as well as higher cortisol production compared to individuals with non-PRKACA-mutated adrenal adenomas. Cytogenetics In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, Beuschlein et al. (2014) identified germline heterozygous duplications of chromosome 19p13. The duplications ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformation, or both. Molecular Genetics In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome, Beuschlein et al. (2014) identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (601639.0001) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. PRKACA genomic alterations were not found in patients with subclinical Cushing syndrome. Simultaneously and independently, Cao et al. (2014), Sato et al. (2014), and Goh et al. (2014) found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations, which were found by whole-exome sequencing, were confirmed in additional cohorts of tumor samples. Cao et al. (2014) identified the mutation in up to 69.2% of samples, Sato et al. (2014) in 52.3%, and Goh et al. (2014) in 35%. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. Sato et al. (2014) and Goh et al. (2014) found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect. INHERITANCE \- Autosomal dominant GROWTH Weight \- Weight gain HEAD & NECK Face \- Moon facies CARDIOVASCULAR Vascular \- Hypertension SKELETAL \- Osteoporosis \- Osteopenia SKIN, NAILS, & HAIR Skin \- Skin fragility \- Stria \- Easy bruising \- Acne Hair \- Hirsutism \- Alopecia MUSCLE, SOFT TISSUES \- Proximal muscle weakness \- Buffalo hump NEUROLOGIC Behavioral Psychiatric Manifestations \- Emotional lability \- Depression ENDOCRINE FEATURES \- Cushing syndrome \- ACTH-independent hypercortisolemia \- Adrenal adenomas, bilateral \- Adrenal hyperplasia, bilateral \- Diabetes mellitus LABORATORY ABNORMALITIES \- Increased serum cortisol MISCELLANEOUS \- Variable age at onset \- Somatic mutations occur in adrenal tumor tissue ( 601639.0001 ) MOLECULAR BASIS \- Caused by duplication of 294 kb to 2.7 Mb including the PRKACA gene on chromosome 19p13 ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 4	c4014425	3,333	omim	https://www.omim.org/entry/615830	2019-09-22T15:50:52	{"doid": ["0060280"], "omim": ["615830"], "orphanet": ["189439"], "synonyms": ["CUSHING SYNDROME, ADRENAL, DUE TO PPNAD4", "Primary pigmented nodular adrenal dysplasia", "Alternative titles", "CHROMOSOME 19p13 DUPLICATION SYNDROME", "PPNAD"]}
## Description Pseudohypoaldosteronism type II (PHA2), also known as Gordon hyperkalemia-hypertension syndrome, is characterized by hyperkalemia despite normal renal glomerular filtration, hypertension, and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin (179820) activity are variable associated findings (summary by Mansfield et al., 1997). ### Genetic Heterogeneity of Pseudohypoaldosteronism Type II PHA2A has been mapped to chromosome 1q31-q42. PHA2B (614491) is caused by mutations in the WNK4 gene on chromosome 17q21 (601844). PHA2C (614492) is caused by mutations in the WNK1 gene on chromosome 12p13 (605232). PHA2D (614495) is caused by mutations in the KLHL3 gene (605775) on chromosome 5q31. PHA2E (614496) is caused by mutations in the CUL3 gene (603136) on chromosome 2q36. Boyden et al. (2012) observed that families with PHA type II due to mutation in the WNK1 gene (PHA2C) are significantly less severely affected than those with mutation in WNK4 (PHA2B) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutations in the CUL3 gene (PHA2E). Clinical Features Brautbar et al. (1978) described a 52-year-old man with hypertension, persistent hyperkalemia, and hyperchloremic metabolic acidosis. Four other members of the family, including the brother and son of the proband, were identically affected. Renal and adrenal functions were grossly normal. Plasma aldosterone was normal, although plasma renin activity was undetectable. Inability to increase potassium excretion when exogenous mineralocorticoid was given indicated a distal tubular defect in potassium handling. Reduction of the hyperkalemia with an ion exchange resin (polystyrene sodium sulfonate) given by mouth corrected the hyperchloremic acidosis. Gordon et al. (1970) studied an isolated case. Male-to-male transmission was observed by Roy (1977). Limal et al. (1978) reported 7 affected persons in 3 generations with no male-to-male transmission. Lee et al. (1979) emphasized the good response to bendrofluazide. Iitaka et al. (1980) observed affected brother and sister. Type II pseudohypoaldosteronism was the designation used by Schambelan et al. (1981) for this syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. Whereas the primary defect in type I PHA (see 264350 and 177735) is a specific abnormality in renal response to mineralocorticoid hormone (600983) (a receptor disorder) leading to the coexistence of salt wasting and potassium retention, the primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoid. Licht et al. (1985) reported a 3-generation family. They noted that in some cases, short stature, intellectual impairment, and dental abnormalities had been observed. Gordon et al. (1988) described an Australian family with 6 affected members in 2 generations and referred to the condition as Gordon syndrome or hyporeninemic hypoaldosteronism. (Gordon (1995) stated that de Wardener first termed it Gordon syndrome.) Studies suggested dysregulation of atrial natriuretic factor (ANP; 108780). Pasman et al. (1989) described a 14-year-old boy who had secondary hyperkalemic periodic paralysis caused by the Gordon syndrome. They suggested that in this disorder the kidney may lack sensitivity to ANP. After treatment with hydrochlorothiazide, serum potassium and plasma aldosterone values, plasma renin activity, and blood pressure became normal and the attacks of periodic paralysis disappeared. Take et al. (1991) described a 50-year-old Japanese man, his 24-year-old son and 21-year-old daughter with persistent hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular function with occasional elevation of blood pressure. The results of investigations supported the existence of sodium chloride shunting as the primary abnormality, as had been suggested by Schambelan et al. (1981), who found an abnormal increase in the reabsorption of chloride by the renal tubule. Throckmorton and Bia (1991) described an affected male who was 41 years old at the time that his disorder was first discovered. He complained of leg cramps and except for mild hypertension was otherwise found to be well. Hydrochlorothiazide controlled both his hyperkalemia and hypertension. At the other end of the age range were the infants with neonatal onset of Gordon syndrome described by Gereda et al. (1996). Two sisters developed Gordon syndrome within the first 2 weeks of life. The mother, who had been reported by Sanjad et al. (1982), also had Gordon syndrome. She had been seen at 13 years of age with severe hypertension, hyperkalemic metabolic acidosis, short stature, and pitted enamel hypoplasia of the teeth. Similar dental anomalies were observed in her father who did not have the metabolic abnormality. Clinical Management Thiazide diuretics correct abnormalities in virtually all PHA type II patients (Boyden et al., 2012). Mapping By analysis of linkage in 8 families in which PHA type II showed autosomal dominant transmission, Mansfield et al. (1997) demonstrated locus heterogeneity of the trait, with a multilocus lod score of 8.1 for linkage of the disorder to 1q31-q42 (PHA2A) and 17p11-q21 (PHA2B; 614491). Analysis of both chromosome regions together yielded a lod score of 8.1 for linkage of all families to either chromosome 1 (68% of families) or chromosome 17 (32% of families), with odds of 130 million:1 favoring linkage to 2 loci over the null hypothesis of no linkage. The lod score for linkage to only chromosome 1 with locus heterogeneity was 3.95 with 68% of the families linked including the family described by Throckmorton and Bia (1991). The lod score for linkage to only chromosome 17 with locus heterogeneity was 3.14 with 45% of families linked. The model specifying 2 linked loci had a likelihood 14,800-fold higher than the next most likely model of linkage only to chromosome 1, thus providing strong support for the 2-locus model. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension, mild MUSCLE, SOFT TISSUES \- Muscle aches, intermittent LABORATORY ABNORMALITIES \- Hyperkalemia MISCELLANEOUS \- Responsive to thiazide diuretics ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PSEUDOHYPOALDOSTERONISM, TYPE IIA	c1449844	3,334	omim	https://www.omim.org/entry/145260	2019-09-22T16:39:53	{"mesh": ["D011546"], "omim": ["145260"], "orphanet": ["757", "88938"], "synonyms": ["Alternative titles", "HYPERPOTASSEMIA AND HYPERTENSION, FAMILIAL", "HYPERTENSIVE HYPERKALEMIA, FAMILIAL", "GORDON HYPERKALEMIA-HYPERTENSION SYNDROME"], "genereviews": ["NBK65707"]}
## Description Rock et al. (2008) provided an overview of the brachyolmias, a heterogeneous group of skeletal dysplasias that affect primarily the spine. Type 1 brachyolmia includes the Hobaek and Toledo (BCYM1B; 271630) forms, which are inherited in an autosomal recessive fashion. Both forms of type 1 are characterized by scoliosis, platyspondyly with rectangular and elongated vertebral bodies, overfaced pedicles, and irregular, narrow intervertebral spaces. The Toledo form is distinguished by the presence of corneal opacities and precocious calcification of the costal cartilage. Type 2 brachyolmia (BCYM2; 613678), sometimes referred to as the Maroteaux type, is also an autosomal recessive disorder, primarily distinguished from type 1 by rounded vertebral bodies and less overfaced pedicles. Some cases are associated with precocious calcification of the falx cerebri. Type 3 brachyolmia (BCYM3; 113500) is an autosomal dominant form, caused by mutation in the TRPV4 gene (605427), with severe kyphoscoliosis and flattened, irregular cervical vertebrae. Paradoxically, although the limbs are mildly shortened in all types of brachyolmia, they show minimal epiphyseal and metaphyseal abnormalities on radiographs. Type 4 brachyolmia (BCYM4; 612847) is an autosomal recessive form, caused by mutation in the PAPSS2 gene (603005), with mild epiphyseal and metaphyseal changes. Clinical Features Brachyolmia comes from the Greek for 'short trunk.' Occasional patients have been described with short stature limited to the trunk and with radiologic changes likewise only in the spine (reviews by Fontaine et al., 1975, and Shohat et al., 1989). Hobaek (1961) included probable cases in his series; some of these were instances of multiple affected sibs and consanguineous parents. Kozlowski et al. (1982) stated that pure brachyolmia does not exist and that metaphyseal involvement may be minimal and scattered but always is present along with involvement of the spine in cases labeled brachyolmia. Horton et al. (1983) described 2 brothers and a sister with this disorder. In addition to universal platyspondyly, they pointed to lateral extension of the vertebral bodies beyond the pedicles and irregularity of the vertebral endplates. Histologic changes on iliac crest biopsy of growth plate were considered typical. Chondrocyte clusters at the growth plate and fibrous cartilage matrix were combined with enlarged chondrocyte lacunae and reciprocal perilacunar loss of glycoaminoglycan and excessive collagen aggregation. Hobaek's families 20 to 26 may be the same as Horton's, and differentiation from the Toledo type of spondyloepiphyseal dysplasia (SED) tarda (271630) was not certain. Shohat et al. (1989) raised the question of whether this disorder is the same as the Toledo form of brachyolmia (271630). The radiologic features are similar, but precocious ossification of costal cartilage is seen in the Toledo type. Shohat et al. (1989) distinguished a Maroteaux type of brachyolmia (613678) on the basis of differences in the conformation of the vertebral bodies. The Maroteaux type may be associated with precocious calcification of the falx cerebri and minor facial anomalies. McKusick (1993) consulted in the case of a Norwegian patient (El.Dr.), 1 of 2 sisters, who may have had brachyolmia of the Hobaek type. Skeletal changes were predominantly in the spine where spinal stenosis was evident throughout the entire length. Precocious calcification of costal cartilages was a striking feature. Height was about 145 cm. The parents, not known to be consanguineous, were of normal stature. One of the sisters had 2 normal children. Hoo and Oliphant (2003) described a brother and sister with brachyolmia and radiologic findings that were thought to be compatible with the Hobaek type. The features were platyspondyly, horizontal acetabular roof, short femoral neck, and vertical 'mixed lucent and dense' striation pattern in the metaphyses of large long bones. Despite normal birth weight and length, the platyspondyly was present at infancy, but clinically the condition was not noticeable until late childhood or early puberty when stunted growth became apparent. Beyond puberty, the patients were short of stature, mainly due to a short trunk with decreased upper and lower body segment ratio. Mukamel et al. (2003) described an 8.5-year-old boy and his 19-year-old sister who had Hobaek-type brachyolmia complicated by spinal stenosis. The parents were healthy, unrelated Jews of Moroccan descent. INHERITANCE \- Autosomal recessive GROWTH Height \- Normal birth length \- Short stature, disproportionate (short trunk), identifiable late childhood-early puberty HEAD & NECK Eyes \- No corneal opacities Neck \- Short neck CHEST Ribs Sternum Clavicles & Scapulae \- Pectus carinatum SKELETAL \- Mild osteopenia Spine \- Squared-off platyspondyly (infancy) \- Lateral extension of vertebral bodies beyond the pedicles \- Irregular vertebral end plates \- Narrow intervertebral spaces \- Scoliosis \- Kyphosis \- Occasional back pain Pelvis \- Horizontal acetabular roof (puberty) \- Short femoral neck \- Short iliac bones Limbs \- Vertical linear mixed lucent and sclerotic pattern of metaphyses (distal radii and ulnae, femoral necks) \- Flattened proximal radial epiphyses \- Slightly short long bones LABORATORY ABNORMALITIES \- Elevated urine unsulfated chondroitin sulfate \- Irregular distribution of chondrocytes, enlarged chondrocyte lacunae, excessive fibrous matrix, perilacunar loss of glycosaminoglycan, excessive collagen aggregation ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	BRACHYOLMIA TYPE 1, HOBAEK TYPE	c1849055	3,335	omim	https://www.omim.org/entry/271530	2019-09-22T16:22:13	{"doid": ["0050690"], "mesh": ["C537099"], "omim": ["271530"], "orphanet": ["93301", "448242"], "synonyms": ["Alternative titles", "BRACHYOLMIA, RECESSIVE TYPE OF HOBAEK", "SPONDYLODYSPLASIA WITH PURE BRACHYOLMIA"]}
Healthy Samoyed dog Samoyed hereditary glomerulopathy (SHG) is a hereditary, X-linked, noninflammatory disease of the renal glomeruli, occurring in the Samoyed breed of dog. The disease has been shown to be a model for hereditary nephritis (HN) in humans[1] in that the disease resembles that of the human disease. Because of this, it is sometimes referred to by the name given to the disease in humans when referring to the conditions in Samoyed dogs. Alternatively, it may also be known as X-linked hereditary nephritis. Genetically, the trait is inherited as a sex-linked, genetically dominant disease,[2] and thus affects male dogs to a greater degree than female dogs, since males only have one X chromosome. ## Contents * 1 Description * 2 Diagnosis * 3 Treatment * 4 References * 5 Further reading * 6 External links ## Description[edit] SHG is caused by a nonsense mutation in codon 1027 of the COL4A5 gene on the X chromosome (glycine to stop codon), which is similar to Alport's syndrome in humans.[3] The disease is simply inherited, X-linked dominant, with males generally having more severe symptoms than females. Clinically, from the age of three to four months, proteinuria in both sexes is seen. In dogs older than this, kidney failure in combination with more or less pronounced hearing loss occurs swiftly, and death at the age of 8 to 15 months is expected. In heterozygous females, whereby only one of the two X chromosomes carry the mutation, the disease develops slowly.[4][5] The disease is specific to the Samoyed in that, the Samoyed, is the only breed of dog to show the more rapid progression to kidney failure and death, as well as affecting males to a much more severe degree than females. The Samoyed, however is not the only breed of dog to suffer from life-threatening renal diseases. Proteinuria has been found consistently in Samoyeds, Doberman Pinschers, and Cocker spaniels.[6][7] ## Diagnosis[edit] Affected male and carrier female dogs generally begin to show signs of the disease at two to three months of age, with proteinuria. By three to four months of age, symptoms include for affected male dogs: bodily wasting and loss of weight, proteinuria & hypoalbuminemia. Past nine months of age, hypercholesterolemia may be seen.[1] In the final stages of the disease, at around 15 months of age for affected males, symptoms are reported as being kidney failure, hearing loss and death. Since the condition is genetically dominant, diagnosis would also include analysis of the health of the sire and dam of the suspected affected progeny if available. ## Treatment[edit] The disease can be treated only to slow down the development, by use of cyclosporine A[5] and ACE inhibitors, but not stopped or cured.[8] ## References[edit] 1. ^ a b Jansen, B; Valli, VE; Thorner, P; Baumal, R; Lumsden, JH (1987). "Samoyed hereditary glomerulopathy: serial, clinical and laboratory (urine, serum biochemistry and hematology) studies". Canadian Journal of Veterinary Research. 51 (3): 387–93. PMC 1255344. PMID 3651895. 2. ^ Jansen, B; Tryphonas L; Wong J; Thorner P; Maxie MG; Valli VE; Baumal R; Basrur PK. (June 1986). "Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans". J Lab Clin Med. (6). 107 (6): 551–5. PMID 3711721. 3. ^ Jansen, B; Tryphonas, L; Wong, J; Thorner, P; Maxie, MG; Valli, VE; Baumal, R; Basrur, PK (1986). "Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans". The Journal of Laboratory and Clinical Medicine. 107 (6): 551–5. PMID 3711721. 4. ^ Zheng, K; Thorner, PS; Marrano, P; Baumal, R; McInnes, RR (1994). "Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV". Proceedings of the National Academy of Sciences of the United States of America. 91 (9): 3989–93. Bibcode:1994PNAS...91.3989Z. doi:10.1073/pnas.91.9.3989. PMC 43708. PMID 8171024. 5. ^ a b Chen, D.; Jefferson, B; Harvey, SJ; Zheng, K; Gartley, CJ; Jacobs, RM; Thorner, PS (2003). "Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis): Results from a Canine Model". Journal of the American Society of Nephrology. 14 (3): 690–8. doi:10.1097/01.ASN.0000046964.15831.16. PMID 12595505. 6. ^ Wilcock, BP; Patterson, JM (1979). "Familial glomerulonephritis in Doberman pinscher dogs". The Canadian Veterinary Journal. 20 (9): 244–9. PMC 1789598. PMID 498006. 7. ^ Steward, A. P.; MacDougall, D. F. (1984). "Familial nephropathy in the Cocker Spaniel". Journal of Small Animal Practice. 25: 15–24. doi:10.1111/j.1748-5827.1984.tb00475.x. 8. ^ Grodecki, K; Gains, M; Baumal, R; Osmond, D; Cotter, B; Valli, V; Jacobs, R (1997). "Treatment of X-linked hereditary nephritis in samoyed dogs with angiotensin converting enzyme (ACE) inhibitor". Journal of Comparative Pathology. 117 (3): 209–25. doi:10.1016/S0021-9975(97)80016-3. PMID 9447482. ## Further reading[edit] * Thorner, P; Jansen, B; Baumal, R; Valli, VE; Goldberger, A (1987). "Samoyed hereditary glomerulopathy. Immunohistochemical staining of basement membranes of kidney for laminin, collagen type IV, fibronectin, and Goodpasture antigen, and correlation with electron microscopy of glomerular capillary basement membranes". Laboratory Investigation. 56 (4): 435–43. PMID 3550289. * Jansen, B; Thorner, P; Baumal, R; Valli, V; Maxie, MG; Singh, A (1986). "Samoyed hereditary glomerulopathy (SHG). Evolution of splitting of glomerular capillary basement membranes". The American Journal of Pathology. 125 (3): 536–45. PMC 1888463. PMID 3799818. * Rawdon, TG (2001). "Juvenile nephropathy in a Samoyed bitch". The Journal of Small Animal Practice. 42 (5): 235–8. doi:10.1111/j.1748-5827.2001.tb02027.x. PMID 11380016. * Zheng, Keqin; Perry, Julie; Harvey, Scott J; Sado, Yoshikazu; Ninomiya, Yoshifumi; Jefferson, Barbara; Jacobs, Robert; Hudson, Billy G; Thorner, Paul S (2005). "Regulation of collagen type IV genes is organ-specific: Evidence from a canine model of Alport syndrome". Kidney International. 68 (5): 2121–30. doi:10.1111/j.1523-1755.2005.00668.x. PMID 16221211. ## External links[edit] * "Hereditary Nephritis-Samoyed Hereditary Glomerulopathy". VetGen. Retrieved 21 May 2011. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Samoyed hereditary glomerulopathy	None	3,336	wikipedia	https://en.wikipedia.org/wiki/Samoyed_hereditary_glomerulopathy	2021-01-18T19:01:30	{"wikidata": ["Q7410058"]}
A number sign (#) is used with this entry because of evidence that polycystic liver disease-3 with or without kidney cysts (PCLD3) is caused by heterozygous mutation in the ALG8 gene (608103) on chromosome 11q14. Description PCLD3 is an autosomal dominant disorder characterized by the development of multiple liver cysts that usually becomes apparent in adulthood. Liver cysts range in size and number, and the clinical severity is variable. Most patients also have a few renal cysts, but they do not result in significant renal disease or renal failure (summary by Besse et al., 2017). For a discussion of genetic heterogeneity of polycystic liver disease, see PCLD1 (174050). Clinical Features Besse et al. (2017) reported 5 unrelated patients with liver cysts. The patients ranged in age from 48 to 63 years. Four had innumerable large or small cysts apparent on imaging, whereas 1 (patient FINN59) had about 10 cysts. All patients also had a few (less than 10) kidney cysts, except for the patient with 10 liver cysts; this patient had no kidney cysts. One man had severe liver disease requiring procedural intervention, whereas another had only minute cysts. One patient (W-YU363), a 63-year-old man, had both liver and kidney cysts, whereas his 19-year-old daughter had 8 kidney cysts and no liver cysts. Additional phenotypic details were not reported. Inheritance The transmission pattern of PCLD3 in one of the families reported by Besse et al. (2017) was consistent with autosomal dominant inheritance. Molecular Genetics In 5 unrelated patients with PCLD3, Besse et al. (2017) identified 3 different heterozygous loss-of-function mutations in the ALG8 gene (608103.0007-608103.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. One patient (W-YU363) had an affected daughter who also carried the mutation. Otherwise, family members were not available for segregation analysis. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found at low frequencies in the ExAC database. Statistical analysis of the frequency of loss-of-function ALG8 variants among patients compared to controls suggested that ALG8 is a candidate gene for the disorder. Functional studies of the variants and studies of patient cells were not performed, but CRISPR/Cas9 inactivation of both Alg8 alleles in a mouse epithelial cell line resulted in decreased levels of the Pkd1 (601313) protein, decreased posttranslational glycosylation and modification of Pkd1, and impaired trafficking of Pkd1 to the cell surface and, by extension, to cilia. Reexpression of wildtype Alg8 rescued these defects. These findings suggested that defective biogenesis of PKD1 in the endoplasmic reticulum and impaired PKD1 function and signaling mechanistically underlies the development of cysts. The patients were ascertained from a cohort of 102 patients with polycystic liver disease who did not have mutations in the PRKCSH (177060) or SEC63 (608648) genes and who underwent whole-exome sequencing. INHERITANCE \- Autosomal dominant ABDOMEN Liver \- Liver cysts, small and large GENITOURINARY Kidneys \- Kidney cysts (in some patients) MISCELLANEOUS \- Variable phenotype \- Cysts are usually detected in adulthood \- Patients do not develop severe renal disease \- Liver disease can be mild or severe MOLECULAR BASIS \- Caused by mutation in the homolog of the S. Cerevisiae ALG8 gene (ALG8, 608103.0007 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	POLYCYSTIC LIVER DISEASE 3 WITH OR WITHOUT KIDNEY CYSTS	c4693472	3,337	omim	https://www.omim.org/entry/617874	2019-09-22T15:44:36	{"omim": ["617874"]}
Condition characterized by an abnormal bone growth in the middle ear Otosclerosis Other namesOtospongiosis Chain of ossicles and their ligaments. (Stapes visible near center right.) SpecialtyOtorhinolaryngology Otosclerosis is a condition of the inner ear where one or more foci of irregularly laid spongy bone replace part of normally dense enchondral layer of bony otic capsule in the bony labyrinth. This condition affects one of the ossicles (the stapes) resulting in hearing loss, tinnitus, vertigo or a combination of symptoms.[1][2] The term otosclerosis is something of a misnomer. Much of the clinical course is characterized by lucent rather than sclerotic bony changes, so the disease is also known as otospongiosis. ## Contents * 1 Presentation * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential testing * 4.2 Audiometry * 4.3 CT imaging * 5 Treatment * 5.1 Medical * 5.2 Surgery * 6 Amplification * 7 Society and culture * 7.1 Notable cases * 8 References * 9 External links ## Presentation[edit] The primary form of hearing loss in otosclerosis is conductive hearing loss (CHL) whereby sounds reach the ear drum but are incompletely transferred via the ossicular chain in the middle ear, and thus partly fail to reach the inner ear (cochlea). This can affect one ear or both ears. On audiometry, the hearing loss is characteristically low-frequency, with higher frequencies being affected later.[3] Sensorineural hearing loss (SNHL) has also been noted in patients with otosclerosis; this is usually a high-frequency loss, and usually manifests late in the disease. The causal link between otosclerosis and SNHL remains controversial. Over the past century, leading otologists and neurotologic researchers have argued whether the finding of SNHL late in the course of otosclerosis is due to otosclerosis or simply to typical presbycusis.[citation needed] Most patients with otosclerosis notice tinnitus (head noise) to some degree. The amount of tinnitus is not necessarily related to the degree or type of hearing impairment. Tinnitus develops due to irritation of the delicate nerve endings in the inner ear. Since the nerve carries sound, this irritation is manifested as ringing, roaring or buzzing. It is usually worse when the patient is fatigued, nervous or in a quiet environment.[citation needed] ## Causes[edit] Otosclerosis can be caused by both genetic and environmental factors, such as a viral infection (like measles).[4][5][6] Ribonucleic acid of the measles virus has been found in stapes footplate in most patients with otosclerosis.[7] Populations that have been vaccinated against measles had a significant reduction in otosclerosis.[8] While the disease is considered to be hereditary, its penetrance and the degree of expression is so highly variable that it may be difficult to detect an inheritance pattern. Most of the implicated genes are transmitted in an autosomal dominant fashion. One genome-wide analysis associates otosclerosis with variation in RELN gene.[9] Loci include: Name OMIM Locus OTSC1 166800 15q26.1 OTSC2 605727 7q OTSC3 608244 6p OTSC4 611571 16q OTSC5 608787 3q22-q24 OTSC7 611572 6q13 OTSC8 612096 9p13.1-q21.11 ## Pathophysiology[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) This section 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. (November 2015) (Learn how and when to remove this template message) The pathophysiology of otosclerosis is complex. The key lesions of otosclerosis are multifocal areas of sclerosis within the endochondral temporal bone.[10] These lesions share some characteristics with Paget's Disease, but they are not thought to be otherwise related. Histopathological studies have all been done on cadaveric temporal bones, so only inferences can be made about progression of the disease histologically. It seems that the lesions go through an active "spongiotic" or hypervascular phase before developing into "sclerotic" phase lesions. There have been many genes and proteins identified that, when mutated, may lead to these lesions. Also there is mounting evidence that measles virus is present within the otosclerotic foci, implicating an infectious etiology (this has also been noted in Paget's Disease). CHL in otosclerosis is caused by two main sites of involvement of the sclerotic (or scar-like) lesions. The best understood mechanism is fixation of the stapes footplate to the oval window of the cochlea. This greatly impairs movement of the stapes and therefore transmission of sound into the inner ear ("ossicular coupling"). Additionally the cochlea's round window can also become sclerotic, and in a similar way impair movement of sound pressure waves through the inner ear ("acoustic coupling"). Conductive hearing loss is usually concomitant with impingement of abnormal bone on the stapes footplate. This involvement of the oval window forms the basis of the name fenestral otosclerosis. The most common location of involvement of otosclerosis is the bone just anterior to the oval window at a small cleft known as the fissula ante fenestram. The fissula is a thin fold of connective tissue extending through the endochondral layer, approximately between the oval window and the cochleariform process, where the tensor tympani tendon turns laterally toward the malleus. The mechanism of sensorineural hearing loss in otosclerosis is less well understood. It may result from direct injury to the cochlea and spiral ligament from the lytic process or from release of proteolytic enzymes into the cochlea. There are certainly a few well documented instances of sclerotic lesions directly obliterating sensory structures within the cochlea and spiral ligament, which have been photographed and reported post-mortem. Other supporting data includes a consistent loss of cochlear hair cells in patients with otosclerosis; these cells being the chief sensory organs of sound reception. A suggested mechanism for this is the release of hydrolytic enzymes into the inner ear structures by the spongiotic lesions. ## Diagnosis[edit] Otosclerosis is traditionally diagnosed by characteristic clinical findings, which include progressive conductive hearing loss, a normal tympanic membrane, and no evidence of middle ear inflammation. The cochlear promontory may have a faint pink tinge reflecting the vascularity of the lesion, referred to as the Schwartz sign.[citation needed] Approximately 0.5% of the population will eventually be diagnosed with otosclerosis. Post-mortem studies show that as many as 10% of people may have otosclerotic lesions of their temporal bone, but apparently never had symptoms warranting a diagnosis. Caucasians are the most affected race, with the prevalence in the Black and Asian populations being much lower. In clinical practice otosclerosis is encountered about twice as frequently in females as in males, but this does not reflect the true sex ratio. When families are investigated it is found that the condition is only slightly more common in women.[11] Usually noticeable hearing loss begins at middle-age, but can start much sooner. The hearing loss was long believed to grow worse during pregnancy, but recent research does not support this belief.[12][13] ### Differential testing[edit] ### Audiometry[edit] Fixation of the stapes within the oval window causes a conductive hearing loss. In pure-tone audiometry, this manifests as air-bone gaps on the audiogram (i.e. a difference of more than 10 dB between the air-conduction and bone-conduction thresholds at a given test frequency). However, medial fixation of the ossicular chain impairs both the inertial and osseotympanic modes of bone conduction, increasing the bone-conduction thresholds between 500 Hz and 4 kHz, and reducing the size of air-bone gaps. As 2 kHz is the resonant frequency of the ossicular chain, the largest increase in bone-conduction threshold (around 15 dB) occurs at this frequency – the resultant notch is called Carhart's notch and is a useful clinical marker for medial ossicular-chain fixation.[14] Tympanometry measures the peak pressure (TPP) and peak-compensated static admittance (Ytm) of the middle ear at the eardrum. As the stapes is ankylosed in otosclerosis, the lateral end of the ossicular chain may still be quite mobile. Therefore, otosclerosis may only slightly reduce the admittance, resulting in either a shallow tympanogram (type AS), or a normal tympanogram (type A). Otosclerosis increases in the stiffness of the middle-ear system, raising its resonant frequency. This can be quantified using multi-frequency tympanometry. Thus, a high resonant-frequency pathology such as otosclerosis can be differentiated from low resonant-frequency pathologies such as ossicular discontinuity.[citation needed] In the absence of a pathology, a loud sound (generally greater than 70 dB above threshold) causes the stapedius muscle to contract, reducing the admittance of the middle ear and softening the perceived loudness of the sound. If the mobility of the stapes is reduced due to otosclerosis, then stapedius muscle contraction does not significantly decrease the admittance. When acoustic reflex testing is conducted, the acoustic reflex thresholds (ART) cannot be determined when attempting to measure on the affected side. Also, a conductive pathology will attenuate the test stimuli, resulting in either elevated reflex thresholds or absent reflexes when the stimulus is presented in the affected ear and measured in the other ear.[15] ### CT imaging[edit] Imaging is usually not pursued in those with uncomplicated conductive hearing loss and characteristic clinical findings. Those with only conductive hearing loss are often treated medically or with surgery without imaging. The diagnosis may be unclear clinically in cases of sensorineural or mixed hearing loss and may become apparent only on imaging. Therefore, imaging is often performed when the hearing loss is sensorineural or mixed.[citation needed] A high-resolution CT shows very subtle bone findings. However, CT is usually not needed prior to surgery.[citation needed] Otosclerosis on CT can be graded using the grading system suggested by Symons and Fanning.[16] * Grade 1, solely fenestral; * Grade 2, patchy localized cochlear disease (with or without fenestral involvement) to either the basal cochlear turn (grade 2A), or the middle/apical turns (grade 2B), or both the basal turn and the middle/apical turns (grade 2C); and * Grade 3, diffuse confluent cochlear involvement (with or without fenestral involvement). ## Treatment[edit] Further information: Hearing aids and Stapedectomy This article may need to be rewritten to comply with Wikipedia's quality standards, as section. You can help. The talk page may contain suggestions. (February 2018) This section 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: "Otosclerosis" – news · newspapers · books · scholar · JSTOR (February 2018) (Learn how and when to remove this template message) ### Medical[edit] Earlier workers suggested the use of calcium fluoride; now sodium fluoride is the preferred compound. Fluoride ions inhibit the rapid progression of disease. In the otosclerotic ear, there occurs formation of hydroxylapatite crystals which lead to stapes (or other) fixation. The administration of fluoride replaces the hydroxyl radical with fluoride leading to the formation of fluorapatite crystals. Hence, the progression of disease is considerably slowed down and active disease process is arrested. This treatment cannot reverse conductive hearing loss, but may slow the progression of both the conductive and sensorineural components of the disease process. Otofluor, containing sodium fluoride, is one treatment. Recently, some success has been claimed with a second such treatment, bisphosphonate medications that inhibit bone destruction.[17][18][19] However, these early reports are based on non-randomized case studies that do not meet standards of clinical trials.[20] There are numerous side-effects to both pharmaceutical treatments, including occasional stomach upset, allergic itching, and increased joint pains which can lead to arthritis.[21] In the worst case, bisphosphonates may lead to osteonecrosis of the auditory canal itself.[22] Finally, neither approach has been proven to be beneficial after the commonly preferred method of surgery has been undertaken. ### Surgery[edit] There are various methods to treat otosclerosis. However the method of choice is a procedure known as stapedectomy.[23] Early attempts at hearing restoration via the simple freeing of the stapes from its sclerotic attachments to the oval window were met with temporary improvement in hearing, but the conductive hearing loss would almost always recur. A stapedectomy consists of removing a portion of the sclerotic stapes footplate and replacing it with an implant that is secured to the incus. This procedure restores continuity of ossicular movement and allows transmission of sound waves from the eardrum to the inner ear. A modern variant of this surgery called a stapedotomy, is performed by drilling a small hole in the stapes footplate with a micro-drill or a laser, and the insertion of a piston-like prothesis. The success rate of either surgery depends greatly on the skill and the familiarity with the procedure of the surgeon.[12] However, comparisons have shown stapedotomy to yield results at least as good as stapedectomy, with fewer complications, and thus stapedotomy is preferred in normal circumstances.[24] ## Amplification[edit] Although hearing aids cannot prevent, cure or inhibit the progression of otosclerosis, they can help treat the largest symptom, hearing loss. Hearing aids can be tuned to specific frequency losses. However, due to the progressive nature of this condition, use of a hearing aid is palliative at best. Without eventual surgery, deafness is likely to result.[citation needed] ## Society and culture[edit] ### Notable cases[edit] * German composer Beethoven was theorized to suffer from otosclerosis, although this is controversial.[25] * Victorian journalist Harriet Martineau gradually lost her hearing during her young life, and later medical historians have diagnosed her with probably suffering from otosclerosis as well.[26] * Margaret Sullavan, American stage and film actress, suffered from the congenital hearing defect otosclerosis that worsened as she aged, making her more and more hard of hearing. * Howard Hughes the pioneering American aviator, engineer, industrialist, and film producer also suffered from otosclerosis.[27] * Frankie Valli, lead singer of The Four Seasons, suffered from it in the late 1960s and early 1970s, forcing him to "sing from memory" in the latter part of the 70s (surgery restored most of his hearing by 1980).[28] * Pittsburgh Penguins forward Steve Downie suffers from otosclerosis.[29] * The British queen Alexandra of Denmark suffered from it, leading to her social isolation; Queen Alexandra's biographer, Georgina Battiscombe, was able to have "some understanding of Alexandra's predicament" because she too had otosclerosis.[30][31] * Adam Savage, co-host of MythBusters, uses a hearing aid due to otosclerosis.[32] * Sir John Cornforth, Australian-British Nobel Prize in Chemistry laureate[33] ## References[edit] 1. ^ "otosclerosis" at Dorland's Medical Dictionary 2. ^ Uppal, S.; Bajaj, Y.; Rustom, I.; Coatesworth, A. P. (2009-10-10). "Otosclerosis 1: the aetiopathogenesis of otosclerosis". International Journal of Clinical Practice. 63 (10): 1526–1530. doi:10.1111/j.1742-1241.2009.02045.x. PMID 19769709. 3. ^ Danesh, Ali A.; Shahnaz, Navid; Hall, James W. (2018-04-04). "The Audiology of Otosclerosis". Otolaryngologic Clinics of North America. 51 (2): 327–342. doi:10.1016/j.otc.2017.11.007. PMID 29397946. 4. ^ Markou, Konstantinos; Goudakos, John (2009-10-10). "An overview of the etiology of otosclerosis". European Archives of Oto-Rhino-Laryngology. 266 (1): 25–35. doi:10.1007/s00405-008-0790-x. ISSN 0937-4477. PMID 18704474. 5. ^ Schrauwen, Isabelle; Van Camp, Guy (2010). "The etiology of otosclerosis: A combination of genes and environment". The Laryngoscope. 120 (6): 1195–202. doi:10.1002/lary.20934. PMID 20513039. 6. ^ Rudic, M.; Keogh, I.; Wagner, R.; Wilkinson, E.; Kiros, N.; Ferrary, E.; Sterkers, O.; Bozorg Grayeli, A.; Zarkovic, K. (2015-12-15). "The pathophysiology of otosclerosis: Review of current research". Hearing Research. 330 (Pt A): 51–56. doi:10.1016/j.heares.2015.07.014. PMID 26276418. 7. ^ Brookler, Kenneth (2006-01-10). "Basis for Understanding Otic Capsule Bony Dyscrasias". The Laryngoscope. 116 (1): 160–161. doi:10.1097/01.mlg.0000187403.56799.21. ISSN 0023-852X. PMID 16481833. 8. ^ Niedermeyer, H.P.; Arnold, W. (2008). "Otosclerosis and Measles Virus – Association or Causation?". ORL. 70 (1): 63–70. doi:10.1159/000111049. ISSN 0301-1569. PMID 18235207. 9. ^ Schrauwen I, Ealy M, Huentelman MJ, Thys M, Homer N, Vanderstraeten K, Fransen E, Corneveaux JJ, Craig DW, Claustres M, Cremers CW, Dhooge I, Van de Heyning P, Vincent R, Offeciers E, Smith RJ, Van Camp G (February 2009). "A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis". Am. J. Hum. Genet. 84 (3): 328–38. doi:10.1016/j.ajhg.2009.01.023. PMC 2667982. PMID 19230858. 10. ^ Niedermeyer, Hans P.; Arnold, Wolfgang (2002). "Etiopathogenesis of Otosclerosis". ORL. 64 (2): 114–119. doi:10.1159/000057789. ISSN 0301-1569. PMID 12021502. 11. ^ Morrison AW (1970). "Otosclerosis: a synopsis of natural history and management". British Medical Journal. 2 (5705): 345–348. doi:10.1136/bmj.2.5705.345. PMC 1700130. PMID 5429458. 12. ^ a b de Souza, Christopher; Glassock, Michael (2003). Otosclerosis and Stapedectomy: Diagnosis, Management & Complications. New York, NY: Thieme. ISBN 978-1-58890-169-9. 13. ^ Lippy WH, Berenholz LP, Schuring AG, Burkey JM (October 2005). "Does pregnancy affect otosclerosis?". Laryngoscope. 115 (10): 1833–6. doi:10.1097/01.MLG.0000187573.99335.85. PMID 16222205. Archived from the original on 2013-01-05. 14. ^ Carhart, R (1950). "Clinical application of bone conduction audiometry". Archives of Otolaryngology. 51 (6): 798–808. doi:10.1001/archotol.1950.00700020824003. PMID 15419943. 15. ^ Katz, J; Chasin, M; English, K; Hood, LJ; Tillery, KL (2015). Katz's Handbook of Clinical Audiology (7th ed.). Philadelphia: Wolters Kluwer Health. ISBN 978-1-4511-9163-9. 16. ^ Lee TC, Aviv RI, Chen JM, Nedzelski JM, Fox AJ, Symons SP (2009). "CT grading of otosclerosis". American Journal of Neuroradiology. 30 (7): 1435–1439. doi:10.3174/ajnr.a1558. PMID 19321627. 17. ^ Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J. 14 (2): 92–6. PMID 19205157. 18. ^ "Use of bisphosphonates for otosclerosis" Archived 2014-10-28 at the Wayback Machine, Fresh Patents. 19. ^ Chris De Souza, Michael E. Glasscock, Otosclerosis and Stapedectomy: Diagnosis, Management, and Complications, Thieme, 2004. 20. ^ Chole RA & McKenna M, "Pathophysiology of otosclerosis", Otology & Neurotology, 22(2): 249–257, 2001. 21. ^ Otosclerosis at the American Hearing Research Foundation, Chicago, Illinois 2008. 22. ^ Polizzotto MN, Cousins Polizzotto & Schwarer AP, "Bisphosphonate-associated osteonecrosis of the auditory canal", British Journal of Haematology, 132(1): 114, 2005. 23. ^ Abu-yagoub Y, Mahafza T, AL-Layla A, Tawalbeh M (Oct 2013). "Surgical Treatment of Otosclerosis: Eight years' Experience at the Jordan University Hospital". Iran Journal of Otorhinolaryngology. PMID 24303446. Retrieved 20 Oct 2020. Cite journal requires `\|journal=` (help) 24. ^ Thamjarayakul T, Supiyaphun P, & Snidvongs K, "Stapes fixation surgery: Stapedectomy versus stapedotomy", Asian Biomedicine, 4(3): 429–434, 2010. 25. ^ The Ludwig van Beethoven biography, http://www.kunstderfuge.com/bios/beethoven.html Archived 2013-09-04 at the Wayback Machine 26. ^ Mary Jo Deegan, "Making Lemonade: Harriet Martineau on Being Deaf, pp. 41–58 in Harriet Martineau: Theoretical and Methodological Perspectives, NY, NY: Routledge, 2001. 27. ^ Charles Higham, Howard Hughes: The Secret Life. 28. ^ Fred Bronson, The Billboard Book of Number One Hits (3rd edition), Billboard Books, 1992. ISBN 0-8230-8298-9 29. ^ "Downie dreaming of invite". Slam-Canoe.ca. 2005-11-29. Retrieved 2005-11-29. 30. ^ Battiscombe, Georgina (1969). Queen Alexandra. Constable. pp. 88. ISBN 978-0-09-456560-9. 31. ^ Duff, David (1980). Alexandra: Princess and Queen. Collins. pp. 82. ISBN 978-0-00-216667-6. 32. ^ Adam Savage [@donttrythis] (5 May 2009). "@jayyoozee Yes I wear a hearing aid. Not from the explosions tho. It's a congenital condition. Titanium earbones on my left side" (Tweet) – via Twitter. 33. ^ John Cornforth Archived 15 February 2011 at the Wayback Machine, biotechnology-innovation.com.au ## External links[edit] * NIH/Medline * NIH/NIDCD Classification D * ICD-10: H80 * ICD-9-CM: 387 * OMIM: 166800 605727 * MeSH: D010040 * DiseasesDB: 29289 External resources * MedlinePlus: 001036 * eMedicine: article/994891 article/859760 * Patient UK: Otosclerosis * v * t * e Disorders of hearing and balance Hearing Symptoms * Hearing loss * Excessive response * Tinnitus * Hyperacusis * Phonophobia Disease Loss * Conductive hearing loss * Otosclerosis * Superior canal dehiscence * Sensorineural hearing loss * Presbycusis * Cortical deafness * Nonsyndromic deafness Other * Deafblindness * Wolfram syndrome * Usher syndrome * Auditory processing disorder * Spatial hearing loss Tests * Hearing test * Rinne test * Tone decay test * Weber test * Audiometry * pure tone * visual reinforcement Balance Symptoms * Vertigo * nystagmus Disease * Balance disorder * Peripheral * Ménière's disease * Benign paroxysmal positional vertigo * Labyrinthitis * Labyrinthine fistula Tests * Dix–Hallpike test * Unterberger test * Romberg's test * Vestibulo–ocular reflex [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Otosclerosis	c0029899	3,338	wikipedia	https://en.wikipedia.org/wiki/Otosclerosis	2021-01-18T18:30:33	{"mesh": ["D010040"], "umls": ["C0029696", "C0029899"], "orphanet": ["2794"], "wikidata": ["Q756610"]}
"YSS" redirects here. For other uses, see YSS (disambiguation). Young–Simpson syndrome Other namesHypothyroidism-dysmorphism-postaxial polydactyly-intellectual disability syndrome, Say-Barber-Biesecker-Young-Simpson syndrome This condition is inherited via autosomal dominant manner Young–Simpson syndrome (YSS) is a rare congenital disorder with symptoms including hypothyroidism, heart defects, facial dysmorphism, cryptorchidism in males, hypotonia, mental retardation and postnatal growth retardation.[1][2] Other symptoms include transient hypothyroidism, macular degeneration and torticollis.[3] The condition was discovered in 1987 and the name arose from the individuals who first reported the syndrome.[4][5] An individual with YSS has been identified with having symptoms to a similar syndrome known as Ohdo Blepharophimosis syndrome, showing that it is quite difficult to diagnose the correct condition based on the symptoms present.[6] Some doctors therefore consider these syndromes to be the same.[7] The mode of inheritance has had mixed findings based on studies undertaken.[5][8] One study showed that the parents of an individual with YSS are unrelated and phenotypically normal, indicating a sporadic mutation, thus making it difficult to base the cause of the condition on genetic makeup alone.[5] However, another study was done of an individual with YSS who had first cousins as parents, giving the possibility of autosomal recessive inheritance.[8] ## Contents * 1 KAT6B * 2 See also * 3 References * 4 External links ## KAT6B[edit] In 2011, it was demonstrated that de novo mutations in the gene KAT6B caused YSS.[9] ## See also[edit] * Genitopatellar syndrome ## References[edit] 1. ^ Masuno M, Imaizumi K, Okada T, et al. (May 1999). "Young-Simpson syndrome: further delineation of a distinct syndrome with congenital hypothyroidism, congenital heart defects, facial dysmorphism, and mental retardation". Am J Med Genet. 84 (1): 8–11. doi:10.1002/(SICI)1096-8628(19990507)84:1<8::AID-AJMG2>3.0.CO;2-2. PMID 10213038. 2. ^ Young Simpson syndrome at NIH's Office of Rare Diseases 3. ^ Kondoh T, Kinoshita E, Moriuchi H, Niikawa N, Matsumoto T, Masuno M (January 2000). "Young-Simpson syndrome comprising transient hypothyroidism, normal growth, macular degeneration and torticolis". Am J Med Genet. 90 (1): 85–6. doi:10.1002/(SICI)1096-8628(20000103)90:1<85::AID-AJMG17>3.0.CO;2-R. PMID 10602125. 4. ^ Young ID, Simpson K (November 1987). "Unknown syndrome: abnormal facies, congenital heart defects, hypothyroidism, and severe retardation". J Med Genet. 24 (11): 715–6. doi:10.1136/jmg.24.11.715. PMC 1050356. PMID 3430551. 5. ^ a b c Nakamura T, Noma S (August 1997). "A Japanese boy with Young-Simpson syndrome". Acta Paediatr Jpn. 39 (4): 472–4. doi:10.1111/j.1442-200x.1997.tb03621.x. PMID 9316295. 6. ^ Marques-de-faria AP, Maciel-Guerra AT, Júnior GG, Baptista MT (July 2000). "A boy with mental retardation, blepharophimosis and hypothyroidism: a diagnostic dilemma between Young-Simpson and Ohdo syndrome". Clin Dysmorphol. 9 (3): 199–204. doi:10.1097/00019605-200009030-00009. PMID 10955481. 7. ^ OHDO SYNDROME: Contact a Family - for families with disabled children: information on rare syndromes and disorders 8. ^ a b Bonthron DT, Barlow KM, Burt AM, Barr DG (March 1993). "Parental consanguinity in the blepharophimosis, heart defect, hypothyroidism, mental retardation syndrome (Young-Simpson syndrome)". J Med Genet. 30 (3): 255–6. doi:10.1136/jmg.30.3.255. PMC 1016313. PMID 8474111. 9. ^ Clayton-Smith, Jill; O'Sullivan James; Daly Sarah; Bhaskar Sanjeev; Day Ruth; Anderson Beverley; Voss Anne K; Thomas Tim; Biesecker Leslie G; Smith Philip; Fryer Alan; Chandler Kate E; Kerr Bronwyn; Tassabehji May; Lynch Sally-Ann; Krajewska-Walasek Malgorzata; McKee Shane; Smith Janine; Sweeney Elizabeth; Mansour Sahar; Mohammed Shehla; Donnai Dian; Black Graeme (November 2011). "Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome". Am. J. Hum. Genet. United States. 89 (5): 675–81. doi:10.1016/j.ajhg.2011.10.008. PMC 3213399. PMID 22077973. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 603736 * MeSH: C536717 C536717, C536717 * SNOMED CT: 699298009 External resources * Orphanet: 3047 This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Young–Simpson syndrome	c1863557	3,339	wikipedia	https://en.wikipedia.org/wiki/Young%E2%80%93Simpson_syndrome	2021-01-18T19:07:04	{"mesh": ["C536717"], "umls": ["C1863557"], "orphanet": ["3047"], "wikidata": ["Q8058422"]}
Metaphyseal chondrodysplasia, Schmid type (MCDS) is a type of skeletal disorder in which there is abnormal bone formation at the end of the long bones (metaphyses). Symptoms include short stature with abnormally short arms and legs (short-limbed dwarfism) and bowed legs (genu varum). Additional signs and symptoms may include lumbar lordosis, leg pain, joint pain, hip deformities, and an outward flaring of the bones of the lower rib cage. As a result of the hip and leg findings, individuals with this condition may have an unusual walk that resembles a waddle. The condition is often mistaken for vitamin D-deficient rickets. MCDS is caused by a mutation in one of the collagen genes known as COL10A1. The mutation may be inherited from a parent or may happen for the first time in an affected individual. The MCDS mutation is passed on in an autosomal dominant manner. Treatment may include physical therapy and/or orthopedic surgery and often requires a team of specialists. Early intervention is important to help children with MCDS reach their potential. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Metaphyseal chondrodysplasia Schmid type	c0265289	3,340	gard	https://rarediseases.info.nih.gov/diseases/7029/metaphyseal-chondrodysplasia-schmid-type	2021-01-18T17:59:07	{"mesh": ["C537352"], "omim": ["156500"], "umls": ["C0265289"], "orphanet": ["174"], "synonyms": ["MCDS"]}
Human disease Burning mouth syndrome Other namesglossodynia,[1] orodynia,[2] oral dysaesthesia,[3] glossopyrosis,[3] stomatodynia,[1] burning tongue,[4] stomatopyrosis,[3] sore tongue,[3] burning tongue syndrome,[5] burning mouth,[3] or sore mouth[6] SpecialtyOral medicine Burning mouth syndrome (BMS) is a burning sensation in the mouth with no underlying known dental or medical cause.[3] No related signs of disease are found in the mouth.[3] People with burning mouth syndrome may also have a subjective xerostomia (dry mouth sensation where no cause can be found such as reduced salivary flow), paraesthesia (altered sensation such as tingling in the mouth), or an altered taste or smell.[3] A burning sensation in the mouth can be a symptom of another disease when local or systemic factors are found to be implicated, and this is not considered to be burning mouth syndrome,[3] which is a syndrome of medically unexplained symptoms.[3] The International Association for the Study of Pain defines burning mouth syndrome as "a distinctive nosological entity characterized by unremitting oral burning or similar pain in the absence of detectable mucosal changes",[1] and "burning pain in the tongue or other oral mucous membranes",[7] and the International Headache Society defines it as "an intra-oral burning sensation for which no medical or dental cause can be found".[6]To ensure the correct diagnosis of burning mouth syndrome Research Diagnostic Criteria (RDC/BMS) have been developed.[8] Insufficient evidence leaves it unclear if effective treatments exist.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Theories * 2.2 Other causes of an oral burning sensation * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 Notable cases * 8 References * 9 External links ## Signs and symptoms[edit] By definition, BMS has no signs. Sometimes affected persons will attribute the symptoms to sores in the mouth, but these are in fact normal anatomic structures (e.g. lingual papillae, varices).[9] Symptoms of BMS are variable, but the typical clinical picture is given below, considered according to the Socrates pain assessment method (see table). If clinical signs are visible, then another explanation for the burning sensation may be present. Erythema (redness) and edema (swelling) of papillae on the tip of the tongue may be a sign that the tongue is being habitually pressed against the teeth. The number and size of filiform papillae may be reduced. If the tongue is very red and smooth, then there is likely a local or systemic cause (e.g. eythematous candidiasis, anemia).[5] Parameter Usual findings in burning mouth syndrome.[1][3][7][9][10][11] Site Usually bilaterally located on the tongue or less commonly the palate, lips or lower alveolar mucosa Onset Pain is chronic, and rarely spontaneously remits Character Burning, scalded or tingling. Sometimes the sensation is described as 'discomfort', 'tender', 'raw' and 'annoying' rather than pain or burning. Radiation Associations Possibly subjective xerostomia, dysgeusia (altered taste), thirst, headaches, chronic back pain, irritable bowel syndrome, dysmenorrhea, globus pharyngis, anxiety, decreased appetite, depression and personality disorders Time course Type 2 (most common) pain upon waking and throughout day, less commonly other patterns. Exacerbating/Relieving factors Possible exacerbating factors (make the pain worse) include tension, fatigue, speaking, and hot, acidic or spicy foods. Possible relieving factors include sleeping, cold, distraction, and alcohol. The pain is often relieved by eating and drinking (unlike pain caused by organic lesions or neuralgia) or when the person's attention is occupied. Temporary relief while eating is described as "almost pathognomonic" by the IASP. Pain is not often relieved by systemic analgesics, but can sometimes be relieved by topical anesthetics. Severity Moderate to severe, rated 5-8 out of 10, similar in intensity to toothache Effect on sleep May not disturb sleep, or may change sleep patterns, e.g. insomnia. Previous treatment Often multiple consultations and unsuccessful attempts at dental and/or medical treatment ## Causes[edit] ### Theories[edit] In about 50% of cases of burning mouth sensation no identifiable cause is apparent;[1] these cases are termed (primary) BMS.[10] Several theories of what causes BMS have been proposed, and these are supported by varying degrees of evidence, but none is proven.[5][10] As most people with BMS are postmenopausal women, one theory of the cause of BMS is of estrogen or progesterone deficit, but a strong statistical correlation has not been demonstrated.[5] Another theory is that BMS is related to autoimmunity, as abnormal antinuclear antibody and rheumatoid factor can be found in the serum of more than 50% of persons with BMS, but these levels may also be seen in elderly people who do not have any of the symptoms of this condition.[5] Whilst salivary flow rates are normal and there are no clinical signs of a dry mouth to explain a complaint of dry mouth, levels of salivary proteins and phosphate may be elevated and salivary pH or buffering capacity may be reduced.[5] Depression and anxiety are strongly associated with BMS.[5][12][13] It is not known if depression is a cause or result of BMS, as depression may develop in any setting of constant unrelieved irritation, pain, and sleep disturbance.[5][11][14] It is estimated that about 20% of BMS cases involve psychogenic factors,[13] and some consider BMS a psychosomatic illness,[5][12] caused by cancerophobia,[12][13] concern about sexually transmitted infections,[13] or hypochondriasis.[12] Chronic low-grade trauma due to parafunctional habits (e.g. rubbing the tongue against the teeth or pressing it against the palate), may be involved.[11] BMS is more common in persons with Parkinson's disease, so it has been suggested that it is a disorder of reduced pain threshold and increased sensitivity. Often people with BMS have unusually raised taste sensitivity, termed hypergeusia ("super tasters").[1] Dysgeusia (usually a bitter or metallic taste) is present in about 60% of people with BMS, a factor which led to the concept of a defect in sensory peripheral neural mechanisms.[11] Changes in the oral environment, such as changes in the composition of saliva, may induce neuropathy or interruption of nerve transduction.[1][10] The onset of BMS is often spontaneous, although it may be gradual. There is sometimes a correlation with a major life event or stressful period in life.[9] In women, the onset of BMS is most likely three to twelve years following menopause.[5] ### Other causes of an oral burning sensation[edit] Substances capable of causing an oral burning sensation.[1] Foods and additives * Benzoic acid * Chestnuts * Cinnamaldehyde * Instant coffee * Nicotinic acid * Peanuts * Sodium metabisulphite * Sorbic acid Metals * Cadmium * Cobalt chloride * Mercury * Nickel * Palladium Plastics * Benzoyl peroxide * Bisphenol A * Epoxy resins * Methyl methacrylate * Octyl gallate * Propylene glycol See also: Glossitis Several local and systemic factors can give a burning sensation in the mouth without any clinical signs, and therefore may be misdiagnosed as BMS. Some sources state that where there is an identifiable cause for a burning sensation, this can be termed "secondary BMS" to distinguish it from primary BMS.[15][16] However, the accepted definitions of BMS hold that there are no identifiable causes for BMS,[1][3][6] and where there are identifiable causes, the term BMS should not be used.[3] Some causes of a burning mouth sensation may be accompanied by clinical signs in the mouth or elsewhere on the body. For example, burning mouth pain may be a symptom of allergic contact stomatitis. This is a contact sensitivity (type IV hypersensitivity reaction) in the oral tissues to common substances such as sodium lauryl sulfate, cinnamaldehyde or dental materials.[4] However, allergic contact stomatitis is accompanied by visible lesions and gives positive response with patch testing. Acute (short term) exposure to the allergen (the substance triggering the allergic response) causes non-specific inflammation and possibly mucosal ulceration. Chronic (long term) exposure to the allergen may appear as chronic inflammatory, lichenoid (lesions resembling oral lichen planus), or plasma cell gingivitis, which may be accompanied by glossitis and cheilitis.[11] Apart from BMS itself, a full list of causes of an oral burning sensation is given below: * Deficiency of iron, folic acid or various B vitamins (glossitis e.g. due to anemia), or zinc[17] * Neuropathy, e.g. following damage to the chorda tympani nerve. * Hypothyroidism. * Medications ("scalded mouth syndrome", unrelated to BMS) - protease inhibitors and angiotensin-converting-enzyme inhibitors (e.g. captopril).[1][5][12] * Type 2 diabetes[12] * True xerostomia, caused by hyposalivation e.g. Sjögren's syndrome * Parafunctional activity, e.g. nocturnal bruxism or a tongue thrusting habit. * Restriction of the tongue by poorly constructed dentures. * Geographic tongue.[12] * Oral candidiasis.[12] * Herpetic infection (herpes simplex virus).[18] * Fissured tongue.[1] * Lichen planus.[1] * Allergies and contact sensitivities to foods, metals, and other substances (see table). * Hiatal hernia.[1] * Human immunodeficiency virus.[1] * Multiple myeloma[19] ## Diagnosis[edit] BMS is a diagnosis of exclusion, i.e. all other explanations for the symptoms are ruled out before the diagnosis is made.[1][15] There are no clinically useful investigations that would help to support a diagnosis of BMS[3] (by definition all tests would have normal results),[1] but blood tests and / or urinalysis may be useful to rule out anemia, deficiency states, hypothyroidism and diabetes. Investigation of a dry mouth symptom may involve sialometry, which objectively determines if there is any reduction of the salivary flow rate (hyposalivation). Oral candidiasis can be tested for with use of a swabs, smears, an oral rinse or saliva samples.[10] It has been suggested that allergy testing (e.g., patch test) is inappropriate in the absence of a clear history and clinical signs in people with a burning sensation in the mouth.[10] The diagnosis of a people with a burning symptom may also involve psychologic screening e.g. depression questionnaires.[1] The second edition of the International Classification of Headache Disorders lists diagnostic criteria for "Glossodynia and Sore Mouth": A. Pain in the mouth present daily and persisting for most of the day, B. Oral mucosa is of normal appearance, C. Local and systemic diseases have been excluded.[20] ### Classification[edit] A burning sensation in the mouth may be primary (i.e. burning mouth syndrome) or secondary to systemic or local factors.[1] Other sources refer to a "secondary BMS" with a similar definition, i.e. a burning sensation which is caused by local or systemic factors,[15] or "where oral burning is explained by a clinical abnormality".[16] However this contradicts the accepted definition of BMS which specifies that no cause can be identified. "Secondary BMS" could therefore be considered a misnomer. BMS is an example of dysesthesia, or a distortion of sensation.[5] Some consider BMS to be a variant of atypical facial pain.[21] More recently, BMS has been described as one of the 4 recognizable symptom complexes of chronic facial pain, along with atypical facial pain, temporomandibular joint dysfunction and atypical odontalgia.[22] BMS has been subdivided into three general types, with type two being the most common and type three being the least common.[1] Types one and two have unremitting symptoms, whereas type three may show remitting symptoms.[1] * Type 1 - Symptoms not present upon waking, and then increase throughout the day * Type 2 - Symptoms upon waking and through the day * Type 3 - No regular pattern of symptoms Sometimes those terms specific to the tongue (e.g. glossodynia) are reserved for when the burning sensation is located only on the tongue.[20] ## Treatment[edit] If a cause can be identified for a burning sensation in the mouth, then treatment of this underlying factor is recommended. If symptom persist despite treatment a diagnosis of BMS is confirmed.[10] BMS has been traditionally treated by reassurance and with antidepressants, anxiolytics or anticonvulsants. A 2016 Cochrane review of treatment for burning mouth syndrome concluded that strong evidence of an effective treatment was not available, [3] however, a systematic review in 2018 found that the use of antidepressants and alpha-lipoic acids gave promising results.[23][24] Other treatments which have been used include atypical antipsychotics, histamine receptor antagonists, and dopamine agonists.[25] ## Prognosis[edit] BMS is benign (importantly, it is not a symptom of oral cancer), but as a cause of chronic pain which is poorly controlled, it can detriment quality of life, and may become a fixation which cannot be ignored, thus interfering with work and other daily activities.[9] Two thirds of people with BMS have a spontaneous partial recovery six to seven years after the initial onset, but in others the condition is permanent.[5][14] Recovery is often preceded by a change in the character of the symptom from constant to intermittent.[14] No clinical factors predicting recovery have been noted.[14] If there is an identifiable cause for the burning sensation, then psychologic dysfunctions such as anxiety and depression often disappear if the symptom is successfully treated.[5] ## Epidemiology[edit] BMS is fairly uncommon worldwide, affecting up to five individuals per 100,000 general population. [3]People with BMS are more likely to be middle aged or elderly, and females are three to seven times more likely to have BMS than males.[1][26] Some report a female to male ratio of as much as 33 to 1.[6] BMS is reported in about 10-40% of women seeking medical treatment for menopausal symptoms, and BMS occurs in about 14% of postmenopausal women.[5][14] Males and younger individuals of both sexes are sometimes affected.[9] Asian and Native American people have considerably higher risk of BMS.[5] ## Notable cases[edit] Sheila Chandra, a singer of Indian heritage, retired due to this condition.[27] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u Scully, Crispian (2008). Oral and maxillofacial medicine : the basis of diagnosis and treatment (2nd ed.). Edinburgh: Churchill Livingstone. pp. 171–175. ISBN 9780443068188. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 3. ^ a b c d e f g h i j k l m n o p q McMillan, Roddy; Forssell, Heli; Buchanan, John Ag; Glenny, Anne-Marie; Weldon, Jo C.; Zakrzewska, Joanna M. (2016). "Interventions for treating burning mouth syndrome". The Cochrane Database of Systematic Reviews. 11: CD002779. doi:10.1002/14651858.CD002779.pub3. ISSN 1469-493X. PMC 6464255. PMID 27855478. 4. ^ a b James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. p. 63. ISBN 978-0-7216-2921-6. 5. ^ a b c d e f g h i j k l m n o p Brad W. Neville; Douglas D. Damm; Carl M. Allen; Jerry E. Bouquot (2002). Oral & maxillofacial pathology (2. ed.). Philadelphia: W.B. Saunders. pp. 752–753. ISBN 978-0721690032. 6. ^ a b c d Mock, David; Chugh, Deepika (1 March 2010). "Burning Mouth Syndrome". International Journal of Oral Science. 2 (1): 1–4. doi:10.4248/IJOS10008. PMC 3475590. PMID 20690412. 7. ^ a b "Classification of Chronic Pain, Part II, B. Relatively Localized Syndromes of the Head and Neck; GROUP IV: LESIONS OF THE EAR, NOSE, AND ORAL CAVITY". IASP. Archived from the original on 19 December 2012. Retrieved 7 May 2013. 8. ^ Currie, C. C.; Ohrbach, R.; Leeuw, R. De; Forssell, H.; Imamura, Y.; Jääskeläinen, S. K.; Koutris, M.; Nasri‐Heir, C.; Tan, H.; Renton, T.; Svensson, P. "Developing a Research Diagnostic Criteria for Burning Mouth Syndrome: Results from an International Delphi Process". Journal of Oral Rehabilitation. n/a (n/a). doi:10.1111/joor.13123. ISSN 1365-2842. 9. ^ a b c d e Treister, Jean M. Bruch, Nathaniel S. (2010). Clinical oral medicine and pathology. New York: Humana Press. pp. 137–138. ISBN 978-1-60327-519-4. 10. ^ a b c d e f g Coulthard [], P; et al. (2008). Master dentistry (2nd ed.). Edinburgh: Churchill Livingstone/Elsevier. pp. 231–232. ISBN 9780443068966. 11. ^ a b c d e Glick, Martin S. Greenberg, Michael (2003). Burket's oral medicine diagnosis & treatment (10th ed.). Hamilton, Ont.: BC Decker. pp. 60–61, 332–333. ISBN 978-1550091861. 12. ^ a b c d e f g h Kalantzis, Crispian Scully, Athanasios (2005). Oxford handbook of dental patient care (2nd ed.). New York: Oxford University Press. p. 302. ISBN 9780198566236. 13. ^ a b c d Scully C (2013). Oral and maxillofacial medicine : the basis of diagnosis and treatment (3rd ed.). Edinburgh: Churchill Livingstone. pp. 249–253. ISBN 9780702049484. 14. ^ a b c d e Grushka, M; Epstein, JB; Gorsky, M (Feb 15, 2002). "Burning mouth syndrome". American Family Physician. 65 (4): 615–20. PMID 11871678. 15. ^ a b c Maltsman-Tseikhin, A; Moricca, P; Niv, D (June 2007). "Burning mouth syndrome: will better understanding yield better management?". Pain Practice. 7 (2): 151–62. doi:10.1111/j.1533-2500.2007.00124.x. PMID 17559486. 16. ^ a b Balasubramaniam, R; Klasser, GD; Delcanho, R (December 2009). "Separating oral burning from burning mouth syndrome: unravelling a diagnostic enigma". Australian Dental Journal. 54 (4): 293–9. doi:10.1111/j.1834-7819.2009.01153.x. PMID 20415926. 17. ^ Gurvits, GE; Tan, A (Feb 7, 2013). "Burning mouth syndrome". World Journal of Gastroenterology. 19 (5): 665–72. doi:10.3748/wjg.v19.i5.665. PMC 3574592. PMID 23429751. 18. ^ Zakrzewska, JM (Apr 25, 2013). "Multi-dimensionality of chronic pain of the oral cavity and face". The Journal of Headache and Pain. 14 (1): 37. doi:10.1186/1129-2377-14-37. PMC 3642003. PMID 23617409. 19. ^ Vučićević-Boras, V.; Alajbeg, I.; Brozovic, S.; Mravak-Stipetic, M. (2004). "Burning mouth syndrome as the initial sign of multiple myeloma". Oral Oncology Extra. 40: 13–15. doi:10.1016/j.ooe.2003.11.003. 20. ^ a b "2nd Edition of The International Headache Classification (ICHD-2)". International Headache Society. Archived from the original on 28 September 2013. Retrieved 7 May 2013. 21. ^ Porter, R.A. Cawson, E.W. Odell; avec la collab. de S. (2002). Cawsonś essentials of oral pathology and oral medicine (7. ed.). Edinburgh: Churchill Livingstone. p. 216. ISBN 978-0443071065. 22. ^ Aggarwal, VR; Lovell, K; Peters, S; Javidi, H; Joughin, A; Goldthorpe, J (Nov 9, 2011). "Psychosocial interventions for the management of chronic orofacial pain". Cochrane Database of Systematic Reviews (11): CD008456. doi:10.1002/14651858.CD008456.pub2. PMID 22071849. 23. ^ Souza, Isadora Follak de; Mármora, Belkiss Câmara; Rados, Pantelis Varvaki; Visioli, Fernanda (2018). "Treatment modalities for burning mouth syndrome: a systematic review". Clinical Oral Investigations. 22 (5): 1893–1905. doi:10.1007/s00784-018-2454-6. ISSN 1432-6981. PMID 29696421. 24. ^ "Burning mouth syndrome" (PDF). Retrieved 1 February 2019. 25. ^ Charleston L, 4th (June 2013). "Burning mouth syndrome: a review of recent literature". Current Pain and Headache Reports. 17 (6): 336. doi:10.1007/s11916-013-0336-9. PMID 23645183. 26. ^ Greenberg MS; Glick M; Ship JA. Burket's Oral Medicine. 11th edition. 2012 27. ^ "Sheila Chandra United Kingdom". Real World Records. Retrieved 1 August 2013. * Scala A; Checchi L; Montevecchi M; Marini I; Giamberardino MA (2003). "Update on burning mouth syndrome: overview and patient management". Crit Rev Oral Biol Med. 14 (4): 275–91. doi:10.1177/154411130301400405. PMID 12907696. ## External links[edit] Classification D * ICD-10: K14.6 * ICD-9-CM: 529.6 * MeSH: D005926 External resources * Orphanet: 353253 * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Burning mouth syndrome	c2930806	3,341	wikipedia	https://en.wikipedia.org/wiki/Burning_mouth_syndrome	2021-01-18T18:33:17	{"gard": ["5974"], "mesh": ["C531639", "D002054"], "umls": ["C2930806"], "icd-9": ["529.6"], "icd-10": ["K14.6"], "orphanet": ["353253"], "wikidata": ["Q230047"]}
Lactate dehydrogenase deficiency is a condition that affects how the body breaks down sugar to use as energy in cells, primarily muscle cells. There are two types of this condition: lactate dehydrogenase-A deficiency (sometimes called glycogen storage disease XI) and lactate dehydrogenase-B deficiency. People with lactate dehydrogenase-A deficiency experience fatigue, muscle pain, and cramps during exercise (exercise intolerance). In some people with lactate dehydrogenase-A deficiency, high-intensity exercise or other strenuous activity leads to the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown. This protein can also damage the kidneys, in some cases leading to life-threatening kidney failure. Some people with lactate dehydrogenase-A deficiency develop skin rashes. The severity of the signs and symptoms among individuals with lactate dehydrogenase-A deficiency varies greatly. People with lactate dehydrogenase-B deficiency typically do not have any signs or symptoms of the condition. They do not have difficulty with physical activity or any specific physical features related to the condition. Affected individuals are usually discovered only when routine blood tests reveal reduced lactate dehydrogenase activity. ## Frequency Lactate dehydrogenase deficiency is a rare disorder. In Japan, this condition affects 1 in 1 million individuals; the prevalence of lactate dehydrogenase deficiency in other countries is unknown. ## Causes Mutations in the LDHA gene cause lactate dehydrogenase-A deficiency, and mutations in the LDHB gene cause lactate dehydrogenase-B deficiency. These genes provide instructions for making the lactate dehydrogenase-A and lactate dehydrogenase-B pieces (subunits) of the lactate dehydrogenase enzyme. This enzyme is found throughout the body and is important for creating energy for cells. There are five different forms of this enzyme, each made up of four protein subunits. Various combinations of the lactate dehydrogenase-A and lactate dehydrogenase-B subunits make up the different forms of the enzyme. The version of lactate dehydrogenase made of four lactate dehydrogenase-A subunits is found primarily in skeletal muscles, which are muscles used for movement. Skeletal muscles need large amounts of energy during high-intensity physical activity when the body's oxygen intake is not sufficient for the amount of energy required (anaerobic exercise). During anaerobic exercise, the lactate dehydrogenase enzyme is involved in the breakdown of sugar stored in the muscles (in the form of glycogen) to create additional energy. During the final stage of glycogen breakdown, lactate dehydrogenase converts a molecule called pyruvate to a similar molecule called lactate. Mutations in the LDHA gene result in the production of an abnormal lactate dehydrogenase-A subunit that cannot attach (bind) to other subunits to form the lactate dehydrogenase enzyme. A lack of functional subunit reduces the amount of enzyme that is formed, mostly affecting skeletal muscles. As a result, glycogen is not broken down efficiently, leading to decreased energy in muscle cells. When muscle cells do not get sufficient energy during exercise or strenuous activity, the muscles become weak and muscle tissue can break down, as experienced by people with lactate dehydrogenase-A deficiency. The version of lactate dehydrogenase made of four lactate dehydrogenase-B subunits is found primarily in heart (cardiac) muscle. In cardiac muscle, lactate dehydrogenase converts lactate to pyruvate, which can participate in other chemical reactions to create energy. LDHB gene mutations lead to the production of an abnormal lactate dehydrogenase-B subunit that cannot form the lactate dehydrogenase enzyme. Even though lactate dehydrogenase activity is decreased in the cardiac muscle of people with lactate dehydrogenase-B deficiency, they do not appear to have any signs or symptoms related to their condition. It is unclear why this type of enzyme deficiency does not cause any health problems. ### Learn more about the genes associated with Lactate dehydrogenase deficiency * LDHA * LDHB ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lactate dehydrogenase deficiency	c2931743	3,342	medlineplus	https://medlineplus.gov/genetics/condition/lactate-dehydrogenase-deficiency/	2021-01-27T08:25:27	{"gard": ["3160", "3161", "3159"], "mesh": ["C538133"], "omim": ["612933", "614128"], "synonyms": []}
X-linked myopathy with postural muscle atrophy is a rare progressive muscular dystrophy characterized by an adult-onset scapulo-axio-peroneal myopathy. Clinical presentation includes shoulder girdle atrophy, scapular winging, axial muscular atrophy of postural muscles combined with a generalized hypertrophy. Typically, neck rigidity, rigid spine, Achilles tendon shortening, and respiratory insufficiency later in disease course are present. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-linked myopathy with postural muscle atrophy	c2678055	3,343	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=178461	2021-01-23T19:11:11	{"mesh": ["C567480"], "omim": ["300696"], "umls": ["C2678055"], "icd-10": ["G71.0"], "synonyms": ["XMPMA"]}
Dermatitis herpetiformis is a rare, chronic, skin disorder characterized by groups of severely itchy blisters and raised skin lesions. These are more common on the knees, elbows, buttocks and shoulder blades. The slow onset of symptoms usually begins during adulthood, but children can also be affected. Other symptoms may include fluid-filled sores; red lesions that resemble hives; and itchiness, redness and burning. The exact cause of this disease is not known, but it is frequently associated with the inability to digest gluten. People with this disease are typically treated with the drug dapsone. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Dermatitis herpetiformis	c0011608	3,344	gard	https://rarediseases.info.nih.gov/diseases/1917/dermatitis-herpetiformis	2021-01-18T18:00:55	{"mesh": ["D003874"], "omim": ["601230"], "umls": ["C0011608"], "orphanet": ["1656"], "synonyms": ["Duhring Brocq disease", "Brocq-Duhring disease ", "Duhring's disease", "DH", "Duhring-Brocq disease"]}
A number sign (#) is used with this entry because of evidence that familial hyperaldosteronism type III (HALD3) is caused by heterozygous mutation in the KCNJ5 gene (600734) on chromosome 11q24. For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900). Description This form of hyperaldosteronism is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or FH I; 103900), patients with FH III present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in FH III are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (Geller et al., 2008). ### Reviews Mulatero et al. (2013) reviewed the role of KCNJ5 in adrenal pathophysiology and provided an overview of the clinical and biochemical phenotypes resulting from KCNJ5 mutations in patients with sporadic and familial primary aldosteronism. The authors stated that the prevalence of FH III appeared to be 7% of patients with familial aldosteronism and 0.3% of all cases of primary hyperaldosteronism. In addition, they noted that the total prevalence of reported KCNJ5 mutations in aldosterone-producing adrenal adenomas (APAs) was 40%. Clinical Features Geller et al. (2008) reported a novel familial form of aldosteronism in a father and 2 daughters. All were diagnosed with severe secondary hypertension (HTN) refractory to medical treatment by age 7 years. Geller et al. (2008) performed a variety of clinical, biochemical, and genetic studies to attempt to clarify the underlying molecular defect. Biochemical studies revealed hyporeninemia, hyperaldosteronism, and very high levels of 18-oxocortisol and 18-hydroxycortisol, steroids that reflect oxidation by both steroid 17-alpha hydroxylase and aldosterone synthase. These enzymes are normally compartmentalized in the adrenal fasciculata and glomerulosa, respectively. Administration of dexamethasone failed to suppress either aldosterone or cortisol secretion; these findings distinguished this clinical syndrome from glucocorticoid-remediable aldosteronism (GRA; 103900), another autosomal dominant form of HTN, and suggested a global defect in the regulation of adrenal steroid production. Because of unrelenting HTN, all 3 subjects underwent bilateral adrenalectomy, which in each case corrected the HTN. Adrenal glands showed dramatic enlargement, with paired adrenal weights as high as 82 grams. Histology revealed massive hyperplasia and cellular hypertrophy of a single cortical compartment that had features of adrenal fasciculata or a transitional zone, with an atrophic glomerulosa. Mulatero et al. (2012) described an Italian mother and daughter with primary hyperaldosteronism, in whom the presence of the chimeric gene responsible for GRA had been excluded. The mother, who had a history of polyuria in the first decade of life, was initially reported to be hypertensive at age 18 years. Primary aldosteronism was diagnosed at 27 years of age, when she presented with hypertension, hypokalemia, decreased plasma renin activity, and elevated aldosterone levels that did not normalize after dexamethasone administration. On electrocardiogram, QTc was slightly prolonged at 456 ms, even after normalization of potassium levels. The daughter had polyuria and polydipsia at 2 years of age, and evaluation revealed hypertension, hypokalemia, and severe hyperaldosteronism with hypotonic urine and hypercalciuria. CT scans of the adrenal glands were normal in both patients, and symptoms in both were controlled with medication. Scholl et al. (2012) studied 4 unrelated kindreds with very early-onset primary aldosteronism, with all but 1 of the 10 affected members diagnosed before 6 years of age. In 2 of the families, blood pressure was difficult to control, and aldosteronism progressed with age. The 38-year-old proband of the first family presented at 22 months of age with muscle weakness, severe hypokalemia, and hypertension that persisted despite treatment with spironolactone. She underwent removal of a hyperplastic left adrenal gland at 32 months of age, but her symptoms persisted, and the right adrenal gland was removed at 4.3 years of age; both adrenal glands were markedly enlarged and showed hyperplasia of the zona glomerulosa and fasciculata. The bilateral adrenalectomy normalized blood pressure and K+ levels. The proband had 2 affected daughters, both of whom were diagnosed before 2 years of age and had hypertension refractory to spironolactone treatment; both had normalization of blood pressure, potassium, and aldosterone levels after bilateral adrenalectomy. The affected individual in the second family presented at 4 years of age with hypertension, hypokalemia, metabolic alkalosis, and an elevated serum aldosterone level with suppressed plasma renin activity. Ultrasound of the abdomen was normal. She had difficult-to-control hypertension, and was lost to follow-up. In the third and fourth families, spironolactone normalized blood pressure, and there was no progression of disease with age. The proband of the third family was a 38-year-old woman, previously described by Greco et al. (1982), who presented at 26 months of age with hypertension and hyperaldosteronism. Treatment with spironolactone normalized her blood pressure, and she did not have progression of hypertension or growth of the adrenal glands with age; CT scan at age 37 years revealed no adrenal abnormality. She had 2 affected children, both diagnosed before 2 years of age and successfully treated with spironolactone. Her affected father, who was reported by Bartter and Biglieri (1958), had early hypertension and aldosteronism and underwent near-total bilateral adrenalectomy at 14 years of age, before the availability of mineralocorticoid receptor antagonists. The glands were described as histologically normal, and he was normotensive and normokalemic thereafter. The fourth family consisted of a father and son who both presented in the first few years of life with hypertension and elevated aldosterone. The father underwent bilateral adrenalectomy at 6 years of age; the son was successfully treated with spironolactone. Charmandari et al. (2012) reported a mother and daughter with severe primary aldosteronism and bilateral massive adrenal hyperplasia resulting in early-onset hypertension refractory to medical treatment. The mother, who was diagnosed at 7 years of age, underwent bilateral adrenalectomy at age 13 due to persistent hypertension, with complete normalization of blood pressure and serum potassium levels postoperatively. The daughter, who presented at 2 years of age with severe hypertension, hypokalemia, hyperaldosteronism, and suppressed plasma renin activity, had normal growth and development, with no hirsutism or virilization at puberty. Hypertension persisted at age 15 despite treatment with multiple medications, including spironolactone. MRI of the adrenal glands confirmed massive bilateral adrenal hyperplasia, and she underwent near-total bilateral adrenalectomy. Over subsequent years, further hyperplasia of the remaining right adrenal gland was documented, and she had recurrence of the symptoms and signs of primary hyperaldosteronism; removal of the remaining gland was planned. Molecular Genetics In the family with hyperaldosteronism reported by Geller et al. (2008), Choi et al. (2011) identified a missense mutation in the potassium channel gene KCNJ5 at codon 158 (T158A; 600734.0002). This mutation produced increased sodium conductance and caused severe hypertension. Choi et al. (2011) also identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5, G151R (600734.0004), and L168R, that were present in 8 of 22 human aldosterone-producing adrenal adenomas studied. These 2 mutations produced increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. Mulatero et al. (2012) analyzed the candidate gene KCNJ5 in 21 European families with primary hyperaldosteronism in which the presence of the chimeric gene responsible for type I familial hyperaldosteronism had been excluded. In an affected Italian mother and daughter, they identified heterozygosity for a missense mutation (G151E; 600734.0005) that was not found in 7 unaffected family members. In addition, they identified 3 somatic KCNJ5 mutations, T158A, G151R, and L168R, in aldosterone-producing adenomas (APAs) from 3 unrelated affected individuals. After exclusion of chimeric fusion of CYP11B1/CYP11B2 or mutation in the AT1R gene (106165) in a mother and daughter with severe aldosteronism requiring total adrenalectomy, Charmandari et al. (2012) sequenced the candidate genes KCNK3 (603220), KCNK5 (603493), KCNK9 (605874), and KCNJ5, and identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; 600734.0006). Murthy et al. (2014) analyzed the KCNJ5 gene in 251 patients with apparent sporadic florid primary aldosteronism, and identified 3 heterozygous missense mutations, G247R (rs200170681; 600734.0003), E246K (600734.0007), and R52H (rs144062083). In addition, 12 (5%) of the 251 patients carried the rare SNP E282Q (rs7102584), present at a population frequency of 2% in the 1000 Genomes cohort. Although remote from the KCNJ5 selectivity filter, 3 of the 4 variants (E246K, R52H, and E282Q) were shown to alter inward rectification, conduction of Na+ currents, and angiotensin II (106150)-induced aldosterone release in the H295R cell line, a well-established model for the human zona glomerulosa cell. Results of electrophysiologic analysis of the G247R channel, however, were indistinguishable from those of the wildtype channel. Kokunai et al. (2014) identified the T158A mutation in the KCNJ5 gene in a patient with prolonged QU on ECG who developed a hypokalemic paralytic attack and primary aldosteronism 2 years later. The patient was 1 of 21 patients with a phenotype resembling Andersen-Tawil syndrome (LQT7; 170390) who did not carry a mutation in the KCNJ2 gene (600681). The findings expanded the phenotype associated with this mutation. ### Exclusion Studies In a family with hyperaldosteronism, Geller et al. (2008) excluded mutation at the aldosterone synthase locus (CYP11B2; 124080), further distinguishing the disorder from glucocorticoid-remediable aldosteronism. They also failed to identify disease-causing mutations in DAX1 (300473), AD4BP (NR5A1; 184757), NUR77 (NR4A1; 139139), and NURR1 (NR4A2; 601828) by direct sequencing of coding exons. Genotype/Phenotype Correlations In affected individuals with early-onset primary aldosteronism from 4 unrelated families that were known to be negative for chimeric fusion of the CYP11B1 (610613) and CYP11B2 (124080) genes, Scholl et al. (2012) identified heterozygosity for 2 different missense mutations at the same codon in the KCNJ5 gene: G151R (600734.0004) in 2 families with severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control, and G151E (600734.0005) in 2 families that had more easily controlled hypertension and no evidence of adrenal hyperplasia. Histopathology of adrenalectomized patients with the G151R mutation showed adrenal enlargement and hyperplasia of the adrenal cortex in all but the youngest patient, who underwent surgery at 18 months of age. Adrenal histology from 1 patient carrying the G151E mutation, who underwent adrenalectomy before availability of spironolactone for the treatment of hypertension, was reported as normal. Electrophysiologic analysis demonstrated that although both mutations alter the K+ selectivity of the channel, the G151E mutation causes much greater Na+ conductance than G151R, resulting in rapid Na(+)-dependent cell lethality. Scholl et al. (2012) proposed that the increased lethality associated with the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus paradoxically resulting in a milder phenotype in those patients. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension, severe GENITOURINARY Kidneys \- Adrenal hyperplasia, bilateral \- Elevated aldosterone secretion \- Hyperplasia of zona fasciculata of adrenal gland \- Hyperplasia of zona glomerulosa of adrenal gland \- Atrophic zona glomerulosa of adrenal gland (rare) \- Histologically normal adrenal gland (in some patients) \- Polyuria (in some patients) \- Hypotonic urine (in some patients) \- Hypercalciuria (in some patients) MUSCLE, SOFT TISSUES \- Muscle weakness, hypokalemia-related METABOLIC FEATURES \- Metabolic acidosis (in some patients) \- Polydipsia (in some patients) ENDOCRINE FEATURES \- Adrenal hyperplasia, bilateral \- Elevated serum aldosterone \- Elevated 18-hydroxycortisol \- Elevated 18-oxocortisol LABORATORY ABNORMALITIES \- Hypokalemia \- Hypercalciuria (in some patients) \- Decreased plasma renin activity \- Paradoxical increase or no change in serum aldosterone and blood pressure after dexamethasone administration MISCELLANEOUS \- Onset of symptoms in first decade of life \- Patients with medication-resistant hypertension require bilateral adrenalectomy MOLECULAR BASIS \- Caused by mutation in the member-5 subfamily-J inwardly rectifying potassium channel gene (KCNJ5, 600734.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPERALDOSTERONISM, FAMILIAL, TYPE III	c3150933	3,345	omim	https://www.omim.org/entry/613677	2019-09-22T15:57:54	{"doid": ["446"], "omim": ["613677"], "orphanet": ["251274"], "synonyms": ["FH-III", "Alternative titles", "Familial hyperaldosteronism type 3", "FH III", "FH3"]}
A rare, genetic skeletal dysplasia characterized by severe disproportionate short stature with mesomelic and rhizomelic shortening of the upper and lower limbs. ## Epidemiology The exact prevalence is unknown. More than 100 cases have been described in the literature to date, with most of the patients being reported from populations with a high level of consanguinity. ## Clinical description Langer mesomelic dysplasia (LMD) is a more severe form of Léri-Weill dyschondrosteosis (LWD) and presents at birth with a severely shortened long bones of the limbs (involving both the middle and proximal segments), deformity of the humeral head, angulation of the radial shaft, carpal distortion, a short femoral neck, and absence or hypoplasia of the proximal half of the fibula. Mild hypoplasia of the mandible has been reported in some cases. In contrast to LWD, Madelung deformity is not typically present in LMD. Associated malformations are rare and intellect is normal in almost all reported LMD cases. ## Etiology LMD is inherited in a pseudoautosomal recessive manner and is associated with homozygous or compound heterozygous mutations and deletions of the Short stature HomeobOX (SHOX) gene (which maps to the pseudoautosomal region 1 (PAR1) of the sex chromosomes; Xp22.33 and Yp11.32) or of the upstream or downstream PAR1 (where SHOX enhancer elements are located). LMD is part of a spectrum of disorders (ranging from the most severe, LMD, to LWD, isolated Madelung deformity and so-called idiopathic short stature), all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000. ## Diagnostic methods Diagnosis of LMD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX). ## Differential diagnosis During the antenatal period differential diagnosis includes femur-fibula-ulna complex and the Reinhardt-Pfeiffer mesomelic dysplasia. ## Antenatal diagnosis LMD may be suspected by ultrasound at 20 weeks of gestation. Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD. ## Genetic counseling Genetic counseling should be proposed and families should be informed that SHOX/PAR1 anomalies are inherited in a pseudoautosomal dominant manner. Each child of an individual with LWD has a 50% risk of inheriting the mutation. If both parents have LWD, the offspring have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition. All children of an individual with LMD and an unaffected parent will present with LWD. ## Management and treatment There is no effective treatment for LMD. The symptomatic medical management of children with LMD begins at birth and continues into adulthood. Careful monitoring of height, weight, and head circumference is essential. ## Prognosis The short stature and limb deformities are severe but life expectancy is normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Langer mesomelic dysplasia	c0432230	3,346	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2632	2021-01-23T18:19:50	{"gard": ["3553"], "mesh": ["C537267"], "omim": ["249700"], "umls": ["C0432230"], "icd-10": ["Q87.1"], "synonyms": ["Mesomelic dwarfism, Langer type"]}
## Description Human herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman disease (Pedergnana et al., 2012). See 148000 for general phenotypic information on these diseases, as well as information on HHV-8-associated pathogenesis. Mapping Using an immunofluorescence assay, Pedergnana et al. (2012) determined that HHV-8 seroprevalence was 60% and increased with age among 608 individuals, aged 1 to 88 years, belonging to the Bantu ethnic group, primarily the Fang tribe, in southern Cameroon, where HHV-8 infection is endemic. Segregation analysis provided evidence for a recessive major gene conferring predisposition to HHV-8 infection, with almost all homozygous predisposed individuals (about 7% of the population) becoming infected by 10 years of age. Linkage analysis on the 15 most informative families, corresponding to 205 genotyped individuals, identified a single region on chromosome 3p22 that was significantly linked to HHV-8 infection (lod = 3.83; P = 2.0 x 10(-5)). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HUMAN HERPESVIRUS 8, SUSCEPTIBILITY TO	c3553840	3,347	omim	https://www.omim.org/entry/614836	2019-09-22T15:54:05	{"omim": ["614836"], "synonyms": ["Alternative titles", "HHV-8, SUSCEPTIBILITY TO"]}
A number sign (#) is used with this entry because of evidence that syndromic microphthalmia-3 (MCOPS3) is caused by heterozygous mutation in the SOX2 gene (184429) on chromosome 3q26. Description Syndromic microphthalmia-3 (MCOPS3) is characterized by clinical anophthalmia or microphthalmia with or without defects of the optic nerve, optic chiasm, and optic tract. Extraocular abnormalities include brain anomalies, seizures, motor disability, neurocognitive delays, sensorineural hearing loss, and esophageal atresia. Hypoplasia of the anterior pituitary is another major complication, which frequently results in growth hormone deficiency; however, gonadotropin deficiency is likely to be the most consistent endocrinopathy in patients with SOX2 mutation (summary by Numakura et al., 2010). Nomenclature The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.' Clinical Features Rogers (1988) reported an 11-month-old male infant with bilateral clinical anophthalmia, esophageal atresia with tracheoesophageal fistula, and glanular hypospadias. The patient was noted to have normal intellectual development but delayed motor development. Arroyo et al. (1992) reported a male infant with bilateral clinical anophthalmia and esophageal atresia who had no other pathologic findings except for right cryptorchidism with normal scrotum and penis. The authors believed that this represented a second case of the disorder described by Rogers (1988). Sandler et al. (1995) reported a boy and a girl from unrelated families with bilateral anophthalmia and proximal esophageal atresia. In addition to vestigial optic nerves and chiasma, MRI studies showed other central nervous system abnormalities: one had ectopic tissue in the hypothalamic region and the other had generalized ventriculomegaly associated with atrophy. Sandler et al. (1995) concluded that these defects represent a nonrandom concurrence. Ulman et al. (1996) reported a boy with esophageal atresia, tracheoesophageal fistula, unilateral microphthalmia, and glanular hypospadias. Shah et al. (1997) reported a male infant with bilateral microphthalmia, esophageal atresia with distal tracheoesophageal fistula, micropenis, and cryptorchidism. Other features included low-set posteriorly angulated ears with simple flat pinnae, right facial palsy, and hockey-stick palmar creases. CT scan revealed cavum septi pellucidi and extensive low attenuation of white matter bilaterally, suggesting leukomalacia. The patient was treated palliatively and died at day 8; autopsy revealed an absent gallbladder, extensive bilateral periventricular leukomalacia, olfactory aplasia, and multiple cerebellar cortical heterotopia. Shah et al. (1997) suggested the name 'anophthalmia-esophageal-genital syndrome' (AEG syndrome) for this disorder. Imaizumi et al. (1999) reported 2 male patients with unilateral microphthalmia and esophageal atresia. Mild psychomotor delay and severe bilateral hearing loss were present in 1 patient; the other had T4-S hemivertebrae and 11 ribs on the left side. The authors concluded that these cases provide further support for recognizing this association as a distinct syndrome. Menetrey et al. (2002) reported a newborn female with bilateral anophthalmia and esophageal atresia, who died shortly after birth. They stated that this was the seventh reported case of this syndrome and noted that all cases had been sporadic. Messina et al. (2003) reported a male infant with left microphthalmia, esophageal atresia, and marked hypoplasia of the entire left half of the body. A chorioretinal coloboma was noted in the right eye; on CT scan, there was diffuse hypodensity of the white matter of both hemispheres. Petrackova et al. (2004) reported a male infant with bilateral clinical anophthalmia and esophageal atresia with distal tracheoesophageal fistula. He had normal genitals, duplication of the left kidney, and significant psychomotor delay. Bonneau et al. (2004) reported the eleventh case of anophthalmia/microphthalmia and esophageal atresia (AMEA). In her neonatal period, the proband had been operated on for type III esophageal atresia. At the age of 6 years, she received an ocular prosthesis for colobomatous microphthalmia of the right eye. The left eye was normal. No deletion of the SOX2 locus (184429), which had been implicated in anophthalmia/microphthalmia, was found; a search for SOX2 mutations was not performed. Bardakjian and Schneider (2005) reported 3 unrelated boys and an unrelated girl with clinical anophthalmia/microphthalmia and esophageal atresia. All 3 boys had genital anomalies involving hypospadias and cryptorchidism, and 2 also had cardiac anomalies: 1 had a large ventricular septal defect and the other, patent ductus arteriosus and a patent foramen ovale. One boy had holoprosencephaly with marked dilation of the ventricles seen on head CT. Three of the 4 patients also had vertebral anomalies: 1 boy had underdeveloped vertebrae; a second boy had 2 ossified ribs on the right and 11 on the left and multiple vertebral anomalies between T3 and T8, including 2 hemivertebrae; and the girl had cervical hemivertebrae and T1-T7 hemivertebrae as well as 13 ribs. Although 1 patient was developmentally delayed, another had been valedictorian in high school and was attending college. Bardakjian and Schneider (2005) suggested that because the association of anophthalmia/microphthalmia and esophageal atresia is so rare and most cases have associated anomalies of the CNS, genitalia, and vertebrae as well as other systems, the entity might be better described as anophthalmia/microphthalmia and esophageal atresia with other associated malformations. Hill et al. (2005) reported a female infant with right-sided clinical anophthalmia, esophageal atresia and tracheoesophageal fistula, and vertebral anomalies, including a T6 hemivertebra, T5 butterfly vertebra, fusion of the posterolateral third and fourth ribs, and fusion of S3 to S5 on the left sacrum. She had low-set ears with a slightly simple ear on the right, her fourth and fifth fingers overlapped the third fingers, and she had a right single palmar crease. Morini et al. (2005) reported a female infant with pure esophageal atresia without tracheoesophageal fistula, bilateral clinical anophthalmia, and a patent ductus arteriosus. Microcephaly and mild developmental retardation were also observed. Ragge et al. (2005) described the clinical features of 5 patients reported by Fantes et al. (2003) and 4 additional patients with bilateral clinical anophthalmia/microphthalmia. Extraocular features included mild facial dysmorphism, seizure disorder, global developmental delay, mesial temporal brain malformations, disordered muscle tone with evidence of mild basal ganglia dysfunction, growth failure, and male genital tract abnormalities. The authors noted that the neurologic features were relatively consistent but highly variable in severity. Pedace et al. (2009) reported a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis. Ophthalmic examination confirmed the clinical anophthalmia/microphthalmia as well as congenital cataract; in addition, the patient had a depressed and widened nasal bridge and frontal bossing. Penile length was 2 cm, with normally descended testes. Brain MRI revealed that the right globe was virtually absent, whereas the left one was reduced in size with coloboma of the optic nerve. The hypothalamic-pituitary axis appeared normal, but there was bilateral dilatation of the temporal horns and hypoplasia of the hippocampus. Repeated endocrinologic evaluation and brain MRI in this patient did not reveal any morphologic or functional anomaly of the hypothalamic-pituitary axis. Numakura et al. (2010) studied a 21-year-old Japanese man who had bilateral clinical anophthalmia, midface hypoplasia with a patulous lower lip, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability. Brain MRI showed a defect of the septum pellucidum and absence of the optic nerve, chiasm, and optic tract. In addition, the patient had difficulty with mastication, and mobility of the mandibular incisors as well as bilateral maxillary and mandibular deciduous molars were observed. Panoramic radiography revealed 9 unerupted teeth, including 5 premolars showing delayed eruption and 4 supernumerary impacted teeth. Noting that multiple supernumerary teeth are rare and usually associated with congenital malformation syndromes, Numakura et al. (2010) concluded that the supernumerary teeth in this patient were likely to be a manifestation of the SOX2 anophthalmia syndrome. Cytogenetics In a female infant with had bilateral clinical anophthalmia, congenital heart disease, and abnormal genitalia who died 45 hours after delivery, Chitayat et al. (1996) identified a terminal deletion of the long arm of chromosome 3 involving 3q27-qter. In a female infant with bilateral clinical anophthalmia and a patent foramen ovale or small atrial septal defect on echocardiogram, and a male infant who was large for gestational age and had mild hypertelorism, severe bilateral microphthalmia, bilateral large colobomatous cysts, severe optic nerve hypoplasia, and bilateral sensorineural hearing loss, Driggers et al. (1999) and Kurbasic et al. (2000), respectively, reported de novo apparently balanced reciprocal translocations involving 3q27. In 2 unrelated infants with clinical anophthalmia and microphthalmia who had constitutional deletions involving 3q27, Male et al. (2002) identified a 6.7-Mb minimum deleted region common to both patients at 3q26.33-q28. The male infant, who died at 40 days of age from respiratory failure, had multiple abnormalities including bilateral clinical anophthalmia, abnormalities of the first and second cranial nerves, partial absence of the corpus callosum, cleft palate and laryngeal cleft, 13 pairs of ribs, cleft odontoid peg, small penis with hypoplastic scrotum, and bilateral cryptorchidism. The female infant had right clinical anophthalmia and left microphthalmia. Both patients had intrauterine growth retardation with microcephaly and had strikingly similar dysmorphic facies consisting of bossed forehead, downward-slanting palpebral fissures, grooved bridge of the nose, prominent low-set ears, small downturned mouth, and small mandible. Molecular Genetics In the female infant reported by Driggers et al. (1999) with bilateral clinical anophthalmia and a de novo t(3;11)(q27;p11.2), Fantes et al. (2003) identified a submicroscopic deletion at the 3q breakpoint, containing the SOX2 gene. By subsequent SOX2 mutation analysis in 102 individuals with microphthalmia, clinical anophthalmia, or coloboma, they identified 3 heterozygous de novo truncating mutations in the SOX2 gene (184429.0001-184429.0003) in 4 unrelated individuals, 2 with bilateral clinical anophthalmia and 2 with unilateral clinical anophthalmia and contralateral microphthalmia. All 4 patients had associated extraocular abnormalities, including male genital tract abnormalities, myopathy, and spastic diplegia. In 4 patients with bilateral clinical anophthalmia/microphthalmia, Ragge et al. (2005) identified heterozygous de novo mutations in the SOX2 gene, including a missense mutation (184429.0004) and 3 frameshift mutations. In a 12-year-old girl with bilateral clinical anophthalmia and aplasia of the optic nerve, chiasm, and optic tracts, Hagstrom et al. (2005) identified heterozygosity for a de novo nonsense mutation in the SOX2 gene (184429.0005). The patient also had mild bilateral sensorineural hearing loss and global developmental delay. In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay, Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion in the SOX2 gene (70del20; 184429.0010). The patient had frontal bossing and a broad nasal root, as well as congenital left hip dislocation. Orbital and brain CT scan demonstrated absence of eye globes, rudimentary optic nerves, partial agenesis of the corpus callosum, and marked cystic dilation of the third ventricle due to a suprasellar cyst. Williamson et al. (2006) identified heterozygous loss-of-function mutations in the SOX2 gene (184429.0006-184429.0008) in 3 unrelated patients with microphthalmia and esophageal atresia: 1 was the original patient reported by Rogers (1988); another was the male infant described by Petrackova et al. (2004); and the third was a new case, a female infant with extreme bilateral microphthalmia, severe blepharophimosis, and esophageal atresia with distal tracheoesophageal fistula. In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation, Faivre et al. (2006) identified heterozygosity for a missense mutation in the SOX2 gene (184429.0009). Cerebral MRI revealed a normal corpus callosum, ventricular diameter, and gray and white matter; ocular MRI showed empty orbits except for the presence of intraorbital muscles, and the optic nerve and chiasm could not be visualized. At 1 year of age, the patient could not sit unaided and expressed no sounds. Her unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated at 17 weeks' gestation due to severe hydrocephaly; the fetus was found to have a significantly increased occipitofrontal circumference, left cryptophthalmos and bilateral clinical anophthalmos, major dilation of the lateral and third ventricles with hypoplastic white matter and optic nerve agenesis, absence of the corpus callosum, and minor hypoplasia of the inferior cerebellar vermis. Zenteno et al. (2006) described male monozygotic twin infants with esophageal atresia and a discordant ocular phenotype in whom they identified heterozygosity for the 70del20 mutation in the SOX2 gene. One twin had an irregular skull, facial asymmetry, left clinical anophthalmia, flat nasal bridge, retrognathia, low-set ears, bilateral cryptorchidism, and tracheoesophageal fistula. The other twin had normal ocular globes, narrowing of the right palpebral fissure, flat nasal bridge, normal genitalia, and tracheoesophageal fistula. Zenteno et al. (2006) stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia. Kelberman et al. (2006) screened 235 probands with congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene and identified 6 patients with clinical anophthalmia or microphthalmia who had heterozygous de novo mutations (see, e.g., 184429.0001 and 184429.0010) and 2 patients with bilateral optic nerve hypoplasia who had heterozygous inherited mutations (see 184429.0012 and 184429.0013), One of the patients was a 13-year-old girl with bilateral clinical anophthalmia and a history of esophageal atresia who had previously been reported by Morini et al. (2005); she was found to be heterozygous for a 1-bp insertion in the SOX2 gene (184429.0011). In addition to bilateral eye defects, all patients with SOX2 mutations had various associated anomalies, including anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural hearing loss, and esophageal atresia. In 2 female sibs, 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion in the SOX2 gene (184429.0014). The first sib had bilateral anophthalmia and esophageal atresia and died shortly after birth. During the mother's subsequent pregnancy, the fetus showed severe and progressive triventricular hydrocephalus on ultrasound, and the pregnancy was interrupted. Autopsy showed stenosis of the Sylvian aqueduct, hypoplasia of the corpus callosum, and 11 rib pairs, but normal external ocular examination and gestational age-appropriate ocular length. Extensive microscopic examination revealed no subtle anomaly of the ocular structures. The mother was found to have germinal mosaicism for the mutation, estimated at approximately 3%. Chassaing et al. (2007) concluded that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia. In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies, Schneider et al. (2008) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0015). The younger sister's development was more advanced than her older sib at the same age, showing that differences in development can occur in sibs with the same SOX2 mutation. The younger sister also had hypothyroidism, which had not previously been reported in MCOPS3. The unaffected mother, who had 2 healthy older children, was found to have a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. Schneider et al. (2008) noted that this was the third report of a family in which an unaffected mosaic mother transmitted bilateral clinical anophthalmia to 2 female offspring (see Faivre et al., 2006 and Chassaing et al., 2007). In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis, Pedace et al. (2009) analyzed the SOX2 gene and identified heterozygosity for a 2-bp insertion (184429.0016). The mutation was not detected in the patient's unaffected second-cousin parents or in his unaffected dizygotic twin, and was not found in 200 control chromosomes. In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability, who was negative for mutation in the HESX1 gene (601802), Numakura et al. (2010) identified heterozygosity for a nonsense mutation in SOX2 (184429.0017). The patient also had a dental anomaly, consisting of multiple supernumerary impacted teeth and persistence of deciduous teeth. Although the role of SOX2 in dental development was as yet unknown, the authors considered the supernumerary teeth to be an extraocular symptom of the SOX2 anophthalmia syndrome. Alatzoglou et al. (2011) reported 2 unrelated patients with bilateral clinical anophthalmia and nonprogressive pituitary tumors of early onset associated with SOX2 haploinsufficiency, due to heterozygosity for a 731-kb deletion on chromosome 3q26 encompassing SOX2 in 1 patient and a SOX2 nonsense mutation (F48X; 184429.0018) in the other. Alatzoglou et al. (2011) stated that this was the first time that SOX2 haploinsufficiency had been implicated in the generation of pituitary tumors. The patient with the deletion was born with bilateral clinical anophthalmia and had severely impaired language development and delayed motor milestones. She presented at 18 years of age with pubertal delay and was Tanner stage I with short stature on examination; endocrine evaluation revealed undetectable estradiol with low basal gonadotropins and flat luteinizing hormone (LH; 152780) and follicle-stimulating hormone (FSH: 136530) responses to GnRH (152760) stimulation, consistent with a diagnosis of hypogonadotropic hypogonadism. MRI revealed a sellar tumor with a cystic component, extending into the suprasellar area, with no evidence of compression syndrome. Hormone replacement therapy was declined, and at 24 years of age the patient developed spontaneous but incomplete puberty (breast Tanner stage 2). Repeat MRI at that time as well as sequential MR imaging over a 10-year period showed no significant change in size or morphology of the tumor, and there was no evidence of development of additional pituitary hormone deficiencies. In an 8-year-old boy with bilateral clinical anophthalmia and endocrinologic abnormalities and his 8-month-old sister who had unilateral microphthalmia and retinal coloboma, Stark et al. (2011) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0019). Their mother, who was diagnosed with isolated hypogonadotropic hypogonadism (see 147950) and had undergone assisted reproduction to achieve fertility, was also heterozygous for the deletion. She had no dysmorphic features and a normal sense of smell, and ophthalmologic examination was normal. Sequencing results in the mother suggested possible mosaicism. Genotype/Phenotype Correlations Schneider et al. (2009) screened the SOX2 gene in 51 unrelated patients with clinical anophthalmia and/or microphthalmia and identified heterozygous SOX2 mutations in 10 of them, including 3 patients with the recurrent 20-bp deletion (70del20; 184429.0010). Analysis of all reported patients with SOX2 mutations suggested a potential genotype/phenotype correlation, with missense changes generally resulting in less severe ocular defects. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Growth failure, postnatal HEAD & NECK Head \- Microcephaly Face \- Frontal bossing Ears \- Hearing loss, sensorineural Eyes \- Microphthalmia \- Anophthalmia, clinical \- Optic nerve hypoplasia \- Coloboma Teeth \- Multiple supernumerary teeth (rare) CARDIOVASCULAR Heart \- Ventricular septal defect Vascular \- Patent ductus arteriosus CHEST Ribs Sternum Clavicles & Scapulae \- Absent ribs \- Extra ribs \- Fused ribs ABDOMEN Gastrointestinal \- Esophageal atresia GENITOURINARY External Genitalia (Male) \- Hypospadias \- Micropenis Internal Genitalia (Male) \- Cryptorchidism SKELETAL Spine \- Hemivertebrae \- Underdeveloped vertebrae \- Fused vertebrae \- Butterfly vertebrae NEUROLOGIC Central Nervous System \- Reduction of white matter, generalized \- Hypothalamic hamartoma \- Mesial temporal brain malformations \- Agenesis of corpus callosum \- Hypoplasia of corpus callosum \- Anterior pituitary hypoplasia \- Learning difficulties \- Psychomotor delay \- Hypotonia \- Spastic diplegia \- Spastic quadriplegia ENDOCRINE FEATURES \- Anterior pituitary hypoplasia \- Hypogonadotropic hypogonadism MOLECULAR BASIS \- Caused by mutation in the SRY (sex determining region Y)-box 2 gene (SOX2, 184427.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MICROPHTHALMIA, SYNDROMIC 3	c1859773	3,348	omim	https://www.omim.org/entry/206900	2019-09-22T16:30:57	{"doid": ["10629"], "mesh": ["C565948"], "omim": ["206900"], "orphanet": ["77298"], "synonyms": ["Alternative titles", "MICROPHTHALMIA AND ESOPHAGEAL ATRESIA SYNDROME", "ANOPHTHALMIA, CLINICAL, WITH ASSOCIATED ANOMALIES", "ANOPHTHALMIA-ESOPHAGEAL-GENITAL SYNDROME", "AEG SYNDROME"], "genereviews": ["NBK1378", "NBK1300"]}
For background information on susceptibility and resistance to Mycobacterium tuberculosis, see 607948. Description The tuberculin skin test (TST), or Mantoux test, measures induration of the skin after intradermal inoculation of M. tuberculosis purified protein derivative and thereby detects M. tuberculosis-infected and -noninfected persons. The TST triggers a classical T cell-mediated delayed-type hypersensitivity reaction against mycobacterial antigens. About 20% of individuals living in areas hyperendemic for tuberculosis show persistent absence of TST reactivity, suggesting T cell-independent resistance to M. tuberculosis infection. Genetic epidemiologic studies in endemic areas have suggested that host genetic factors contribute to resistance to M. tuberculosis infection and to the immune reactions underlying TST reactivity (summary by Cobat et al., 2009). Mapping Cobat et al. (2009) performed genomewide linkage analysis for TST reactivity in 128 families, including 186 parents and 350 children, from a suburb of Cape Town, South Africa, hyperendemic for tuberculosis. They identified a quantitative trait locus for TST reactivity measured in millimeters, which they called TST2, on chromosome 5p15 with a multipoint lod score of 4.00 at position 2.70 Mb (P = 9 x 10(-6)). Cobat et al. (2009) concluded that TST2 represents a major locus controlling the intensity of T cell-mediated delayed-type hypersensitivity reaction to tuberculin. They suggested that SLC6A3 (126455) is a candidate gene on chromosome 5p15 for TST2. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TUBERCULIN SKIN TEST REACTIVITY QUANTITATIVE TRAIT LOCUS	c3150893	3,349	omim	https://www.omim.org/entry/613637	2019-09-22T15:58:03	{"omim": ["613637"], "synonyms": ["Alternative titles", "TST REACTIVITY QUANTITATIVE TRAIT LOCUS", "TST2"]}
Overlap myositis (OM) is a form of idiopathic inflammatory myopathy (IIM) characterized by myositis with at least one clinical and/or autoantibody overlap feature. ## Epidemiology Prevalence and annual incidence of OM are not known. Estimates are difficult to determine because of low recognition levels of this form of IIM. ## Clinical description Overlap myositis is a clinically heterogeneous, poorly recognized subtype of inflammatory myopathy. Patients with myositis and one clinical and/or autoantibody overlap feature are considered to have OM, excluding pure polymyositis and pure dermatomyositis (see these terms). Possible clinical overlap features include polyarthritis, Raynaud phenomenon, sclerodactyly, scleroderma (proximal to metacarpalphalangeal joints), lung interstitial pneumonia, and/or clinical signs of systemic lupus erythematosus (SLE). Overlap autoantibodies include those observed with scleroderma, SLE, and/or some inflammatory myopathies such as anti-synthetase syndrome (see these terms). ## Etiology OM covers a range of inflammatory myopathies and other connective tissue diseases for which the etiology is generally poorly understood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Overlap myositis	None	3,350	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=206572	2021-01-23T18:11:33	{"synonyms": ["Adult-onset overlap myositis", "Non-specific myositis"]}
A rare, genetic, vitreous-retinal disease characterized by ocular developmental anomalies such as microcornea, a shallow anterior chamber, glaucoma and cataract. Abnormal chorioretinal pigmentation is present, usually lying between the vortex veins and the ora serrata for 360 degrees. ## Epidemiology At least 3 pedigrees have been reported to have ADVIRC. ## Clinical description Age of onset is variable, but can occur in childhood. ADVIRC is associated with developmental ocular anomalies including microphthalmos/nanophthalmos, microcornea, hypermetropia/high myopia, shallow anterior chamber, angle closure glaucoma, iris dysgenesis, abnormal pupillary ruff, microspherophakia with mild lens opacities (congenital or early-onset posterior/subcapsular cataract), disc gliosis and optic nerve dysplasia. Some patients may experience vision loss. Color vision is generally normal. Discrete rotatory nystagmus may be present. Retinal edema due to vascular incompetence may also be observed. ADVIRC is characterized by a peripheral retinal circumferential hyperpigmented band, punctuate white retinal opacities, fibrillar condensation of the vitreous, vascular abnormalities and neovascularisation. There are no identifiable systemic or skeletal abnormalities. ## Etiology ADVIRC is caused by mutations in BEST1 (11q12) (Val86Met, Val235Ala and Tyr236Cys), which encodes bestrophin-1 (expressed specifically in the retinal pigment epithelium (RPE)) forming a calcium activated chloride channel involved in regulation of voltage-dependent calcium channels. These mutations may alter normal splicing of BEST1 and result in in-frame alteration of bestrophin-1. However, functional consequences of such in-frame protein alterations remain undefined. ## Diagnostic methods Diagnosis of ADVIRC is based on low normal to non-recordable amplitudes of cones and rods on full-field electroretinogram (generalized rod and cone dysfunction), an abnormal electro-oculogram (EOG) (the light rise of EOG is decreased giving a reduced Arden ratio), and normal macular thickness on optical coherence tomography. Funduscopy typically reveals a concentric band of hyperpigmentation in the extreme periphery of one quadrant, with well-defined posterior demarcation, midperipheral chorioretinal atrophy and optic nerve dysplasia. Fundus autofluorescence imaging may show a normal autofluorescence pattern. Goldmann perimetry is often initially normal; however visual field tends to constrict mildly with age. Diagnosis is confirmed by genetic screening of BEST1. ## Differential diagnosis MRCS syndrome (see this term) is generally more severe than ADVIRC. However, both of these BEST1-related conditions show retinal pigmentary abnormalities, retinal dystrophy, microcornea, and early-onset cataract, conditions that overlap and likely form a continuum. Differential diagnosis also includes Best vitelliform macular dystrophy (BVMD), adult-onset foveomacular vitelliform dystrophy and autosomal recessive bestrophinopathy (see these terms). ## Genetic counseling Transmission is autosomal dominant and genetic counseling is possible. ## Management and treatment Management is mainly symptomatic. When choroidal neovascularization occurs, treatment may require laser photocoagulation or intravitreal delivery of anti-vascular endothelial growth factor agents such as bevacizumab and ranibizumab. Cystoid macular edema can be treated with conventional carbonic anhydrase inhibitors (CAIs) either systemically or topically. If presentation is complicated by glaucoma, conventional treatment may require topical agents to lower intraocular pressure, such as CAIs. Laser iridotomy may be advocated if angle closure glaucoma is a risk. Some cases may require additional surgical intervention. ## Prognosis Most patients retain a fairly good visual acuity throughout life, although visual acuity may decrease considerably due to macular edema, chorioretinal atrophy, or rarely, retinal detachment and vitreous hemorrhage. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal dominant vitreoretinochoroidopathy	c3888099	3,351	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3086	2021-01-23T18:11:32	{"gard": ["5507"], "mesh": ["C536352"], "omim": ["193220"], "umls": ["C3888099"], "icd-10": ["H35.5"], "synonyms": ["ADVIRC"]}
Schamberg's disease Rust-colored spots typical of Schamberg disease on the lower left leg and left foot of a 26-year-old Caucasian male. SpecialtyDermatology Schamberg's disease, (also known as "progressive pigmentary dermatosis of Schamberg",[1] "purpura pigmentosa progressiva" (PPP),[1] and "Schamberg's purpura"[1]) is a chronic discoloration of the skin found in people of all ages, usually only affecting the feet, legs or thighs or a combination. It may occur as a single event or subsequent bouts may cause further spread. It is most common in males.[2]:829 It is named after Jay Frank Schamberg, who described it in 1901. There is no known cure for this disease but it is not a life-threatening condition and is mainly of cosmetic concern, although, because it can appear so suddenly, so extensively and because it usually leaves permanent discoloration of the skin, it can cause understandable psychological concern. The skin lesions sometimes cause itching, which can be treated by applying cortisone cream. The cortisone cream will only help with the itching and does not improve the discoloration of the skin. Schamberg's disease causes no other symptoms beside skin discoloration and itching. The condition is caused by inflammation of capillaries near the surface of skin and subsequent leaking of red blood cells into surrounding tissues. As the red blood cells break down and get mostly resorbed, some of the iron released by the red blood cells remains in the skin and causes the characteristic rust-colored appearance. The cause of the capillary inflammation is usually unknown. ## Contents * 1 Symptoms * 2 Causes * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Recent research * 8 References * 9 External links ## Symptoms[edit] The lesions are most frequent on the lower limbs, but may occur anywhere on the body, including the hands, arms, torso and even the neck. They may vary in number and erupt in mass numbers. They consist of irregular patches of orange or brown pigmentation with characteristic "cayenne pepper" spots appearing within and at the edge of old lesions. There are usually no symptoms, although there may be some slight itching, but there is no pain. The eruption may persist for many years. The pattern of the eruption changes, with slow extension and often some clearing of the original lesions. Schamberg's disease, or progressive pigmented purpuric dermatosis, is a chronic discoloration of the skin which usually affects the legs and often spreads slowly. This disease is more common in males and may occur at any age from childhood onward. This condition is observed worldwide and has nothing to do with race or ethnic background.[3] ## Causes[edit] Schamberg's disease is caused by leaky blood vessels near the surface of the skin, capillaries, which allow red blood cells to slip through into the skin.[3] The red blood cells in the skin then fall apart and release their iron, which is released from hemoglobin.[3] The iron causes a rust color and this accounts for the orange tint of the rash.[4] Although the underlying cause for the leaky blood vessels is almost always unknown, researchers suggest some potential triggers.[5] These include the body's inflammatory reaction to some agent, such as a viral infection or a prescription or over the counter medication or supplement, such as thiamine and aspirin.[5] Even though there is no correlation with genetics, there have been a few cases where few people in a family had this condition.[5] Although a definite cause for capillary inflammation is almost always unknown, certain preventive measures can be taken.[6] Doctors may prescribe medications that enhance the circulation of blood, which can keep blood vessels strong and healthy.[6] ## Mechanism[edit] Schamberg's disease is a skin disorder that causes a discoloration of the lower extremities.[4] It usually occurs in the lower extremities and rarely elsewhere.[4] This condition is caused by leaky blood vessels near the surface of the skin.[7] The cause of the leaky capillaries is usually not known.[7] When the red blood cells escape the blood vessels, they end up close under the skin surface, where they break apart, releasing hemoglobin, which in turn breaks apart, releasing Iron.[7] (Iron is the part of hemoglobin that enables it to transfer oxygen from the lungs to the cells and carbon dioxide from the cells to the lungs.) The iron released into the skin gets bound up into a complex called hemosiderin, which causes the discoloration of the skin.[7] ## Diagnosis[edit] With a complete history, the results from visual examination, and the aid of appropriate laboratory testing, a dermatologist can usually determine whether the skin lesions are in fact due Schamberg's disease. Schamberg's disease can only be properly diagnosed by a healthcare provider. For a trained skin specialist such as a dermatologist, the condition is often readily diagnosed, because the visual appearance of the lesions on the skin itself usually suggests the possibility that the cause may be Schamberg's disease. While reviewing medical history is important to diagnose this condition, it is essential that the skin be physically examined. To ensure that the skin lesions are not caused by other skin conditions or infections, a doctor will often order a complete blood count (CBC) and other blood tests.[3] Blood test results are usually normal. They are performed primarily to rule out other bleeding disorders that cause purpura. Since Schamberg's disease is usually asymptomatic beyond the visible lesions themselves, few other tests are usually indicated. Micrograph of Schamberg disease, suggesting the spongiotic stage of a purpuric dermatitis. Additional testing may aid diagnosis. A skin biopsy may be taken to determine capillaritis of dermal vessels.[8] Capillaritis or pigmented purpura is skin condition that has brown-reddish patches on the skin, which is caused by leaky capillaries.[9] Such skin biopsies are sent to a laboratory for a pathological examination, where each biopsy is observed under a microscope.[3] A dermatologists may also perform a dermatoscopy.[3] ## Treatment[edit] There is no cure for Schamberg's disease, however, this condition is not life-threatening or a major health concern. The most usual problems that patients will encounter is discoloration of the skin and, occasionally, itching.[10] Itching may be improved by applying a cortisone cream. Rarely, in very severe or concerning cases, Colchicine treatment has been used to prevent recurrence.[10] Some recommend that patients take a vitamin C supplement to promote collagen production, but this is not proven to be helpful.[8] In cases where there is a known trigger, people should avoid re-exposure to that trigger, e.g., people suspected to be sensitive to food with artificial colors or preservatives should avoid foods containing those items.[7] This is because some people have been observed to be sensitive to these agents, and the body initiates an inflammatory reaction if exposed to them again, which causes further capillary inflammation and red blood cell leakage.[7] Several research studies have indicated that Schamberg's disease can be controlled and the number of lesions can be reduced with use a drug called aminaphtone.[11] This drug helps reduce capillary fragility and red blood cell leakage.[11] A study published in 2014 on the Journal of the German Society of Dermatology (Deutsche Dermatologische Gesellschaft) concludes that oral rutoside and ascorbic acid may be an efficient and well tolerated treatment for PPPD, with a recommendation for early treatment for best clinical outcome.[12] Many topical and systemic therapies for Schamberg disease have been tried without consistent results. A case series published in 2012 describes the treatment of five patients with Schamberg's disease of the lower extremities using Advanced Fluorescence Technology (AFT) pulsed light with favorable results.[13] ## Prognosis[edit] A patient with Schamberg's disease can live a normal and healthy life. Since there is no proven cure for this condition, the patient will have to endure the lesions on his or her skin. With appropriate treatments, the condition may get better.[3] Although the skin lesions are not life-threatening, it may cause a cosmetic concern for some individuals.[3] Skin lesions may cause psychological discomfort, where patients may require reassurance to help with stress and anxiety.[3] There are a few rare cases of T-cell lymphoma that have developed from Schamberg's disease.[3] This is not a cause for concern, since the risk factors associated with Schamberg's disease are relatively low. ## Recent research[edit] A few very small non-blinded studies of treatment with narrow-band ultraviolet light have been reported as promising.[14] ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 3. ^ a b c d e f g h i j "Schamberg Disease". DoveMed. Retrieved 2017-11-05. 4. ^ a b c "Causes Of Schamberg's Disease: Symptoms, Diagnosis & Treatment". www.tandurust.com. Retrieved 2017-11-05. 5. ^ a b c "What is Schamberg's Disease? - Skin Site". Skin Site. Retrieved 2017-11-05. 6. ^ a b "Schamberg's Disease Treatment - Home Remedies for Schamberg's Disease". www.best-home-remedies.com. Retrieved 2017-11-06. 7. ^ a b c d e f "Progressive Pigmentary Purpura - American Osteopathic College of Dermatology (AOCD)". www.aocd.org. Retrieved 2017-11-07. 8. ^ a b "Schamberg's Disease. Read About Schamberg's Disease". patient.info. Retrieved 2017-11-06. 9. ^ "Capillaritis \| DermNet New Zealand". www.dermnetnz.org. Retrieved 2017-11-07. 10. ^ a b "How to get rid of Schamberg's Disease \| Chronic Lesions on Legs". www.depression-guide.com. Retrieved 2017-11-06. 11. ^ a b de Godoy, José Maria Pereira; Batigália, Fernando (2009-06-11). "Aminaphtone in the control of Schamberg's disease". Thrombosis Journal. 7: 8. doi:10.1186/1477-9560-7-8. ISSN 1477-9560. PMC 2703626. PMID 19515261. 12. ^ Schober, S. M.; Peitsch, W. K.; Bonsmann, G.; Metze, D.; Thomas, K.; Goerge, T.; Luger, T. A.; Schneider, S. W. (2014). "Early treatment with rutoside and ascorbic acid is highly effective for progressive pigmented purpuric dermatosis". Journal of the German Society of Dermatology. 12 (12): 1112–9. doi:10.1111/ddg.12520. PMID 25482694. 13. ^ Manolakos, Danielle; Weiss, Jonathan; Glick, Brad (2012). "Treatment of Schamberg's Disease with Advanced Fluorescence Technology". Journal of Drugs in Dermatology. 11 (4): 528–29. PMID 22453593. Retrieved 8 September 2020. 14. ^ Summarized in 2015 by Dhali TK, Chahar M, Haroon MA (2015). "Phototherapy as an effective treatment for Majocchi's disease--case report". An Bras Dermatol. 90: 96–9. doi:10.1590/abd1806-4841.20153067. PMC 4323703. PMID 25672304.CS1 maint: multiple names: authors list (link) ## External links[edit] Classification D * ICD-10: L81.7 * ICD-9-CM: 709.09 * MeSH: D010859 * DiseasesDB: 30753 External resources * eMedicine: derm/327 * Patient UK: Schamberg disease * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Schamberg disease	c0036305	3,352	wikipedia	https://en.wikipedia.org/wiki/Schamberg_disease	2021-01-18T18:37:26	{"mesh": ["D010859"], "icd-9": ["709.09"], "icd-10": ["L81.7"], "wikidata": ["Q3281296"]}
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: "Hay fever in Japan" – news · newspapers · books · scholar · JSTOR (June 2016) (Learn how and when to remove this template message) Cryptomeria stamens and pollen Hay fever in Japan (花粉症, kafunshō, "pollen illness") is most commonly caused by pollen from Cryptomeria japonica (known as sugi in Japanese and often translated as "cedar" though it is not a member of the Cedrus genus) and Japanese cypress (known as hinoki), two native Japanese tree species. ## Contents * 1 Cause * 2 Pollen season * 3 Media information * 4 Commercial response * 5 Government response * 6 References * 7 External links ## Cause[edit] Hay fever was relatively uncommon in Japan until the early 1960s[citation needed]. Shortly after World War II, reforestation policies resulted in large forests of cryptomeria and Japanese cypress trees, which were an important resource for the construction industry. As these trees matured, they started to produce large amounts of pollen. Peak production of pollen occurs in trees of 30 years and older.[1] As the Japanese economy developed in the 1970s and 1980s, cheaper imported building materials decreased the demand for cryptomeria and Japanese cypress materials. This resulted in increasing forest density and aging trees, further contributing to pollen production and thus, hay fever. In 1970, about 50% of cryptomeria were more than 10 years old, and just 25% were more than 20 years old. By 2000, almost 85% of cryptomeria were over 20 years old, and more than 60% of trees were over 30 years old. This cryptomeria aging trend has continued since then, and though cryptomeria forest acreage has hardly increased since 1980, pollen production has continued to increase.[2] Furthermore, urbanization of land in Japan led to increasing coverage of soft soil and grass land by concrete and asphalt. Pollen settling on such hard surfaces can easily be swept up again by winds to recirculate and contribute to hay fever. As a result[citation needed], approximately 25 million people (about 20% of the population) currently suffer from this type of seasonal hay fever in Japan. ## Pollen season[edit] Cryptomeria pollen dispersal starts when average daily temperatures reach 10 degrees Celsius, partly depending on wind and terrain. Like the cherry blossom season, the pollen season moves from south to north across Japan, and from lower to higher elevations as spring progresses. For western and eastern Japan (including Tokyo and the surrounding Kantō region) this means the hay fever season starts between end of January and mid-February. The cryptomeria pollen season peaks in the second half of March - first half of April in these areas, then declining over the following six to eight weeks. Japanese cypress pollination lags cryptomeria by about a month. Some people are more sensitive to one of the two pollen types and therefore may experience allergic symptoms earlier or later than others. ## Media information[edit] Japanese media track and report on the developing pollen season in ways similar to the prediction and tracking of the cherry blossom season. The Japan Weather Association (JWA) and Weathernews Japan particularly collect and provide detailed information on pollen counts in locations across Japan. Besides daily or even hourly information during the pollen season, JWA provides a long term forecast in the fall of the expected severity of the coming season. The amount of flowering and pollen production depends primarily on the weather during the preceding summer, with long hot summers resulting in higher pollen production the following spring. JWA issues this long-term prediction as an indication of the relative severity of the coming pollen season compared to the average of the preceding ten years. ## Commercial response[edit] A sizable industry has developed in Japan around services and products that help people deal with hay fever, including protective wear such as coats with smooth surfaces, masks, and glasses; medication and remedies; household goods such as air-conditioner filters and fine window screens; and even "hay fever relief vacations" to low-pollen areas such as Okinawa and Hokkaido. Some people in Japan use medical laser therapy to desensitize the parts of their nose that are sensitive to pollen. ## Government response[edit] As the impact of the allergy season on the population has mounted, the Japanese government has increasingly focused attention on the issue. In 1990, the Ministry of Agriculture started a series of annual Hay Fever Conferences to coordinate among government institutions involved. The Liberal Democratic Party (the governing party at the time) submitted a motion on Anti Allergy and Hay Fever Measures in 1995, greatly influenced by increasing lobbying. The government budget for addressing pollen allergies has greatly increased since then. The 2002 budget for hay fever issues was 7,372,000,000 yen, 27 times the amount of seven years earlier. Administrative measures include basic research, improved forecasting and the development of therapies, as well as research to develop low pollen producing cryptomeria and Japanese cypress varieties. However, devastation of the forestry industry and the diminishing number of forestry workers as result of cheap and high quality imports has made actual implementation of measures in forest plantations slow. In 2005, the Forestry Agency announced plans to plant 600,000 low pollen-producing cryptomeria trees over the following five years. Nonetheless, cryptomeria forests in Japan cover a total of 45,300 square kilometres so a meaningful migration to such varieties proves to be a considerable challenge. ## References[edit] 1. ^ MEDICAL CONSULTATION RATE OF ALLERGIC RHINITIS AND POLLINOSIS SURVEILLANCE IN AICHI, JAPAN 2. ^ Yahoo Japan hay fever column 5302 detailing history of postwar cryptomeria forests (in Japanese) ## External links[edit] * Weathernews Japan Pollen Channel (in Japanese) * JWA pollen channel on tenki.jp (in Japanese) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hay fever in Japan	None	3,353	wikipedia	https://en.wikipedia.org/wiki/Hay_fever_in_Japan	2021-01-18T18:33:11	{"wikidata": ["Q15662673"]}
A rare neurologic disorder characterized by a unique non-REM and REM parasomnia with sleep breathing dysfunction, gait instability and repetitive episodes of respiratory insufficiency, as well as autoantibodies against IgLON5. Patients may present stridor, chorea, limb ataxia, abnormal ocular movements, and bulbar symptoms (i.e. dysphagia, dysarthria, episodic central hypoventilation) with normal brain MRI. Excessive day sleepiness and cognitive deterioration have also been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autoimmune encephalopathy with parasomnia and obstructive sleep apnea	c4707562	3,354	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=420789	2021-01-23T17:29:36	{"icd-10": ["G04.8"], "synonyms": ["Anti-IgLON5 disease", "Anti-IgLON5 syndrome"]}
A number sign (#) is used with this entry because Van Maldergem syndrome-2 (VMLDS2) is caused by homozygous or compound heterozygous mutation in the FAT4 gene (612411) on chromosome 4q28. Biallelic mutation in the FAT4 gene can also cause Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), a distinct disorder that shows overlapping features with VMLDS. Description Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). For a discussion of genetic heterogeneity of Van Maldergem syndrome, see 601390. Clinical Features Mansour et al. (2012) reported 2 unrelated patients (patients 1 and 6) with Van Maldergem syndrome-2. The patients had a distinctive facial appearance that included large fontanels, maxillary hypoplasia, micrognathia, flat face, blepharophimosis, telecanthus, broad nasal bridge, and microtia and atresia of the external auditory meatus resulting in hearing loss. Patients showed neonatal hypotonia, intellectual disability, poor growth and feeding, and respiratory problems due to tracheomalacia. One patient required a tracheostomy. Skeletal abnormalities included osteopenia, thickened skull base and frontal bones, narrow thorax, short clavicles, subluxation of the radial heads, and hand and feet abnormalities with clinodactyly due to flexion deformities. Both had small kidneys. Brain MRI of 1 patient showed nodular periventricular heterotopia and a dysmorphic corpus callosum; MRI of the other patient showed agenesis of the corpus callosum. Seizures were not noted. Neuhann et al. (2012) reported a boy, born of consanguineous Caucasian parents, with Van Maldergem syndrome. He presented at age 4 years with severe developmental delay, hypotonia, inability to walk, and no speech development. Physical examination showed talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, and bilateral microtia. Dysmorphic facial features included epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, downturned mouth, and dental malocclusion. He had a history of pharyngeal instability requiring a tracheostomy, poor feeding requiring tube feeding, inguinal hernia, hip subluxation, small kidneys, and genital abnormalities, including micropenis, cryptorchidism, and bifid scrotum. He also had a sacral dimple and an anteriorly placed anus. Brain MRI showed hypoplastic corpus callosum. Cappello et al. (2013) reported 2 sibs with VMLDS2. Features included periventricular nodular heterotopia, renal hypoplasia, hand anomalies, and skeletal dysplasia. Inheritance The transmission pattern of Van Maldergem syndrome-2 in the families reported by Cappello et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In 5 patients from 4 unrelated families with Van Maldergem syndrome-2, Cappello et al. (2013) identified biallelic mutations in the FAT4 gene (612411.0001-612411.0006). The first mutations were found by whole-exome sequencing and the subsequent mutations were found by whole-exome sequencing or targeted Sanger sequencing. All mutations segregated with the disorder in the families. Functional studies were not performed, but animal studies suggested that loss of Fat4 resulted in defects of neocortical development similar to those observed in the patients. Two of the patients had been reported by Mansour et al. (2012) and one by Neuhann et al. (2012). Animal Model Cappello et al. (2013) found that Fat4-null and Dchs1 (603057)-null embryonic mice had no evidence of a malformation of cortical development at days E16 and E18. Postnatal examination was precluded by the lethality of both genotypes. These findings indicated a discordance between the human and mice knockout models. However, intraventricular electroporation of shRNAs against Fat4 and Dchs1 in mouse embryos showed that the electroporated cells accumulated in the proliferative zones of the developing cortex, with significantly fewer cells reaching the cortical plate in the knockdown embryos compared to controls. This was observed also at later stages (P7), when many electroporated cells failed to migrate to the upper layers or accumulated below the gray matter, forming distinct regions of neuronal heterotopia that were reminiscent of the periventricular neuronal heterotopia phenotype in human patients with mutations in these genes. Immunostaining studies indicated increased proliferation of the cells in the ventricular and subventricular zones as well as a decrease in neuronal cell differentiation. These effects were countered by concurrent knockdown of Yap (606608), a transcriptional effector of the Hippo signaling pathway. These findings implicated Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Large anterior fontanels Face \- Flat midface \- Bitemporal narrowing \- Micrognathia \- Maxillary hypoplasia Ears \- Microtia \- Atresia of the external auditory canals \- Hearing loss, conductive \- Hearing loss, sensorineural Eyes \- Hypertelorism \- Short palpebral fissures \- Ptosis \- Epicanthal folds Nose \- Broad nasal bridge \- Thickening of the nasal alae Mouth \- Tented upper lip \- Downturned mouth \- High-arched palate \- Thick gums Teeth \- Dental malocclusion \- Irregular dentition RESPIRATORY \- Respiratory difficulties due to tracheomalacia Airways \- Tracheomalacia (tracheostomy may be required) CHEST External Features \- Narrow thorax Ribs Sternum Clavicles & Scapulae \- Short clavicles ABDOMEN Gastrointestinal \- Poor feeding \- Anteriorly positioned anus GENITOURINARY External Genitalia (Male) \- Hypospadias \- Bifid scrotum \- Micropenis Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Hypoplastic kidneys SKELETAL \- Joint laxity \- Skeletal dysplasia \- Osteopenia Skull \- Wide cranial sutures \- Thickened skull base \- Thickened frontal bones Spine \- Scoliosis Limbs \- Subluxation of the radial heads Hands \- Hand deformities \- Short fourth metacarpals \- Clinodactyly \- Flexion of the PIP joints \- Webbing of the fingers \- Syndactyly, cutaneous Feet \- Foot deformities \- Talipes equinovarus \- Short fourth metatarsals SKIN, NAILS, & HAIR Skin \- Sacral dimple MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Mental retardation \- Intellectual disability \- Periventricular nodular heterotopia \- Subcortical band heterotopia \- Thin corpus callosum MISCELLANEOUS \- Onset at birth \- Some features may be variable MOLECULAR BASIS \- Caused by mutation in the FAT atypical cadherin 4 gene (FAT4, 612411.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	VAN MALDERGEM SYNDROME 2	c1832390	3,355	omim	https://www.omim.org/entry/615546	2019-09-22T15:51:50	{"doid": ["0080586"], "mesh": ["C536530"], "omim": ["615546"], "orphanet": ["314679"]}
Beighton (1981) reported a kindred in which 20 members in at least 3 generations had opalescent teeth, blue sclerae, wormian bones, and normal height. In the 6 affected individuals who had skeletal surveys, moderate generalized osteoporosis was noted; the older individuals had mild flattening and biconcavity of the vertebral bodies. Only 1 affected individual, an adolescent male, had pronounced platybasia and had sustained 10 femoral fractures on mild trauma. Only the proband had hearing loss. No individuals had joint hyperextensibility. It is not known whether the syndrome is the same as OI type I (166200). Radiology \- Moderate generalized osteoporosis \- Mild flattening and biconcavity of the vertebral bodies \- Platybasia uncommon Skel \- Multiple fractures rare Eyes \- Blue sclerae Growth \- Normal height Skull \- Wormian bones Teeth \- Opalescent teeth Joints \- No joint hyperextensibility Inheritance \- Autosomal dominant \- ? same as OI type I (166200) Ears \- Hearing loss uncommon ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	OSTEOGENESIS IMPERFECTA WITH OPALESCENT TEETH, BLUE SCLERAE AND WORMIAN BONES, BUT WITHOUT FRACTURES	c0023931	3,356	omim	https://www.omim.org/entry/166230	2019-09-22T16:37:01	{"doid": ["0110335"], "mesh": ["D010013"], "omim": ["166230", "166200"], "orphanet": ["216796", "666"], "synonyms": ["Adair-Dighton syndrome", "Mild osteogenesis imperfecta", "Non-deforming osteogenesis imperfecta", "OI type 1", "Van der Hoeve syndrome"]}
Protein S deficiency Protein S structure SpecialtyHematology SymptomsPurpura fulminans[1] CausesVitamin K deficiency[1] Diagnostic methodCoagulation test[1] TreatmentHeparin, Warfarin[2] Protein S deficiency is a disorder associated with increased risk of venous thrombosis.[1] Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa.[3] Decreased (antigen) levels or impaired function of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free, only free protein S has activated protein C cofactor activity[medical citation needed] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 4.2 Types * 5 Treatment * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] Among the possible presentation of protein S deficiency are:[1][2][4] * Thrombosis of lower extremities * Superficial thrombophlebitis * Redness in affected area * Purpura fulminans ## Cause[edit] Human Chr 3 In terms of the cause of protein S deficiency it can be in inherited via autosomal dominance. A mutation in the PROS1 gene triggers the condition. The cytogenetic location of the gene in question is chromosome 3, specifically 3q11.1[5][6] Protein S deficiency can also be acquired due to vitamin K deficiency, treatment with warfarin, liver disease, and acute thrombosis (antiphospholipid antibodies may also be a cause as well)[1] ## Pathophysiology[edit] In regards to the mechanism of protein S deficiency, Protein S is made in liver cells and the Endothelium.[7][8] Protein S is a cofactor of APC both work to degrade factor V and factor VIII. It has been suggested that Zn2+ might be necessary for Protein S binding to factor Xa.[2][9] Mutations in this condition change amino acids, which in turn disrupts blood clotting. Functional protein S is lacking, which normally turns off clotting proteins, this increases risk of blood clots.[5] ## Diagnosis[edit] PTT blood tests Vacutainer tube The diagnosis for deficiency of protein S can be done via reviewing family history of condition and genetic testing, as well as the following:[1][10][11] * Protein S antigen test * Coagulation test (prothrombin time test) * Thrombotic disease investigation * Factor V Leiden test ### Differential diagnosis[edit] Among the possibilities for differential diagnosis of protein S deficiency are- Antiphospholipid syndrome, disseminated intravascular coagulation and antithrombin deficiency (though this list is not exhaustive)[2] ### Types[edit] There are three types of hereditary protein S deficiency:[2][5] * Type I – decreased protein S activity: decreased total protein S levels, as well as decreased free protein S levels * Type II – decreased in regards to the cofactor activity of the protein * Type III – decreased protein S activity: decreased free protein S levels (normal total protein S levels) ## Treatment[edit] Dabigatran In terms of treatment for protein S deficiency the following are consistent with the management (and administration of) individuals with this condition (the prognosis for inherited homozygotes is usually in line with a higher incidence of thrombosis for the affected individual[1]):[2][9] * Unfractionated heparin (w/ warfarin) * LMWH/Low molecular weight heparin * Dabigatran * Direct Factor Xa Inhibitors * Graduated compressed stocking * High degree of prophylaxis ## References[edit] 1. ^ a b c d e f g h "Protein S Deficiency. Learn about Protein S Deficiency \| Patient". Patient. Retrieved 2016-10-16. 2. ^ a b c d e f "Protein S Deficiency: Background, Pathophysiology, Epidemiology". 2016-05-02. Cite journal requires `\|journal=` (help) 3. ^ "Protein S: Reference Range, Collection and Panels, Interpretation". 2016-06-01. Cite journal requires `\|journal=` (help) 4. ^ "Congenital protein C or S deficiency: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 16 October 2016. 5. ^ a b c Reference, Genetics Home. "PROS1 gene". Genetics Home Reference. Retrieved 16 October 2016. 6. ^ Reference, Genetics Home. "protein S deficiency". Genetics Home Reference. Retrieved 16 October 2016. 7. ^ "Endothelial Cells, Volume 1, 1988, p158, By Una S." books.google.co.uk. Retrieved 24 January 2019. 8. ^ Burstyn-Cohen, T.; Heeb, M. J.; Lemke, G. (2009). "J Clin Invest. 2009 Oct, 119(10):2942-53, Burstyn-Cohen T1, Heeb MJ, Lemke G: Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis". The Journal of Clinical Investigation. 119 (10): 2942–53. doi:10.1172/JCI39325. PMC 2752078. PMID 19729839. 9. ^ a b Ten Kate, M. K.; Van Der Meer, J. (1 November 2008). "Protein S deficiency: a clinical perspective". Haemophilia. 14 (6): 1222–1228. doi:10.1111/j.1365-2516.2008.01775.x. ISSN 1365-2516. PMID 18479427. S2CID 26719614. 10. ^ "Protein S blood test: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 16 October 2016. 11. ^ "Protein S deficiency - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 16 October 2016. ## Further reading[edit] * ten Kate M, Mulder R, Platteel M, Brouwer J, van der Steege G, van der Meer J (2006). "Identification of a novel PROS1 c.1113T-->GG frameshift mutation in a family with mixed type I/type III protein S deficiency". Haematologica. 91 (8): 1151–2. PMID 16885060. * García de Frutos, Pablo; Fuentes-Prior, Pablo; Hurtado, Begoña; Sala, Núria (17 October 2007). "Molecular basis of protein S deficiency". Thrombosis and Haemostasis. 98 (3): 543–56. doi:10.1160/TH07-03-0199. hdl:10261/89408. ISSN 0340-6245. PMID 17849042. Retrieved 16 October 2016. * Wypasek, Ewa; Undas, Anetta (1 August 2016). "Protein C and protein S deficiency - practical diagnostic issues". Advances in Clinical and Experimental Medicine. 22 (4): 459–467. ISSN 1899-5276. PMID 23986205. ## External links[edit] * Protein S deficiency at Curlie Classification D * ICD-10: D68.5 * ICD-9-CM: 289.81 * OMIM: 176880 * MeSH: D018455 * DiseasesDB: 10814 * SNOMED CT: 1563006 External resources * eMedicine: med/1924 * Patient UK: Protein S deficiency Wikimedia Commons has media related to Thrombosis. Scholia has a topic profile for Protein S deficiency. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical 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MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia * Thrombocytopenic purpura: ITP * Evans syndrome * TM * TTP * Upshaw–Schulman syndrome * Heparin-induced thrombocytopenia * May–Hegglin anomaly Platelet function * adhesion * Bernard–Soulier syndrome * aggregation * Glanzmann's thrombasthenia * platelet storage pool deficiency * Hermansky–Pudlak syndrome * Gray platelet syndrome Clotting factor * Hemophilia * A/VIII * B/IX * C/XI * von Willebrand disease * Hypoprothrombinemia/II * Factor VII deficiency * Factor X deficiency * Factor XII deficiency * Factor XIII deficiency * Dysfibrinogenemia * Congenital afibrinogenemia Signs and symptoms * Bleeding * Bruise * Hematoma * Petechia * Purpura * Nonthrombocytopenic purpura By site * head * Epistaxis * Hemoptysis * Intracranial hemorrhage * Hyphema * Subconjunctival hemorrhage * torso * Hemothorax * Hemopericardium * Pulmonary hematoma * abdomen * Gastrointestinal bleeding * Hemobilia * Hemoperitoneum * Hematocele * Hematosalpinx * joint * Hemarthrosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Protein S deficiency	c0242666	3,357	wikipedia	https://en.wikipedia.org/wiki/Protein_S_deficiency	2021-01-18T18:55:35	{"gard": ["4524"], "mesh": ["D018455"], "umls": ["C0242666"], "icd-9": ["289.81"], "wikidata": ["Q3043153"]}
Severe congenital nemaline myopathy is a severe form of nemaline myopathy (NM; see this term) characterized by severe hypotonia with little spontaneous movement in neonates. ## Epidemiology The annual incidence of NM has been estimated at 1/50,000 live births and the severe congenital form might represent 10-20% of all cases. ## Clinical description Neonates have sucking and swallowing difficulties, and gastroesophageal reflux, which leads to failure to thrive. Involvement of diaphragm and intercostal muscles contributes to respiratory insufficiency. Cardiomyopathy and arthrogryposis may occur. Survival after infancy is rare. ## Etiology The ACTA1 (1q42.13) and NEB (2q22) genes are associated with this form of NM. ## Genetic counseling NM is transmitted in an autosomal recessive fashion or occurs sporadically. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Severe congenital nemaline myopathy	c3711389	3,358	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171430	2021-01-23T17:11:17	{"gard": ["12821"], "mesh": ["C579880"], "omim": ["161800", "256030", "615348", "615731", "616165"], "icd-10": ["G71.2"]}
## Summary ### Clinical characteristics. Mitochondrial DNA (mtDNA)-associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) are part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation. * Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms typically between ages three and 12 months, often following a viral infection. Decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness is typically associated with psychomotor retardation or regression. Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure. * NARP is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. Individuals with NARP can be relatively stable for many years, but may suffer episodic deterioration, often in association with viral illnesses. ### Diagnosis/testing. The diagnosis of mtDNA-associated Leigh syndrome is established clinically in a proband with progressive neurologic disease with motor and intellectual developmental delay, signs and symptoms of brain stem and/or basal ganglia disease, raised lactate concentration in blood and/or cerebrospinal fluid, and any one of the following: * Characteristic features on brain imaging * Typical neuropathologic changes * Typical neuropathology in a similarly affected sib Identification of a pathogenic variant in one of the 14 mitochondrial genes known to be involved in mtDNA-associated Leigh syndrome confirms the diagnosis. The diagnosis of NARP is established in a proband with suggestive clinical features and identification of a heteroplasmic pathogenic variant in one of the three mitochondrial genes known to be involved in NARP. ### Management. Treatment of manifestations: Supportive treatment includes use of sodium bicarbonate or sodium citrate for acute exacerbations of acidosis and antiepileptic drugs for seizures. Dystonia is treated with benzhexol, baclofen, tetrabenazine, and gabapentin alone or in combination, or by injections of botulinum toxin. Anticongestive therapy may be required for cardiomyopathy. Regular nutritional assessment of daily caloric intake and adequacy of diet and psychological support for the affected individual and family are essential. Surveillance: Neurologic, ophthalmologic, and cardiologic evaluations at regular intervals to monitor progression and appearance of new symptoms. Care is frequently coordinated by a biochemical geneticist in North America, and by a metabolic physician/pediatrician elsewhere in the world. Agents/circumstances to avoid: Sodium valproate and barbiturates, anesthesia, and dichloroacetate. ### Genetic counseling. Mitochondrial DNA-associated Leigh syndrome and NARP are transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In most cases, the mother has a much lower proportion of abnormal mtDNA than the proband and usually remains asymptomatic or develops only mild symptoms. Occasionally the mother has a substantial proportion of abnormal mtDNA and develops severe symptoms in adulthood. Offspring of males with a mtDNA pathogenic variant are not at risk; all offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. The risk to offspring of a female proband of developing symptoms depends on the tissue distribution and proportion of abnormal mtDNA. Prenatal testing and preimplantation genetic testing for couples at increased risk of having children with mtDNA-associated Leigh syndrome or NARP are possible by analysis of mtDNA extracted from non-cultured fetal cells or from single blastomeres, respectively. However, long-term outcome cannot be reliably predicted on the basis of molecular genetic test results. ## Diagnosis ### Suggestive Findings #### Mitochondrial DNA-Associated Leigh Syndrome Mitochondrial DNA-associated Leigh syndrome should be suspected in individuals with the following findings. Clinical features * Motor and intellectual developmental delay, usually with neurodevelopmental regression * Signs and symptoms of brain stem and/or basal ganglia disease (e.g., respiratory abnormalities, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia) * Seizures * Progressive neurologic disease Laboratory findings * Lactate concentration in blood is increased. Elevation tends to be more marked in postprandial samples. * Lactate concentration in cerebrospinal fluid (CSF) is increased. Increased lactate is more consistent in CSF than blood samples, but is not an invariant finding. * Plasma amino acids may show increased alanine concentration, reflecting persistent hyperlactatemia. * Decreased plasma citrulline concentration was reported in individuals with the m.8993T>G pathogenic variant [Rabier et al 1998]. * Urine organic acid analysis often detects lactic aciduria and Krebs cycle intermediates. Note: Identification of increased methylmalonic acid or proprionic acid is suggestive of other specific types of Leigh syndrome or organic acidemias (e.g., 3-methylglutaconic aciduria with sensorineural deafness, encephalopathy and Leigh-like (MEGDEL) syndrome, succinylCoA-ligase deficiency, methylmalonic aciduria, propionic aciduria) (see Differential Diagnosis). Radiographic findings on brain imaging * Characteristic bilateral symmetric hypodensities in the basal ganglia on computed tomography or bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T2-weighted magnetic resonance imaging (MRI) [Bonfante et al 2016] * Proton magnetic resonance spectroscopy can also be useful in detecting regional elevations in brain lactate levels. * In individuals with NARP, cerebral and cerebellar atrophy may be noted on brain MRI. Note: Specific brain lesions affecting the mammillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum appear to be characteristic of Leigh syndrome caused by pathogenic variants in the nuclear gene NDUFAF2 [Barghuti et al 2008, Hoefs et al 2008, Herzer et al 2010]. MEGDEL syndrome is associated with a distinctive brain MRI pattern affecting the basal ganglia, especially the putamen. Initially there are T2-weighted signal changes of the pallidum, and later swelling of the putamen and caudate nucleus with an "eye" representing early sparing of the dorsal putamen, followed by progressive involvement of the putamina [Wortmann et al 2015] (see Differential Diagnosis). Histopathology of muscle tissue shows only minimal if any changes, such as accumulation of intracytoplasmic neutral lipid droplets. Ragged red fibers are rarely (if ever) seen. Cytochrome c oxidase-negative fibers are occasionally found in individuals with Leigh syndrome caused by certain mtDNA and nuclear gene variants. Note: (1) Although muscle biopsy is only occasionally abnormal, when it is abnormal it can be as much of a contributor to diagnostic certainty as respiratory chain enzymes or molecular testing. (2) If an affected individual is having a muscle biopsy for enzyme testing, histologic examination should also be performed. Respiratory chain enzyme studies. Biochemical analysis of tissue biopsies or cultured cells often detects deficient activity of one or more of the respiratory chain enzyme complexes. Isolated defects of complex I or complex IV are the most common enzyme abnormalities observed and can help guide subsequent molecular genetic testing of mtDNA or nuclear genes. Biochemical results can also be normal, usually in individuals with mtDNA pathogenic variants affecting complex V subunits such as the pathogenic variants at mitochondrial nucleotides 8993 and 9176 (see Table 5). * Skeletal muscle is usually the tissue of choice for enzyme studies. * Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts. * Approximately 10%-20% of individuals with normal skeletal muscle respiratory chain enzymes may have an enzyme defect detected in liver or cardiac muscle, particularly if those tissues are involved clinically [Thorburn et al 2004]. #### NARP NARP should be suspected in individuals with the clinical, electrophysiologic, and radiographic features listed below. However, not all features may be present, at least initially, and the diagnosis should be suspected in individuals with several of the following features: * Muscle weakness * Neuropathy * Ataxia * Seizures * Retinitis pigmentosa or optic atrophy * Learning difficulties * Other: * Electromyography and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy). * Cerebral and cerebellar atrophy may be noted on brain MRI. * Electroretinogram may reveal abnormalities (including small-amplitude waveform) or may be normal. ### Establishing the Diagnosis Leigh syndrome. The diagnosis of mtDNA-associated Leigh syndrome is established in a proband fulfilling the criteria for Leigh syndrome (see following) in whom a heteroplasmic or homoplasmic pathogenic variant in one of the genes listed in Table 1a or Table 1b has been identified. Stringent diagnostic criteria for Leigh syndrome were defined by Rahman et al [1996]:* * Progressive neurologic disease with motor and intellectual developmental delay * Signs and symptoms of brain stem and/or basal ganglia disease * Raised lactate concentration in blood and/or cerebrospinal fluid (CSF) * One or more of the following: * Characteristic features of Leigh syndrome on neuroradioimaging (see Suggestive Findings) * Typical neuropathologic changes: multiple focal symmetric necrotic lesions in the basal ganglia, thalamus, brain stem, dentate nuclei, and optic nerves. Histologically, lesions have a spongiform appearance and are characterized by demyelination, gliosis, and vascular proliferation. Neuronal loss can occur, but typically the neurons are relatively spared. * Typical neuropathology in a similarly affected sib * Note: Prior to the development of modern imaging techniques, definitive diagnosis of Leigh syndrome was based on characteristic neuropathologic features and thus could only be made postmortem. Baertling et al [2014] described similar diagnostic criteria that allow for the diagnosis of Leigh syndrome in the absence of raised lactate levels. Their criteria include the following: * Neurodegenerative disease with variable symptoms resulting from mitochondrial dysfunction * Mitochondrial dysfunction caused by a hereditary genetic defect * Bilateral CNS lesions that can be associated with further abnormalities in diagnostic imaging Lake et al [2016] revised the diagnostic criteria to include "abnormal energy metabolism indicated by a severe defect in oxidative phosphorylation (OXPHOS) or pyruvate dehydrogenase complex (PDHc) activity, a molecular diagnosis in a gene related to mitochondrial energy generation, or elevated serum or CSF lactate." NARP. Strict diagnostic criteria for NARP have not yet been established. The diagnosis of NARP is established in a proband with the above suggestive clinical features and identification of a mtDNA pathogenic variant on molecular genetic testing. Molecular genetic testing approaches for Leigh syndrome and NARP can include targeted single-gene testing, mitochondrial genome sequencing, and more comprehensive genomic testing. Option 1 (preferred in children)* 1. Targeted analysis for the two common MT-ATP6 pathogenic variants (see Table 1) is performed concurrently with deletion/duplication analysis on leukocyte DNA. 2. Mitochondrial genome sequencing is performed next if an MT-ATP6 pathogenic variant or deletion/duplication is not detected. Option 2 (preferred in adults)* 1. Targeted sequence analysis of leukocyte DNA for the two common MT-ATP6 pathogenic variants can be performed first (see Table 1). 2. Mitochondrial genome sequencing is performed next if an MT-ATP6 pathogenic variant is not detected by targeted analysis. Option 3. Mitochondrial genome sequencing is performed first (see Table 1). * Note: (1) Most mtDNA pathogenic variants are "heteroplasmic" (i.e., mutated mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the mutation load may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [Rahman et al 2001]; therefore, in adults with milder symptoms and for asymptomatic older maternal relatives, the pathogenic variant may only be detected in tissues such as hair follicles, urine sediment cells, or skeletal muscle, which is the most reliable source of mtDNA for analysis [McDonnell et al 2004, Shanske et al 2004]. (3) Leukocyte (vs skeletal muscle) testing is acceptable in children, particularly when using next-generation sequencing methods, which allow detection of very low heteroplasmy levels. (4) Deletions are not usually detectable in leukocyte DNA from adults; in this age group, muscle (or urinary epithelial cells) is the tissue of choice for analysis. (5) Deletions/duplications of mtDNA are an extremely rare cause of Leigh syndrome in adults. The authors are not aware of any published reports of children with Leigh syndrome, Leigh-like syndrome, or NARP where a pathogenic mtDNA variant was not detected in blood. More comprehensive genomic testing (when available) including exome 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. See Table 1a for the most common genetic causes (i.e., pathogenic variants of any one of the mtDNA-encoded genes included in this table account for >1% of mtDNA-associated Leigh syndrome and NARP) and Table 1b for less common genetic causes (i.e., pathogenic variants of any one of the mitochondrial genes included in this table are reported in only a few families). ### Table 1a. Molecular Genetics of Mitochondrial DNA-Associated Leigh Syndrome and NARP: Most Common Genetic Causes View in own window Gene 1, 2% of mtDNA-Associated Leigh Syndrome (LS) or NARP Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 MT-ATP6mtDNA-associated LS~50% 6>95%<5% 7 NARP>50% 8>95%None MT-ND3mtDNA-associated LS21 individuals 9>95%None MT-ND5mtDNA-associated LS48 individuals 10>95%None MT-ND6mtDNA-associated LS22 individuals 11>95%None NARP1 individual>95%None Pathogenic variants in the genes included in this table account for >1% of mtDNA-associated Leigh syndrome and NARP. 1\. Genes are listed alphabetically. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on pathogenic variants detected. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small deletions/insertions and missense and nonsense variants; typically, larger deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Single-gene deletions have not been reported in mtDNA disease so deletion/duplication analysis is typically targeted to the entire mitochondrial genome. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a microarray designed to detect deletions or duplications in the mtDNA genome. 6\. Of 106 individuals with Leigh or Leigh-like syndrome, ten of the 30 individuals with mtDNA pathogenic variants had variants in MT-ATP6 [Ogawa et al 2017]. 7\. Yamashita et al [2008] 8\. The variant m.8993T>G is most common; m.8993T>C has also been described [Rantamäki et al 2005]. 9\. Lebon et al [2003], Bugiani et al [2004] Crimi et al [2004]. McFarland et al [2004], Leshinsky-Silver et al [2005], Sarzi et al [2007], Lim et al [2009], Naess et al [2009], Leshinsky-Silver et al [2010], Levy et al [2014], Chen et al [2015], Han et al [2015] 10\. 36 individuals had pathogenic variant m.13513G>A [Taylor et al 2002, Chol et al 2003, Crimi et al 2003, Kirby et al 2003, Lebon et al 2003, Petruzzella et al 2003, Bugiani et al 2004, Sudo et al 2004, Blok et al 2007, Ruiter et al 2007, Zhadanov et al 2007, Brautbar et al 2008, Shanske et al 2008, Wang et al 2008, Lim et al 2009, Ching et al 2013, Monlleo-Neila et al 2013, Han et al 2015]. 11\. Total of 22 reported probands: 14 probands with m.14487T>C (1 of whom had NARP), five probands with m.14459G>A, one with m.14600G>A; one with m.14439G>A, and an additional proband with no specified variant [Kirby et al 2000, Funalot et al 2002, Lebon et al 2003, Ugalde et al 2003, Bugiani et al 2004, Malfatti et al 2007, Naess et al 2009, Wang et al 2009, Dermaut et al 2010, Leshinsky-Silver et al 2011, Ronchi et al 2011, Tarnopolsky et al 2013, Uehara et al 2014, Han et al 2015] ### Table 1b. Molecular Genetics of mtDNA-Associated Leigh Syndrome and NARP: Less Common Genetic Causes View in own window Gene 1, 2CommentsReferences MT-CO33 probands: 2 w/variant m.9478T>C, 1 w/variant m.9357insCTiranti et al [2000], Mkaouar-Rebai et al [2011] MT-ND19 probands (only 1 w/LLS): 4 probands w/var m.3697G>A, 2 w/var m.3980G>A, 1 w/var m.3928G>C LS, 1 w/var m.3308T>C, 1 w/var m.3688G>ACampos et al [1997], Moslemi et al [2008], Valente et al [2009], Caporali et al [2013], Wray et al [2013], Negishi et al [2014], Spangenberg et al [2016] MT-ND22 probands w/var m.4681T>CHinttala et al [2006], Ugalde et al [2007] MT-ND48 probands: 4 w/var m.1777C>A, 1 w/var m.11984T>C, 1 w/var m.11240C>T, 1 w/var m.11246G>A, 1 path var not specifiedKomaki et al [2003], Bugiani et al [2004], Vanniarajan et al [2006], Hadzsiev et al [2010], Uehara et al [2014], Han et al [2015], Xu et al [2017] MT-TI4 probands: 2 w/var m.4296G>A, 2 sibs w/var m.4290T>CLimongelli et al [2004], Cox et al [2012], Martikainen et al [2013] MT-TK12 probands w/Leigh syndrome: all w/var m.8344A>GBerkovic et al [1989], Zeviani et al [1991], Silvestri et al [1993], Rahman et al [1996], Buda et al [2013] MT-TL12 probands w/var.m.3243A>GVilarinho et al [1997] MT-TL22 sibs w/var m.12311T>CVeerapandiyan et al [2016] MT-TV5 probands: 4 w/LS & homoplasmic pathogenic variants (1 w/var m.1624C>T, 3 w/var m.1644G>A), 1 proband w/NARP & 71% abnormal mtDNA (m.1606G>A)Chalmers et al [1997], McFarland et al [2002], Sacconi et al [2002], Fraidakis et al [2014] MT-TW6 probands w/LS: 3 w/an insertion at position 5537, 2 w/var m.5559A>G, 1 w/var m.5523T>GSantorelli et al [1997], Tulinius et al [2003], Mkaouar-Rebai et al [2009], Duff et al [2015] Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of mtDNA-associated Leigh syndrome and NARP). LLS = Leigh-like syndrome; LS = Leigh syndrome 1\. Genes are listed alphabetically. 2\. See Table A. Genes and Databases for chromosome locus and protein. ## Clinical Characteristics ### Clinical Description Mitochondrial DNA-associated Leigh syndrome (subacute necrotizing encephalomyelopathy). Onset of symptoms can be from the neonatal period through adulthood but is typically between age three and 12 months, often following a viral infection. Later onset (i.e., age >1 year, including presentation in adulthood) and slower progression occur in up to 25% of individuals [Sofou et al 2014]. Leigh syndrome is a progressive neurodegenerative disorder. Initial features may be nonspecific, such as failure to thrive and persistent vomiting. Decompensation (often with raised blood and/or CSF lactate concentrations) during an intercurrent illness is typically associated with psychomotor retardation or regression. A period of recovery may follow the initial decompensation, but the individual rarely returns to the developmental status achieved prior to the presenting illness. Neurologic features include hypotonia, spasticity, dystonia, muscle weakness, hypo- or hyperreflexia, seizures (myoclonic or generalized tonic-clonic), infantile spasms, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Brain stem lesions may cause respiratory difficulty (apnea, hyperventilation, or irregular respiration), bulbar problems such as abnormal swallowing and speech, persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia). Ophthalmologic findings include optic atrophy, retinitis pigmentosa, and eye movement disorders. Pigmentary retinopathy occurs in up to 40% of individuals with a mtDNA 8993 pathogenic variant [Santorelli et al 1993]. Other. Individuals with Leigh syndrome may present with extraneurologic multisystem manifestations. These can include cardiac (hypertrophic or dilated cardiomyopathy [Wang et al 2008, Hadzsiev et al 2010]), hepatic (hepatomegaly or liver failure [Van Hove et al 2010, Duff et al 2015]), or renal (renal tubulopathy or diffuse glomerulocystic kidney damage [López et al 2006, Naess et al 2009] manifestations. Leigh syndrome as a whole is the most phenotypically heterogeneous mitochondrial disease, with more than 200 associated phenotypes [Rahman et al 2017]. Most affected individuals have episodic deterioration interspersed with "plateaus" during which development may be quite stable or even show some progress. The duration of these plateaus is variable and in rare cases may be ten years or more. More typically, death occurs by age two to three years, most often from respiratory or cardiac failure. In undiagnosed individuals, death may appear to be sudden and unexpected. Leigh-like syndrome. The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and CSF lactate levels, or incomplete evaluation. The heterogeneous clinical presentation that occurs in Leigh syndrome is also present in Leigh-like syndromes. NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. NARP is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, pigmentary retinopathy, seizures, learning difficulties, and dementia. Other clinical features include short stature, sensorineural hearing loss, progressive external ophthalmoplegia, cardiac conduction defects (heart block) and a mild anxiety disorder [Santorelli et al 1997, Sembrano et al 1997, Rawle & Larner 2013]. Visual symptoms may be the only clinical feature. One individual had obstructive sleep apnea requiring tracheostomy and nocturnal mechanical ventilation [Sembrano et al 1997]. Individuals with NARP can be relatively stable for many years, but may experience episodic deterioration, often in association with viral illnesses. Intermediate phenotypes in the continuum. Maternal relatives of individuals with Leigh syndrome or NARP can have any one or a combination of the individual symptoms associated with Leigh syndrome, NARP, or other mitochondrial disorders. These include mild learning difficulties, muscle weakness, night blindness, deafness, diabetes mellitus, migraine, or sudden unexpected death. ### Genotype-Phenotype Correlations For most mtDNA pathogenic variants, it is difficult to distinguish a correlation between genotype and phenotype because clinical expression of a mtDNA pathogenic variant is influenced not only by the pathogenicity of the variant itself but also by the relative amount of mutated and wild type mtDNA (the heteroplasmic mutant load), the variation in the proportion of abnormal mtDNA among different tissues, and the energy requirements of brain and other tissues, which may vary with age. The m.8993T>G and m.8993T>C pathogenic variants probably show the strongest genotype-phenotype correlation of any mtDNA pathogenic variants. Notably, they show very little tissue-dependent or age-dependent variation in the proportion of abnormal mtDNA [White et al 1999c] as well as a strong correlation between the proportion of abnormal mtDNA and disease severity, allowing White et al [1999a] to generate logistic regression models that predict the probability of a severe outcome in an individual based on the measured proportion of abnormal mtDNA of m.8993T>G and m.8993T>C (Figure 1). Note, however, that in such retrospective studies it is not possible to completely avoid ascertainment bias, and the data should be regarded as broadly indicative rather than precise. #### Figure 1. Estimated probability of a severe outcome (95% CI) for an individual with the mtDNA m.8993T>G or m.8993T>C variant, based on the proportion of abnormal mtDNA (mutant load) in the individual. A severe outcome is defined as severe symptoms (more...) * m.8993T>G. Individuals in whom the proportion of abnormal mtDNA is below 60% are usually asymptomatic, or have only mild pigmentary retinopathy or migraine headaches; however, asymptomatic adults with levels of abnormal mtDNA as high as 75% have been reported [Tatuch et al 1992, Ciafaloni et al 1993]. As a generalization, individuals with moderate levels (~70%-90%) of the m.8993T>G pathogenic variant present with the NARP phenotype, while those with more than 90% abnormal mtDNA have maternally inherited Leigh syndrome [Claeys et al 2016]. Note: Overlap in the proportion of abnormal mtDNA is observed between some asymptomatic individuals and others with NARP, and between some individuals with NARP and others with Leigh syndrome. * m.8993T>C is a less severe variant than m.8993T>G, and virtually all symptomatic individuals with m.8993T>C ve more than 90% abnormal mtDNA. Genotype-phenotype correlations are much weaker for other mtDNA pathogenic variants detected in multiple unrelated individuals with Leigh syndrome (e.g., m.3243A>G in MT-TL1, m.8344A>G in MT-TK, m.9176T>C in MT-ATP6, m.14459G>A and m.14487T>C in MT-ND6, m.10158T>C and m.10191T>C in MT-ND3, and m.13513G>A in MT-ND5). The presence of any of these variants in individuals with symptoms of Leigh syndrome identifies the genetic cause of the disorder. However, unlike the m.8993T>G and m.8993T>C variants, it is usually not possible to interpret the heteroplasmic mutant load to predict outcome (e.g., in asymptomatic family members or in prenatal diagnosis) unless the value is near 0% or near 100%. ### Penetrance See Genotype-Phenotype Correlations. ### Nomenclature Leigh syndrome was originally described by Leigh [1951] as "subacute necrotizing encephalomyelopathy" in an infant age seven months. Individuals with Leigh syndrome caused by a mtDNA pathogenic variant are often referred to as having "maternally inherited Leigh syndrome" (MILS) [Ciafaloni et al 1993]. ### Prevalence The following prevalence data are for all Leigh syndrome. In southeastern Australia, Leigh syndrome occurs in 1:77,000 infants, and the combined birth prevalence of Leigh syndrome plus Leigh-like syndrome was 1:40,000 [Rahman et al 1996]. In western Sweden, the prevalence of Leigh syndrome in preschool children was 1:34,000 [Darin et al 2001]. Thus, the prevalence of Leigh syndrome is likely to be 1:30,000 to 1:40,000. Analyses of a large series of 67 individuals with Leigh or Leigh-like syndrome reported by Rahman et al [1996] have identified mtDNA pathogenic variants in 34% [Author, personal communication]. The prevalence of mtDNA-associated Leigh syndrome is likely to be 1:100,000 to 1:140,000. No data on the prevalence of NARP exist. NARP is substantially less common than Leigh syndrome. ## Differential Diagnosis Leigh syndrome and Leigh-like syndrome. In most individuals with Leigh syndrome, the disease is not caused by a mtDNA pathogenic variant but by an autosomal recessive or X-linked disorder of mitochondrial energy generation. Pathogenic variants in nuclear genes that result in respiratory chain complex deficiencies and Leigh and Leigh-like syndromes are summarized in Tables 2-4. See also Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview. ### Table 2. Autosomal Recessive Leigh Syndrome View in own window GeneProportion of AR LS Caused by Mutation of GeneDistinguishing Clinical FeaturesReference HCMNeurologic 1Other Complex I-deficient Leigh syndrome 2 NDUFS1<5%Cystic leukoencephalopathyBénit et al [2001] NDUFS2<5%+Loeffen et al [2001] NDUFS3<5%Bénit et al [2004] NDUFS4~5%+Budde et al [2000] NDUFS7<5%Triepels et al [1999] NDUFS8<5%+LeukodystrophyLoeffen et al [1998] NDUFV1<5%Cystic leukoencephalopathyBénit et al [2001] NDUFV21 person+SpasticityOptic atrophyCameron et al [2015] NDUFA21 family+Hoefs et al [2008] NDUFA91 familyvan den Bosch et al [2012] NDUFA101 family+Hoefs et al [2011] NDUFA121 familySevere dystoniaHypertrichosisOstergaard et al [2011] NDUFAF2<5%MRI: symmetric lesions in mamillothalamic tracts, substantia nigra/medial lemniscus, medial longitudinal fasciculus, & spinothalamic tractsBarghuti et al [2008] NDUFAF31 familyBaertling et al [2017a] NDUFAF41 familyBaertling et al [2017b] NDUFAF5 (C20orf7)<5%FILA (1 person); survival into 20s in 1 familySugiana et al [2008], Gerards et al [2010] NDUFAF6 (C8orf38)1 familyPagliarini et al [2008] FOXRED1<5%Seizures & myoclonusSlowly progressive; survival possible into 20sCalvo et al [2010], Fassone et al [2010] NUBPLCalvo et al [2010] NDUFAF8 (C17ORF89)1 personFloyd et al [2016] Complex II-deficient Leigh syndrome 3 SDHA<5%\+ (may occur)Course may be indolent w/survival into adulthood.Bourgeron et al [1995], Pagnamenta et al [2006] SDHAF1<5%Leukoencephalopathy on MRI (1 person w/neuropathologic LS)Ohlenbusch et al [2012] Complex III-deficient Leigh syndrome 4 UQCRQ1 familySlowly progressive; survival into 30sBarel et al [2008] TTC19<5%Severe olivopontocerebellar atrophySlowly progressive; survival into 20s/30sGhezzi et al [2011] BCS1L<5%SNHLProximal renal tubulopathy, hepatic involvement, pili tortide Lonlay et al [2001] Complex IV-deficient Leigh syndrome 5 NDUFA41 familyEpilepsy, sensory axonal peripheral neuropathySlowly progressive; survival into 20s/30sPitceathly et al [2013] COX8A1 personSeizures, hypotonia, spasticityHallmann et al [2016] SURF1~50% of complex IV-deficient LS (~10% of all LS)Developmental regression (71%), nystagmus + ophthalmoplegia (52%), movement disorder (52%)Hypertrichosis (48%); median survival 5.4 yrsWedatilake et al [2013], Péquignot et al [2001] COX10<5%+SNHLAnemia (due to defect of mitochondrial heme A biosynthesis)Antonicka et al [2003] COX15<5%+SeizuresOquendo et al [2004] SCO2<5%+Joost et al [2010] LRPPRC 6<5%Metabolic & neurologic (stroke-like) crisesSurvival 5 days – >30 yrs; median age at death 1.6 yrsDebray et al [2011], Mootha et al [2003] TACO11 familyCognitive dysfunction, dystonia, visual impairmentLate onset (4-16 yrs), slowly progressiveWeraarpachai et al [2009] PET100 7<5%Prominent seizuresSurvival to 20s (50%)Lim et al [2014] FILA = fatal infantile lactic acidosis; HCM = hypertrophic cardiomyopathy; LS = Leigh syndrome; SNHL = sensorineural hearing loss 1\. Neurologic findings other than those of classic Leigh syndrome 2\. Defining feature: complex I deficiency (identified on muscle biopsy) 3\. Complex II deficiency on muscle biopsy; also succinate peak on brain magnetic resonance spectroscopy (MRS) 4\. Complex III deficiency on muscle biopsy 5\. Complex IV deficiency on muscle biopsy. Note: In SURF1-related LS, complex IV deficiency is more severe in cultured skin fibroblasts than in muscle. 6\. Founder pathogenic variant in French-Canadian population from Saguenay-Lac St Jean 7\. Founder pathogenic variant in Lebanese population ### Table 3. Autosomal Recessive Leigh-Like Syndromes View in own window Disease NameGeneDistinguishing Clinical FeaturesLaboratory FindingsReference NeurologicOther Mitochondrial DNA depletion syndrome (hepatocerebral)POLGRoving eye movements, prominent seizuresHepatocerebral diseaseMultiple RCE deficiencies 1, isolated complex IV defic (rare)Taanman et al [2009] Mitochondrial DNA depletion syndrome (encephalopathic)SUCLA2 2Hypotonia, muscle atrophy, hyperkinesia, severe SNHLGrowth retardationMMA, multiple RCE deficElpeleg et al [2005], Ostergaard et al [2007] SUCLG1Severe myopathyRecurrent hepatic failureMMA, multiple RCE deficVan Hove et al [2010] FBXL4SeizuresFacial dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosisMultiple RCE deficShamseldin et al [2012] Defect of mt tRNA modificationTRMULS reported in 1 personUsually → benign reversible liver failure w/o neurologic symptomsTaylor et al [2014] GTPBP3LLS in 4 unrelated personsHypertrophic cardiomyopathyKopajtich et al [2014] Mitochondrial translation (formylation) defectMTFMTCystic leukoencephalopathy in someMay be slowly progressive in some, w/survival into 20sTucker et al [2011], Haack et al [2014] Mitochondrial translation (mitoribosome) defectMRPS34LS in 4 unrelated persons, LLS in 2 affected sibsMay be slowly progressive in some, w/survival into late teensLake et al [2017] Phenylalanyl aminoacyl tRNA synthetase deficiency (mt translation defect)FARS2Severe epilepsy; Alpers neuropathology in othersIsolated complex IV defic in 1 person; enzymology not performed in any othersShamseldin et al [2012] Glutamyl aminoacyl tRNA synthetase deficiency (mt translation defect)EARS2Leukoencephalopathy w/thalamus & brain stem involvement & ↑ lactate on MRIImprovement can occur, liver failure in some personsMultiple RCE deficMartinelli et al [2012] Isoleucyl aminoacyl tRNA synthetase deficiency (mt translation defect)IARS2LS causing death at 18 mo in 1 child; SNHL, peripheral sensory neuropathyCataracts, growth hormone defic, skeletal dysplasia in 3 adultsEnzymology not performedSchwartzentruber et al [2014] Asparaginyl aminoacyl tRNA synthetase deficiency (mt translation defect)NARS2Seizures, myoclonus, & SNHL in 2 sibsMultiple RCE deficSimon et al [2015] Mitochondrial translation (elongation) defectGFM1Axial hypotonia, spasticity, refractory seizuresProgressive hepato-encephalopathy in someMultiple RCE deficValente et al [2007] TSFMJuvenile-onset, ataxia, neuropathy, optic atrophyGrowth retardation, HCMAhola et al [2014] GFM2LL encephalopathy in 2 sibsScoliosis, bradycardiaLow CIII+IV activityFukumura et al [2015] Mitochondrial translation defectMTRFR (C12orf65)Ophthalmoplegia, optic atrophy, axonal neuropathyRelatively slow disease progressionMultiple RCE defic (fbs)Antonicka et al [2010] Polyribonucleotide nucleotidyltransferase deficiencyPNPT1 3Choreoathetosis & dyskinesia; also isolated SNHLSevere hypotoniaComplex III+IV defic in liver in 1 person (nml activ in mb & fbs)Vedrenne et al [2012] Primary coenzyme Q10 deficiencyPDSS2Refractory seizuresNephrotic syndrome 4Complexes I+III, II+III & coenzyme Q10 defic (mb)López et al [2006] COQ9Hypotonia, seizuresComplexes II+III & coenzyme Q10 deficDanhauser et al [2016] Pyruvate dehydrogenase (PDH) defectPDHBCC agenesis / hypoplasiaPDH defic (fbs)Quintana et al [2009] PDHXThin CC / CC agenesis; status epilepticus late in disease (teens/20s)Schiff et al [2006] DLATHypotonia, seizures, ataxiaHead et al [2005] DLDEpisodic encephalopathyHypoglycemia, ketoacidosis, liver failurePDH defic (fbs), ↑ plasma branched-chain amino acidsGrafakou et al [2003], Quinonez et al [2013] Lipoic acid synthesis defectLIASSeizures w/burst suppression (EEG)Mild HCMCombined defic of PDH + glycine cleavage enzyme, ↑ urine & plasma glycine, defic lipoylated proteins on western blotBaker et al [2014] LIPT11 person w/LS; 2 w/FILALiver dysfunction↑ glutamine & proline, ↓ levels of lysine & branched-chain amino acids & nml glycine (vs other lipoic acid synthesis defects); severe ↓ of PDH & α-KGDH activ & strongly ↓ BCKDH activ (fbs); nml RCE activSoreze et al [2013], Tort et al [2014] MEGDEL syndromeSERAC1SNHLMay have liver involvement in infancy; later normalizes3-methylglutaconic aciduriaWortmann et al [2012] Defects of mitochondrial dynamicsDNM1LHypotonia, seizuresMultiple RCE deficZaha et al [2016] MFFSeizures, microcephalyKoch et al [2016] OPA1Hypotonia, peripheral neuropathy, cerebellar ataxiaOphthalmoplegiaComplex IV deficRubegni et al [2017] SLC25A46Spastic diplegiaJaner et al [2016] Mitochondrial chaperone deficiencyCLPBDevelopmental regression, seizuresCataracts3-methylglutaconic aciduriaSaunders et al [2015] Thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration & progressive polyneuropathy type) 5SLC25A19Bilateral striatal necrosis; episodic encephalopathy; chronic progressive polyneuropathy → distal weakness & contracturesEnzymology not performedSpiegel et al [2009] Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)TPK1Episodic encephalopathy, ataxia, dystonia, spasticity2-ketoglutaric aciduriaMayr et al [2011] Biotinidase deficiencyBTDDeafness, optic atrophy, seizures, ataxia 4Alopecia, eczemaCharacteristic organic aciduriaMitchell et al [1986] Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency)SLC19A3See footnote 4Nml RCE activityGerards et al [2013], Fassone et al [2013] Ethylmalonic encephalopathyETHE1Neurodevelopmental delay & regression, pyramidal & extrapyramidal signsAcrocyanosis, petechiae & diarrhea in infancyEthylmalonic aciduriaMineri et al [2008] 3-hydroxyisobutyryl-CoA hydrolase deficiencyHIBCHDevelopmental regression, seizures, ataxia↑ plasma 4-hydroxybutyrylcarnitine levels; variable defic of RCEs & PDHFerdinandusse et al [2013] Short-chain enoyl-CoA hydratase deficiencyECHS1 3Psychomotor delay, SNHL, nystagmus, hypotonia, spasticity, athetoid mvmtsHCM in 1 person↑ urinary excretion of S-(2-carboxypropyl) cysteine; nml RCE activ in 1 person, mult RCE defic in 1 otherPeters et al [2014], Sakai et al [2015] Manganese-dependent β-galactosyltransferase deficiencySLC39A8Psychomotor delay, dystonia, seizuresHypertrichosis↓ manganese levels, complex IV defic (muscle)Riley et al [2017] α-KGDH = alpha-ketoglutarate dehydrogenase; BCKDH = branched chain ketoacid dehydrogenase; CC = corpus callosum; EEG = electroencephalogram; fbs = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; HCM = hypertrophic cardiomyopathy; LLS = Leigh-like syndrome; LS = Leigh syndrome; mb = muscle biopsy; MMA = methylmalonic aciduria; mt = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss 1\. RCE activity measured on muscle biopsy except in one individual noted 2\. Founder variant in Faroe Islands 3\. One family reported 4\. Treatable; see Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview, Management. 5\. Allelic with Amish lethal microcephaly, mitochondrial thiamine pyrophosphate carrier deficiency ### Table 4. X-Linked Leigh Syndrome and Leigh-Like Syndrome View in own window Disease NameGeneDistinguishing FeaturesLaboratory FindingsReference PDH deficiencyPDHA1Psychomotor retardation; seizures; choreoathetosis; dystonia; episodic ataxia in some; microcephaly; cerebral atrophy; cystic lesions in basal ganglia, brain stem, & cerebral hemispheres; agenesis of corpus callosum; facial dysmorphismLow/low-normal lactate/pyruvate ratio in blood & CSF; PDH deficiency (fbs)Rahman et al [1996] Complex I-deficient LSNDUFA1Developmental delay; axial hypotonia; nystagmus; choreoathetosis; myoclonic epilepsy; survival to 30s in 2 personsComplex I deficiency (mb)Fernandez-Moreira et al [2007] X-linked mt encephalomyopathyAIFM1Encephalomyopathy w/bilateral striatal lesionsMultiple RCE deficiencies (mb)Ghezzi et al [2010] CSF = cerebrospinal fluid; fbs = cultured skin fibroblasts; LS = Leigh syndrome; mb = muscle biopsy; mt = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme Other disorders that cause or resemble Leigh syndrome: * Bilateral striatal necrosis [De Meirleir et al 1995, Thyagarajan et al 1995]. Autosomal recessive infantile bilateral striatal necrosis may be caused by mutation of: * NUP62 (OMIM 605815), encoding a component of the nuclear pore [Basel-Vanagaite et al 2006]; and * ADAR (OMIM 146920), encoding the editing protein adenosine deaminase acting on RNA [Livingston et al 2014]. * Acute necrotizing encephalopathy, which may be triggered by viral infections. Mutation of RANBP2, encoding another nuclear pore component, is associated with susceptibility to infection-induced acute encephalopathy 3 (OMIM 608033). * Viral encephalopathies [Suwa et al 1999] * Other neurodegenerative disorders with similar changes on neuroimaging. These include pantothenate kinase-associated neurodegeneration, neuroferritinopathy, and methylmalonic acidemia and propionic acidemia. NARP. Disorders in the differential diagnosis: * Neurogenic weakness and neuropathy (see Charcot-Marie-Tooth Hereditary Neuropathy Overview) * Ataxia (see Hereditary Ataxia Overview) * Retinitis pigmentosa (see Retinitis Pigmentosa Overview) ## Management ### Evaluation Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with mtDNA-associated Leigh syndrome or NARP, the following evaluations are recommended: * Developmental assessment * Neurologic evaluation, MRI, MRS, EEG (if seizures are suspected), and nerve conduction studies (if neuropathy is suspected) * Metabolic evaluation, including plasma and cerebrospinal fluid lactate and pyruvate concentrations, urine organic acids * Ophthalmologic evaluation * Cardiac evaluation * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations As for most mitochondrial diseases, no specific curative treatment for mtDNA-associated Leigh syndrome and NARP exists [Kanabus et al 2014]. Supportive management includes treatment of the following: * Acidosis. Sodium bicarbonate or sodium citrate for acute exacerbations of acidosis * Seizures. Appropriate antiepileptic drugs tailored to the type of seizure under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain [Anderson et al 2002]. * Dystonia * Benzhexol, baclofen, tetrabenazine, and gabapentin may be useful, alone or in various combinations; an initial low dose should be started and gradually increased until symptom control is achieved or intolerable side effects occur. * Botulinum toxin injection has also been used in individuals with Leigh syndrome and severe intractable dystonia. * Cardiomyopathy. Anticongestive therapy may be required and should be supervised by a cardiologist. Regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients and feeding management is indicated. Psychological support for the affected individual and family is essential. ### Surveillance Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression and the appearance of new symptoms. Neurologic, ophthalmologic, and cardiologic evaluations are recommended. ### Agents/Circumstances to Avoid Sodium valproate and barbiturates should be avoided because of their inhibitory effect on the mitochondrial respiratory chain [Anderson et al 2002]. Anesthesia can potentially aggravate respiratory symptoms and precipitate respiratory failure, so careful consideration should be given to its use and to monitoring of the individual prior to, during, and after anesthetic procedures [Parikh et al 2015]. Dichloroacetate (DCA) reduces blood lactate by activating the pyruvate dehydrogenase complex. * Anecdotal reports have suggested that DCA may cause some short-term clinical improvement in mtDNA-associated Leigh syndrome [Fujii et al 2002]. * A double-blind, placebo-controlled trial of DCA in a different mitochondrial disease, MELAS, found no benefit and in fact documented a toxic effect of DCA on peripheral nerves [Kaufmann et al 2006]. * A subsequent report described the results of long-term administration of DCA to 36 children with congenital lactic acidosis (randomized control trial followed by an open label extension) [Stacpoole et al 2008]. This study concluded that oral DCA is well tolerated in young children with congenital lactic acidosis and that it was not possible to determine whether the peripheral neuropathy associated with long-term DCA administration is attributable to the drug or to the underlying disease process. It therefore appears prudent for individuals with mtDNA-associated Leigh syndrome or NARP to avoid DCA, in view of the underlying risk of peripheral neuropathy caused by the disease itself in these conditions. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Antioxidants, including coenzyme Q10 and analogs such as idebenone, can enhance the function and viability of cultured cells from individuals with the m.8993T>G pathogenic variant [Geromel et al 2001, Mattiazzi et al 2004] but have no proven efficacy in the treatment of Leigh syndrome. Newer mitochondrial-targeted antioxidants (e.g., mitoQ) that show much greater protection against oxidative stress in cultured cell and animal models [Jauslin et al 2003, Adlam et al 2005] have been proposed as potential therapies for a range of oxidative stress-related disorders. However, no clinical trials relevant to Leigh syndrome have been reported. EPI-743 is a structurally modified variant of CoQ10 (bis-methyl instead of bis-methoxy groups on the quinone ring, and chain length of 3 instead of 10 prenyl units) and was identified in a drug screen to have 1000-fold increased antioxidant properties compared to native CoQ10 [Enns et al 2012]. Open-label trials in end-of-life settings appeared to slow disease progression compared to historical natural history data [Enns et al 2012, Martinelli et al 2012], but the extremely unpredictable natural history of Leigh syndrome causes difficulty in interpretation of open-label studies. A Phase 2B randomized placebo-controlled double-blind crossover clinical trial of EPI-743 in children with Leigh syndrome completed in May 2015; findings have not yet been reported (ClinicalTrials.gov). Gene therapy provides a potential approach to decreasing the proportion of abnormal mtDNA in the cells of an individual. However, all of the approaches discussed below are still a long way from clinical applicability. In allotopic gene expression, mtDNA genes are recoded so that they can be inserted into and expressed from the nucleus. This technique was used successfully to transfer recoded mitochondrial MT-ATP6 and thereby rescue the ATP synthesis defect in cybrids containing the m.8993T>G pathogenic variant associated with maternally inherited Leigh syndrome and NARP [Manfredi et al 2002]. Studies in cultured cells have shown that a mitochondrially targeted restriction endonuclease can recognize and degrade mtDNA containing the m.8993T>G pathogenic variant found in NARP and mtDNA-associated Leigh syndrome, while leaving wild-type mtDNA intact [Tanaka et al 2002]. Another study used an adenoviral vector to deliver the restriction endonuclease to the mitochondrion and showed that there was no evidence of nuclear DNA damage in treated cells [Alexeyev et al 2008]. Transcription activator-like effector nucleases (TALENs) engineered to localize to mitochondria ("mito-TALENs") were used to eliminate mutated mtDNA from cybrids containing the m.14459G>A pathogenic variant, a maternally inherited variant that can cause Leigh syndrome [Bacman et al 2013]. More recently mito-TALENs were demonstrated to be efficacious in eliminating NARP-associated m.9176T>C mutated mtDNA from artificial mammalian oocytes [Reddy et al 2015]. Selective elimination of mutated mtDNA using mitochondrially targeted zinc-finger nucleases (mtZFNs) has also been achieved for the m.8993T>G NARP-causing variant [Gammage et al 2016]. Promising results have been obtained using a similar proof-of-principle approach in a mouse model of mtDNA heteroplasmy to shift the mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses [Bayona-Bafaluy et al 2005]. This strategy could potentially prevent disease onset or reverse clinical symptoms in individuals harboring certain heteroplasmic pathogenic variants in mtDNA. 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 A range of vitamins and other compounds are often used in the hope of improving mitochondrial function. Most commonly these include riboflavin, thiamine, and coenzyme Q10 (each at 50-100 mg/3x/day) [Kanabus et al 2014]. The ketogenic diet (KD) has been proposed as a therapy for mitochondrial disease, in particular complex I deficiency. Although this high-fat, low-carbohydrate diet has proven efficacy for refractory epilepsies, evidence for its use in the treatment of primary mitochondrial disorders is currently lacking. Preliminary reports of reducing mtDNA deletion load in cybrid models using ketones [Santra et al 2004] were not replicated in a mouse model of mitochondrial disease, although there did appear to be some improvement of myopathy in these mice [Ahola-Erkkilä et al 2010]. More recently KD was reported to attenuate liver disease in a mouse model of complex III deficiency [Purhonen et al 2017]. However, a modified Atkins diet (also high fat, low carbohydrate) led to muscle pain and elevation of creatine kinase in a small series of individuals with mitochondrial myopathy, suggesting that KD may not be well tolerated in individuals with mitochondrial disease [Ahola et al 2016]. Further clinical trials are required to determine the efficacy of KD in mitochondrial disorders. Another promising option is supplementation with the fatty acid decanoic acid, which is thought to be the active component of the KD and appears to stimulate mitochondrial biogenesis in cell models [Hughes et al 2014], including fibroblasts from individuals with complex I-deficient Leigh syndrome [Kanabus et al 2016]; clinical trials have yet to be performed. Biotin, creatine, succinate, and idebenone have also been used. Some of these agents may show partial efficacy in some individuals with milder mitochondrial disorders, but sustained therapeutic response in individuals with NARP or Leigh syndrome has not been described. Several studies have investigated whether upregulation of mitochondrial biogenesis may provide an effective therapeutic approach for mitochondrial respiratory chain diseases. This approach involves using agonists such as bezafibrate or resveratrol to stimulate the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) pathway. Alternatively, nicotinamide analogs such as nicotinamide riboside or nicotinamide mononucleotide have been used to boost nicotinamide adenine dinucleotide (NAD) levels and induce mitochondrial biogenesis via the same PGC1-alpha pathway. * A study by Bastin et al [2008] showed promising results in fibroblasts from individuals with a range of respiratory chain enzyme defects; nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient respiratory chain enzyme after bezafibrate treatment. These findings are likely to prompt clinical trials; however, no data showing that such approaches will be effective in individuals with mitochondrial disorders have been reported to date. * Oral administration of nicotinamide riboside to two mouse models with predominantly myopathic phenotypes showed improvements in NAD levels in mouse tissues and induced mitochondrial biogenesis, delaying disease progression [Cerutti et al 2014, Khan et al 2014]. Nicotinamide riboside also showed promising results in fibroblasts from an individual with pathogenic variants in NDUFS1, a Leigh syndrome-associated nuclear gene [Felici et al 2015], with increased NAD levels and restoration of mitochondrial membrane potential. It remains unclear whether nicotinamide riboside can effectively boost NAD levels in brain, and nicotinamide mononucleotide may show more promise for neurologic disorders such as Leigh syndrome, since it has been shown to boost mitochondrial respiratory function in a mouse model of Alzheimer disease [Long et al 2015]. Clinical trials of nicotinamide analogs in individuals with Leigh syndrome have yet to be reported. Another study explored the use of alpha-ketoglutarate and aspartate in transmitochondrial cybrids heteroplasmic for the m.8993T>G pathogenic variant [Sgarbi et al 2009]. The rationale was that these substrates would increase flux through the citric acid cycle, thereby increasing ATP production independently of oxidative phosphorylation (so-called "substrate level phosphorylation"). Initial results were promising, but further studies are needed before clinical applications can be considered. Finally, two promising approaches have been suggested by recent studies in the Ndufs4-/- mouse model of Leigh syndrome. * Rapamycin markedly delayed the onset and progression of symptoms in Ndufs4-/- mice [Johnson et al 2013]. The mechanism of action was unclear, as it did not appear to be acting via known mechanisms such as immune suppression, stimulating macroautophagy or induction of the mitochondrial unfolded protein response. However, the Ndufs4-/- mouse brains showed activation of the rapamycin target mTOR, which is a central coordinator of nutrient sensing and growth. Rapamycin suppressed mTOR activation, indicating that restoration of cellular signaling pathways may be a key to the beneficial effect. Rapamycin has a number of side effects (e.g., immunosuppression, hyperlipidemia, decreased wound healing) that may limit its clinical utility; however, this report identifies a potential new pathway to target for treatment of Leigh syndrome and other mitochondrial disorders. * Chronic exposure of Ndufs4-/- mice to hypoxia (11% O2 instead of 21% O2, equivalent to an elevation of ~4500 m) extended life span and alleviated physiologic abnormalities such as defects in locomotor activity, body temperature instability, and poor weight gain [Jain et al 2016]. While humans can acclimatize to comparable oxygen tensions, the authors emphasized that caution was needed in subjecting affected individuals to altered O2 levels. Further studies are needed to elucidate whether partial or intermittent hypoxia or pharmacologic agents influencing the hypoxic response may be suitable therapeutic approaches. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mitochondrial DNA-Associated Leigh Syndrome and NARP	None	3,359	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1173/	2021-01-18T21:11:35	{"synonyms": ["mtDNA-Associated Leigh Syndrome and NARP"]}
Reis-Bücklers corneal dystrophy Other namesCorneal dystrophy of Bowman layer, type I Reis-Bücklers corneal dystrophy. Reticular opacity in the superficial cornea SpecialtyOphthalmology Reis-Bücklers corneal dystrophy, is a rare, corneal dystrophy of unknown cause, in which the Bowman's layer of the cornea undergoes disintegration. The disorder is inherited in an autosomal dominant fashion, and is associated with mutations in the gene TGFB1. Reis-Bücklers dystrophy causes a cloudiness in the corneas of both eyes, which may occur as early as 1 year of age, but usually develops by 4 to 5 years of age. It is usually evident within the first decade of life. This cloudiness, or opacity, causes the corneal epithelium to become elevated, which leads to corneal opacities. The corneal erosions may prompt attacks of redness and swelling in the eye (ocular hyperemia), eye pain, and photophobia. Significant vision loss may occur. Reis-Bücklers dystrophy is diagnosed by clinical history physical examination of the eye. Labs and imaging studies are not necessary. Treatment may include a complete or partial corneal transplant, or photorefractive keratectomy. ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Patients with Reis-Bücklers dystrophy develop a reticular pattern of cloudiness in the cornea. This cloudiness, or opacity, usually appears in both eyes (bilaterally) in the upper cornea by 4 or 5 years of age. The opacity elevates the corneal epithelium, eventually leading to corneal erosions that prompt attacks of ocular hyperemia, pain, and photophobia. These recurrent painful corneal epithelial erosions often begin as early as 1 year of age.[1] With time, the corneal changes progress into opacities in Bowman's membrane, which gradually becomes more irregular and more dense.[1] Significant vision loss may occur.[2] However, vascularization of the cornea is not present.[2] ## Pathogenesis[edit] The disease has been associated with mutations in TGFBI gene on chromosome 5q which encodes for keratoepithelin.[1] The inheritance is autosomal dominant.[1][2] Reis-Bücklers corneal dystrophy. Light microscopy of cornea showing characteristic red stained deposits of mutated transforming growth factor beta-induced protein in the superficial corneal stroma. Masson's trichrome stain. ## Diagnosis[edit] The diagnosis of Reis-Bücklers corneal dystrophy is based on the clinical presentation, rather than labs or imaging. Sometimes it is difficult to distinguish the disease from honeycomb dystrophy. ## Treatment[edit] Treatment is aimed at managing the symptoms of the disease. A form of laser eye surgery named keratectomy may help with the superficial corneal scarring. In more severe cases, a partial or complete corneal transplantation may be considered.[3] However, it is common for the dystrophy to recur within the grafted tissue.[3] ## Epidemiology[edit] Reis-Bücklers corneal dystrophy is not associated with any systemic conditions.[1] ## History[edit] The dystrophy was described in 1917 by Reis[4] and in 1949 by Bücklers.[5] ## See also[edit] * Corneal dystrophy ## References[edit] 1. ^ a b c d e Yanoff, Myron; Duker, Jay S. (2008). Ophthalmology (3rd ed.). Edinburgh: Mosby. p. 306. ISBN 978-0323057516.CS1 maint: ref=harv (link) 2. ^ a b c Biswell, R. "Chapter 6. Cornea.". Vaughan & Asbury's general ophthalmology (18th ed.). New York: McGraw-Hill Medical. ISBN 978-0071634205. 3. ^ a b "Reis-Bücklers' Dystrophy". Columbia University. Digital Reference of Ophthalmology. Retrieved 16 December 2012. 4. ^ Reis W: Familiäre, fleckige Hornhautentartung. Dtsch Med Wochenschr 1917, 43:575. 5. ^ Bücklers M: Über eine weitere familiäre Hornhautdystrophie (Reis). Klin Monatsbl Augenheilkd 1949, 114:386–397. ## External links[edit] Classification D * OMIM: 608470 * MeSH: C535476 * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Reis–Bucklers corneal dystrophy	c0339278	3,360	wikipedia	https://en.wikipedia.org/wiki/Reis%E2%80%93Bucklers_corneal_dystrophy	2021-01-18T18:58:05	{"gard": ["9276"], "mesh": ["C535476"], "umls": ["C0339278"], "orphanet": ["98961"], "wikidata": ["Q4162390"]}
A very rare tumor of the intestine, originating from the epithelium of the anal canal (including the mucosal surface, anal glands, and lining of fistulous tracts), macroscopically appearing as a nodular, often ulcerated, invasive mass located in the anal canal. Patients often present with rectal bleeding, as well as difficulty and pain during defecation. Inguinal lymphadenopathy, if present, usually indicates metastatic spread. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Adenocarcinoma of the anal canal	c1332259	3,361	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=424016	2021-01-23T18:26:46	{"icd-10": ["C21.1"]}
GNAO1 encephalopathy is a rare neurologic disorder that causes developmental delay, early infantile seizures, and abnormal movements. Specific symptoms may include seizures that start early in childhood, severe intellectual disability, poor muscle tone (hypotonia), irregular muscle contractions (chorea), and involuntary movements of the face and tongue (dyskinesia). The severity of symptoms can vary. Symptoms may be triggered by strong emotions, illness, and purposeful movements. GNAO1 encephalopathy is caused by mutations in the GNAO1 gene and inheritance is autosomal dominant. Treatment aims to relieve individual symptoms and may not be effective for all people. In some cases, movement disorders have improved after the placement of a deep brain stimulator (DBS) device. Some have had improvement of seizures with anti-seizure medications or with a ketogenic diet, but others have not. While the long-term outcome has not been well-studied, the disease is typically very severe, with some people losing their motor skills in the early stages of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GNAO1 encephalopathy	c3809606	3,362	gard	https://rarediseases.info.nih.gov/diseases/13378/gnao1-encephalopathy	2021-01-18T18:00:14	{"omim": ["615473"], "synonyms": ["Early infantile epileptic encephalopathy-17"]}
Acyl-CoA oxidase deficiency Other namesACOX1 deficiency Acyl CoA oxidase enzyme SpecialtyMedical genetics Acyl-CoA oxidase deficiency is a rare disorder that leads to significant damage and deterioration of nervous system functions (neurodegeneration).[1] It is caused by pathogenic variants in ACOX1, which codes for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase (ACOX1).[1] This specific enzyme is responsible for the breakdown of very long chain fatty acids (VLCFAs).[2] Defective function of the ACOX1 enzyme prevents proper breakdown of these VLCFAs, leading to accumulation and interference with the nervous system.[1][2] Acyl-CoA oxidase deficiency affects a person from birth, and most newborns affected with this condition will not survive past early childhood.[1] Affected individuals can be born with hypotonia, seizures, and dysmorphic features, such as widely spaced eyes, a low nasal bridge and low set ears. Polydactyly and hepatomegaly have also been described.[1] Most babies will learn to walk and begin speaking, before experiencing a rapid decline in motor function between the ages of 1 and 3.[3] As the person ages, and the conditions worsens, they begin to experience exaggerated reflexes (hyperreflexia), more severe and frequent seizures, and gradual loss of vision and hearing.[1][2] There is no cure for this condition, however there are a range of symptom-based treatments, used to provide supportive care. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Children are born with this condition and their symptoms can be seen immediately.[2] In the early stages these can appear quite mild; weak muscle tone (often extreme hypotonia), lack of neonatal reflexes, seizures and abnormal (dysmorphic) facial features such as widely spaced eyes, a low nasal bridge, low set ears and an abnormally large forehead.[1][2] Due to the nature of the disease, in the build-up of VLCFAs, symptoms worsen progressively over time.[4] Children can often reach the stage at which they begin to walk and talk, before experiencing a rapid decline in motor skills due to demyelination and subsequent nerve damage.[2][3] A hearing deficit may develop, eyesight and response to visual and physical stimuli begins to diminish and eventually becomes non-existent.[1][2] The life expectancy of an individual with ACOX1 deficiency is 5 years.[2][3] ## Genetics[edit] Acyl-CoA oxidase deficiency is an autosomal recessive disorder that is caused by biallelic pathogenic variants in ACOX1.[1][5] This is the gene that codes for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase which is responsible for the breakdown of VLCFAs.[1][2] It is not completely clear how the build-up of these VLCFAs causes the symptoms seen with this condition, however research suggests that this abnormal accumulation triggers an inflammation in the nervous system which leads to demyelination.[1] Demyelination leads to the loss of white matter, leukodystrophy, in the brain and spinal cord.[1][5] It is this leukodystrophy that is related to the development of neurological abnormalities in people with Acyl-CoA oxidase deficiency.[5] Acyl-CoA oxidase deficiency is an extremely rare condition.[1] ## Diagnosis[edit] Diagnosis can be done both prenatally based on family history and after birth based on clinical suspicion.[1][5] The primary prenatal diagnosis techniques involve the assessment of amniotic fluid for an abnormal elevation in VLCFAs, and a reduced presence (or in some cases complete absence) of acyl-CoA oxidase in fibroblasts. If the causative variants in a family are known, prenatal diagnosis can be performed by molecular testing.[4] After birth, there are a number of diagnostic techniques available for use. A blood sample can be taken, from which the serum levels of VLCFAs and acyl-CoA oxidase activity can be assessed. Analysis of VLCFAs is important for the identification of ACOX1 deficiency, if a leukodystrophy has been identified[5] Since the condition is genetic, and is caused by pathogenic variants in ACOX1, it can be confirmed by sequence or copy number analysis.[1] Due to the rarity of this condition, people who have it may not be diagnosed early in their disease progression. As a result, acyl-CoA oxidase deficiency may be misdiagnosed as similar conditions such as Usher syndrome and neonatal adrenoleukodystrophy.[5][6] ## Treatment[edit] There are no cures for ACOX1 deficiency, supportive care is used to manage specific clinical symptoms for affected individuals.[1] Treatment is based upon symptoms, with the aim the provide some relief.[5] Pharmacologic agents are used to help improve muscle tone (management of dystonia) and to block neurological signalling to the muscle. Physical therapy is used to improve movement and function.[5] For the specific treatment of recurrent seizures, there are both pharmaceutical and surgical options.[5] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p "Peroxisomal acyl-CoA oxidase deficiency". Genetics Home Reference, NIH. October 23, 2018. 2. ^ a b c d e f g h i Thomas, Janet A.; Lam, Christina; Berry, Gerard T. (2018). "Chapter 23: Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and Smith–Lemli–Opitz Syndrome Presenting in the Neonate". Avery's Diseases of the Newborn (Tenth ed.). Elsevier. pp. 253–272.e3. doi:10.1016/B978-0-323-40139-5.00023-1. ISBN 978-0-323-40139-5. 3. ^ a b c Aubourg, P; Wanders, R (2013). Peroxisomal disorders. Handbook of Clinical Neurology. 113. pp. 1593–609. doi:10.1016/B978-0-444-59565-2.00028-9. ISBN 9780444595652. PMID 23622381. 4. ^ a b "264470 - Peroxisomal Acyl-CoA Oxidase Deficiency". OMIM, Johns Hopkins University. September 9, 2008. Retrieved 2018-10-25. 5. ^ a b c d e f g h i Vanderver, Adeline; Tonduti, Davide; Schiffmann, Raphael; Schmidt, Johanna; van der Knaap, Marjo S. (6 February 2014). "Leukodystrophy Overview". GeneReviews. PMID 24501781. 6. ^ Parikh, S; Bernard, G; Leventer, RJ; van der Knaap, MS; van Hove, J; Pizzino, A; McNeill, NH; Helman, G; Simons, C; Schmidt, JL; Rizzo, WB; Patterson, MC; Taft, RJ; Vanderver, A; GLIA, Consortium. (April 2015). "A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies". Molecular Genetics and Metabolism. 114 (4): 501–515. doi:10.1016/j.ymgme.2014.12.434. PMC 4390485. PMID 25655951. ## External links[edit] Classification D * ICD-10: E71.50 * OMIM: 26440 * MeSH: C536662 C536662, C536662 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Acyl-CoA oxidase deficiency	c1849678	3,363	wikipedia	https://en.wikipedia.org/wiki/Acyl-CoA_oxidase_deficiency	2021-01-18T18:43:28	{"gard": ["4543"], "mesh": ["C536662"], "umls": ["C0342871"], "orphanet": ["2971"], "wikidata": ["Q18553481"]}
Autosomal recessive spastic paraplegia type 53 (SPG53) is a very rare, complex type of hereditary spastic paraplegia characterized by early-onset spastic paraplegia (with spasticity in the lower extremities that progresses to the upper extremities) associated with developmental and motor delay, mild to moderate cognitive and speech delay, skeletal dysmorphism (e.g. kyphosis and pectus), hypertrichosis and mildly impaired vibration sense. SPG53 is due to mutations in the VPS37A gene (8p22) encoding vacuolar protein sorting-associated protein 37A. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal recessive spastic paraplegia type 53	c3539494	3,364	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319199	2021-01-23T17:01:52	{"omim": ["614898"], "icd-10": ["G11.4"], "synonyms": ["SPG53"]}
Andersen-Tawil syndrome is a disorder that causes episodes of muscle weakness (periodic paralysis), changes in heart rhythm (arrhythmia), and developmental abnormalities. Periodic paralysis begins early in life, and episodes last from hours to days. These episodes may occur after exercise or long periods of rest, but they often have no obvious trigger. Muscle strength usually returns to normal between episodes. However, mild muscle weakness may eventually become permanent. In people with Andersen-Tawil syndrome, the most common changes affecting the heart are ventricular arrhythmia, which is a disruption in the rhythm of the heart's lower chambers (the ventricles), and long QT syndrome. Long QT syndrome is a heart condition that causes the heart (cardiac) muscle to take longer than usual to recharge between beats. The irregular heartbeats can lead to discomfort, such as the feeling that the heart is skipping beats (palpitations). Uncommonly, the irregular heartbeats can cause fainting (syncope), and even more rarely, sudden death. Physical abnormalities associated with Andersen-Tawil syndrome typically affect the face, other parts of the head, and the limbs. These features often include a very small lower jaw (micrognathia), dental abnormalities (such as crowded teeth), low-set ears, widely spaced eyes, fusion (syndactyly) of the second and third toes, and unusual curving of the fingers or toes (clinodactyly). Some affected people also have short stature and an abnormal side-to-side curvature of the spine (scoliosis). The signs and symptoms of Andersen-Tawil syndrome vary widely, and they can be different even among affected members of the same family. About 60 percent of affected individuals have all three major features (periodic paralysis, cardiac arrhythmia, and physical abnormalities). ## Frequency Andersen-Tawil syndrome is a rare genetic disorder. Its exact prevalence is unknown, although it is estimated to affect 1 in 1 million people worldwide. About 200 affected individuals have been described in the medical literature. Researchers believe that Andersen-Tawil syndrome accounts for less than 10 percent of all cases of periodic paralysis. ## Causes Mutations in the KCNJ2 gene cause about 60 percent of all cases of Andersen-Tawil syndrome. When the disorder is caused by mutations in this gene, it is classified as type 1 (ATS1). The KCNJ2 gene provides instructions for making channels that transport positively charged potassium ions across the membrane of muscle cells. The movement of potassium ions through these channels is critical for maintaining the normal function of muscles used for movement (skeletal muscles) and cardiac muscle. Mutations in the KCNJ2 gene alter the usual structure and function of these potassium channels. These changes disrupt the flow of potassium ions in skeletal and cardiac muscle, leading to the periodic paralysis and irregular heart rhythm characteristic of Andersen-Tawil syndrome. Researchers have not determined the role of the KCNJ2 gene in bone development, and it is not known how mutations in the gene lead to the skeletal changes and other physical abnormalities often found in Andersen-Tawil syndrome. In the 40 percent of cases not caused by KCNJ2 gene mutations, the cause of Andersen-Tawil syndrome is usually unknown. These cases are classified as type 2 (ATS2). Studies suggest that variations in at least one other potassium channel gene may underlie the disorder in some of these affected individuals. ### Learn more about the genes associated with Andersen-Tawil syndrome * KCNJ2 * KCNJ5 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. When the condition results from a mutation in the KCNJ2 gene, an affected individual may inherit the mutation from one affected parent. In other cases, the condition results from a new (de novo) mutation in the KCNJ2 gene. These cases occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Andersen-Tawil syndrome	c1563715	3,365	medlineplus	https://medlineplus.gov/genetics/condition/andersen-tawil-syndrome/	2021-01-27T08:24:48	{"gard": ["9453"], "mesh": ["D050030"], "omim": ["170390"], "synonyms": []}
Haemophilia C Other namesPlasma thromboplastin antecedent (PTA) deficiency, Rosenthal syndrome Haemophilia C caused by deficiency in Factor XI[1] SpecialtyHaematology SymptomsOral bleeding[2] CausesDeficiency of coagulation factor XI[1] Diagnostic methodProthrombin time[1] PreventionPhysical activity precautions[1] Haemophilia C (also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome) is a mild form of haemophilia affecting both sexes, due to factor XI deficiency.[3] It predominantly occurs in Ashkenazi Jews. It is the fourth most common coagulation disorder after von Willebrand's disease and haemophilia A and B. In the United States, it is thought to affect 1 in 100,000 of the adult population, making it 10% as common as haemophilia A.[1][4] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] In terms of the signs/symptoms of haemophilia C, unlike individuals with Haemophilia A and B, people affected by it are not ones to bleed spontaneously. In these cases, haemorrhages tend to happen after a major surgery or injury.[5] However, people affected with haemophilia C might experience symptoms closely related to those of other forms of haemophilia such as the following:[2] * Oral bleeding. * Nosebleeds * Blood in the urine * Post-partum bleeding (20% of cases) * Tonsils (bleeding) ## Cause[edit] Chromosome 4 Haemophilia C is caused by a deficiency of coagulation factor XI and is distinguished from haemophilia A and B by the fact it does not lead to bleeding into the joints. Furthermore, it has autosomal recessive inheritance, since the gene for factor XI is located on chromosome 4 (near the prekallikrein gene); and it is not completely recessive, individuals who are heterozygous also show increased bleeding.[1][6] Many mutations exist, and the bleeding risk is not always influenced by the severity of the deficiency. Haemophilia C is occasionally observed in individuals with systemic lupus erythematosus, because of inhibitors to the FXI protein.[1][7] ## Diagnosis[edit] The diagnosis of haemophilia C (factor XI deficiency) is centered on prolonged activated partial thromboplastin time (aPTT).One will find that the factor XI has decreased in the individuals body. In terms of differential diagnosis one must consider: haemophilia A, haemophilia B, lupus anticoagulant and heparin contamination.[3][8] The prolongation of the activated partial thromboplastin time should completely correct with a 1:1 mixing study with normal plasma if haemophilia C is present; in contrast, if a lupus anticoagulant is present as the cause of a prolonged aPTT, the aPTT will not correct with a 1:1 mixing study.[citation needed] ## Treatment[edit] Cyklokapron (Tranexamic acid) Fresh Frozen Plasma In terms of haemophilia C medication cyklokapron is often used for both treatment after an incident of bleeding and as a preventive measure to avoid excessive bleeding during oral surgery.[9] Treatment is usually not necessary, except in relation to operations, leading to many of those having the condition not being aware of it. In these cases, fresh frozen plasma or recombinant factor XI may be used, but only if necessary.[3][10] The afflicted may often suffer nosebleeds, while females can experience unusual menstrual bleeding which can be avoided by taking birth control such as: IUDs and oral or injected contraceptives to increase coagulation ability by adjusting hormones to levels similar to pregnancy.[medical citation needed] ## See also[edit] * Bleeding diathesis * Bernard–Soulier syndrome * Von Willebrand disease * Vitamin K deficiency * Congenital afibrinogenemia * Coagulopathy ## References[edit] 1. ^ a b c d e f g eMedicine - Hemophilia C : Article by Prasad Mathew, MBBS, DCH 2. ^ a b Seligsohn, U. (2009-07-01). "Factor XI deficiency in humans". Journal of Thrombosis and Haemostasis. 7: 84–87. doi:10.1111/j.1538-7836.2009.03395.x. ISSN 1538-7836. PMID 19630775. S2CID 37670882. 3. ^ a b c "Factor XI Deficiency: Background, Pathophysiology, Epidemiology". 2018-07-02. Cite journal requires `\|journal=` (help) 4. ^ "Factor XI deficiency \| Disease \| Overview \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-07-09. 5. ^ Gomez, K.; Bolton-Maggs, P. (2008-11-01). "Factor XI deficiency". Haemophilia. 14 (6): 1183–1189. doi:10.1111/j.1365-2516.2008.01667.x. ISSN 1365-2516. PMID 18312365. S2CID 27557689. 6. ^ "OMIM Entry - # 612416 - FACTOR XI DEFICIENCY". omim.org. Retrieved 2016-07-12. 7. ^ Kitchens, Craig S.; Konkle, Barbara A.; Kessler, Craig M. (2013-02-20). Consultative Hemostasis and Thrombosis. Elsevier Health Sciences. p. 70. ISBN 978-1455733293. 8. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Congenital factor XI deficiency Hemophilia C". www.orpha.net. Retrieved 2016-07-12. 9. ^ Anderson, J. a. M.; Brewer, A.; Creagh, D.; Hook, S.; Mainwaring, J.; McKernan, A.; Yee, T. T.; Yeung, C. A. (23 November 2013). "Guidance on the dental management of patients with haemophilia and congenital bleeding disorders". British Dental Journal. 215 (10): 497–504. doi:10.1038/sj.bdj.2013.1097. ISSN 0007-0610. PMID 24264665. 10. ^ Orkin, Stuart H.; Nathan, David G.; Ginsburg, David; Look, A. Thomas; Fisher, David E.; IV, Samuel Lux (2014-11-14). Nathan and Oski's Hematology and Oncology of Infancy and Childhood. Elsevier Health Sciences. p. 136. ISBN 9780323291774. ## Further reading[edit] * Zucker, M.; Zivelin, A.; Landau, M.; Salomon, O.; Kenet, G.; Bauduer, F.; Samama, M.; Conard, J.; Denninger, M.-H.; Hani, A.-S.; Berruyer, M.; Feinstein, D.; Seligsohn, U. (1 October 2007). "Characterization of seven novel mutations causing factor XI deficiency". Haematologica. 92 (10): 1375–1380. doi:10.3324/haematol.11526. ISSN 0390-6078. PMID 18024374. * Orkin, Stuart H.; Nathan, David G. (2008). Nathan and Oski's Hematology of Infancy and Childhood. Elsevier Health Sciences. ISBN 978-1416034308. Retrieved 12 July 2016. * Goldman, Lee; Schafer, Andrew I. (2016). Goldman-Cecil Medicine Elsevieron VitalSource. Elsevier Health Sciences. ISBN 9780323322850. Retrieved 12 July 2016. ## External links[edit] Classification D * ICD-10: D68.1 * ICD-9-CM: 286.2 * OMIM: 264900 * MeSH: D005173 * DiseasesDB: 29376 External resources * eMedicine: ped/964 med/3515 Scholia has a topic profile for Haemophilia C. * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythaemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia * Thrombocytopenic purpura: ITP * Evans syndrome * TM * TTP * Upshaw–Schulman syndrome * Heparin-induced thrombocytopenia * May–Hegglin anomaly Platelet function * adhesion * Bernard–Soulier syndrome * aggregation * Glanzmann's thrombasthenia * platelet storage pool deficiency * Hermansky–Pudlak syndrome * Gray platelet syndrome Clotting factor * Haemophilia * A/VIII * B/IX * C/XI * von Willebrand disease * Hypoprothrombinemia/II * Factor VII deficiency * Factor X deficiency * Factor XII deficiency * Factor XIII deficiency * Dysfibrinogenemia * Congenital afibrinogenemia Signs and symptoms * Bleeding * Bruise * Haematoma * Petechia * Purpura * Nonthrombocytopenic purpura By site * head * Epistaxis * Haemoptysis * Intracranial haemorrhage * Hyphaema * Subconjunctival haemorrhage * torso * Haemothorax * Haemopericardium * Pulmonary haematoma * abdomen * Gastrointestinal bleeding * Haemobilia * Haemoperitoneum * Haematocele * Haematosalpinx * joint * Haemarthrosis * v * t * e Medicine 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Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Haemophilia C	c0015523	3,366	wikipedia	https://en.wikipedia.org/wiki/Haemophilia_C	2021-01-18T18:34:17	{"gard": ["9670"], "mesh": ["D005173"], "umls": ["C0015523"], "orphanet": ["329"], "wikidata": ["Q1393718"]}
Microcornea-myopic chorioretinal atrophy-telecanthus syndrome is rare, genetic, developmental defect of the eye disease characterized by childhood onset of mild to severe myopia with microcornea and chorioretinal atrophy, typically associated with telecanthus and posteriorly rotated ears. Other variable features include early-onset cataracts, ectopia lentis, ecotpia pupilae and retinal detachment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Microcornea-myopic chorioretinal atrophy-telecanthus syndrome	c3809567	3,367	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=369970	2021-01-23T17:26:38	{"omim": ["615458"], "icd-10": ["Q15.8"], "synonyms": ["MMCAT syndrome"]}
Ankle fracture Other namesBroken ankle[1] Fracture of both sides of the ankle with dislocation as seen on anteroposterior X-ray. (1) fibula, (2) tibia, (arrow) medial malleolus, (arrowhead) lateral malleolus SpecialtyOrthopedics SymptomsPain, swelling, bruising, inability to walk[1] ComplicationsHigh ankle sprain, compartment syndrome, decreased range of motion, malunion[1][2] Usual onsetYoung males, older females[2] TypesLateral malleolus, medial malleolus, posterior malleolus, bimalleolar, trimalleolar[1] CausesRolling the ankle, blunt trauma[2] Diagnostic methodX-rays based on the Ottawa ankle rule[2] Differential diagnosisRheumatoid arthritis, gout, septic arthritis, Achilles tendon rupture[2] TreatmentSplinting, casting, surgery[1] Frequency~1 per 1000/year[2] An ankle fracture is a break of one or more ankle bones.[1] Symptoms may include pain, swelling, bruising, and an inability to walk on the leg.[1] Complications may include an associated high ankle sprain, compartment syndrome, decreased range of motion, and malunion.[1][2] The cause may include excessive stress on the joint such as from rolling an ankle or blunt trauma.[2][1] Types include lateral malleolus, medial malleolus, posterior malleolus, bimalleolar, and trimalleolar fractures.[1] The need for X-rays may be determined by the Ottawa ankle rule.[2] Treatment is with splinting, casting, or surgery.[1] Ruling out other injuries may also be required.[2] Significant recovery generally occurs within four months; however, completely recovery may take up to two years.[1] They occur in about 1.7 per 1000 adults and 1 per 1000 children per year.[3][2] The occur most commonly in young males and older females.[2] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 X-ray * 2.2 Classification * 2.3 Fracture types * 3 Treatment * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Symptoms of an ankle fracture can be similar to those of ankle sprains (pain), though typically they are often more severe by comparison. It is exceedingly rare for the ankle joint to dislocate in the presence of ligamentous injury alone. However, in the setting of an ankle fracture the talus can become unstable and subluxate or dislocate. Patients may notice ecchymosis ("black and blue" coloraction from bleeding under the skin), or there may be an abnormal position, alignment, gross instability, or lack of normal motion secondary to pain. In a displaced fracture the skin is sometimes tented over a sharp edge of broken bone. The sharp fragments of broken bone sometimes tear the skin and form a laceration that communicates with the broken bone or joint space. This is known as an 'open' fracture and has a high incidence of infection if not promptly treated. Nearly all displaced ankle fractures are now treated surgically to insure proper alignment of the displaced fragments.[citation needed] ## Diagnosis[edit] On clinical examination, it is important to evaluate the exact location of the pain, the range of motion and the condition of the nerves and vessels. It is important to palpate the calf bone (fibula) because there may be an associated fracture proximally (Maisonneuve fracture), and to palpate the sole of the foot to look for a Jones fracture at the base of fifth metatarsal (avulsion fracture).[citation needed] Evaluation of ankle injuries for fracture is done with the Ottawa ankle rules, a set of rules that were developed to minimize unnecessary X-rays. There are three x-ray views in a complete ankle series: anteroposterior, lateral, and oblique (or "mortise view"). The mortise view an anteroposterior x-ray taken with the ankle internally rotated until the lateral malleolus is on the same horizontal plane as the medial malleolus, and a line drawn through both malleoli would be parallel to the tabletop, resulting in a position where there normally is no superimposition of tibia and fibula on each other.[4] It usually requires 10 to 20 degrees of internal rotation.[4] ### X-ray[edit] On X-rays, there can be a fracture of the medial malleolus, the lateral malleolus, or of the anterior/posterior margin of the distal tibia. The posterior margin (known as the posterior malleolus) is much more frequently injured than the anterior aspect of the distal tibia. If both the lateral and medial malleoli are broken, this is called a bimalleolar fracture (some of them are called Pott's fractures). If the posterior malleolus is also fractured, this is called a trimalleolar fracture.[citation needed] * A triplane fracture of the ankle as seen on plain X-ray * A triplane fracture of the ankle as seen on CT * A triplane fracture of the ankle as seen on CT ### Classification[edit] Danis-Weber classification (type A, B and C) There are several classification schemes for ankle fractures:[citation needed] * The Lauge-Hansen classification categorises fractures based on the mechanism of the injury as it relates to the position of the foot and the deforming force (most common type is supination-external rotation) * The Danis-Weber classification categorises ankle fractures by the level of the fracture of the distal fibula (type A = below the syndesmotic ligament, type B = at its level, type C = above the ligament), with use in assessing injury to the syndesmosis and the interosseous membrane * The Herscovici classification categorises medial malleolus fractures of the distal tibia based on level. * The Ruedi-Allgower classification categorizes pilon fractures of the distal tibia. ### Fracture types[edit] * Pilon fracture (Plafond fracture), a fracture of the distal part of the tibia, involving its articular surface at the ankle joint. * Wagstaffe-Le Fort avulsion fracture¨, a vertical fracture of the antero-medial part of the distal fibula with avulsion of the anterior tibiofibular ligament.[5] * Tillaux fracture, a Salter–Harris type III fracture through the anterolateral aspect of the distal tibial epiphysis.[6] * Triplane fractures are a special type of fracture that involves the immature skeleton. It has a coronal plane in the metaphysis, an axial plane in the physis and a sagittal plane in the epiphysis.[7] * Pilon fracture. * Tillaux fracture ## Treatment[edit] Surgically fixated bimalleolar ankle fracture Treatment of ankle fractures is dictated by the stability of the ankle joint. Certain fractures patterns are deemed stable, and may be treated similar to ankle sprains. All other types require surgery, most often an open reduction and internal fixation (ORIF), which is usually performed with permanently implanted metal hardware that holds the bones in place while the natural healing process occurs. A cast or splint will be required to immobilize the ankle following surgery.[citation needed] In children, recovery may be faster with an ankle brace rather than a full cast in those with otherwise stable fractures.[3] ## Epidemiology[edit] In children ankle fractures occur in about 1 per 1000 per year.[3] ## See also[edit] * Maisonneuve fracture ## References[edit] 1. ^ a b c d e f g h i j k l "Ankle Fractures (Broken Ankle) - OrthoInfo - AAOS". www.orthoinfo.org. Retrieved 20 June 2019. 2. ^ a b c d e f g h i j k l Wire, Jessica (9 May 2019). "Ankle Fractures". StatPearls. PMID 31194464. 3. ^ a b c Yeung, DE; Jia, X; Miller, CA; Barker, SL (1 April 2016). "Interventions for treating ankle fractures in children". The Cochrane Database of Systematic Reviews. 4: CD010836. doi:10.1002/14651858.CD010836.pub2. PMC 7111433. PMID 27033333. 4. ^ a b Ankle Injuries: A Sprained Ankle? Radiology Cases in Pediatric Emergency Medicine Volume 3, Case 3 Alson S. Inaba MD Kapiolani Medical Center For Women And Children University of Hawaii John A. Burns School of Medicine. Retrieved May 2011 5. ^ Tim B Hunter; Leonard F Peltier; Pamela J Lund (2000). "Musculoskeletal Eponyms: Who Are Those Guys?" (PDF). RadioGraphics. 20: 829. doi:10.1148/radiographics.20.3.g00ma20819. PMID 10835130. Retrieved 2009-11-13. 6. ^ "Wheeless Online". Retrieved 30 October 2014. 7. ^ Hirsch M, et al. Understanding triplane distal tibia fractures. http://dx.doi.org/10.1016/j.rchira.2016.09.002 ## External links[edit] * Medical information about Ankle Fractures Classification D * MeSH: D064386 * SNOMED CT: 16114001 Wikimedia Commons has media related to Fractures of the human ankles. Wikiquote has quotations related to: Ankle fracture * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Ankle fracture	c0435907	3,368	wikipedia	https://en.wikipedia.org/wiki/Ankle_fracture	2021-01-18T18:48:08	{"mesh": ["D064386"], "wikidata": ["Q2314265"]}
A number sign (#) is used with this entry because of evidence that Stargardt disease-1 (STGD1) is caused by homozygous or compound heterozygous mutation in the ABCA4 gene (601691) on chromosome 1p22. Stargardt disease-3 (STGD3; 600110) is caused by mutation in the ELOVL4 gene (605512) on chromosome 6q14, and Stargardt disease-4 is caused by mutation in the PROM1 gene (604365) on chromosome 4. A locus for Stargardt disease mapped to chromosome 13q34 and designated STGD2 was found to be in error; the disorder in the family in which the linkage was made was correctly mapped to chromosome 6q14 (STGD3). One patient with a diagnosis of juvenile macular degeneration was found to be compound heterozygous for mutations in the CNGB3 gene (605080) on chromosome 8q. Fundus flavimaculatus (FFM) is an allelic subtype of Stargardt disease that has been associated with mutation in the ABCA4 gene and the PRPH2 gene (179605). FFM has a later age of onset. If loss of visual acuity begins in the first 2 decades, the designation Stargardt disease is preferred; if it begins later in life and has a more progressive course, the term FFM is preferred (Weleber, 1994). An early-onset severe form of retinal dystrophy (CORD3; 604116) is caused by homozygous null mutations in the ABCA4 gene. Clinical Features Stargardt disease is one of the most frequent causes of macular degeneration in childhood. It has onset between 7 and 12 years, a rapidly progressive course, and a poor final visual outcome. Although visual acuity is severely reduced, peripheral visual fields remain normal throughout life. Degeneration limited to the macular area of the retina was described in multiple sibs by Ford (1961) and by Walsh (1957). Fundus flavimaculatus, which is a form of fleck fundus disease (see 228980), derives its name from the occurrence of many yellow spots rather uniformly distributed over the fundus. In some older patients the flecks fade with time as atrophy of the retinal pigment epithelium (RPE) increases. Round, linear, or pisciform lesions are distributed in the posterior pole, sometimes with extension to the equator, and with macular involvement. Network atrophy of the retinal pigment epithelium, and choroidal vascular atrophy are features. Central visual loss, loss of color vision, photophobia, paracentral scotoma, and slow dark adaptation are features. This is probably an autosomal recessive disorder. Klien and Krill (1967) observed a 'familial incidence...in 10 of 27 patients.' The 10 familial cases included 4 pairs of affected sibs with ostensibly normal parents who were, however, not examined in most instances. No parental consanguinity was described. In 1 instance the father and 2 daughters were affected. In the instance of an affected brother and sister, the father was black and the mother white. Krill and Deutman (1972) concluded that recessive macular dystrophy was the disorder described and beautifully illustrated by Stargardt (1909), and also was the disorder that Franceschetti (1963) renamed fundus flavimaculatus. Krill and Deutman (1972) suggested the possibility of a rarer, phenotypically indistinguishable, autosomal dominant form. Hadden and Gass (1976) presented evidence that fundus flavimaculatus is the same as the Stargardt form of macular dystrophy. Pearce (1975) reported 4 families with 9 affected persons. In 1 instance, 2 affected persons married and both of their children were affected. Carpel and Kalina (1975) described 3 affected sisters. Isashiki and Ohba (1985) remarked on variable expression. Among the 3 children of normal first-cousin parents were a 12-year-old boy with bull's eye macular change and sparse fundus flavimaculatus type flecks, and an 11-year-old girl with numerous fleck lesions of FFM throughout the posterior fundus and virtually no macular change. As pointed out by Weleber (1994), Rosehr (1954) found that 2 of the original patients described by Stargardt (1909), when seen almost 50 years later, still did not complain of night blindness and their visual fields were, at most, only mildly constricted. The macular regions showed marked atrophy in each patient, and 1 patient had peripheral pigment clumping and drusen. Whereas Stargardt disease shows juvenile to young adult age of onset, the clinically similar retinal disorder fundus flavimaculatus often displays later age of onset and slower progression. Histologically the disorder is characterized by subretinal deposition of lipofuscin-like material. As pointed out by Meitinger (1997), Stargardt disease had always been considered to be a retinal degeneration originating in the retinal pigment epithelium, which underlies the photoreceptors, predominantly cones, of the macula. Thus, the findings of Allikmets et al. (1997) that it is a disease of the rods and that the particular mutant ABC transporter is expressed in rod photoreceptors but not in blue cones came as a surprise. To understand better the shared characteristics of Stargardt macular dystrophy and fundus flavimaculatus, Armstrong et al. (1998) surveyed 52 patients with STGD and 48 patients with FFM over a period ranging from 1 to 22 years. They found that morphologic changes and retinal function degeneration were more severe in patients with FFM than in patients with STGD. The duration of the disease had a greater effect on patients with FFM than on patients with STGD. Rotenstreich et al. (2003) reviewed the clinical findings in 361 patients with Stargardt disease. Eighty-two (23%) had visual acuity of 20/40 or better, whereas only 16 (4%) had acuity of worse than 20/400. The presence of foveal sparing on ophthalmoscopy was associated with a higher prevalence of 20/40 acuity or better. Survival analysis showed that the prognosis of patients who were seen initially with visual acuity of 20/40 or better was related to age at initial visit: the earlier the patient presented, the more rapidly the acuity was likely to decrease below 20/40. Chen et al. (2011) studied the relationship between macular cone structure, fundus autofluorescence (AF), and visual function in 12 patients with Stargardt disease and 27 age-matched healthy individuals. Patients were 15 to 55 years old, and visual acuities ranged from 20/25 to 20/320. At least 1 disease-causing mutation in the ABCA4 gene was found in 11 of the patients. High-resolution images of the macula were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Central scotomas were present in all patients, although the fovea was spared in 3. The earliest cone spacing abnormalities were observed in regions of homogeneous AF, normal visual function, and normal outer retinal structure. Outer retinal structure and AF were most normal near the optic disc. Longitudinal studies showed progressive increases in AF followed by reduced AF associated with losses of visual sensitivity, outer retinal layers, and cones. Chen et al. (2011) concluded that their findings support a model of STGD disease progression in which lipofuscin accumulation results in homogeneously increased AF with cone spacing abnormalities, followed by heterogeneously increased AF with cone loss, and then reduced AF with cone and RPE cell death. By AOSLO in a family in which 2 brothers had early-onset STGD1, Song et al. (2015) found increased cone and rod spacing in areas that appeared normal in conventional images. Cone loss predominated closer to the fovea with a greater contribution from rod loss in the periphery. Fujinami et al. (2015) performed a retrospective study of 42 patients diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. Median ages of onset and baseline examination were 8.5 and 12.0 years, respectively. Median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 (67%) of 39 patients with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) has macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (35%), macular and generalized cone dysfunction in 1 patient (4%), and macular and generalized cone and rod dysfunction in 15 patients (60%). Fujinami et al. (2015) concluded that childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, although patients typically have less severe fundus abnormalities on examination. Lambertus et al. (2015) performed a retrospective study of 51 patients, aged 7 to 64 years, who were diagnosed with STGD at or younger than age 10 years. Among the patients were 37 with 2 or more ABCA4 mutations, 7 with 1 ABCA4 mutation and the presence of yellow-white flecks, and 7 not known to have an ABCA4 mutation but with yellow-white flecks and either a dark choroid or an atrophic macular lesion. The mean age at onset was 7.2 years (range, 1-10). The median times to develop best corrected visual acuity (BCVA) of 20/32, 20/80, 20/200, and 20/500 were 3, 5, 12, and 23 years, respectively. Initial ophthalmoscopy in 41 patients revealed either no abnormalities or foveal RPE changes in 10 and 9 patients, respectively; the other 22 patients had foveal atrophy, atrophic RPE lesions, and/or irregular yellow-white fundus flecks. On fluorescein angiography (FA), a dark choroid was found in 21 of 29 patients. On fundus autofluorescence (FAF), there was centrifugal expansion of disseminated atrophic spots, which progressed to eventual profound chorioretinal atrophy. SD-OCT revealed early photoreceptor damage followed by atrophy of the outer retina, RPE, and choroid. On full-field electroretinogram (ffERG) in 26 patients, 15 had normal amplitudes and 11 had reduced photopic and/or scotopic amplitudes at their first visit. No correlation between ffERG abnormalities and rate of visual loss was found. Thirteen of 25 patients had progressive ffERG abnormalities. Lambertus et al. (2015) concluded that early-onset STGD1 falls on the severe end of the spectrum of ABCA4-associated retinal phenotypes. Parodi et al. (2015) performed a prospective study of 27 patients (54 eyes) with STGD1 to identify a correlation between near-infrared (NIR) and short-wavelength (SW) fundus autofluorescence (FAF) patterns within the foveal region and best corrected visual acuity (BCVA) values. Eyes showing a pattern of foveal hyper-FAF on NIR-FAF had a higher BCVA than eyes with a reduced FAF signal. Similarly, mean sensitivity within 2 degrees of the foveal region was significantly better in eyes with hyper-FAF than in eyes with hypo-FAF. Moreover, eyes with hyper-FAF on SW-FAF did not present a significant difference in BCVA and mean retinal sensitivity compared with the subgroup with foveal hypo-FAF. The integrity of both the photoreceptor inner/outer segment junction and the photoreceptor outer segment/retinal pigmented epithelium junction was significantly correlated with a preserved BCVA and a foveal hyper-FAF pattern on NIR-FAF. The findings suggested that NIR-FAF patterns correlate with morpho-functional outcomes in eyes affected by Stargardt disease. Biochemical Features Radu et al. (2003) demonstrated that treatment with isotretinoin (Accutane), an agent used in the treatment of acne, slows the accumulation of lipofuscin pigments in the eyes of Abcr-null mice. The results corroborated a proposed mechanism of biogenesis of N-retinylidene-N-retinylethanolamine (A2E), the main lipofuscin pigment that accumulates in cells of the RPE in patients with STGD. Radu et al. (2003) suggested that treatment with isotretinoin may inhibit lipofuscin accumulation in patients with STGD and thus delay the onset of visual loss. Commenting on the work of Radu et al. (2003), Sparrow (2003) provided an explanation for the fact that the RPE cells underlying the macula have the highest accumulation of lipofuscin and that STGD primarily involves the center of the field of vision. He suggested that it is not a coincidence that the macula of the retina also has the highest concentration of 11-cis-retinal-containing visual pigment, a feature reflecting, in part, the packing density of cone and rod photoreceptor cells. The heightened capacity for photon absorption conferred by the density of visual pigment in the macula translates into a higher probability that all-trans-retinal will be available for A2E formation. Sparrow (2003) noted that the well-known cause of birth defects by orally administered isotretinoin would be problematic for female patients with STGD who might be treated with this agent. Shroyer et al. (2001) analyzed DNA from 8 patients with clinically confirmed chloroquine or hydroxychloroquine retinopathy. Two patients had heterozygous ABCA4 mutations previously associated with Stargardt disease. None of the 80 controls had these missense mutations. Three other patients had other missense polymorphisms. The authors concluded that some individuals with ABCA4 mutations may be predisposed to develop retinal toxicity when exposed to chloroquine/ hydroxychloroquine, and they urged further study of a larger cohort of patients with this retinopathy. Pathogenesis Allikmets et al. (1997) commented that the accumulation in the retinal pigment epithelium (RPE) of a lipofuscin-like substance in STGD suggests that the site of ABCR-mediated transport may be on the apical face of the photoreceptor cell and that this transport may affect exchange between the RPE and the photoreceptors. The RPE participates in the continual renewal of visual pigments and of photoreceptor outer segments. The best-studied molecules that cycle between photoreceptors and the RPE are the retinoids. Allikmets et al. (1997) commented that if ABCR is involved in either export or import of retinoids, mutations in ABCR should lead to an accumulation of retinoids or their derivatives in the outer segment or the RPE, respectively. Histopathologic studies of the eyes in Stargardt disease, and its somewhat milder variant fundus flavimaculatus (FFM), show massive accumulation of lysosomal material similar to lipofuscin within RPE cells. Birnbach et al. (1994) additionally emphasized abnormal photoreceptor morphology and abnormal accumulation of lipofuscin in photoreceptor segments. Cideciyan et al. (2004) studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in STGD1 and CORD3 (604116) patients with ABCA4 mutations and a wide spectrum of disease severity. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in retinal degeneration due to ABCA4 mutation, which predicted lipofuscin accumulation as a key early component of disease expression with abnormal slowing of the rod and cone retinoid cycle occurring at later stages of the disease sequence. Population Genetics Stargardt disease is the most common hereditary recessive macular dystrophy, with an estimated incidence of 1 in 10,000 (Blacharski, 1988). Mapping By genetic linkage analysis, using (CA)n microsatellite markers of known chromosomal location (Weissenbach et al., 1992) in 8 families, Kaplan et al. (1993) assigned the STGD locus to 1p21-p13. The combined maximum lod score was 6.88 at theta = 0.02 for the D1S236 locus. From linkage studies, Gerber et al. (1995) concluded that fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders despite differences in age at onset, clinical course, and severity. In 4 families with late-onset FFM with macular dystrophy they found linkage to 1p21-p13, in the genetic interval defined by microsatellite loci D1S435 and D1S415; maximum lod score = 4.79 at theta = 0.0 for D1S435. They considered 1p13 to be the likely location of the gene that is mutant in these allelic disorders. The age at onset ranged from 17 to 60 years in adult patients. By combined linkage analysis of 47 families with autosomal recessive STGD and/or FFM, Anderson et al. (1995) found significant linkage to marker D1S188 on chromosome 1p (maximum lod score of 32.7). Analysis of recombinants localized the disease locus to a 4-cM interval between D1S435 and D1S236. The findings indicated genetic homogeneity for STGD and FFM. Hoyng et al. (1996) carried out linkage analysis in 7 families with recessive Stargardt disease and confirmed the location of a major recessive STGD gene on chromosome 1p22-p21. The maximum 2-point lod score for all families combined was 5.35 at theta = 0.04 for the marker D1S188 and the disease locus. Hoyng et al. (1996) genotyped 9 markers in 7 families to construct haplotypes, and this enabled them to reduce the STGD critical region to 2 cM, flanked by D1S406 and D1S236. In 1 family they encountered an affected female who, on the basis of haplotype analysis, carried only 1 disease allele. Hoyng et al. (1996) proposed several possible explanations for this finding, including the occurrence of genetic heterogeneity and the possibility that dominant and recessive mutations may be observed at 1 gene locus. They reported apparent nonpenetrance in a 45-year-old male. Molecular Genetics Allikmets et al. (1997) performed mutation analysis of the ABCA4 gene in STGD families and identified a total of 19 different mutations, including homozygous mutations in 2 families with consanguineous parentage (see, e.g., 601691.0002). Shroyer et al. (1999) analyzed the ABCA4 gene in a 3-generation family manifesting both Stargardt disease and age-related macular degeneration (ARMD; see 153800), and identified heterozygosity for a missense mutation (P1380L; 601691.0026) in the paternal grandmother with ARMD, whereas the proband and his 2 paternal cousins with Stargardt disease were compound heterozygous for the P1380L mutation and another missense mutation in the ABCA4 gene (601691.0036 and 601691.0037, respectively). Shroyer et al. (1999) suggested that carrier relatives of STGD patients may have an increased risk of developing ARMD. Single-copy variants of the ABCA4 gene have been shown to confer enhanced susceptibility to ARMD. By mutation analysis in a cohort of families that manifested both STGD and ARMD, Shroyer et al. (2001) found that ARMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. Shroyer et al. (2001) used an in vitro biochemical assay to test for protein expression and ATP-binding defects, and found that mutations associated with ARMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCA4 mutations reported in patients with ARMD, 16 (76%) showed abnormalities in protein expression, ATP-binding, or ATPase activity. They inferred that carrier relatives of STGD patients are predisposed to develop ARMD. Bernstein et al. (2002) examined 19 of 33 sibs from 15 Stargardt families who carried their respective proband's variant ABCA4 allele. Some families exhibited concordance of ABCA4 alleles with the macular degeneration phenotype, but others did not. Exudative ARMD was uncommon among both probands and sibs. Fingert et al. (2006) reported a case of Stargardt disease in a patient homozygous for a mutation in the ABCA4 gene (601691.0026) as a result of uniparental isodisomy of chromosome 1. The patient's father was heterozygous for the mutation. In a patient with juvenile macular degeneration in whom mutation in the ABCA4 gene was excluded (Briggs et al., 2001), Nishiguchi et al. (2005) identified mutations in the CNGB3 gene (605080.0002 and 605080.0006). Stargardt disease had not previously been associated with mutations in the cone channel subunits. Pal Singh et al. (2006) identified homozygous null ABCA4 mutations (601691.0028-601691.0029) causing autosomal recessive nonsyndromic retinal dystrophy in 2 Indian families. Affected individuals in both families had early-onset visual loss, diminished rod and cone electroretinographic responses, and widespread atrophy of the retinal pigment epithelium. In a retrospective study of 42 patients diagnosed with STGD in childhood, Fujinami et al. (2015) detected 2 or more disease-causing ABCA4 variants in 80% of the children. They also found a higher proportion of definitely or possibly deleterious variants in these children compared with 64 adult-onset ABCA4-positive STGD patients. Genotype/Phenotype Correlations Rozet et al. (1998) reported a genotype/phenotype correlation in ABCA4 gene mutations. They found that nonsense mutations truncating the ABCA4 protein consistently led to Stargardt disease, whereas all mutations they identified in the ABCA4 gene in fundus flavimaculatus were missense mutations affecting uncharged amino acids. In a family segregating retinitis pigmentosa-19 (RP19; 601718) and STGD1 in 2 first cousins, Rozet et al. (1999) found that heterozygosity for a splice acceptor site mutation in the ABCA4 gene (601691.0017) resulted in STGD1, whereas hemizygosity for this mutation resulted in RP19. In the patient with RP19, a partial deletion of the maternal ABCA4 gene was presumed to be the source of a null allele, although this was not conclusively proven. Duncker et al. (2015) used ABCR600 microarray analysis, next-generation sequencing, or both, to screen 37 patients with what the authors called 'bull's eye maculopathy' for mutations in the ABCA4 gene. ABCA4 mutations were identified in 22 patients, who tended to be younger than those without ABCA4 mutations. Whereas phenotypic differences were not obvious on the basis of either qualitative fundus autofluorescence (AF) or SD-OCT, with quantitative AF (qAF), the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF-8 of more than the 95% confidence interval for age, whereas in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF-8 within the normal range. History Stargardt disease has sometimes been called central retinitis pigmentosa or retinitis pigmentosa with macular involvement. However, ordinary retinitis pigmentosa does not affect the macula. HEENT \- Macular degeneration \- Central retinitis pigmentosa Misc \- Onset in first 2 decades Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	STARGARDT DISEASE 1	c0271093	3,369	omim	https://www.omim.org/entry/248200	2019-09-22T16:25:43	{"doid": ["0050817"], "mesh": ["C535804"], "omim": ["248200"], "icd-10": ["H35.53"], "orphanet": ["827"], "synonyms": ["Alternative titles", "STGD", "MACULAR DEGENERATION, JUVENILE", "MACULAR DYSTROPHY WITH FLECKS, TYPE 1"]}
Non-distal trisomy 10q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 10, characterized by mild to moderate developmental delay, postnatal growth retardation, central hypotonia, craniofacial dysmorphism (incl. microcephaly, prominent forehead, flat, thick ear helices, deep-set, small eyes, epicanthus, upturned nose, bow-shaped mouth, highly arched palate, micrognathia), ocular anomalies (e.g. iris coloboma, retinal dysplasia, strabismus), long, slender limbs and skeletal and digital anomalies (scoliosis, poly/syndactyly). Additional features reported include cardiac defects (e.g. septal ventricular defect), anal atresia, and cryptorchidism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Non-distal trisomy 10q	c2936831	3,370	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1695	2021-01-23T17:48:46	{"mesh": ["C537804"], "umls": ["C2936831"], "icd-10": ["Q92.3"], "synonyms": ["Non-distal duplication 10q", "Non-telomeric trisomy 10q"]}
Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which family members display a seizure disorder from the GEFS+ spectrum which ranges from simple febrile seizures (FS) to the more severe phenotype of myoclonic-astatic epilepsy (MAE) or Dravet syndrome (DS) (see these terms). ## Epidemiology Prevalence is unknown but hundreds of cases have been described in the literature. ## Clinical description Phenotypes in patients can be variable, ranging from simple FS to epileptic encephalopathies including MAE and DS. Disease onset is variable. FS plus (FS+) is the characteristic phenotype seen in most GEFS+ families, described as febrile seizures that persist beyond the age of 6 or that occur with other afebrile seizure types including generalized tonic-clonic seizures, myoclonic, or absence seizures that usually remit by late childhood or early adolescence. Occasional seizures in adulthood are possible. Partial seizure types can also be observed. ## Etiology Mutations in SCN1A (2q24.3) (most commonly) and SCN1B (19q13.12) have been identified as causal in several families with GEFS+. These genes encode two subunits of the neuronal sodium channel. Other causal mutations include those in the gamma 2 subunit (GABRG2) gene (5q34). SCN2A (2q24.3), SCN9A (2q24), and GABRD (1p36.3) have been suggested as possible susceptibility genes for GEFS+. ## Diagnostic methods GEFS+ is diagnosed clinically through the seizure type of the patient and the family history. Molecular genetic testing can confirm the diagnosis. ## Differential diagnosis Differential diagnoses include other genetic epilepsies such as benign familial infantile seizures (due to PRRT2 mutations) or encephalopathy due to GLUT1 deficiency (see these terms) or a sporadic epilepsy caused by injury or infections. ## Antenatal diagnosis Given the broad phenotypic range of known GEFS+ mutations, prenatal diagnosis is usually not performed. ## Genetic counseling In most large families, GEFS+ is inherited in an autosomal dominant manner, often with incomplete penetrance. In other families it follows complex inheritance where several genes or environmental factors are thought to be involved. Genetic counseling is possible in families with a known disease causing mutation. However, precise phenotypes cannot be predicted as wide phenotypic variability is seen within families. ## Management and treatment As most patients with GEFS+ have a mild phenotype, treatment may not be necessary. Seizure control with antiepileptic drugs is essential in patients with recurrent seizures. The drugs mainly used include valproic acid, benzodiazepines (i.e. clobazam), ethosuximide, levetiracetam and topiramate. Given the relatedness to DS, lamotrigine and phenytoin may not be considered. Temporal lobe surgery resulted in a positive outcome in two patients with GEFS+. Regular follow-up and neuropsychological evaluations are recommended along with electroencephalographic monitoring when a new seizure pattern is suspected. In patients with active epilepsy, activities where a seizure could lead to injury or death should be avoided. ## Prognosis The overall prognosis depends on the exact phenotype within the GEFS+ spectrum. In patients with mild phenotypes (FS, FS+) seizures often remit by adolescence. Patients with more severe phenotypes may require life-long treatment and may have lasting neurocognitive sequelae. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Generalized epilepsy with febrile seizures-plus	c3502809	3,371	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36387	2021-01-23T18:54:59	{"mesh": ["C565808"], "omim": ["604233", "604403", "609800", "611277", "612279", "613060", "613828", "613863", "616172", "618482"], "umls": ["C3502809"], "icd-10": ["G40.3"], "synonyms": ["GEFS+", "Genetic epilepsy with febrile seizures-plus"]}
Uniparental disomy Play media Animation of uniparental isodisomy SpecialtyMedical genetics Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or of part of a chromosome, from one parent and no copy from the other parent.[1] UPD can be the result of heterodisomy, in which a pair of non-identical chromosomes are inherited from one parent (an earlier stage meiosis I error) or isodisomy, in which a single chromosome from one parent is duplicated (a later stage meiosis II error).[2] Uniparental disomy may have clinical relevance for several reasons. For example, either isodisomy or heterodisomy can disrupt parent-specific genomic imprinting, resulting in imprinting disorders. Additionally, isodisomy leads to large blocks of homozygosity, which may lead to the uncovering of recessive genes, a similar phenomenon seen in inbred children of consanguineous partners.[3] UPD has been found to occur in about 1 in 2,000 births.[4] ## Contents * 1 Pathophysiology * 2 Phenotype * 3 All chromosomes * 4 History * 5 See also * 6 References * 7 External links ## Pathophysiology[edit] UPD can occur as a random event during the formation of egg cells or sperm cells or may happen in early fetal development. It can also occur during trisomic rescue. * When the child receives two (different) homologous chromosomes (inherited from both grandparents) from one parent, this is called a heterodisomic UPD. Heterodisomy (heterozygous) indicates a meiosis I error if the gene loci in question didn't cross over.[5] * When the child receives two (identical) replica copies of a single homologue of a chromosome, this is called an isodisomic UPD. Isodisomy (homozygous) indicates either a meiosis II (if the gene loci in question didn't cross over[5]) or postzygotic chromosomal duplication. * A meiosis I error can result in isodisomic UPD if the gene loci in question crossed over, for example, a distal isodisomy would be due to duplicated gene loci from the maternal grandmother that crossed over and due to an error during Meiosis I, ended up in the same gamete.[5] * A meiosis II error can result in heterodisomy UPD if the gene loci crossed over in a similar fashion.[5] ## Phenotype[edit] Most occurrences of UPD result in no phenotypical anomalies. However, if the UPD-causing event happened during meiosis II, the genotype may include identical copies of the uniparental chromosome (isodisomy), leading to the manifestation of rare recessive disorders. UPD should be suspected in an individual manifesting a recessive disorder where only one parent is a carrier. Uniparental inheritance of imprinted genes can also result in phenotypical anomalies. Although few imprinted genes have been identified, uniparental inheritance of an imprinted gene can result in the loss of gene function, which can lead to delayed development, mental retardation, or other medical problems. * The most well-known conditions include Prader–Willi syndrome and Angelman syndrome. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15.[6] * Other conditions, such as Beckwith–Wiedemann syndrome, are associated with abnormalities of imprinted genes on the short arm of chromosome 11. * Chromosome 14 is also known to cause particular symptoms such as skeletal abnormalities, intellectual disability, and joint contractures, among others.[7][8] UPD has rarely been studied prospectively, with most reports focusing on either known conditions or incidental findings. It has been proposed that the incidence may not be as low as believed, rather it may be under-reported.[9] ## All chromosomes[edit] Main article: Isodisomy Occasionally, all chromosomes will be inherited from one parent. As a result, recessive traits can be expressed.[10] ## History[edit] The first clinical case of UPD was reported in 1988 and involved a girl with cystic fibrosis and unusually short stature who carried two copies of maternal chromosome 7.[11] Since 1991, out of the 47 possible disomies, 29 have been identified among individuals ascertained for medical reasons. This includes chromosomes 2, 5–11, 13–16, 21 and 22. ## See also[edit] * Aneuploidy ## References[edit] 1. ^ Robinson WP (May 2000). "Mechanisms leading to uniparental disomy and their clinical consequences". BioEssays. 22 (5): 452–9. doi:10.1002/(SICI)1521-1878(200005)22:5<452::AID-BIES7>3.0.CO;2-K. PMID 10797485. 2. ^ Human Molecular Genetics 3. Garland Science. pp. 58. ISBN 0-8153-4183-0. 3. ^ King DA (2013). "A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders". Genome Research. 24 (4): 673–687. doi:10.1101/gr.160465.113. PMC 3975066. PMID 24356988. 4. ^ Nakka, Priyanka; Smith, Samuel Pattillo; O’Donnell-Luria, Anne H.; McManus, Kimberly F.; Agee, Michelle; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Elson, Sarah L.; Fontanillas, Pierre; Furlotte, Nicholas A. (2019-11-07). "Characterization of Prevalence and Health Consequences of Uniparental Disomy in Four Million Individuals from the General Population". The American Journal of Human Genetics. 105 (5): 921–932. doi:10.1016/j.ajhg.2019.09.016. ISSN 0002-9297. PMC 6848996. PMID 31607426. 5. ^ a b c d "Meiosis: Uniparental Disomy". Retrieved 29 February 2016. 6. ^ Angelman Syndrome, Online Mendelian Inheritance in Man 7. ^ "OMIM Entry - # 608149 - KAGAMI-OGATA SYNDROME". omim.org. Retrieved 1 September 2020. 8. ^ Duncan, Malcolm (1 September 2020). "Chromosome 14 uniparental disomy syndrome information Diseases Database". www.diseasesdatabase.com. Retrieved 1 September 2020. 9. ^ Bhatt, Arpan; Liehr, Thomas; Bakshi, Sonal R. (2013). "Phenotypic spectrum in uniparental disomy: Low incidence or lack of study". Indian Journal of Human Genetics. 19 (3): 131–34. doi:10.4103/0971-6866.120819. PMC 3841555. PMID 24339543. Archived from the original on 2014-02-20.CS1 maint: unfit URL (link) 10. ^ "Heterodisomy and isodisomy: imprinting or unmasking of a mutant recessive allele?" (PDF). Expert Reviews in Molecular Medicine. Retrieved 11 June 2017. 11. ^ Spence JE, Perciaccante RG, Greig GM, Willard HF, Ledbetter DH, Hejtmancik JF, Pollack MS, O'Brien WE, Beaudet AL (1988). "Uniparental disomy as a mechanism for human genetic disease". American Journal of Human Genetics. 42 (2): 217–226. PMC 1715272. PMID 2893543. ## External links[edit] Classification D * ICD-10: Q99.8 * MeSH: D024182 * "Uniparental disomy". Department of Medical Genetics, University of British Columbia. Archived from the original on 2002-06-17.CS1 maint: unfit URL (link) * T. Liehr: Cases with uniparental disomy * UPD Animations: UPD Animations This article incorporates public domain text from The U.S. National Library of Medicine * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Uniparental disomy	c0949628	3,372	wikipedia	https://en.wikipedia.org/wiki/Uniparental_disomy	2021-01-18T18:39:19	{"mesh": ["D024182"], "icd-10": ["Q99.8"], "wikidata": ["Q1207929"]}
Generalized trichoepithelioma SpecialtyDermatology Generalized trichoepitheliomas are characterized histologically by replacement of the hair follicles by trichoepithelioma-like epithelial proliferations associated with hyperplastic sebaceous glands.[1]:578 ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This Genodermatoses article is a stub. You can help Wikipedia by expanding it. * v * t * e * v * t * e Cancers of skin and associated structures Glands Sweat gland Eccrine * Papillary eccrine adenoma * Eccrine carcinoma * Eccrine nevus * Syringofibroadenoma * Spiradenoma Apocrine * Cylindroma * Dermal cylindroma * Syringocystadenoma papilliferum * Papillary hidradenoma * Hidrocystoma * Apocrine gland carcinoma * Apocrine nevus Eccrine/apocrine * Syringoma * Hidradenoma or Acrospiroma/Hidradenocarcinoma * Ceruminous adenoma Sebaceous gland * Nevus sebaceous * Muir–Torre syndrome * Sebaceous carcinoma * Sebaceous adenoma * Sebaceoma * Sebaceous nevus syndrome * Sebaceous hyperplasia * Mantleoma Hair * Pilomatricoma/Malignant pilomatricoma * Trichoepithelioma * Multiple familial trichoepithelioma * Solitary trichoepithelioma * Desmoplastic trichoepithelioma * Generalized trichoepithelioma * Trichodiscoma * Trichoblastoma * Fibrofolliculoma * Trichilemmoma * Trichilemmal carcinoma * Proliferating trichilemmal cyst * Giant solitary trichoepithelioma * Trichoadenoma * Trichofolliculoma * Dilated pore * Isthmicoma * Fibrofolliculoma * Perifollicular fibroma * Birt–Hogg–Dubé syndrome Hamartoma * Basaloid follicular hamartoma * Folliculosebaceous cystic hamartoma * Folliculosebaceous-apocrine hamartoma Nails * Neoplasms of the nailbed [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Generalized trichoepithelioma	None	3,373	wikipedia	https://en.wikipedia.org/wiki/Generalized_trichoepithelioma	2021-01-18T18:33:06	{"wikidata": ["Q5532517"]}
A number sign (#) is used with this entry because of evidence that multiple genes are involved in the causation of systemic lupus erythematosus. Description Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). ### Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE. Clinical Features Lappat and Cawein (1968) suggested that drug-induced, specifically procainamide-induced, systemic lupus erythematosus is an expression of a pharmacogenetic polymorphism. Among close relatives of a procainamide SLE proband, they found antinuclear antibody in the serum in 3, and in all 5, 'significant' history or laboratory findings suggesting an immunologic disorder. Three had a coagulation abnormality. The finding of complement deficiency (see 120900) in cases of lupus as well as association with particular HLA types points to genetic factors responsible for familial aggregation of this disease. On the other hand, the evidence for viral etiology suggests nongenetic explanations. Lupus-like illness occurs (Schaller, 1972) in carriers of chronic granulomatous disease (306400). Lessard et al. (1997) demonstrated that CYP2D6 (124030) is the major isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus syndrome observed with procainamide. Lessard et al. (1999) stated that further studies were needed to demonstrate whether genetically-determined or pharmacologically-modulated low CYP2D6 activity could prevent drug-induced lupus during procainamide therapy. Reed et al. (1972) described inflammatory vasculitis with persistent nodules in members of 2 generations. Three females in the preceding generation had rheumatoid arthritis. They noted aggravation on exposure to sunlight and suppression of lesions with chloroquine therapy. They considered this to be related to lupus erythematosus profunda (Tuffanelli, 1971), which has a familial occurrence and is probably related to SLE. Brustein et al. (1977) described a woman with discoid lupus who had one child in whom lesions of discoid lupus began at age 2 months and a second child who developed a rash probably of lupus erythematosus at age 1 week. Sibley et al. (1993) described a family in which a brother and sister and a niece of theirs had SLE complicated by ischemic vasculopathy. Photographs of the hands and feet of 1 patient showing gangrene of several fingers and all toes were presented. Extensive osteonecrosis occurred in the niece. Elcioglu and Hall (1998) reported 2 sibs with chondrodysplasia punctata born to a mother with systemic lupus erythematosus. One child was stillborn at 36 weeks' gestation and the other miscarried at 24 weeks' gestation following the exacerbation of the mother's SLE. Austin-Ward et al. (1998) also reported an infant with neonatal lupus and chondrodysplasia punctata born to a mother with SLE. The infant also had features similar to those seen in children exposed to oral anticoagulants, although there was no history of this. Elcioglu and Hall (1998) and Austin-Ward et al. (1998), along with Toriello (1998) in a commentary on these 2 papers, suggested that there is evidence for an association between maternal SLE and chondrodysplasia punctata in a fetus. The pathogenesis of this association, however, remained unclear. Kelly et al. (1999) reported a male infant with neonatal lupus erythematosus manifested as a rash typical of the disorder, who also had midface hypoplasia and multiple stippled epiphyses. It was the skin abnormality in the infant that led to the diagnosis of SLE in his mother. Over a 3-year follow-up, the child demonstrated strikingly short stature, midface hypoplasia, anomalous digital development, slow resolution of the stippled epiphyses, and near-normal cognitive development. Kozlowski et al. (2004) described 2 brothers with chondrodysplasia punctata, whose mother had longstanding lupus erythematosus and epilepsy, for which she had been treated with chloroquine and other therapeutic agents during both pregnancies. Kozlowski et al. (2004) pointed to 7 reported instances of the association between chondrodysplasia punctata and maternal SLE. Kamat et al. (2003) described the first reported incidence of identical triplets who developed SLE. The diagnosis of SLE was made at ages 8, 9, and 11 years (in reverse birth order, the last born developing the disorder at age 8). Photosensitivity and skin lesions were all early manifestations. The 3 girls manifested different clinical signs and symptoms; however, all 3 had skin rash, fatigue, and biopsy-proven glomerulonephritis. The findings of laboratory studies were similar, including positivity for antinuclear antibodies, anti-native DNA, and anti-double-stranded DNA (dsDNA), as well as low levels of complement. ### SLE and Nephritis Stein et al. (2002) analyzed 372 affected individuals from 160 multiplex SLE families, of which 25 contained at least 1 affected male relative. The presence of renal disease was significantly increased in female family members with an affected male relative compared to those with no affected male relative (p = 0.002); the trend remained after stratifying by race and was most pronounced in European Americans. Stein et al. (2002) concluded that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families. Xing et al. (2005) added 392 individuals from 181 new multiplex SLE families to the sample previously studied by Stein et al. (2002) and replicated the finding that the prevalence of renal disease was increased in families with affected male relatives compared to families with no affected male relatives. Xing et al. (2005) concluded that multiplex SLE families with at least 1 affected male relative constitute a distinct subpopulation of multiplex SLE families. Other Features DeHoratius et al. (1975) found anti-RNA antibodies in 82% of SLE cases and 16% of their relatives, as compared with 5% of control cases. The relatives who showed antibody were exclusively close household contacts of SLE cases. Anti-RNA antibody was not found in unrelated household contacts of SLE cases. The findings supported the hypothesis that both an environmental agent, perhaps a virus, and genetic response are involved in the pathogenesis of SLE. See 601821 for information about Ro ribonucleoproteins. Beaucher et al. (1977) found clinical and serologic abnormalities in the household dogs of 2 families with multiple cases of clinical and serologic SLE, as well as other autoimmune disorders. Since spontaneous SLE occurs in dogs, a transmissible agent may be involved. Horn et al. (1978) described mixed connective tissue disease (MCTD) in a brother and sister from a sibship of 8. They were HLA-identical (A11B12; A2B12). MCTD has characteristics overlapping SLE, scleroderma and polymyositis. Sera give positive indirect immunofluorescence tests for antinuclear antibodies with a characteristic coarse, speckled pattern. The diagnosis is confirmed by finding antibodies against ribonucleoprotein. Batchelor et al. (1980) found an association of hydralazine-induced SLE with HLA-DR4. Slow acetylators without SLE and cases of nondrug-induced SLE did not show the association. Thus, spontaneous SLE may be a fundamentally different entity. In an extensive kindred in which elliptocytosis and lipomatosis (151900) were segregating as independent dominants, Weinberg et al. (1980) found a high frequency of biologic false-positive serologic tests for syphilis (BFP STS). The latter trait appeared also to be a dominant, independent of the other two traits. Two female pedigree members with BFP STS developed SLE. Reidenberg et al. (1980) found an excess of slow acetylator phenotype in SLE. On the other hand, Baer et al. (1986) could find no association between acetylator phenotype and SLE and from a review of the literature concluded that most workers have had similar results. See C3b receptor (120620) for information on a polymorphism related to SLE. Sakane et al. (1989) studied T- and B-cell function, using an IL-2 activity assay and spontaneous plaque-forming cell assay, respectively, in 34 family members of 6 patients with SLE. Impaired IL2 activity was found in 15 of 29 relatives but in none of 5 unrelated persons sharing households with the probands. The B-cell assay was abnormal in 22 of 29 relatives but was also abnormal in 4 of 5 unrelated household members. The authors concluded that there is a strong genetic component to the impaired IL2 activity in relatives of patients with SLE; the evidence suggests a genetic basis for the B-cell abnormalities, but environmental influences may also play a role. Benke et al. (1989) observed increased oxidative metabolism in PHA-stimulated lymphocytes from a subgroup of patients with systemic lupus erythematosus. The authors suggested that the increased oxidative activity may generate a chemical change in the endogenous DNA in vivo and therefore may be a primary event in the pathogenesis of autoimmunity in some patients with SLE. Using EMSA analysis, Solomou et al. (2001) showed that whereas stimulated T cells from normal individuals had increased binding of phosphorylated CREB (123810) to the -180 site of the IL2 promoter, nearly all stimulated T cells from SLE patients had increased binding primarily of phosphorylated CREM (123812) at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells. Xu et al. (2004) demonstrated that activated T cells of lupus patients resisted anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX2, or PTGS2; 600262) expression. Inhibition of COX2 caused apoptosis of the anergy-resistant lupus T cells by augmenting FAS (134637) signaling and markedly decreasing the survival molecule FLIP (603599), and this mechanism was found to involve anergy-resistant lupus T cells selectively. Xu et al. (2004) noted that the gene encoding COX2 is located in a lupus susceptibility region on chromosome 1. They also found that only some COX2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of PGE2. Xu et al. (2004) suggested that these findings could be useful in the design of lupus therapies. Zhang et al. (2001) determined that SLE patients have increased serum levels of B-lymphocyte stimulator (BLYS, or TNFSF13B; 603969) compared with normal controls. Immunoprecipitation and Western blot analyses revealed expression of a 17-kD soluble form of BLYS in patients but not controls. Functional analysis demonstrated that most patient serum-derived BLYS exhibited increased costimulatory activity for B-cell proliferation in vitro. Patients with higher levels of BLYS also had significantly higher levels of anti-dsDNA in IgG, IgM, and IgA classes than did patients with low levels of BLYS. Although there was no correlation between increased BLYS levels and clinical SLE activity, there were slightly higher BLYS levels in patients with antinuclear antibodies (ANA) and significantly increased BLYS levels in patients with both ANA and a clinical impression of SLE, suggesting that elevated BLYS precedes the formal fulfillment of the criteria for SLE. Zhang et al. (2001) suggested that BLYS may play an antiapoptotic role in B-cell tolerance loss and that anti-BLYS may be a potential therapy for SLE and other autoimmune diseases. Baechler et al. (2003) used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguished most SLE patients from healthy controls. Strikingly, approximately half of the patients studied showed dysregulated expression of genes in the interferon pathway. Furthermore, this interferon gene expression 'signature' served as a marker for more severe disease involving the kidneys, hematopoietic cells, and/or the central nervous system. These results provided insight into the genetic pathways underlying SLE, and identified a subgroup of patients who may benefit from therapies targeted at the interferon pathway. Using ELISA, Balada et al. (2008) determined that the DNA deoxymethylcytosine content of purified CD4 (186940)-positive T cells was lower in patients with SLE than in controls. RT-PCR analysis detected no differences in DNMT1 (126375), DNMT3A (602769), or DNMT3B (602900) transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-dsDNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels. Population Genetics Kelly et al. (2002) stated that SLE primarily affects women of child-bearing age (F:M ratio, 9:1) and has a prevalence of approximately 1 case/2,500. Among African American populations, SLE is 3 times more prevalent than in European Americans, manifests at a younger age, and is more severe than in other American populations. Clinical Management Glucocorticoids are widely used to treat patients with autoimmune diseases such as SLE. However, in the majority of SLE patients such treatment regimens cannot maintain disease control, and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reduction in disease activity. Guiducci et al. (2010) demonstrated that, in vitro and in vivo, stimulation of plasmacytoid dendritic cells (PDCs) through TLR7 (300365) and TLR9 (605474) can account for the reduced activity of glucocorticoids to inhibit the interferon pathway in SLE patients and in 2 lupus-prone mouse strains. The triggering of PDCs through TLR7 and TLR9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-kappa-B (see 164011) pathway essential for PDC survival. Glucocorticoids do not affect NF-kappa-B activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-alpha (147660) levels. Guiducci et al. (2010) concluded that their findings unveiled a new role for self nucleic acid recognition by TLRs and indicated that inhibitors of TLR7 and TLR9 signaling could prove to be effective corticosteroid-sparing drugs. Inheritance Block et al. (1975) comprehensively reviewed evidence from twin studies. Higher concordance for clinical and serologic abnormality for monozygotic twins supported a significant genetic factor. Lahita et al. (1983) observed father-to-son transmission and noted prepubertal onset of familial SLE in males. Fielder et al. (1983) found an unexpectedly high frequency of null (silent) alleles at the C4A (120810), C4B (120820) and C2 (613927) loci in patients with SLE. HLA-DR3 showed a high frequency in these patients, and a strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B was found. On the basis of the data reported by Fielder et al. (1983), Green et al. (1986) concluded that association with null alleles at the C4 loci is primary and the DR3 association secondary to that. In addition to the association of SLE with MHC antigens DR2 and DR3 and with homozygous deficiency of early complement components, the fact that SLE occurs 3 to 4 times more frequently in blacks than in whites (Siegel et al., 1970; Fessel, 1974) points to genetic factors. Genotype/Phenotype Correlations Sturfelt et al. (1990) found homozygous C4A deficiency in 13 of 80 patients (16%). Photosensitivity was a more impressive feature in these homozygotes than in other lupus patients. The T4/Leu-3 molecule (186940) is a T-cell differentiation antigen expressed on the surface of T helper/inducer cells. Monoclonal antibodies that can recognize this molecule include OKT4 and anti-Leu-3a, which bind to different determinants (epitopes) on the T4/Leu-3 molecule. This molecule has an important role in the recognition of class II MHC antigens by T cells. Polymorphism of the T4 epitope had, by the time of the report of Stohl et al. (1985), been identified only in blacks. Three phenotypes, corresponding to 3 genotypes, were identified: the most common, the T4 epitope-intact phenotype, is manifest when fluorescence intensity upon staining of T cells is as great with OKT4 as with anti-Leu-3a. The T4 epitope-deficient phenotype shows no staining with OKT4, and an intermediate phenotype, representing heterozygosity for deficiency, shows fluorescence intensity with OKT4 that is half that with anti-Leu-3a. Mapping ### Genomewide Linkage Studies Lee and Nath (2005) conducted a metaanalysis of 12 genome scans generated from 9 independent studies involving 605 SLE families with 1,355 affected individuals. They identified 2 loci, 6p22.3-6p21.1 and 16p12.3-16q12.2, that met genomewide significance (p less than 0.000417). Lee and Nath (2005) noted that 6p22.3-6p21.1 contains the HLA region. Gaffney et al. (1998) reported the results of a genomewide microsatellite marker screen in 105 SLE sib-pair families. Eighty of the families were Caucasian; 5 were African American. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus; D6S257 gave a lod score of 3.90. D16S415 at 16q13 yielded a lod score of 3.64; D14S276 at 14q21-q23 yielded a lod score of 2.81; and D20S186 at 20p12 yielded a lod score of 2.62. Another 9 regions were identified with lod scores equal to or greater than 1.00. The data supported the hypothesis that multiple genes, including 1 in the HLA region, influence susceptibility to human SLE. Gaffney et al. (2000) performed a second genomewide screen in a 'new' cohort of 82 SLE sib-pair families. Highest evidence of linkage was found in 4 intervals: 10p13, 7p22, 7q21, and 7q36; all 4 had a lod score greater than 2.0, and the locus on 7p22 had a lod score of 2.87. A combined analysis of cohorts 1 and 2 (187 sib-pair families total) showed that markers in 6p21-p11 (D6S426, lod score of 4.19) and 16q13 (D16S415, lod score of 3.85) met the criteria for significant linkage. Using the ABI Prism linkage mapping set, which includes 350 polymorphic markers with an average spacing of 12 cM, Shai et al. (1999) screened the human genome in a sample of 188 lupus patients belonging to 80 lupus families, each with 2 or more affected relatives per family, to localize genetic intervals that may contain lupus susceptibility loci. Nonparametric multipoint linkage analysis suggested evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, support for a gene in the 1q44 region, as well as for a gene in the 1p36 region, was found clearly only in Mexican American families with SLE, but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial. Lindqvist et al. (2000) performed genome scans in families with multiple SLE patients from Iceland and from Sweden. A number of regions gave lod scores greater than 2: among Icelandic families, 4p15-p13, Z = 3.20; 9p22, Z = 2.27; and 19q13, Z = 2.06, which are homologous to the murine regions containing the lmb2, sle2, and sle3 loci, respectively. The fourth region among Icelandic families is located on 19p13 (D19S247, Z = 2.58) and a fifth on 2q37 (D2S125, Z = 2.06). Only 2 regions showed lod scores above 2.0 in the Swedish families: 2q11 (D2S436, Z = 2.13) and 2q37 (D2S125, Z = 2.18). The combination of both family sets gave a highly significant lod score at D2S125, with a Z of 4.24 in favor of linkage for 2q37 (see 605218). Gray-McGuire et al. (2000) presented the result of a genome scan of 126 pedigrees with 2 or more cases of SLE, including 469 sib pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sib pairs and a conditional logistic regression technique for affected relative pairs, they identified linkage to chromosome 4p16-p15.2 (P = 0.0003, lod = 3.84) and presented evidence of an epistatic interaction between 4p16-p15.2 and chromosome 5p15 in European American families. Using data from an independent pedigree collection, they confirmed the linkage to 4p16-p15.2 in European American families. The most significant linkage that they found in the African American subset was to the previously identified region on 1q (601744). Johanneson et al. (2002) genotyped a set of 87 multicase families with SLE from various European countries and recently admixed populations of Mexico, Colombia, and the United States for 62 microsatellite markers on chromosome 1. By parametric 2-point linkage analysis, 6 regions previously described as being related to SLE (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that had lod scores greater than or equal to 1.50. CD45 (151460) was considered a strong candidate gene because of its position in 1q31-q32 and because of its involvement in the regulation of the antigen-induced signaling of naive B and T cells. Johanneson et al. (2002) found no association between the 77C-G (151460.0001) mutation in the CD45 gene and SLE in the families they studied. The locus at 1q31 showed a significant 3-point lod score of 3.79 and was contributed by families from all populations, with several markers and under the same parametric model. They concluded that a locus at 1q31 contains a major susceptibility gene, important to SLE in 'general populations.' Scofield et al. (2003) selected 38 pedigrees that had an SLE patient with thrombocytopenia from a collection of 184 pedigrees with multiple cases of SLE. They established linkage at chromosome 1q22-q23 (maximum lod = 3.71) in all 38 pedigrees and at 11p13 (maximum lod = 5.72) in the 13 African American pedigrees. Nephritis, serositis, neuropsychiatric involvement, autoimmune hemolytic anemia, anti-double-stranded DNA, and antiphospholipid antibody were associated with thrombocytopenia. The results showed that SLE was more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient was considered. ### Susceptibility Loci for SLE Mapped by Linkage Studies See SLEB1 (601744) for discussion of an SLE susceptibility locus on chromosome 1q41. Variations in the TLR5 gene (603031) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB2 (605218) for discussion of an SLE susceptibility locus on chromosome 2q37. Variations in the PDCD1 gene (605218) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB3 (605480) for discussion of an SLE susceptibility locus on chromosome 4p. See SLEB4 (608437) for discussion of an SLE susceptibility locus on chromosome 12q24. See SLEB5 (609903) for discussion of an SLE susceptibility locus on chromosome 13q32. See SLEB6 (609939) for discussion of an SLE susceptibility locus on chromosome 16q12-q13. See SLEB7 (610065) for discussion of an SLE susceptibility locus on chromosome 20p12. See SLEB8 (610066) for discussion of an SLE susceptibility locus on chromosome 20q13.1. See SLEB9 (610927) for discussion of an SLE susceptibility locus on chromosome 1q32. See SLEB10 (612251) for discussion of an SLE susceptibility locus on chromosome 7q32. Variations in the IRF5 gene (607218) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB11 (612253) for discussion of an SLE susceptibility locus on chromosome 2q32.2-q32.3. Variations in the STAT4 gene (600558) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB12 (612254) for discussion of an SLE susceptibility locus on chromosome 8p23.1. See SLEB13 (612378) for discussion of an SLE susceptibility locus on chromosome 6p23. Variations in the TNFAIP3 gene (191163) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB14 (613145) for discussion of an SLE susceptibility locus on chromosome 1q21-q23. Variations in the CRP gene (123260) have been associated with SLE at this locus; see MOLECULAR GENETICS. See SLEB15 (300809) for a discussion of an SLE susceptibility locus on chromosome Xq28. ### Susceptibility Loci for SLE with Nephritis Renal disease occurs in 40 to 75% of SLE patients and contributes significantly to morbidity and mortality (Garcia et al., 1996). Quintero-Del-Rio et al. (2002) used 2 pedigree stratification strategies to explore the impact of the American College of Rheumatology's renal criterion for SLE classification upon genetic linkage with SLE. They identified susceptibility loci for SLE associated with nephritis on chromosomes 10q22.3 (SLEN1; 607965), 2q34-q35 (SLEN2; 607966), and 11p15.6 (SLEN3; 607967). ### Susceptibility Locus for SLE with Hemolytic Anemia A locus for susceptibility to SLE with hemolytic anemia as an early or prominent clinical manifestation shows linkage to 11q14 (SLEH1; 607279). ### Susceptibility Locus for SLE with Vitiligo A locus for susceptibility to SLE associated with vitiligo has been mapped to 17p13 (SLEV1; 606579). ### Association with the HLA-DRB1 Locus Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, Graham et al. (2002) identified 3 distinct haplotypes that encompassed the class II region and exhibited transmission distortion. By visualizing ancestral recombinants, they narrowed the disease-associated haplotypes containing DRB11501 and DRB10801 to a region of approximately 500 kb. They concluded that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE. To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This new cohort replicated the association with HLA-DRB1 at rs3135394 (odds ratio = 1.98, 95% confidence interval = 1.84-2.14; combined P = 2.0 x 10(-60)). ### Association with the TNIP1 Gene on Chromosome 5q32 In a study of 1,963 patients from the United States and Sweden with SLE compared with 4,329 controls, Gateva et al. (2009) identified association with the TNIP1 gene (607714) at chromosome 5q32 (rs7708392, combined P value = 3.8 x 10(-13); odds ratio = 1.27, 95% confidence interval = 1.10-1.35). Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with a SNP in the TNIP1 gene, rs10036748 (combined P = 1.67 x 10(-9); odds ratio = 0.81, 95% confidence interval = 0.75-0.87). Molecular Genetics ### Association with the PTPN22 Gene on Chromosome 1p13 In a study of 525 unrelated North American white individuals with SLE, Kyogoku et al. (2004) found an association with the R620W polymorphism in the PTPN22 gene (600716.0001), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (odds ratio = 4.37). Orru et al. (2009) reported a 788G-A variant, resulting in an arg263-to-gln (R263Q; rs33996649) substitution within the catalytic domain of the PTPN22 gene, that leads to reduced phosphatase activity. They genotyped 881 SLE patients and 1,133 healthy controls from Spain and observed a significant protective effect (p = 0.006; OR, 0.58). Three replication cohorts of Italian, Argentinian, and Caucasian North American populations failed to reach significance; however, the combined analysis of 2,093 SLE patients and 2,348 controls confirmed the protective effect (p = 0.0017; OR, 0.63). To confirm additional risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. Gateva et al. (2009) showed an association with PTPN22 at rs2476601 (combined P value = 3.4 x 10(-12), odds ratio = 1.35, 95% confidence interval = 1.24-1.47). ### Association with the CRP Gene on Chromosome 1q21-q23 Relative deficiency of pentraxin proteins is implicated in the pathogenesis of SLE. The C-reactive protein (CRP; 123260) response is defective in patients with acute flares of disease, and mice with targeted deletions of the APCS (104770) gene develop a lupus-like illness. In humans, the CRP and APCS genes are both within the 1q23-q24 interval that has been linked to SLE. Among 586 simplex SLE families, Russell et al. (2004) found that basal levels of CRP were influenced independently by 2 CRP polymorphisms, which they designated CRP2 (rs1800947) and CRP4 (rs1205), and the latter was associated with SLE and antinuclear autoantibody production. Russell et al. (2004) hypothesized that defective disposal of potentially immunogenic material may be a contributory factor in lupus pathogenesis. ### Association with the FCGR2B Gene on Chromosome 1q22 In 193 Japanese patients with SLE and 303 healthy controls, Kyogoku et al. (2002) found that homozygosity for an ile232-to-thr polymorphism in the FCGR2B gene (I232T; 604590.0002) was significantly increased in SLE patients compared with controls. In membrane separation studies using a human monocytic cell line, Floto et al. (2005) demonstrated that although wildtype FCGR2B readily partitioned into the raft-enriched gradient fractions, FCGR2B-232T was excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is unable to inhibit activating receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE. Su et al. (2004) identified 10 SNPs in the first FCGR2B promoter in 66 SLE patients and 66 controls. They determined that the proximal promoter contains 2 functionally distinct haplotypes. Luciferase promoter analysis showed that the less frequent haplotype, which had a frequency of 9%, was associated with increased gene expression. A case-control study of 243 SLE patients and 366 matched controls demonstrated that the less frequent haplotype was significantly associated with the SLE phenotype and was not in linkage disequilibrium with FCGR2A and FCGR3A (146740) polymorphisms. Su et al. (2004) concluded that an expression variant of FCGR2B is a risk factor for SLE. In 190 European American patients with SLE and 130 European American controls, Blank et al. (2005) found a significant association between homozygosity for a -343C polymorphism in the promoter region of the FCGR2B gene (604590.0001) and SLE. The surface expression of FCGR2B receptors was significantly reduced in activated B cells from -343C/C SLE patients. Blank et al. (2005) suggested that deregulated expression of the mutant FCGR2B gene may play a role in the pathogenesis of human SLE. By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 of the I232T FCGR2B polymorphism was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria (see 611162) is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE. ### Association with the FCGR3B Gene on Chromosome 1q23 Aitman et al. (2006) showed that copy number variation (CNV) of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the rat-specific Fcgr3 paralog 'Fcgr3-related sequence' (Fcgr3rs) as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B (610665), an ortholog of rat Fcgr3, was associated with glomerulonephritis in SLE. Following up on the study of Aitman et al. (2006) in a larger sample, Fanciulli et al. (2007) confirmed and strengthened their previous finding of an association between low FCGR3B copy number and susceptibility to glomerulonephritis in SLE patients. Low copy number was also associated with risk of systemic SLE with no known renal involvement as well as with microscopic polyangiitis and granulomatosis with polyangiitis (608710), but not with organ-specific Graves disease (275000) or Addison disease (240200), in British and French cohorts. Fanciulli et al. (2007) concluded that low FCGR3B copy number or complete FCGR3B deficiency has a key role in the development of specific autoimmunity. Willcocks et al. (2008) confirmed that low copy number of FCGR3B was associated with SLE in a Caucasian U.K. population, but they were unable to find an association in a Chinese population. Investigations of the functional effects of FCGR3B CNV revealed that FCGR3B CNV correlated with cell surface expression, soluble FCGR3B production, and neutrophil adherence to and uptake of immune complexes both in a patient family and in the general population. Willcocks et al. (2008) found that individuals from 3 U.K. cohorts with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) were more likely to have high FCGR3B CNV. They proposed that FCGR3B CNV is involved in immune complex clearance, possibly explaining the association of low CNV with SLE and high CNV with AASV. Niederer et al. (2010) noted linkage disequilibrium (LD) between multiallelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus. Despite LD between FCGR3B CNV and a variant in FCGR2B (I232T; 604590.0002) that abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FCGR2B-232T allele were individually strongly associated with SLE risk. Thus copy number of FCGR3B, which controls immune complex responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Mueller et al. (2013) found that the increased risk of SLE associated with reduced copy number of FCGR3B can be explained by the presence of a chimeric gene, FCGR2B-prime, that occurs as a consequence of FCGR3B deletion on FCGR3B zero-copy haplotypes. The FCGR2B-prime gene consists of upstream elements and a 5-prime coding region that derive from FCGR2C, and a 3-prime coding region that derives from FCGR2B (604590). The coding sequence of FCGR2B-prime is identical to that of FCGR2B, but FCGR2B-prime would be expected to be under the control of 5-prime flanking sequences derived from FCGR2C. Mueller et al. (2013) found by flow cytometry, immunoblotting, and cDNA sequencing that presence of the chimeric FCGR2B-prime gene results in the ectopic presence of Fc-gamma-RIIb on natural killer cells, providing an explanation for SLE risk associated with reduced FCGR3B copy number. The 5 FCGR2/FCGR3 genes are arranged across 2 highly paralogous genomic segments on chromosome 1q23. To pursue the underlying mechanism of SLE disease association with FCGR3B copy number variation, Mueller et al. (2013) aligned the reference sequence (GRCh37) of the proximal block of the FCGR locus (chr1:161,480,906-161,564,008) to that of the distal block (chr1:161,562,570-161,645,839). Identification of informative paralogous sequence variants (PSVs) enabled Mueller et al. (2013) to narrow the potential breakpoint region to a 24.5-kb region of paralogy between then 2 ancestral duplicated blocks. The complete absence of nonpolymorphic PSVs in the 24.5-kb region prevented more precise localization of the breakpoints in FCGR3B-deleted or FCGR3B-duplicated haplotypes. ### Association with the TNFSF6 Gene on Chromosome 1q23 The apoptosis genes FAS (TNFRSF6; 134637) and FASL (TNFSF6; 134638) are candidate contributory genes in human SLE, as mutations in these genes result in autoimmunity in several murine models of this disease. In humans, FAS mutations result in a familial autoimmune lymphoproliferative syndrome (e.g., 134637.0001). Wu et al. (1996) studied DNA from 75 patients with SLE using SSCP analysis for potential mutations of the extracellular domain of FASL. In 1 SLE patient who exhibited lymphadenopathy, they found an 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (see 134638.0001). ### Association with the TNFSF4 Gene on Chromosome 1q25 By use of both a family-based study and a case-control study of SLE in U.K and Minnesota populations to screen the TNFRSF4 (600315) and TNFSF4 (603594) genes, Cunninghame Graham et al. (2008) found that an upstream region of TNFSF4 contains a single risk haplotype (GCTAATCATTTGA) for SLE that correlates with increased cell surface TNFSF4 expression and TNFSF4 transcript. The authors suggested that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T-cell/antigen-presenting cell (APC) interaction or by influencing the functional consequences of T-cell activation via TNFRSF4. Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with the TNFSF4 gene at 2 SNPs, rs1234315 (combined P value = 2.34 x 10(-26), odds ratio = 1.37, 95% confidence interval 1.29-1.45) and rs2205960 (combined P value = 2.53 x 10(-32), odds ratio = 1.46, 95% confidence interval 1.37-1.56). ### Association with the CR2 Gene on Chromosome 1q32 Wu et al. (2007) analyzed the CR2 gene, which lies in the SLEB9 (610927) locus region, in 1,416 individuals from 258 Caucasian and 142 Chinese SLE simplex families and demonstrated that a common 3-SNP haplotype (120650.0001) was associated with SLE susceptibility (p = 0.00001) with a 1.54-fold increased risk for development of disease. Wu et al. (2007) concluded that the CR2 gene is likely a susceptibility gene for SLE. ### Association with the TLR5 Gene on Chromosome 1q41-q42 A polymorphism in the TLR5 gene (R392X; 603031.0001), which maps to the SLEB1 (601744) locus, is associated with resistance to SLE development. ### Association with the STAT4 Gene on Chromosome 2q32 In 1,039 patients with SLE and 1,248 controls, Remmers et al. (2007) identified an association between SLE (SLEB11; 612253) and the minor T allele of rs7574865 in intron 3 of the STAT4 gene (600558.0001). The risk allele was present in 31% of chromosomes of patients with SLE compared with 22% of those of controls (p = 1.87 x 10(-9)). Homozygosity of the risk allele (TT) compared to absence of the allele was associated with a more than doubled risk for lupus. The risk allele was also associated with susceptibility to rheumatoid arthritis (RA; 180300). ### Association with the CTLA4 Gene on Chromosome 2q33 In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between an 49A-G polymorphism in the CTLA4 gene (123890.0001) and SLE. The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. ### Association with the PDCD1 Gene on Chromosome 2q37 Prokunina et al. (2002) analyzed 2,510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in the PDCD1 gene, which maps within the SLEB2 locus (605218). They showed that one intronic SNP (600244.0001) was associated with development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1; 151385) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans. ### Association with the TREX1 Gene on Chromosome 3p21 Lee-Kirsch et al. (2007) analyzed the 3-prime repair exonuclease gene TREX1 (606609) in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They identified only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution. The authors concluded that TREX1 is implicated in the pathogenesis of SLE. ### Association with the BANK1 Gene on Chromosome 4q22-q24 Kozyrev et al. (2008) identified an association between SLE and a nonsynonymous G-to-A transition in the BANK1 gene that results in a substitution of his for arg at codon 61 (610292.0001), with the G allele conferring risk. ### Association with the NKX2-5 Gene on Chromosome 5q34 Oishi et al. (2008) genotyped 3 SNPs in the NKX2-5 gene (600584) in 178 Japanese SLE patients and 1,425 controls and found association with rs3095870 in the 5-prime flanking region of NKX2-5 (p = 0.0037; odds ratio, 1.74). Individuals having the risk genotype for both NKX2-5 and 3748079 of the ITPR3 gene (147267) had a higher risk for SLE (odds ratio, 5.77). ### Association with the ITPR3 Gene on Chromosome 6p21 Oishi et al. (2008) performed a case-control association study using more than 50,000 genomewide gene-based SNPs in a total of 543 Japanese SLE patients and 2,596 controls and identified significant association with a -1009C-T transition (rs3748079) located in a promoter region of the ITPR3 gene (p = 1.78 x 10(-8); odds ratio, 1.88). Studies in HEK293T cells showed that binding of NKX2-5 is specific to the nonsusceptibility -1009T allele, and individuals with the risk genotype of both ITPR3 and NKX2-5 (rs3095870) had a higher risk for SLE (odds ratio, 5.77). Oishi et al. (2008) concluded that genetic and functional interactions of ITPR3 and NKX2-5 play a crucial role in the pathogenesis of SLE. ### Association with the TNFA Gene on Chromosome 6p21.3 In a metaanalysis of 19 studies, Lee et al. (2006) found an association between SLE and a -308A/G promoter polymorphism in the TNFA gene (191160.0004). The findings were significant in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations. ### Association with the C4A and C4B Genes on Chromosome 6p21.3 Yang et al. (2007) investigated interindividual gene copy number variation (CNV) of complement component C4 in relation to susceptibility to SLE. They found that long C4 genes were strongly correlated with C4A (120810); short C4 genes were correlated with C4B (120820). In comparison with healthy subjects, patients with SLE clearly had the gene copy number (GCN) of total C4 and C4A shifted to the lower side. The risk of SLE disease susceptibility increased significantly among subjects with only 2 copies of total C4 (patients 9.3%; unrelated controls 1.5%) but decreased in those with 5 or more copies of C4 (patients 5.79%; controls 12%). Zero copies and 1 copy of C4A were risk factors for SLE, whereas 3 or more copies of C4A appeared to be protective. Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA (191160.0004) was more likely to be transmitted to patients with SLE. Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease. ### Association with the TNXB Gene on Chromosome 6p21.3 In a genomewide case-control association study of 178 Japanese SLE patients and 899 controls, Kamatani et al. (2008) found significant association between SLE and a SNP (rs3130342) in the 5-prime flanking region of the TNXB gene (600985) on chromosome 6p21.3 (p = 9.3 x 10(-7); odds ratio, 3.11). The association was replicated independently with 203 cases and 294 controls (p = 0.04; odds ratio, 1.52). Analysis in their Japanese SLE patients showed that the association with rs3130342 was independent of C4 copy number, suggesting that the association previously reported between SLE and CNV of the C4A gene (see Yang et al., 2007) likely reflected linkage disequilibrium between C4A CNV and rs3130342. Stratified analysis also demonstrated that the association between rs3130342 and SLE was independent of the HLA-DRB11501 allele association with SLE. Kamatani et al. (2008) concluded that TNXB is a candidate gene for SLE susceptibility in the Japanese population. ### Association with the TNFAIP3 Gene on Chromosome 6q23 In separate genomewide association studies, Graham et al. (2008) and Musone et al. (2008) found association between single-nucleotide polymorphisms (SNPs) in the TNFAIP3 region (191163) and risk of SLE. Graham et al. (2008) found association with SLE of a SNP that is also associated with rheumatoid arthritis (RA; 180300). ### Association with the IRF5 Gene on Chromosome 7q32 Sigurdsson et al. (2005) and Graham et al. (2006) showed that a common IRF5 (607218) haplotype, which drives elevated expression of multiple unique forms of IRF5, is an important risk factor for SLE (SLEB10; 612251). ### Association with the DNASE1 Gene on Chromosome 16p13.3 In 2 unrelated females with SLE and no family history of the disorder, Yasutomo et al. (2001) identified heterozygosity for a mutation in the DNASE1 gene (125505.0001). The patients, aged 13 and 17 years, were diagnosed as having SLE based on clinical features, high serum titers of antibodies against double-stranded DNA, and Sjogren syndrome. Both patients had substantially lower levels of DNASE1 activity in the sera than in other SLE patients without a DNASE1 mutation. However, the DNASE1 activity of SLE patients without DNASE1 mutations is lower than that of healthy controls. The patient's B cells had 30 to 50% of the DNASE1 activity of cells from controls, showing that heterozygous mutation of DNASE1 reduces the total activity of this enzyme. In 350 Korean patients with SLE and 330 Korean controls, Shin et al. (2004) identified a nonsynonymous SNP in exon 8 of the DNASE1 gene, 2373A-G (Q244R; 125505.0002), that was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the arg/arg minor allele was much higher in patients who had the anti-RNP antibody (31%) than in patients who did not have this antibody (14%) (P = 0.0006). ### Association with the ITGAM Gene on Chromosome 16p11.2 See SLEB6, 609939. Nath et al. (2008) identified and replicated an association between ITGAM (120980) at 16p11.2 and risk of SLE in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, rs1143679 (120980.0001). Nath et al. (2008) further replicated this association in 2 independent samples of individuals of African descent. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) likewise identified an association between SNPs in ITGAM in 720 women of European ancestry with SLE and in 2 additional independent sample sets. Several previously identified associations such as the strong association between SLE and the HLA region on 6p21 and the previously confirmed non-HLA locus IRF5 (607218) on 7q32 were found. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) also found association with replication for KIAA1542 (611780) at 11p15.5, PXK (611450) in 3p14.3, and a SNP at 1q25.1. Hom et al. (2008) identified SNPs near the ITGAM and ITGAX (151510) genes that were associated with SLE; they believed variants of ITGAM to be driving the association. ### Association with the IL6 Gene on chromosome 7p21 Linker-Israeli et al. (1999) used PCR and RFLP analysis to genotype the AT-rich minisatellite in the 3-prime flanking region and the 5-prime promoter-enhancer of IL6 (147620) in SLE patients and controls. In both African-Americans and Caucasians, short allele sizes (less than 792 bp) at the 3-prime minisatellite were found exclusively in SLE patients, whereas the 828-bp allele was overrepresented in controls. No association was found between SLE and alleles in the 5-prime region of IL6. Patients homo- or heterozygous for the SLE-associated 3-prime minisatellite alleles secreted higher levels of IL6, had higher percentages of IL6-positive monocytes, and showed significantly enhanced IL6 mRNA stability. Linker-Israeli et al. (1999) concluded that the AT-rich minisatellite in the 3-prime region flanking of IL6 is associated with SLE, possibly by increasing accessibility for transcription factors. ### Association with the IL18 Gene on Chromosome 11q22 Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene (600953) and genotyped an independent set of 752 Spanish systemic lupus erythematosus patients and 595 Spanish controls. A -1297T-C SNP (rs360719) survived correction for multiple tests and was genotyped in 2 case-control replication cohorts from Italy and Argentina. Combined analysis for the risk C allele remained significant (pooled odds ratio = 1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a significant increase in the relative expression of IL18 mRNA in individuals carrying the risk -1297C allele; in addition, -1297C allele created a binding site for the transcriptional factor OCT1 (POU2F1; 164175). Sanchez et al. (2009) suggested that the rs360719 variant may play a role in susceptibility to SLE and in IL18 expression. ### Association with the CSK Gene on Chromosome 15q23-q25 The c-Src tyrosine kinase CSK (124095) physically interacts with the intracellular phosphatase LYP (PTPN22; 600716) and can modify the activation state of downstream Src kinases, such as LYN (165120), in lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of CSK with SLE and refined its location to the intronic polymorphism rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of LYN. In carriers of the risk allele, there is increased B-cell receptor-mediated activation of mature B cells, as well as higher concentrations of plasma IgM, relative to individuals in the nonrisk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results suggested that the LYP-CSK complex increases susceptibility to lupus at multiple maturation and activation points in B cells. ### Association with the EGR2 Gene on Chromosome 10q21 Based on phenotypic changes in knockout mice, Myouzen et al. (2010) evaluated if polymorphisms in the EGR2 gene (129010) on chromosome 10q21 influence SLE susceptibility in humans. A significant positive correlation with expression was identified in a SNP located at the 5-prime flanking region of EGR2. In a case-control association study using 3 sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region, a peak of association with SLE susceptibility was observed for rs10761670. This SNP was also associated with susceptibility to rheumatoid arthritis (RA; 180300), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670, 2 SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. The authors proposed that EGR2 may be a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis. ### Association with the NCF1 Gene on Chromosome 7q11 Zhao et al. (2017) reported a missense variant (g.74779296G-A; rs201802880, arg90 to his) in exon 4 of NCF1, encoding the p47-phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by SNP microarray analysis in the GTF2IRD1 (604318)-GTF2I (601679) region on chromosome 7q11.23 with a complex genomic structure. Zhao et al. (2017) showed that the arg90-to-his (R90H) substitution, which was reported by Olsson et al. (2012) to cause reduced reactive oxygen species (ROS) production, was associated with SLE (odds ratio (OR) = 3.47 in Asians (p-meta = 3.1 x 10(-104)), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjogren syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, Zhao et al. (2017) found that decreased and increased copy numbers of NCF1 were associated with predisposition to and protection against SLE, respectively. These data highlighted the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases. Pathogenesis The role of estrogen in determining female preponderance of lupus was reviewed by Talal (1979). Patients with the XXY Klinefelter syndrome are predisposed to lupus. Miller and Schwartz (1979) proposed 'that the development of systemic lupus erythematosus requires the participation of at least two functionally distinct classes of genes.' Stohl et al. (1985) identified 3 unrelated Jamaican black patients with SLE by American Rheumatism Association criteria (Tan et al., 1982) and with homozygous T4 epitope deficiency. Lymphadenopathy was an impressive feature and was present also in an asymptomatic and otherwise apparently healthy T4-deficient brother of one of the SLE patients. In 1 family, 2 heterozygotes had Hb Constant Spring and 1 had idiopathic thrombocytopenic purpura. The anti-DNA antibodies of unrelated SLE patients share cross-reactive idiotypes. Thus, a restricted number of germline genes may encode the autoantibodies involved in the pathogenesis of SLE. Solomon et al. (1983) described a monoclonal antibody, 3I, that recognizes a cross-reactive idiotype on anti-DNA antibodies. Halpern et al. (1985) used this monoclonal antibody to study the sera of 27 members of 3 unrelated kindreds with SLE. Some healthy family members were found to have high-titered reactivity with the antiidiotype. The antigenic specificity of 3I-reactive antibodies in the serum of healthy persons is unknown. Possibly 3I-reactive antibodies are made in response to some unknown antigen and these antibodies subsequently mutate and acquire reactivity with DNA. Diamond and Scharff (1984) showed that a monoclonal antiphosphorylcholine antibody that has undergone a glutamic to alanine substitution in a heavy chain hypervariable region loses affinity for phosphorylcholine and acquires reactivity with DNA and other phosphorylated macromolecules. Schur (1995) reviewed the genetics of SLE, with particular reference to the major histocompatibility complex. He showed that different but related genes may be associated with lupus and autoantibodies in different countries. He suggested that examination of homogeneous (clinical, immunologic, ethnic, etc.) populations offers the best possibility for unraveling the maze of multiple genes involved in the disorder. Kotzin (1996) reviewed the molecular mechanisms in the pathogenesis of SLE. Vyse and Todd (1996) gave a general review of genetic analysis of autoimmune diseases, including this one. Sanghera et al. (1997) noted that beta-2-glycoprotein I (B2GPI, APOH; 138700) is a required cofactor for anionic phospholipid binding by the antiphospholipid autoantibodies found in sera of many patients with SLE and primary antiphospholipid syndrome (107320). These studies suggested that the apoH-phospholipid complex forms the antigen to which the autoantibodies are directed. Yasutomo et al. (2001) identified an early termination mutation in DNASE1 in 2 teenaged girls with SLE from Japan (125505.0001). The nonsense mutations were associated with reduced DNASE activity and extremely high immunoglobulin G titer against nucleosomal antigens. Yasutomo et al. (2001) suggested that their data were consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE. Blanco et al. (2001) hypothesized that SLE may be caused by alterations in the functions of dendritic cells. Consistent with this, monocytes from the blood of SLE patients were found to function as antigen-presenting cells in vitro. Furthermore, serum from SLE patients induced normal monocytes to differentiate into dendritic cells. These dendritic cells could capture antigens from dying cells and present them to CD4-positive T cells. The capacity of SLE patients' serum to induce dendritic cell differentiation correlated with disease activity and depended on the actions of interferon-alpha (147660). Thus, Blanco et al. (2001) concluded that unabated induction of dendritic cells by interferon-alpha may drive the autoimmune response in SLE. Using a rheumatoid factor (RF+) transgenic B cell hybridoma line originally isolated from an autoimmune MRL/lpr mouse used as a model for SLE, Leadbetter et al. (2002) determined that these cells respond only to IgG2a immune complexes containing DNA and not to haptens or proteins. After ruling out complement receptors (i.e., CD21/CR2, 120650) as a potential second receptor on B cells, screening of cells expressing the adaptor protein Myd88 (602170), through which all toll-like receptors signal, revealed that RF+ B cells lacking Myd88 are completely unresponsive to IgG2a antinucleosome monoclonal antibodies (mAb). TLR9 (605474) responsiveness to CpG oligodeoxynucleotides (ODN) is presumed to require endosome acidification. The response to stimulation of RF+ B cells by IgG2a mAb or CpG-ODN, but not by TLR2 (603028) or TLR4 (603030) agonists, was blocked by inhibitors of endosome acidification, notably chloroquine, suggesting a mechanistic basis for its efficacy in the treatment for both RA and SLE. Leadbetter et al. (2002) proposed that other endogenous subcellular nucleic acid-protein autoantigens may signal through other TLRs to abrogate peripheral B-cell tolerance. They also suggested that infectious agent PAMP (patterns associated with microbial pathogens) engaging TLRs may create a synergy with autoantibody-autoantigen immune complexes, thus explaining the association between infection and autoimmune disease flares. Risk of SLE is higher in people of West African descent than in Europeans. Molokhia et al. (2003) attempted to distinguish between genetic and environmental explanations for this ethnic difference by examining the relationship of disease risk to individual admixture (defined as the proportion of the genome that is of West African ancestry). They studied 124 cases of SLE and 219 matched controls resident in Trinidad. Analysis of admixture was restricted to 52 cases and 107 controls who reported no Indian or Chinese ancestry. These individuals were typed with a panel of 26 SNPs and 5 insertion/deletion polymorphisms chosen to have large allele frequency differentials between West African, European, and Native American populations. Mean West African admixture was 0.81 in cases and 0.74 in controls (P = 0.01). The risk ratio for SLE associated with unit change in this admixture was estimated as 32.5. Adjustment for measures of socioeconomic status (household amenities in childhood and years of education) altered this risk ratio only slightly. These results supported an additive genetic model for the ethnic difference in risk of SLE between West Africans and Europeans, rather than an environmental explanation or an 'overdominant' model in which risk is higher in heterozygous than in homozygous individuals. Kowal et al. (2006) demonstrated that human anti-NMDA receptor antibodies isolated from patients with neuropsychiatric lupus caused hippocampal neuron damage and memory deficits when administered to mice with lipopolysaccharide to penetrate the blood-brain barrier. Postmortem brain tissue from 5 patients with neuropsychiatric lupus showed endogenous IgG that bound DNA and colocalized with NMDA receptor antibodies for NR2A (GRIN2A; 138253) and NR2B (GRIN2B; 138252). The findings suggested that some patients with neuropsychiatric lupus have circulating anti-NMDAR antibodies capable of causing neuronal damage and memory deficits if they breach the blood-brain barrier. To examine the role of defensins in SLE pathogenesis, Sthoeger et al. (2009) used ELISA and real-time PCR to measure the levels of the alpha-defensin DEFA2 (125220) and the beta-defensin HBD2 (DEFB4; 602215) in the blood of SLE patients. They found that HBD2 was undetectable in sera from SLE patients, and that HBD2 mRNA was low in whole blood from SLE patients, similar to controls. In contrast, DEFA2 levels were significantly higher in all SLE patients compared with controls, and 60% of patients had very high serum levels. High DEFA2 levels correlated with disease activity, but not with neutrophil numbers, suggesting that neutrophil degranulation may lead to alpha-defensin secretion in SLE patients. Reduction of DEFA2 levels to the normal range correlated with disease improvement. Kshirsagar et al. (2014) reported that enhanced STAT3 (102582) activity in CD4 (186940)-positive/CD45A (see 151460)-negative/FOXP3 (300292)-negative and FOXP3-low effector T cells from children with lupus nephritis (LN) correlated with increased frequency of IL17 (603149)-producing cells within these T-cell populations. Rapamycin treatment reduced both STAT3 activation and Th17 cell frequency in lupus patients. Th17 cells from children with LN exhibited high AKT (164730) activity and enhanced migratory capacity. Inhibition of AKT in cells from LN patients resulted in reduced Th17-cell migration. Kshirsagar et al. (2014) concluded that the AKT signaling pathway plays a significant role in Th17-cell migratory activity in children with LN. They suggested that inhibition of AKT may result in suppression of chronic inflammation in LN. ### Excess Lymphocyte Low Molecular Weight DNA Mackie et al. (1987) found circulating anticoagulants in multiple members of SLE families, but also found coagulation abnormalities in some spouses, suggesting that a transmissible agent or other environmental factors may be involved. All patients with SLE show 2 classes of newly synthesized DNA in sucrose density gradients of phytohemagglutinin-stimulated lymphocytes: a large-molecular-weight fraction that comigrates with control DNA and an excess low molecular weight DNA (LMW-DNA) fraction not found in control lymphocytes. Animal Model Knight and Adams (1978) identified 2 genes in New Zealand white (NZW) mice that determine development of nephritis in crosses with New Zealand black (NZB) mice. Theofilopoulos and Dixon (1985) provided a review of murine models of SLE. F1 hybrids of NZB and NZW mice are a model of human SLE. These mice develop a severe immune complex-mediated nephritis, in which antinuclear autoantibodies seem to play a major role. Vyse et al. (1996) used a genetic analysis of a backcross between F1 hybrid mice and NZW mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin. These loci overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a locus on the distal part of mouse chromosome 4, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production. By linkage analysis, Morel et al. (1994) found that genomic intervals on mouse chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3) and 17 (Sle4) are strongly linked to lupus nephritis. Mohan et al. (1999) showed that on a normal B6 background, the introduction of Sle1, as in the monocongenic B6.NZMc1 mice, led to hyperglobulinemia, a breach in tolerance to chromatin, and a modest expansion of activated lymphocytes. However, serum autoantibodies did not target against double-stranded DNA or basement membrane antigens. When Sle1 and Sle3 were combined, as in the bicongenic B6.NZMc1/c7 mice, high titers of autoantibodies were generated which had specificity not only for the different chromatin epitopes (including dsDNA) but also for the intact glomeruli, leading to fatal lupus glomerulonephritis. These findings lent strong support to a 2-step epistatic model for the formation of pathogenic nephrophilic autoantibodies in lupus. Gross et al. (2000) overexpressed BAFF (BLYS, or TNFSF13B; 603969) in lymphoid cells of transgenic mice and found that the mice develop symptoms characteristic of systemic lupus erythematosus and expand a rare population of splenic B-1a lymphocytes. Circulating BAFF was more abundant in New Zealand BWF1 and MRL lpr/lpr mice during the onset and progression of SLE. Gross et al. (2000) identified 2 TNF receptor family members, TACI (604907) and BCMA (109545), that bind BAFF. Treatment of New Zealand BWF1 mice with soluble TACI-Ig fusion protein inhibited the development of proteinuria and prolonged survival of the animals. These findings demonstrated the involvement of BAFF and its receptors in the develop of SLE and identified TACI/Ig as a promising treatment of autoimmune disease in humans. Systemic lupus erythematosus is characterized by the presence of antinuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It was thought that the resulting immune complexes accumulate in vessel walls, glomeruli, and joints and cause a hypersensitivity reaction type III that manifests as glomerulonephritis, arthritis, and generalized vasculitis. Several studies had suggested that increased liberation or disturbed clearance of nuclear DNA-protein complexes after cell death may initiate and propagate the disease. Consequently, DNASE1 (125505), which is a major nuclease present in serum, urine, and secreta, may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover and thus prevent SLE. To test this hypothesis, Napirei et al. (2000) generated Dnase1-deficient mice by gene targeting. They found that these animals show the classic symptoms of SLE, namely the presence of ANA, the deposition of immune complexes in glomeruli, and full-blown glomerulonephritis in a Dnase1 dose-dependent manner. Moreover, in agreement with earlier reports, they found Dnase1 activities in serum to be lower in SLE patients than in normal subjects. The findings suggested that lack or reduction of Dnase1 is a critical factor in the initiation of human SLE. Sun et al. (2002) reported that treatment with 2A, an agonistic monoclonal antibody to CD137 (TNFRSF9; 602250), blocked lymphadenopathy and spontaneous autoimmune disease in Fas-deficient mice (a model for human SLE), ultimately leading to their prolonged survival. Specifically, 2A treatment rapidly augmented interferon-gamma (IFNG; 147570) production and induced the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. Sun et al. (2002) concluded that agonistic monoclonal antibodies specific for costimulatory molecules could be used as novel therapeutic agents to deplete autoreactive lymphocytes and block autoimmune disease progression. To clarify mechanisms governing the anxiety seen in lupus, Nakamura et al. (2003) carried out genomewide scans in mice and found that the region including interferon-alpha (IFNA; 147660) on chromosome 4 in NZB mice was significantly linked to the anxiety-like behavior seen in SLE-prone BWF1 mice. This finding was confirmed by anxiety-like performances of mice with heterozygous NZB/NZW alleles in the susceptibility region bred onto the NZW background. In BWF1 mice, neuronal IFN-alpha levels were elevated and blockade of the mu-1 opioid receptor (OPRM1; 600018) or corticotropin-releasing hormone receptor-1 (CRHR1; 122561), possible downstream effectors for IFN-alpha in the brain, partially overcame the anxiety-like behavior seen in these mice. Neuronal corticotropin-releasing hormone levels were consistently higher in BWF1 than NZW mice. Furthermore, pretreatment of mu-1 opioid receptor antagonist abolished anxiety-like behavior seen in IFN-alpha-treated NZW mice. Nakamura et al. (2003) concluded that a genetically determined endogenous excess amount of IFN-alpha in the brain may form 1 aspect of anxiety-like behavior seen in SLE-prone mice. In SLE-prone NZB mice and their F1 cross with NZW mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Li et al. (2004) performed a genomewide scan for susceptibility genes for aberrant activation of B1 cells in F1/NZB backcross mice and identified the Ltk gene as a possible candidate. Sequence and functional analyses of the gene revealed that NZB mice have a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PIK3R1; 171833). SLE patients had the equivalent human LTK polymorphism at a significantly higher frequency compared to healthy controls. Li et al. (2004) suggested that this LTK SNP may cause upregulation of the PI3K pathway and possibly form a genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE. Tournoy et al. (2004) reported that in PS1 (104311) +/- PS2 (600759) -/- mice, PS1 protein concentration was considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin (CTNNB1; 116806) downregulation. Their phenotype was normal up to 6 months, when the majority of the mice developed an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in human systemic lupus erythematosus. Besides B cell-dominated infiltrates, the authors observed a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The mice further developed a benign skin hyperplasia similar to human seborrheic keratosis (182000) as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. Despite the heterogeneity of factors influencing susceptibility to lupus, McGaha et al. (2005) demonstrated that the partial restoration of inhibitory Fc receptor (FC-gamma-RIIB; 604590) levels in B cells in lupus-prone mouse strains is sufficient to restore tolerance and prevent autoimmunity. Fc-gamma-RIIB regulates a common B-cell checkpoint in genetically diverse lupus-prone mouse strains, and modest changes in its expression can result in either tolerance or autoimmunity. McGaha et al. (2005) suggested that increasing Fc-gamma-RIIB levels in B cells may be an effective way to treat autoimmune diseases. In the MRL-lpr mouse, Barber et al. (2005) found that pharmacologic inhibition of phosphoinositide 3-kinase-gamma (PIK3CG; 601232), a kinase that regulates inflammation, reduced CD4+ T-cell populations, reduced glomerulonephritis, and prolonged life span. In both mice and humans with SLE, DeGiorgio et al. (2001) found that a subset of antibodies against dsDNA recognized portions of the extracellular domain of the NMDA receptor subunits, NR2A (138253) and NR2B (138252), which are present in the hippocampus, amygdala, and hypothalamus. Murine and human anti-dsDNA/anti-NR2 antibodies mediated apoptotic death of neurons in vitro and in vivo. Huerta et al. (2006) showed that mice immunized to produce anti-dsDNA/anti-NR2 IgG antibodies developed damage to neurons in the amygdala after being given epinephrine to induce leaks in the blood-brain barrier. The resulting neuronal insults were noninflammatory. Mice with antibody-mediated damage in the amygdala developed behavioral changes characterized by a deficient response to fear-conditioning paradigms. Huerta et al. (2006) postulated that when the blood-brain barrier is compromised, neurotoxic antibodies can penetrate the central nervous system and result in cognitive, emotional, and behavioral changes, as seen in neuropsychiatric lupus. By inserting a region from the lupus-prone NZB mouse strain into an autoimmunity-resistant strain, Talaei et al. (2015) had previously found that a locus on chromosome 1 was associated with altered DC function and synergized with T-cell functional defects to promote expansion of pathogenic proinflammatory T-cell subsets. Talaei et al. (2015) showed that Eat2 (SH2D1B; 608510) was polymorphic in its promoter region in NZB mice, leading to a 70% reduction in Eat2 in DCs. Silencing of Eat2 in DCs lacking the NZB polymorphism resulted in increased Il12 (161560) production and enhanced differentiation of T cells into a Th1 phenotype, mimicking the DC phenotype in mice with the NZB polymorphism. Eat2 knockdown resulted in increased Il12 production by Cd40 (109535)-stimulated DCs. Talaei et al. (2015) concluded that EAT2 negatively regulates cytokine production in DCs downstream of SLAM (SLAMF1; 603492) engagement and that a genetic polymorphism disturbing this process promotes lupus development. Bialas et al. (2017) reported behavioral phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signaling. Furthermore, the authors showed that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and the observation of increased type I IFN signaling in postmortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurologic symptoms observed in some patients with SLE. History Fronek et al. (1986) found that the distribution of patterns of RFLPs at the T-cell receptor beta chain locus (see 186930) was the same in SLE patients as in their relatives and in controls. Thus, the authors concluded that the TCRB 'genes are not coinherited with genes responsible for' SLE. Wong et al. (1988) found no linkage to the alpha (see 186880), beta, and gamma (see 186970) genes of the T-cell receptor. Levcovitz et al. (1988) reported a family in which a low-molecular-weight DNA marker for systemic autoimmune disease appeared to be inherited as an autosomal dominant trait; however, the report was later retracted. Using flow cytometric analysis, Tao et al. (2005) found that NKT cells from patients with active SLE were more susceptible to apoptosis induced by anti-CD95 (TNFRSF6; 134637) than NKT cells from patients with inactive SLE or normal controls. Further analysis suggested that deficient expression of CD226 (605397) and survivin (BIRC5; 603352) in NKT cells from patients with active SLE may explain the sensitivity of these cells to apoptosis. However, in 2012, Tao et al. (2005) retracted their paper. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Pericarditis RESPIRATORY Lung \- Pleuritis GENITOURINARY Kidneys \- Nephritis SKELETAL Limbs \- Arthritis SKIN, NAILS, & HAIR Skin \- Erythematous malar rash \- Photosensitivity \- Discoid rash NEUROLOGIC Central Nervous System \- Seizures \- Psychosis HEMATOLOGY \- Leukopenia \- Thrombocytopenia \- Hemolytic anemia IMMUNOLOGY \- Systemic lupus erythematosus LABORATORY ABNORMALITIES \- Antiphospholipid antibody \- Anti dsDNA antibody \- Serum antinuclear antibody MISCELLANEOUS \- Complement deficiency (e.g. C2 and C4 null alleles) are susceptible to developing SLE \- Association between HLA class II alleles and presence of autoantibodies \- Onset between ages 16-55 \- Female to male ratio 8-13:1 MOLECULAR BASIS \- Susceptibility to SLE caused by mutation in the tumor necrosis factor ligand superfamily, member 6 gene (TNFSF6, 134638.0001 ) \- Susceptibility to SLE caused by mutation in the receptor for Fc fragment of IgG, low affinity IIa gene (FCGR2A, 146790.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease	SYSTEMIC LUPUS ERYTHEMATOSUS	c0024141	3,374	omim	https://www.omim.org/entry/152700	2019-09-22T16:38:49	{"doid": ["9074"], "mesh": ["D008180"], "omim": ["152700"], "icd-9": ["710.0"], "icd-10": ["M32.9", "M32"]}
Isochromosomy Yq is a rare gonosomy anomaly with a variable phenotype including a female phenotype with sexual development delay, streak gonads, short stature and Turner syndrome features and male phenotype with infertility due to azoospermia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Isochromosomy Yq	None	3,375	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98798	2021-01-23T17:27:53	{"icd-10": ["Q98.6"]}
## Summary ### Clinical characteristics. Multiple endocrine neoplasia type 2 (MEN 2) includes the following phenotypes: MEN 2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A), and MEN 2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B involve an increased risk for pheochromocytoma; MEN 2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC. ### Diagnosis/testing. The diagnosis of MEN 2 is established in a proband who fulfills existing clinical diagnostic criteria. Molecular genetic testing to identify a heterozygous germline RET pathogenic variant is indicated in all individuals with a diagnosis of primary C-cell hyperplasia or MTC or a clinical diagnosis of MEN 2. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. ### Management. Treatment of manifestations: Treatment for MTC is surgical removal of the thyroid gland and lymph node dissection. External beam radiation therapy or intensity-modulated radiation therapy can be considered for advanced locoregional disease. Kinase inhibitors may be used in metastatic MTC. Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy. Primary hyperparathyroidism is treated with surgery to remove one or more parathyroid glands, or more rarely, with medications to reduce parathyroid hormone secretion. Prevention of primary manifestations: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant. Prevention of secondary complications: Prior to any surgery in an individual with MEN 2A or MEN 2B, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening. Surveillance: Annual measurement of serum calcitonin concentration to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Monitoring for possible hypoparathyroidism in all those who have undergone thyroidectomy and parathyroid autotransplantation. Annual biochemical screening for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma. Agents/circumstances to avoid: Dopamine D2 receptor antagonists and β-adrenergic receptor antagonists present a high risk for adverse reactions in individuals with pheochromocytoma. Evaluation of relatives at risk: RET molecular genetic testing should be offered to all at-risk members of kindreds in which a germline RET pathogenic variant has been identified. Pregnancy management: Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy or as early as possible during an unplanned pregnancy. ### Genetic counseling. All MEN 2 phenotypes are inherited in an autosomal dominant manner. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN 2A and 50% in index cases with MEN 2B. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RET pathogenic variant has been identified in an affected family member. ## Diagnosis Clinical diagnostic criteria for multiple endocrine neoplasia type 2 (MEN 2) have been published [Kloos et al 2009]; see Establishing the Diagnosis. ### Suggestive Findings Multiple endocrine neoplasia type 2 (MEN 2) includes the phenotypes MEN 2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN 2A; and MEN 2B. MEN 2A should be suspected in individuals with one or more specific endocrine tumors: medullary thyroid carcinoma (MTC), pheochromocytoma, or parathyroid adenoma/hyperplasia. FMTC should be suspected in families with more than one individual diagnosed with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. MEN 2B should be suspected in individuals with distinctive facies including lip mucosal neuromas resulting in thick vermilion of the upper and lower lip, mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, marfanoid habitus, and MTC. ### Establishing the Diagnosis The diagnosis of MEN 2 is established in a proband with the following clinical criteria. Identification of a heterozygous germline RET pathogenic variant by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive. Clinical criteria, as outlined by Kloos et al [2009]: * MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (medullary thyroid carcinoma [MTC], pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives. * FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. * MEN 2B is diagnosed clinically by the presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic, marfanoid body habitus. When the phenotypic and laboratory findings suggest the diagnosis of MEN 2, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing. Sequence analysis of RET detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. * Select-exon testing. The majority of pathogenic variants occur in exons 10, 11, and 13-16 (Table 3). Sequence analysis of select exons and targeted analysis for pathogenic variants may be offered by some laboratories. If no pathogenic variant is found by select-exon testing, full-gene sequencing of RET as part of a multigene panel should be considered next. Note: Since MEN 2 occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is not indicated. A cancer predisposition multigene panel that includes RET and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in MEN 2 View in own window Gene 1Method 2Proportion of Probands with a Pathogenic Variant 3 Detectable by Method MEN 2AFMTCMEN 2B RETSequence analysis 4, 5>98% 6, 7>95% 6, 8>98% 9 Sequence analysis of select exons98% 6, 1095% 6, 8 Targeted analysis for pathogenic variants 1198% 9 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. Since MEN 2 occurs through a gain-of-function mechanism, gene-targeted deletion/duplication analysis (such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification [MLPA], and gene-targeted microarray designed to detect single-exon deletions or duplications to detect intragenic deletions or duplications) is not indicated. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Sequence analysis of all RET exons may be performed instead of sequencing of select exons. If sequencing of select exons has been previously performed with no pathogenic variant detected, a multigene panel including RET is recommended (see Establishing the Diagnosis). 6\. Hansford & Mulligan [2000], Kloos et al [2009] 7\. Zbuk & Eng [2007] 8\. Pathogenic variants of codons 618, 620, and 634 each account for 20% to 30% of pathogenic variants. Other pathogenic variants in exons 5, 8, 10, 11, and 13-16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804. 9\. Approximately 95% of individuals have a pathogenic variant at codon 918 in exon 16 [Eng et al 1996]. A pathogenic variant in exon 15 has been identified in several affected individuals [Gimm et al 1997, Smith et al 1997]. 10\. Pathogenic variants in exons 10 and 11 [Eng et al 1996, Kloos et al 2009] 11\. Pathogenic variants typically detected: p.Met918Thr, p.Ala883Phe. Note: Pathogenic variants included in a panel may vary by laboratory. ## Clinical Characteristics ### Clinical Description The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN 2) are: medullary thyroid carcinoma (MTC) and/or its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenoma or hyperplasia. #### MTC and CCH Clinical findings. MTC in persons with MEN 2 typically presents at a younger age than sporadic MTC and is more often associated with C-cell hyperplasia as well as multifocality or bilaterality. * Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [Callender et al 2008]. * Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [Cohen & Moley 2003]. Metastatic spread to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites including the liver, lungs, or bone is also common in symptomatic individuals [Moley et al 1998, Cohen & Moley 2003]. * About 25%-30% of all individuals with MTC have a germline RET pathogenic variant. In a large series of individuals with simplex medullary thyroid carcinoma (i.e., no known family history of MTC or personal history of other endocrine disease), approximately 7% had a germline RET pathogenic variant [Elisei et al 2007]. Biochemical findings. MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration, a sensitive and specific marker. In provocative testing, plasma calcitonin concentration is measured before (basal level), then two and five minutes after intravenous administration of calcium (stimulated level). Other calcitonin secretagogues such as pentagastrin (available in Europe, limited in the US) are also used. A basal or stimulated calcitonin level of ≥100 pg/mL is an indication for surgery [Costante et al 2007, Kloos et al 2009]. Note: All individuals with an MTC-predisposing pathogenic variant who have not undergone prophylactic thyroidectomy demonstrate biochemical evidence of MTC by age 35 years [DeLellis et al 2004]. Histology. MTC originates in calcitonin-producing cells (C cells) of the thyroid gland. MTC is diagnosed histologically when nests of C cells appear to extend beyond the basement membrane and to infiltrate and destroy thyroid follicles. Immunohistochemistry for calcitonin expression may be performed as a pathologic diagnostic adjunct. CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C cells. In MEN 2, the age of transformation from CCH to MTC varies with different germline RET pathogenic variants [Machens et al 2003]. #### Pheochromocytoma Clinical findings. Pheochromocytomas in individuals with MEN 2 are nearly always adrenal and often bilateral [Pomares et al 1998, Pacak et al 2005, Thosani et al 2013]. * Individuals with a confirmed germline RET pathogenic variant who present with head and neck paraganglioma all have a personal and/or family history consistent with MEN 2 [Boedeker et al 2009]. * Although pheochromocytomas in individuals with MEN 2 rarely metastasize, they can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises. Biochemical findings. Pheochromocytoma is suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (e.g., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid [VMA]) in plasma or 24-hour urine collections [Pacak et al 2005, Ilias & Pacak 2009]. In MEN 2, pheochromocytomas consistently produce epinephrine or epinephrine and norepinephrine [Ilias & Pacak 2009]. Imaging. Abdominal MRI and/or CT is performed if plasma or urinary catecholamine values are increased or if a pheochromocytoma is suspected clinically. MRI is more sensitive than CT in detection of a pheochromocytoma. [18F]-fluorodopamine ([18F]DA) PET is the best overall imaging modality in the localization of pheochromocytomas. If [18F]DA PET is unavailable, MIBG (123I- or 131I-labeled metaiodobenzylguanidine) scintigraphy should be used to further evaluate individuals with biochemical or radiographic evidence of pheochromocytoma [Ilias et al 2008]. 68Ga-DOTATATE-PET-CT results correlate best with biochemical parameters (reviewed in Neumann et al [2019]). #### Parathyroid Abnormalities Clinical findings. Parathyroid abnormalities can range from benign parathyroid adenomas to clinically evident hyperparathyroidism with hypercalcemia and renal stones. Biochemical findings. Parathyroid abnormalities are present when elevated serum calcium occurs simultaneously with elevated or high-normal parathyroid hormone (PTH). Imaging. Postoperative parathyroid localizing studies with 99mTc-sestamibi scintigraphy may be helpful if hyperparathyroidism recurs. For preoperative adenoma localization, three-dimensional single-photon emission CT (SPECT) may also be used [Brenner & Jacene 2008]. #### MEN 2 Phenotypes MEN 2 is classified into three phenotypes: MEN 2A, FMTC (which is now considered a variant of MEN 2A), and MEN 2B (Table 2). All three phenotypes involve high risk for MTC; individuals with MEN 2A and MEN 2B are at increased risk for pheochromocytoma; individuals with MEN 2A are at increased risk for parathyroid hyperplasia or adenoma. Classifying an individual or family by MEN 2 phenotype is useful for determining prognosis and management. ### Table 2. Percent of Clinical Features by MEN 2 Phenotype View in own window PhenotypeMedullary Thyroid CarcinomaPheochromocytomaParathyroid Disease MEN 2A95%50%20%-30% FMTC100%0%0% MEN 2B100%50%Uncommon MEN 2A. The MEN 2A phenotype constitutes approximately 70%-80% of cases of MEN 2. MTC is generally the first manifestation of MEN 2A. Since genetic testing for RET pathogenic variants has become available, it has become apparent that 95% of individuals with MEN 2A develop MTC, about 50% develop pheochromocytoma, and about 20%-30% develop hyperparathyroidism (reviewed by Neumann et al [2019]). Pheochromocytomas usually present after MTC or concomitantly; however, they are the first sign in 13%-27% of individuals with MEN 2A [Inabnet et al 2000, Rodriguez et al 2008]. Pheochromocytomas in persons with MEN 2A are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors [Pomares et al 1998, Pacak et al 2005]. Malignant transformation occurs in about 4% of cases [Modigliani et al 1995]. Since pheochromocytoma can be the first manifestation of MEN 2A, the diagnosis of pheochromocytoma in an individual warrants further investigation for MEN 2A [Neumann et al 2019]. Hyperparathyroidism (HPT) in MEN 2A is typically mild and may range from a single adenoma to marked hyperplasia. Most individuals with hyperparathyroidism have no symptoms; however, hypercalciuria and renal calculi may occur [Brandi et al 2001]. HPT usually presents many years after the diagnosis of MTC; the average age at onset is 38 years [Kloos et al 2009]. A small number of families with MEN 2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [Seri et al 1997]. FMTC. The FMTC phenotype constitutes approximately 10%-20% of cases of MEN 2. By operational definition, MTC is the only clinical manifestation of FMTC. Currently, FMTC is viewed as a variant of MEN 2A with decreased penetrance of pheochromocytoma and hyperparathyroidism, rather than a distinct subtype [Kloos et al 2009]. The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN 2A and MEN 2B [Eng et al 1996, Machens et al 2001, Machens & Dralle 2006, Zbuk & Eng 2007, Kloos et al 2009]. To avoid erroneously dismissing a risk for pheochromocytoma, strict criteria should be met before a family is classified as having FMTC (see Establishing the Diagnosis, Clinical criteria). MEN 2B. The MEN 2B phenotype accounts for approximately 5% of cases of MEN 2. MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals [Skinner et al 1996]. Individuals with MEN 2B who do not undergo thyroidectomy before age one year are likely to develop metastatic MTC at an early age. Prior to intervention with early prophylactic thyroidectomy, the median age of death in individuals with MEN 2B was 25 years (range: 0.5-66) [Castinetti et al 2019]. Pheochromocytomas occur in 50% of individuals with MEN 2B; about half are multiple and often bilateral. Individuals with an undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively. Clinically significant parathyroid disease is absent in MEN 2B. Individuals with MEN 2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent (or "blubbery") over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination. About 40% of affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN 2B, 84% reported gastrointestinal symptoms beginning in infancy or early childhood [Wray et al 2008]. About 75% of affected individuals have a marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen. ### Genotype-Phenotype Correlations Pathogenic variants involving the cysteine codons 609, 618, and 620 in exon 10 of RET are associated with MEN 2A, FMTC, and HSCR1 [Mulligan et al 1994, Decker et al 1998, Romeo et al 1998, Inoue et al 1999, Takahashi et al 1999]. A pathogenic variant in one of these codons is detected in about 10% of families with MEN 2A and more than 50% of families with FMTC; these pathogenic variants are associated with low transforming activity of RET [Takahashi et al 1998, Hansford & Mulligan 2000]. RET germline pathogenic variant p.Met918Thr is only associated with MEN 2B; however, somatic pathogenic variants at this codon are frequently observed in MTC in individuals with no known family history of MTC, and are overrepresented in individuals with sporadic MTC who have the RET germline variant p.Ser836 [Gimm et al 1999]. Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism [Eng et al 1996, Yip et al 2003, Zbuk & Eng 2007, Kloos et al 2009]. * A report of 12 Brazilian families indicated that p.Cys634Arg is associated with a higher probability of having metastases at diagnosis than other codon 634 pathogenic variants [Puñales et al 2003]. * Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [Seri et al 1997]. Among 25 individuals from three families with a codon 634 pathogenic variant, 36% had cutaneous lichen amyloidosis [Verga et al 2003]. * While 25% of FMTC kindreds harbor a pathogenic variant in codon 634, p.Cys634Arg pathogenic variants are virtually absent in this subtype [Hansford & Mulligan 2000, Zbuk & Eng 2007]. Pathogenic variants at codons 768, 804, and 891 that were initially only associated with MTC have subsequently been found in families with MEN 2A [Jimenez et al 2004a, Aiello et al 2005, Schulte et al 2010]. * Initially thought to be associated with MTC only, pathogenic variants at codon 804 in exon 14 (e.g., p.Val804Leu and p.Val804Met) were subsequently identified in individuals with pheochromocytoma [Nilsson et al 1999, Høie et al 2000, Gibelin et al 2004, Jimenez et al 2004a]. * Disease expression of pathogenic variants at codon 804 has been shown to be highly variable, even within the same family [Feldman et al 2000, Frohnauer & Decker 2000]. Some individuals with such pathogenic variants have had MTC at age five years and fatal metastatic MTC at age 12 years, whereas other individuals with the same pathogenic variant have been shown to have normal thyroid histology at age 27 years, normal biochemical screening at age 40 years, and no clinical evidence of MTC at age 86 years. * In another large family with a high level of consanguinity, biochemical testing indicated expression of thyroid disease in individuals homozygous but not heterozygous for p.Val804Met [Lecube et al 2002]. * Cutaneous lichen amyloidosis in association with a p.Val804Met pathogenic variant has been reported in one individual [Rothberg et al 2009]. One study suggests that in addition to their association with MTC, pathogenic variants in codons 790 or 804 may be associated with papillary thyroid carcinoma [Brauckhoff et al 2002]. In a large Italian family, 40% of family members with a p.Val804Met pathogenic variant who were examined in detail had concomitant medullary and papillary thyroid carcinoma [Shifrin et al 2009]. The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [Kloos et al 2009]. The classification may be used in (1) predicting phenotype and in (2) recommendations regarding the ages at which to (a) perform prophylactic thyroidectomy and (b) begin biochemical screening for pheochromocytoma and hyperparathyroidism (see Table 3 and Surveillance). ### Penetrance The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 phenotype (see Table 2). ### Nomenclature MEN 2A is also referred to as Sipple syndrome. Mucosal neuroma syndrome is a synonym for MEN 2B. MEN 2B was initially called Wagenmann-Froboese syndrome [Morrison & Nevin 1996]. ### Prevalence The prevalence of MEN 2 has been estimated at 1:35,000 [DeLellis et al 2004]. ## Differential Diagnosis MTC in individuals with no family history of MTC. Medullary thyroid carcinoma accounts for approximately 10% of new cases of thyroid cancer diagnosed annually in the US. Sporadic MTC tends to be unifocal, have a later age of onset, and lack C-cell hyperplasia (CCH) [Kloos et al 2009]. DNA analysis of MTC tissue revealed a 40%-50% incidence of somatic RET variants in the absence of a RET germline pathogenic variant [Schilling et al 2001, de Groot et al 2006, Dvorakova et al 2008, Elisei et al 2008]. The somatic p.Met918Thr variant is the most common; variants at other codons as well as small in-frame deletions have been reported [de Groot et al 2006]. Tumors with a somatic codon 918 variant appear to be more aggressive [Schilling et al 2001, Elisei et al 2008]. C-cell hyperplasia (CCH). CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population. Serum calcitonin levels may be elevated in persons with chronic renal failure, sepsis, neuroendocrine tumors of the lung or gastrointestinal tract, hypergastrinemia, mastocytosis, autoimmune thyroid disease, and type 1A pseudohypoparathyroidism [Costante et al 2009]. Secondary CCH has been described occasionally in the setting of aging and hyperparathyroidism. Secondary CCH rarely transforms to MTC and is not related to MEN 2. Pheochromocytoma. Up to 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma have a heterozygous pathogenic variant in one of several genes: RET, VHL, SDHD, or SDHB [Neumann et al 2002, Bryant et al 2003, Neumann et al 2004]. Approximately 5% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma were heterozygous for a germline RET pathogenic variant [Neumann et al 2002]. Other pheochromocytoma susceptibility genes including SDHC, TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma [Peczkowska et al 2008, Burnichon et al 2009, Bayley et al 2010, Burnichon et al 2010, Qin et al 2010, Comino-Méndez et al 2011, Vandy et al 2011]. An algorithm for prioritizing which gene(s) to test is outlined by Erlic et al [2009], Neumann et al [2009], and Welander et al [2011]. However, multigene panels may also be considered for individuals with no syndromic features. Evaluation of biochemical features can help differentiate MEN 2-associated pheochromocytoma. Pacak et al [2005] compared biochemical profiles for inherited and sporadic pheochromocytoma and found that MEN 2 can be ruled out in pheochromocytomas that exclusively produce normetanephrine. * von Hippel-Lindau (VHL) syndrome. Any individual presenting with a pheochromocytoma should be evaluated for VHL syndrome [Erlic et al 2009]. VHL syndrome is characterized by pheochromocytoma, renal cell carcinoma, cerebellar and spinal hemangioblastoma, and retinal angioma. Some families with apparent autosomal dominant pheochromocytoma have a germline VHL pathogenic variant in the absence of other clinical manifestations of VHL syndrome [Inabnet et al 2000]. Neumann et al [2002] identified germline VHL pathogenic variants in 11% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma. However, a US-based study found no pathogenic variants in VHL in individuals with nonsyndromic pheochromocytoma or paraganglioma [Fishbein et al 2013]. * Hereditary paraganglioma-pheochromocytoma syndrome. Pathogenic variants in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 cause hereditary paraganglioma-pheochromocytoma syndrome. Early studies found that approximately 8.5% of individuals with apparently nonfamilial nonsyndromic pheochromocytoma have a germline pathogenic variant in one of the genes (SDHD or SDHB) encoding the succinate dehydrogenase subunits that cause the hereditary paraganglioma-pheochromocytoma syndromes (reviewed in Neumann et al [2019]). While head and neck paragangliomas are common in individuals with hereditary paraganglioma-pheochromocytoma syndrome, they are extremely rare in MEN 2 [Boedeker et al 2009]. Although pathogenic variants in SDHC initially were thought to only cause head/neck paragangliomas, several cases of SDHC-associated pheochromocytoma have been reported in the literature [Peczkowska et al 2008, Burnichon et al 2009, Vandy et al 2011]. Korpershoek et al [2011] found an SDHA germline pathogenic variant in 3% of individuals with apparently sporadic paragangliomas and pheochromocytomas. The gene SDHAF2 is a rare cause of hereditary head/neck paraganglioma and is not associated with pheochromocytoma [Bayley et al 2010]. * TMEM127-associated susceptibility to pheochromocytoma (OMIM 613403). Recent studies estimate that 1%-2% of individuals with familial or nonfamilial pheochromocytoma have a germline TMEM127 pathogenic variant [Yao et al 2010, Abermil et al 2012]. A few individuals with a germline TMEM127 pathogenic variant have paragangliomas of the head/neck or at extra-adrenal sites [Neumann et al 2011]. * MAX-associated susceptibility to pheochromocytoma (OMIM 154950). A MAX germline pathogenic variant is seen in approximately 1% of individuals with familial or nonfamilial pheochromocytoma [Burnichon et al 2012a]. Pheochromocytomas in individuals with MAX pathogenic variants are often bilateral [Burnichon et al 2012b]. * Neurofibromatosis type 1 (NF1). Pheochromocytomas are observed on occasion in NF1. Most individuals with NF1 can be diagnosed based on clinical features including multiple café au lait macules, neurofibromas, Lisch nodules, axillary or inguinal freckling, and/or positive family history. * Polycythemia and paraganglioma/pheochromocytoma. Germline DNMT3A, EGLN1, EGLN2, EPAS1, FH, HIF2A, IDH1, KIF1B, MDH2, and SLC25A11 pathogenic variants have been identified in individuals with polycythemia and paraganglioma [Lorenzo et al 2013, Taïeb et al 2013, Castro-Vega et al 2014, Cascón et al 2015, Yang et al 2015, Buffet et al 2018, Remacha et al 2018]. Multiple endocrine neoplasia type 1 (MEN 1). This endocrinopathy is genetically and clinically distinct from MEN 2; the similar nomenclature for MEN 1 and MEN 2 may cause confusion. MEN 1 is characterized by a triad of pituitary adenomas, pancreatic islet cell tumors, and parathyroid disease consisting of hyperplasia or adenoma. Affected individuals can also have adrenal cortical tumors, carcinoid tumors, and lipomas [Giraud et al 1998]. MEN 1 is caused by a germline pathogenic variant in MEN1 and inherited in an autosomal dominant manner. Multiple endocrine neoplasia type 4 (MEN 4). While pheochromocytomas developed in the MENX rat model, humans with pathogenic variants in CDKN1B tend to have a phenotype similar to MEN 1, with a high incidence of pituitary tumors and primary hyperparathyroidism [Lee & Pellegata 2013]. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 2 (MEN 2), the following evaluations are recommended if they have not already been completed: * Referral to an endocrinologist * Consultation with a clinical geneticist and/or genetic counselor * Biochemical evaluations: * Plasma calcitonin * Plasma catecholamines and metanephrines * Serum calcium and parathyroid hormone * Evaluation for metastatic disease in individuals with MTC * CT with contrast for chest and abdomen * MRI of liver in the presence of nodal disease or calcitonin >400 pg/mL ### Treatment of Manifestations Medullary thyroid carcinoma (MTC). Standard treatment for MTC is surgical removal of the thyroid and lymph node dissection [Kloos et al 2009, National Comprehensive Cancer Network 2015]. Current NCCN guidelines recommend consideration of therapeutic external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension with positive margins [National Comprehensive Cancer Network 2015]. Several kinase inhibitors – vandetanib, cabozantinib, and BLU-667 – have improved progression-free survival and in some cases cause disease regression in unresectable or advanced metastatic MTC [Elisei et al 2013, Wells et al 2013, Subbiah et al 2018]. All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy. Autotransplantation of parathyroid tissue is not typically performed at the time of thyroidectomy unless there is evidence of hyperparathyroidism [Kloos et al 2009]. Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy, which may be performed using video-assisted laparoscopy. Historically, some specialists recommended bilateral adrenalectomy at the time of demonstration of tumor on just a single adrenal gland because of the strong probability that the other adrenal gland would develop a tumor within ten years. However, because of the risk for adrenal insufficiency and Addisonian crisis following bilateral adrenalectomy, most experts now recommend unilateral adrenalectomy in unilateral tumors and cortical-sparing adrenal surgery with close monitoring of the remnant tissue in persons with one remaining adrenal gland or bilateral pheochromocytoma [Kloos et al 2009, Neumann et al 2019]. Hypertensive treatment prior to adrenalectomy often involves the use of α- and β-adrenergic receptor blockade [Pacak et al 2005], although some centers do not pretreat with α-blockade and use nitroprusside to control blood pressure during surgery [Neumann et al 2019]. Parathyroid adenoma or hyperplasia diagnosed at the time of thyroidectomy is treated either with resection of the visibly enlarged parathyroid gland(s), subtotal parathyroidectomy, or total parathyroidectomy with forearm autograft [Kloos et al 2009]. However, in most individuals with MEN 2A, hyperparathyroidism is diagnosed many years after thyroidectomy. Individuals with biochemical evidence of primary hyperparathyroidism who have undergone prior thyroidectomy should have preoperative localization with excision of the localized hypertrophied parathyroid glands and forearm autotransplantation. Therapy with medications to control primary hyperparathyroidism should be considered in individuals with a high risk for surgical mortality, limited life expectancy, or persistent or recurrent primary hyperparathyroidism after one or more surgical attempts [Kloos et al 2009]. ### Prevention of Primary Manifestations Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET pathogenic variant [Cohen & Moley 2003, Kloos et al 2009]. Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial [Moley et al 1998]. According to the American Thyroid Association Guidelines Task Force consensus statement, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET pathogenic variant (see Table 3 and Genotype-Phenotype Correlations) [Kloos et al 2009]. However, these guidelines continue to be modified as more data become available. ### Table 3. Risk for Aggressive MTC Based on Genotype and Recommended Interventions View in own window ATA Risk LevelPathogenic Variants 1Age of Prophylactic SurgeryAge to Begin Screening For PHEOFor HPT Level D (highest risk)p.Ala883Phe p.Met918Thr p.[Val804Met;Glu805Lys] 2 p.[Val804Met;Tyr806Cys] 2 p.[Val804Met];Ser904Cys] 2As soon as possible in 1st year of life8 yrsNA Level Cp.Cys634Arg p.Cys634Gly p.Cys634Phe p.Cys634Ser p.Cys634Trp p.Cys634Tyr<5 yrs8 yrs8 yrs Level Bp.Cys609Phe p.Cys609Arg p.Cys609Gly p.Cys609Ser p.Cys609Tyr p.Cys611Arg p.Cys611Gly p.Cys611Phe p.Cys611Ser p.Cys611Trp p.Cys611Tyr p.Cys618Arg p.Cys618Gly p.Cys618Phe p.Cys618Ser p.Cys618Tyr p.Cys620Arg p.Cys620Gly p.Cys620Phe p.Cys620Ser p.Cys620Trp p.Cys620Tyr p.Cys630Arg p.Cys630Phe p.Cys630Ser p.Cys630Tyr p.Asp631Tyrp.Cys634_Thr636dup (p.633/9 bp dup 3) p.Lys634_Arg635insHisGluLeuCys (p.634/12 bp dup 3) p.[Val804Met;Val778Ile] 2Consider <5 yrs; may delay if criteria met 4Codon 630 pathogenic variant: 8 yrs All others: 20 yrsCodon 630 pathogenic variant: 8 yrs All others: 20 yrs Level Ap.Arg321Gly p.Glu529_Cys531dup (p.531/9 bp dup 3) p.Gly532dup p.Cys515Ser p.Gly533Cys p.Arg600Gln p.Lys603Glu p.Tyr606Cys p.635/insert ELCR;p.Thr636Pro p.Lys666Glu p.Glu768Asp p.Asn777Ser p.Leu790Phe p.Val804Leu p.Val804Met p.Gly819Lys p.Arg833Cys p.Arg844Gln p.Arg866Trp p.Ser891Ala p.Arg912ProMay delay beyond age 5 yrs if criteria met 420 yrs20 yrs Adapted from Kloos et al [2009] ATA = American Thyroid Association; HPT = hyperparathyroidism; MTC = medullary thyroid carcinoma; PHEO = pheochromocytoma 1\. See Molecular Genetics, Table 5 for details of pathogenic variants. 2\. Two variants identified in a DNA sequence or a protein that derive from one chromosome (in cis) 3\. Variant designation that does not conform to current naming conventions 4\. Criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC Thyroidectomy for C-cell hyperplasia, before progression to invasive MTC, may allow surgery to be limited to thyroidectomy with sparing of lymph nodes [Brandi et al 2001, Kahraman et al 2003]. For all individuals with a RET pathogenic variant who have not had a thyroidectomy, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal [Szinnai et al 2003]. Annual serum calcitonin screening [Kloos et al 2009] should begin at age: * Six months for children with MEN 2B; * Three to five years for children with MEN 2A or FMTC. Caution should be used in interpreting calcitonin results for children younger than age three years, especially those younger than age six months [Kloos et al 2009]. Prophylactic thyroidectomy is not routinely offered to at-risk individuals in whom the disorder has not been confirmed. ### Prevention of Secondary Complications Prior to any surgery, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening in any individual with MEN 2A or MEN 2B. In a prospective study of at-risk family members with the pathogenic variant, 8% had pheochromocytoma detected at the same time as MTC [Nguyen et al 2001]. If pheochromocytoma is detected, adrenalectomy should be performed before thyroidectomy to avoid intraoperative catecholamine crisis [Lee & Norton 2000]. ### Surveillance MTC. Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [Cohen & Moley 2003]. Furthermore, thyroid glands removed from individuals with a germline RET pathogenic variant who had normal plasma calcitonin concentrations have been found to contain MTC [Skinner et al 1996]. Therefore, continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed prior to biochemical evidence of disease. The screening protocol for MTC after prophylactic thyroidectomy is an annual measurement of serum calcitonin [Kloos et al 2009]. More frequent follow up is recommended for those with residual disease. Hypoparathyroidism. All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need monitoring for possible hypoparathyroidism. Pheochromocytoma. For individuals whose initial screening results are negative for pheochromocytoma, annual biochemical screening is recommended, followed by MRI and/or CT if the biochemical results are abnormal [Pacak et al 2005, Kloos et al 2009, Neumann et al 2019]. Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [Kloos et al 2009, Neumann et al 2019]. Other screening studies, such as scintigraphy or positron emission tomography, may be warranted in some individuals. * MEN 2A. Annual biochemical screening beginning at age eight years has been recommended for individuals with a pathogenic variant in codons 630 and 634 and at age 20 years for a pathogenic variant in all other codons [Kloos et al 2009]. * FMTC. Screening as for MEN 2A is indicated, as not all families classified as FMTC are MTC-only [Moers et al 1996]. * MEN 2B. Annual screening should begin at age eight years [Kloos et al 2009]. Parathyroid adenoma or hyperplasia. Annual biochemical screening is recommended for affected individuals who have not had parathyroidectomy and parathyroid autotransplantation. * MEN 2A. Screening should start at age eight years for individuals with a pathogenic variant in codons 630 and 634, and by age 20 years for individuals with other RET pathogenic variants [Kloos et al 2009]. * FMTC. Periodic screening should begin at age 20 years [Kloos et al 2009]. * MEN 2B. Screening is unnecessary as individuals with MEN 2B are not at increased risk for hyperparathyroidism. ### Agents/Circumstances to Avoid Dopamine D2 receptor antagonists (e.g., metoclopramide and veralipride) and β-adrenergic receptor antagonists (β-blockers) have a high potential to cause an adverse reaction in individuals with pheochromocytoma. Other medications including monoamine oxidase inhibitors, sympathomimetics (e.g., ephedrine), and certain peptide and corticosteroid hormones may also cause complications; tricyclic antidepressants are inconsistent in causing adverse reactions [Eisenhofer et al 2007]. ### Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. The American Society of Clinical Oncologists (ASCO) identifies MEN 2 as a Group 1 disorder: a well-defined hereditary cancer syndrome for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. Evaluations can include: * Molecular genetic testing if the pathogenic variant in the family is known: * MEN 2A. RET molecular genetic testing should be offered to at-risk children by age five years. The finding of MTC in the thyroid of a 12-month-old with a germline RET pathogenic variant suggests that molecular genetic testing should be performed even earlier when possible [Machens et al 2004]. * FMTC. Recommendations for families with known FMTC are the same as for MEN 2A. * MEN 2B. RET molecular genetic testing should be performed as soon as possible after birth in all children known to be at risk [Brandi et al 2001]. * The following screening of at-risk family members if the pathogenic variant in the family is not known: * Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC * Albumin-corrected calcium or ionized calcium for hyperparathyroidism * Measurement of plasma or 24-hour urine metanephrines and normetanephrines as appropriate [Kloos et al 2009] for pheochromocytoma See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [Kloos et al 2009]. ### Therapies Under Investigation Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and ponatinib are currently under way. NCCN and ATA guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib and cabozantinib [National Comprehensive Cancer Network 2015, Wells et al 2015]. Newer agents such as BLU-667 are showing promise as well. Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma. In a Phase II clinical trial of sorafenib, 16 individuals with sporadic MTC had a partial response (1/16) or stable disease (15/16) [Lam et al 2010]. A small Phase II trial of treatment with sunitinib demonstrated objective response in three (50%) of six individuals with metastatic MTC and stable disease in two individuals [Carr et al 2010]. Ponatinib has been shown to inhibit RET kinase activity and diminish medullary thyroid cancer in mice [De Falco et al 2013]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Multiple Endocrine Neoplasia Type 2	c0025268	3,376	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1257/	2021-01-18T21:10:14	{"mesh": ["D018813"], "synonyms": ["MEN 2", "MEN 2 Syndrome"]}
Gram-negative folliculitis SpecialtyDermatology Gram-negative folliculitis occurs in patients who have had moderately inflammatory acne for long periods and have been treated with long-term antibiotics, mainly tetracyclines, a disease in which cultures of lesions usually reveals a species of Klebsiella, Escherichia coli, Enterobacter, or, from the deep cystic lesions, Proteus.[1]:242,273 ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. ## External links[edit] Classification D * ICD-10: L08.8 (ILDS L08.842) * v * t * e Bacterial skin disease Gram +ve Firmicutes * Staphylococcus * Staphylococcal scalded skin syndrome * Impetigo * Toxic shock syndrome * Streptococcus * Impetigo * Cutaneous group B streptococcal infection * Streptococcal intertrigo * Cutaneous Streptococcus iniae infection * Erysipelas / Chronic recurrent erysipelas * Scarlet fever * Corynebacterium * Erythrasma * Listeriosis * Clostridium * Gas gangrene * Dermatitis gangrenosa * Mycoplasma * Erysipeloid of Rosenbach Actinobacteria * Mycobacterium-related: Aquarium granuloma * Borderline lepromatous leprosy * Borderline leprosy * Borderline tuberculoid leprosy * Buruli ulcer * Erythema induratum * Histoid leprosy * Lepromatous leprosy * Leprosy * Lichen scrofulosorum * Lupus vulgaris * Miliary tuberculosis * Mycobacterium avium-intracellulare complex infection * Mycobacterium haemophilum infection * Mycobacterium kansasii infection * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Rapid growing mycobacterium infection * Scrofuloderma * Tuberculosis cutis orificialis * Tuberculosis verrucosa cutis * Tuberculous cellulitis * Tuberculous gumma * Tuberculoid leprosy * Cutaneous actinomycosis * Nocardiosis * Cutaneous diphtheria infection * Arcanobacterium haemolyticum infection * Group JK corynebacterium sepsis Gram -ve Proteobacteria * α: Endemic typhus * Epidemic typhus * Scrub typhus * North Asian tick typhus * Queensland tick typhus * Flying squirrel typhus * Trench fever * Bacillary angiomatosis * African tick bite fever * American tick bite fever * Rickettsia aeschlimannii infection * Rickettsialpox * Rocky Mountain spotted fever * Human granulocytotropic anaplasmosis * Human monocytotropic ehrlichiosis * Flea-borne spotted fever * Japanese spotted fever * Mediterranean spotted fever * Flinders Island spotted fever * Verruga peruana * Brill–Zinsser disease * Brucellosis * Cat-scratch disease * Oroya fever * Ehrlichiosis ewingii infection * β: Gonococcemia/Gonorrhea/Primary gonococcal dermatitis * Melioidosis * Cutaneous Pasteurella hemolytica infection * Meningococcemia * Glanders * Chromobacteriosis infection * γ: Pasteurellosis * Tularemia * Vibrio vulnificus * Rhinoscleroma * Haemophilus influenzae cellulitis * Pseudomonal pyoderma / Pseudomonas hot-foot syndrome / Hot tub folliculitis / Ecthyma gangrenosum / Green nail syndrome * Q fever * Salmonellosis * Shigellosis * Plague * Granuloma inguinale * Chancroid * Aeromonas infection * ε: Helicobacter cellulitis Other * Syphilid * Syphilis * Chancre * Yaws * Pinta * Bejel * Chlamydia infection * Leptospirosis * Rat-bite fever * Lyme disease * Lymphogranuloma venereum Unspecified pathogen * Abscess * Periapical abscess * Boil/furuncle * Hospital furunculosis * Carbuncle * Cellulitis * Paronychia / Pyogenic paronychia * Perianal cellulitis * Acute lymphadenitis * Pilonidal cyst * Pyoderma * Folliculitis * Superficial pustular folliculitis * Sycosis vulgaris * Pimple * Ecthyma * Pitted keratolysis * Trichomycosis axillaris * Necrotizing fascitis * Gangrene * Chronic undermining burrowing ulcers * Fournier gangrene * Elephantiasis nostras * Blistering distal dactylitis * Botryomycosis * Malakoplakia * Gram-negative folliculitis * Gram-negative toe web infection * Pyomyositis * Blastomycosis-like pyoderma * Bullous impetigo * Chronic lymphangitis * Recurrent toxin-mediated perineal erythema * Tick-borne lymphadenopathy * Tropical ulcer This infection-related cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Gram-negative folliculitis	c0406101	3,377	wikipedia	https://en.wikipedia.org/wiki/Gram-negative_folliculitis	2021-01-18T18:34:03	{"icd-10": ["L08.8"], "wikidata": ["Q5593571"]}
Verloes et al. (1997) suggested the existence of an autosomal dominant coloboma-obesity-hypogenitalism-mental retardation syndrome. (See the Biemond syndrome II (210350) for an autosomal recessive form.) Cavallacci (1937) reported a mother with bilateral noncolobomatous microphthalmia, unilateral cataract, atypical retinitis pigmentosa, obesity, and borderline intelligence. She had 5 children, including 1 (early-deceased) with microphthalmia and a daughter with severe microphthalmia and cataract, obesity, hypogonadism, and mental retardation. Verloes et al. (1997) found several other reports, possibly of this same disorder, and added 3 sporadic cases: a boy who had microphthalmia noted at birth and hydrocephalus secondary to a large interhemispheric arachnoid cyst, requiring surgery. At age 7, he showed colobomatous microphthalmia with cataract on the left eye and microphthalmia with coloboma of the retina on the right. The second patient, seen at age 38, had extreme microphthalmia on one side and colobomatous microphthalmia on the other. Surgical treatment of bilateral cryptorchidism failed at age 10. Obesity appeared in infancy. After a failed suicide attempt at age 16, he was admitted to a psychiatric hospital where he spent the rest of his life. He showed obesity of the gynecoid type, with impressive bilateral gynecomastia and marked hypogenitalism. I.Q. was 60. The third patient, a girl seen at age 14.5 years, had right extreme microphthalmia and left microphthalmic coloboma noted at birth. Obesity began about age 5. Normal menarche occurred at 14 years of age. Verloes et al. (1997) reviewed other related disorders. Eyes \- Coloboma of retina \- Microphthalmia \- Cataract \- Atypical retinitis pigmentosa Neuro \- Borderline intelligence/mental retardation Hydrocephalus \- Interhemispheric arachnoid cyst Inheritance \- Autosomal dominant form GU \- Hypogonadism \- Cryptorchidism Growth \- Obesity Thorax \- Gynecomastia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	COLOBOMA-OBESITY-HYPOGENITALISM-MENTAL RETARDATION SYNDROME	c1866256	3,378	omim	https://www.omim.org/entry/601794	2019-09-22T16:14:18	{"mesh": ["C566623"], "omim": ["601794"], "orphanet": ["363741"]}
Steatocystoma multiplex is a condition characterized by numerous skin cysts that tend to develop during puberty. Cysts most often develop on the chest, upper arms and face, but may develop all over the body in some cases. The cysts may become inflamed and cause scarring when they heal. The condition can be caused by mutations in the KRT17 gene and is inherited in an autosomal dominant manner. Some cases are sporadic (where there are no other cases in the family). Some researchers have suggested that the condition may be a mild variant of pachyonychia congenita type 2. Treatment may include minor surgery to remove cysts and oral antibiotics or oral isotretinoin to reduce inflammation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Steatocystoma multiplex	c0259771	3,379	gard	https://rarediseases.info.nih.gov/diseases/5003/steatocystoma-multiplex	2021-01-18T17:57:31	{"mesh": ["D062685"], "omim": ["184500"], "orphanet": ["841"], "synonyms": ["Multiple sebaceous cysts", "Sebocystomatosis", "Multiplex steatocystoma"]}
Infantile convulsions and choreoathetosis Other namesParoxysmal kinesigenic dyskinesia and infantile convulsions Infantile convulsions and choreoathetosis is inherited via an autosomal dominant manner Infantile convulsions and choreoathetosis (ICCA) syndrome is a neurological genetic disorder with an autosomal dominant mode of inheritance. It is characterized by the association of benign familial infantile epilepsy (BIFE) at age 3–12 months and later in life with paroxysmal kinesigenic choreoathetosis. The ICCA syndrome was first reported in 1997 in four French families from north-western France and provided the first genetic evidence for common mechanisms shared by benign infantile seizures and paroxysmal dyskinesia.[1] The epileptic origin of PKC has long been a matter of debates[2] and PD have been classified as reflex epilepsies. Indeed, attacks of PKC and epileptic seizures have several characteristics in common, they both are paroxysmal in presentation with a tendency to spontaneous remission, and a subset of PKC responds well to anticonvulsants. This genetic disease has been mapped to chromosome 16p-q12.[3] More than 30 families with the clinical characteristics of ICCA syndrome have been described worldwide so far.[4][5] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Management * 5 References * 6 External links ## Presentation[edit] The specific and familial association of BIFE and PKC defines a novel clinical entity : the infantile convulsions and choreoathetosis syndrome. The first observation was made in four families where children were affected with nonfebrile convulsions at age 3–12 months. Partial epileptic seizures started with a psychomotor arrest and a deviation of the head and eyes to one side, followed inconstantly by unilateral jerks. In some cases, seizures generalized secondarily. None of the interictal electroencephalograms showed epileptiform abnormalities, and magnetic-resonance imaging were normal. These convulsions had a favorable outcome. At 5–8 years of age affected children developed abnormal movements. They presented with twisting movements of the hands of a reptilian type when stressed or embarrassed. They also developed jerky movements of the legs after running. Initially, abnormal movements were intermediate in speed between quick and slow, typical of paroxysmal choreoathetosis. Combinations of abnormal movements involving the arms, legs, trunk and occasionally the head were observed. The attacks lasted only a few minutes, occurring with a frequency of 5-30 episodes per day and were not accompanied by unconsciousness. In all patients, abnormal movements disappeared at 25–30 years of age without any treatment. Since the first report similar clinical presentations have been published which confirm the specificity of the ICCA syndrome.[6][7] ## Genetics[edit] In affected individuals presenting with the ICCA syndrome, the human genome was screened with microsatellite markers regularly spaced, and strong evidence of linkage with the disease was obtained in the pericentromeric region of chromosome 16, with a maximum lod score, for D16S3133 of 6.76 at a recombination fraction of 0. The disease gene has been mapped at chromosome 16p12-q12. This linkage has been confirmed by different authors.[8][9][10][11] The chromosome 16 ICCA locus shows complicated genomic architecture and the ICCA gene remains unknown. ## Diagnosis[edit] This section is empty. You can help by adding to it. (October 2017) ## Management[edit] This section is empty. You can help by adding to it. (October 2017) ## References[edit] 1. ^ Rochette, J; Roll, P; Szepetowski, P (2008). "Genetics of infantile seizures with paroxysmal dyskinesia: The infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes". Journal of Medical Genetics. 45 (12): 773–79. doi:10.1136/jmg.2008.059519. PMID 19047496. 2. ^ Szepetowski et al. 2007. In Fejerman N. eds. Benign focal epilepsies in infancy, childhood and adolescence. Paris. John Libbey Eurotext : 51-62 3. ^ Szepetowski, P; Rochette, J; Berquin, P; Piussan, C; Lathrop, GM; Monaco, AP (1997). "Familial infantile convulsions and paroxysmal choreoathetosis: A new neurological syndrome linked to the pericentromeric region of human chromosome 16". American Journal of Human Genetics. 61 (4): 889–898. doi:10.1086/514877. PMC 1715981. PMID 9382100. 4. ^ Rochette J. et al. 2010. Epileptic Disorders 12 : 199-204 5. ^ Striano P. et al. 2006. Epilepsia 47 : 1029-1034 6. ^ Carabello R. et al. 2002. Am J Hum Genet 68 : 788-794 7. ^ Thiriaux A. et al. 2002. Mov Disord 17 : 98-104 8. ^ Lee WL. et al. 1998. Hum Genet 103 : 608-612 9. ^ Hatori H. et al. 2000. Brain Dev 22 : 432-435 10. ^ Tomita H. et al. 1999. Am J Hum Genet 65 : 1688-1697 11. ^ Svoboda KJ. et al. 2000. Neurology 55 : 224-230 ## External links[edit] Classification D * ICD-10: G40.4 * OMIM: 602066 * MeSH: C535522 External resources * Orphanet: 31709 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Infantile convulsions and choreoathetosis	c1865926	3,380	wikipedia	https://en.wikipedia.org/wiki/Infantile_convulsions_and_choreoathetosis	2021-01-18T18:36:34	{"gard": ["8553"], "mesh": ["C535522"], "umls": ["C1865926"], "orphanet": ["31709"], "wikidata": ["Q6029036"]}
A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood. ## Epidemiology The birth prevalence of Noonan syndrome (NS) is estimated between 1:1000 to 1:2500. ## Clinical description NS typically presents in the neonatal period with feeding difficulties and failure to thrive. Characteristic facial features are often more obvious in infancy : high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, curly hair and a short neck with sometimes a pterygium colli. With age, the face becomes triangular, with marked skinfolds. The most common congenital heart defect is pulmonary valve stenosis (50-60%) with pulmonic valve dysplasia and various types of cardiac malformations (atrial septal defects, ventricular septal defects ect.). Hypertrophic cardiomyopathy of antenatal onset is common (20%) and may be stable or rapidly progressive. Dilation of coronary arteries and moya-moya disease may develop with aging. Growth delay affects 50%, uncommonly associated with growth hormone deficiency. Weight gain is difficult and many patients remain lean throughout life. Major orthopedic manifestations include sternal deformity, talipes equinovarus, and progressive scoliosis (onset at adolescence). Skin is often dry and sometimes hyperkeratotic on hands and feet. Hair is curly and may be thick or sparse. Peripheral lymphedema may be present and may be progressive and extensive in some. Ocular anomalies (strabismus, refractive errors), and dental crowding are common. Hearing loss is present in 10%. Delayed speech and learning difficulties affect 30-40%. Intellectual disability (often mild) is present in 10-20%. Dyspraxia (clumsiness), attention deficit disorder, agitation, mood disorders and emotional disturbances are not rare, as well as difficulties in identifying and expressing emotions, which can lead to more difficult social interactions. Motor development and puberty are delayed and short stature is present in 50%. Unilateral or bilateral cryptorchidism is present in two-thirds of boys, and hypofertility may affect males, but not females. Thyroid dysfunction may occur. Coagulation defects are frequent but rarely clinically significant. In childhood, there is an increased risk of tumors and leukemias (noteworthy juvenile myelomonocytic leukemia), with a cumulative cancer risk of about 4% by age 20. The risk of common adult cancer does not appear increased. ## Etiology NS is caused by mutations in PTPN11 (12q24.13) seen in 50% of cases, SOS1 (2p22.1) in 15%, RAF1 (3p25.2), RIT1 (1q22) and LZTR1(22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. The clinical spectrum of NS may differ slightly between causative genes, and some forms have been described as ''Noonan like'' (NS-like disorder with juvenile myelomonocytic leukemia and NS-like disorder with loose anagen hair). ## Diagnostic methods The diagnosis relies on clinical manifestations but may be difficult because of the highly variable presentation. Molecular genetic testing of the causative genes helps diagnosis and genetic counseling. Mild cases may remain undiagnosed and only brought to clinical attention in adulthood after the birth of a more severely affected child. ## Differential diagnosis Differential diagnoses include Cardio-Facio-Cutaneous syndrome, Costello syndrome, Neurofibromatosis type 1, Noonan syndrome with multiple lentigines (all RASopathies), Baraitser-Winter, Aarskog and Escobar syndromes. ## Antenatal diagnosis Prenatal diagnosis is possible on chorionic villi or amniotic fluid. Prenatal signs of NS are nonspecific: increased nuchal translucency, cystic hygroma and/or ascites (that may lead to fetal demise), polyhydramnios, cardiomyopathy and congenital heart defect. ## Genetic counseling Inheritance of NS is autosomal dominant, except LZTR1 which can be either dominant or recessive. Genetic counseling should be offered to affected families. ## Management and treatment Treatment requires a multidisciplinary approach. Cardiovascular anomalies are treated with standard approaches. Treatment of growth retardation with growth hormone is still controversial. Developmental disabilities should be addressed early. ## Prognosis The prognosis is variable since the presentation ranges from mild/unrecognized manifestations in adulthood to severe disorder with life-threatening heart disease or malignancy in infancy. Severe cardiomyopathy may lead to early demise. * 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Noonan syndrome	c0028326	3,381	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=648	2021-01-23T17:36:30	{"gard": ["10955"], "mesh": ["D009634"], "omim": ["163950", "605275", "609942", "610733", "611553", "613224", "613706", "615355", "616559", "616564", "618499", "618624"], "umls": ["C0028326"], "icd-10": ["Q87.1"]}
Adams–Nance syndrome SpecialtyCardiology Adams–Nance syndrome is a medical condition consisting of persistent tachycardia, paroxysmal hypertension and seizures. It is associated with hyperglycinuria, dominantly inherited microphthalmia and cataracts. It is thought to be caused by a disturbance in glycine metabolism. ## References[edit] * Adams CW, Nance WE (1967). "Persistent tachycardia, paroxymal hypertension, and seizures: association with hyperglycinuria, dominantly inherited microphthalmia, and cataracts". JAMA. 202 (6): 525–30. doi:10.1001/jama.202.6.525. PMID 6072641. ## External links[edit] * Online Mendelian Inheritance in Man (OMIM): 272550 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Adams–Nance syndrome	None	3,382	wikipedia	https://en.wikipedia.org/wiki/Adams%E2%80%93Nance_syndrome	2021-01-18T19:10:36	{"wikidata": ["Q4680535"]}
Spinocerebellar ataxia type 1 (SCA1) is a condition characterized by progressive problems with movement. People with this condition initially experience problems with coordination and balance (ataxia). Other signs and symptoms of SCA1 include speech and swallowing difficulties, muscle stiffness (spasticity), and weakness in the muscles that control eye movement (ophthalmoplegia). Eye muscle weakness leads to rapid, involuntary eye movements (nystagmus). Individuals with SCA1 may have difficulty processing, learning, and remembering information (cognitive impairment). Over time, individuals with SCA1 may develop numbness, tingling, or pain in the arms and legs (sensory neuropathy); uncontrolled muscle tensing (dystonia); muscle wasting (atrophy); and muscle twitches (fasciculations). Rarely, rigidity, tremors, and involuntary jerking movements (chorea) have been reported in people who have been affected for many years. Signs and symptoms of the disorder typically begin in early adulthood but can appear anytime from childhood to late adulthood. People with SCA1 typically survive 10 to 20 years after symptoms first appear. ## Frequency SCA1 affects 1 to 2 per 100,000 people worldwide. ## Causes Mutations in the ATXN1 gene cause SCA1. The ATXN1 gene provides instructions for making a protein called ataxin-1. This protein is found throughout the body, but its function is unknown. Within cells, ataxin-1 is located in the nucleus. Researchers believe that ataxin-1 may be involved in regulating various aspects of producing proteins, including the first stage of protein production (transcription) and processing RNA, a chemical cousin of DNA. The ATXN1 gene mutations that cause SCA1 involve a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 4 to 39 times within the gene. In people with SCA1, the CAG segment is repeated 40 to more than 80 times. People with 40 to 50 repeats tend to first experience signs and symptoms of SCA1 in mid-adulthood, while people with more than 70 repeats usually have signs and symptoms by their teens. An increase in the length of the CAG segment leads to the production of an abnormally long version of the ataxin-1 protein that folds into the wrong 3-dimensional shape. This abnormal protein clusters with other proteins to form clumps (aggregates) within the nucleus of the cells. These aggregates prevent the ataxin-1 protein from functioning normally, which damages cells and leads to cell death. For reasons that are unclear, aggregates of ataxin-1 are found only in the brain and spinal cord (central nervous system). Cells within the cerebellum, which is the part of the brain that coordinates movement, are particularly sensitive to changes in ataxin-1 shape and function. Over time, the loss of the cells of the cerebellum causes the movement problems characteristic of SCA1. ### Learn more about the gene associated with Spinocerebellar ataxia type 1 * ATXN1 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person usually inherits the altered gene from one affected parent. However, some people with SCA1 do not have a parent with the disorder. As the altered ATXN1 gene is passed down from one generation to the next, the length of the CAG trinucleotide repeat often increases. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. Anticipation tends to be more prominent when the ATXN1 gene is inherited from a person's father (paternal inheritance) than when it is inherited from a person's mother (maternal inheritance). Individuals who have around 35 CAG repeats in the ATXN1 gene do not develop SCA1, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with SCA1 (40 repeats or more). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Spinocerebellar ataxia type 1	c0752120	3,383	medlineplus	https://medlineplus.gov/genetics/condition/spinocerebellar-ataxia-type-1/	2021-01-27T08:24:58	{"gard": ["4071"], "mesh": ["D020754"], "omim": ["164400"], "synonyms": []}
A number sign (#) is used with this entry because Smith-McCort dysplasia-2 (SMC2) is caused by homozygous or compound heterozygous mutation in the RAB33B gene (605950) on chromosome 4q31. Description Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short trunk dwarfism with a barrel-shaped chest, rhizomelic limb shortening, and specific radiologic features including marked platyspondyly with double-humped end-plates, kyphoscoliosis, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with a lace-like appearance of iliac crests. These clinical and radiologic features are also common to Dyggve-Melchior-Clausen syndrome (DMC; 223800), which is distinguished from SMC by the additional feature of mental retardation (summary by Dupuis et al., 2013). For a discussion of genetic heterogeneity of Smith-McCort dysplasia, see SMC1 (607326). Clinical Features Alshammari et al. (2012) reported a consanguineous Saudi family in which 4 sibs and 2 first cousins had Dyggve-Melchior-Clausen syndrome and normal intelligence (Smith-McCort dysplasia). All were short and had variable degrees of progressive pectus carinatum deformity, limitation of joint mobility, and lumbar lordosis. The index patient had significant short stature and no gross craniofacial dysmorphism. He had a short neck, significant pectus carinatum, exaggerated lumbar lordosis, and limitation of elbow extension and interphalangeal joint flexion with difficulty making a fist. There was genu valgus and no evidence of organomegaly. Salian et al. (2017) reported 3 unrelated probands with Smith-McCort dysplasia. All had short trunk, barrel chest, limited extension of elbow joints, brachydactyly, and normal intelligence. Radiography in all 3 showed playtspondyly with double humps of the vertebral bodies, short and broad ilia with basilar hypoplasia and lacy iliac crests, short metacarpals, and dysplastic carpal bones. The first patient was a 7-year-old Indian boy who had short stature (-2 SD) and pes planus. The second patient was a 12-year-old Indian boy who had no sonographic findings of skeletal abnormalities at 34-35 weeks' gestation, short stature (-4 SD), normal motor and sensory milestones at age 4 years, coarse facial features, small forehead, posteriorly rotated ears, mild prognathism, and lumbar lordosis. The third patient was a 31-year-old Korean man with short stature (-8 to -9 SD), hip joint pain and weakness, myopia, atlantoaxial instability and compressive myelopathy, ligamentous laxity, thoracolumbar kyphosis, and small hands and feet. Mapping By linkage analysis in a consanguineous Saudi family segregating Smith-McCort syndrome in which mutation in the DYM gene (607461) had been excluded, Alshammari et al. (2012) found linkage of the disorder to a 19-Mb region on chromosome 4 between SNPs rs6844366 and rs2215748 (maximum lod of 3.25). Molecular Genetics By exome sequencing of the proband in a consanguineous Saudi family segregating Smith-McCort syndrome linked to chromosome 4, Alshammari et al. (2012) identified a homozygous missense mutation in the RAB33B gene (K46Q; 605950.0001). Immunoblot analysis showed severe deficiency of RAB33B in patient cells compared with control cells, and patient fibroblasts also displayed a marked reduction in the immunofluorescence signal corresponding to RAB33B but comparable signal intensity to the Golgi marker giantin (602500). In a Turkish patient with Smith-McCort syndrome in whom Neumann et al. (2006) had found no mutation in the DYM gene (607461), Dupuis et al. (2013) identified a homozygous missense mutation in the RAB33B gene (N148K; 605950.0002). By Western blot analysis and immunofluorescence studies, Dupuis et al. (2013) found marked reduction of the RAB33B protein. In 3 unrelated patients with Smith-McCort syndrome who did not have a mutation in the DYM gene (607461), Salian et al. (2017) identified homozygous or compound heterozygous mutations in the the RAB33B gene (605950.0003-605050.0006). The mutations, which included a missense mutation and 3 truncating mutations, segregated with the disorder in each family. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Low weight HEAD & NECK Neck \- Short neck CHEST External Features \- Short trunk \- Barrel-shaped chest Ribs Sternum Clavicles & Scapulae \- Pectus carinatum SKELETAL Spine \- Exaggerated lordosis \- Platyspondyly \- Posterior double humps of vertebral body \- Irregular surface of iliac spine \- Odontoid hypoplasia, mild Limbs \- Elevated shoulder joints \- Limited extension of elbow joints \- Genu valgum \- Flattened femoral heads \- Broad femoral neck, mild \- Reduced trochanter and femur head distance ratio \- Irregular shallow acetabular roofs \- Metaphyseal irregularity of the upper tibia \- Flattened epiphysis of the lower tibia \- Flattened humeral head Hands \- Short metacarpal bones \- Broad metacarpal bones \- Short phalanges \- Broad phalanges \- Broad interphalangeal joints Feet \- Flat feet \- Prominent heels \- Short metatarsal bones \- Broad metatarsal bones \- Short phalanges \- Broad phalanges MOLECULAR BASIS \- Caused by mutation in the Ras-associated protein RAB33B gene (RAB33B, 605950.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SMITH-MCCORT DYSPLASIA 2	c1846431	3,384	omim	https://www.omim.org/entry/615222	2019-09-22T15:52:55	{"doid": ["0060247"], "mesh": ["C564589"], "omim": ["615222"], "orphanet": ["178355"]}
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea) begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this separation does not occur properly, EA/TEF is the result. In esophageal atresia (EA), the upper esophagus does not connect (atresia) to the lower esophagus and stomach. Almost 90 percent of babies born with esophageal atresia also have a tracheoesophageal fistula (TEF), in which the esophagus and the trachea are abnormally connected, allowing fluids from the esophagus to get into the airways and interfere with breathing. A small number of infants have only one of these abnormalities. There are several types of EA/TEF, classified by the location of the malformation and the structures that are affected. In more than 80 percent of cases, the lower section of the malformed esophagus is connected to the trachea (EA with a distal TEF). Other possible configurations include having the upper section of the malformed esophagus connected to the trachea (EA with a proximal TEF), connections to the trachea from both the upper and lower sections of the malformed esophagus (EA with proximal and distal TEF), an esophagus that is malformed but does not connect to the trachea (isolated EA), and a connection to the trachea from an otherwise normal esophagus (H-type TEF with no EA). While EA/TEF arises during fetal development, it generally becomes apparent shortly after birth. Saliva, liquids fed to the infant, or digestive fluids may enter the windpipe through the tracheoesophageal fistula, leading to coughing, respiratory distress, and a bluish appearance of the skin or lips (cyanosis). Esophageal atresia blocks liquids fed to the infant from entering the stomach, so they are spit back up, sometimes along with fluids from the respiratory tract. EA/TEF is a life-threatening condition; affected babies generally require surgery to correct the malformation in order to allow feeding and prevent lung damage from repeated exposure to esophageal fluids. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF). ## Frequency EA/TEF occurs in 1 in 3,000 to 5,000 newborns. ## Causes Isolated EA/TEF is considered to be a multifactorial condition, which means that multiple gene variations and environmental factors likely contribute to its occurrence. In most cases of isolated EA/TEF, no specific genetic changes or environmental factors have been conclusively determined to be the cause. Non-isolated or syndromic forms of EA/TEF can be caused by changes in single genes or in chromosomes, or they can be multifactorial. For example, approximately 10 percent of people with CHARGE syndrome, which is usually caused by mutations in the CHD7 gene, have EA/TEF. About 25 percent of individuals with the chromosomal abnormality trisomy 18 are born with EA/TEF. EA/TEF also occurs in VACTERL association, a multifactorial condition. VACTERL is an acronym that stands for vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities. People diagnosed with VACTERL association typically have at least three of these features; between 50 and 80 percent have a tracheoesophageal fistula. ## Inheritance Pattern When EA/TEF occurs as a feature of a genetic syndrome or chromosomal abnormality, it may cluster in families according to the inheritance pattern for that condition. Often EA/TEF is not inherited, and there is only one affected individual in a family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Esophageal atresia/tracheoesophageal fistula	c1861028	3,385	medlineplus	https://medlineplus.gov/genetics/condition/esophageal-atresia-tracheoesophageal-fistula/	2021-01-27T08:25:54	{"gard": ["7792"], "mesh": ["C531835"], "omim": ["189960"], "synonyms": []}
Malignant peritoneal mesothelioma is a primary peritoneal malignancy occurring in the lining cells (mesothelium) of the peritoneal cavity. ## Epidemiology Peritoneal mesothelioma accounts for 10 to 30% of all malignant mesotheliomas. The annual incidence is approximately 1/500,000 in France but reaches 1/200,000 in some parts of Europe (Italy). Men are predominantly affected. ## Clinical description The tumors are usually diagnosed in late adulthood (median age: 55 years). Typical presenting features are abdominal distention, abdominal pain, presence of an abdominal mass, impaired general state, weight loss, and ascites. Dyspnea, coagulation disorders, edema of the lower limbs and intestinal occlusion may be observed. ## Etiology The relationship between peritoneal mesothelioma and asbestos exposure is unclear, especially in women, and has not been established unlike in malignant pleural mesothelioma. Other causes have been reported such as exposure to erionite, viral infection and vaccine products and/or genetic factors. ## Diagnostic methods Diagnosis is based on imaging techniques, such as ultrasound and chest-abdominal-pelvic computed tomography (CAP-CT). Diagnosis is confirmed histologically on tissue biopsy and by relevant immunostaining results (positive for calretinin and negative for carcinoembryonic antigen (CEA)), and should be performed by two experts. ## Differential diagnosis Differential diagnosis includes peritoneal carcinomatosis secondary to colorectal or gastric cancer and primary peritoneal carcinoma (see this term). ## Management and treatment Treatment strategies require a multidisciplinary approach and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Currently proposed treatment with curative intent involves a combination of cytoreductive surgery (visceral resections and peritonectomy procedures) with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) in specific patients (young, good general status, low tumor volume). Systemic chemotherapy (off-label use) is sometimes used in palliative treatment. ## Prognosis With palliative treatment (systemic chemotherapy), median survival does not reach 1 to 2 years. Following cytoreductive surgery and HIPEC, median survival of more than 50 months, and 5-year survival of more than 50% may be obtained. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Malignant peritoneal mesothelioma	c0346109	3,386	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168811	2021-01-23T18:35:52	{"umls": ["C0346109"], "icd-10": ["C45.1"], "synonyms": ["Diffuse malignant peritoneal mesothelioma", "Primary malignant peritoneal mesothelioma"]}
## Description In moyamoya disease, stenosis of the intracranial portion of the internal carotid artery leads to secondary establishment of intracranial compensatory anastomoses at different levels (leptomeninges, basal ganglia, and transdural) (summary by Sakurai et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350). Mapping Sakurai et al. (2004) searched for loci linked to moyamoya disease in 12 Japanese families using 428 microsatellite markers and found significant evidence for linkage to 8q23 (maximum lod score of 3.6 at marker D8S546) and suggestive evidence for linkage to 12p12 (maximum lod score of 2.3 at marker D12S1690). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MOYAMOYA DISEASE 3	c0026654	3,387	omim	https://www.omim.org/entry/608796	2019-09-22T16:07:08	{"doid": ["13099"], "mesh": ["D009072"], "omim": ["608796"], "orphanet": ["2573"]}
Hume fracture SpecialtyOrthopedic The Hume fracture is an injury of the elbow comprising a fracture of the olecranon with an associated anterior dislocation of the radial head which occurs in children. It was originally described as an undisplaced olecranon fracture,[1] but more recently includes displaced fractures and can be considered a variant of the Monteggia fracture.[2] The injury was described in 1957 by A.C. Hume of the orthopaedic surgery department of St. Bartholomew's Hospital, Rochester.[1] ## Contents * 1 Cause * 2 Management * 3 References * 4 External links ## Cause[edit] Although the precise mechanism of injury is unclear, the injury occurs in children who have fallen heavily with their arm trapped under the body. In his original description of the injury, Hume suggested that the injury occurred as a result of hyperextension of the elbow leading to fracture of the olecranon, with pronation of the forearm leading to the radial head dislocation.[1] ## Management[edit] In the original description by Hume, where the olecranon fractures were not displaced, treatment consisted of closed reduction of the radial head dislocation under general anaesthesia by supination of the forearm. This was followed by immobilisation of the arm in a plaster cast with the elbow flexed at 90° and the forearm in supination for 6 weeks.[1] Where the olecranon fracture is displaced, open reduction internal fixation is recommended. Once the olecranon has been repaired, closed reduction of the radial head dislocation is usually possible. This is followed by immobilisation with the elbow flexed to 90° and the forearm in the neutral position. The duration of immobilisation depends on clinical assessment of the joint, and mobilisation may be possible after as little as 4 weeks.[2] ## References[edit] 1. ^ a b c d HUME AC (August 1957). "Anterior dislocation of the head of the radius associated with undisplaced fracture of the olecranon in children". J Bone Joint Surg Br. 39-B (3): 508–12. PMID 13463039. Retrieved 2009-11-09.[permanent dead link] 2. ^ a b McRae, Ronald; Esser, Max (2008). Practical Fracture Treatment (5th ed.). Elsevier Health Sciences. p. 187. ISBN 978-0-443-06876-8. ## External links[edit] Classification D * ICD-10: S52.0 External resources * AO Foundation: 21-B1 * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hume fracture	None	3,388	wikipedia	https://en.wikipedia.org/wiki/Hume_fracture	2021-01-18T18:54:36	{"wikidata": ["Q5940646"]}
Hemoglobin C disease (HbC) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin C, with no or mild clinical manifestations (hemolytic anemia). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hemoglobin C disease	c0019021	3,389	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2132	2021-01-23T18:19:18	{"gard": ["2640"], "mesh": ["D006445"], "umls": ["C0019021"], "icd-10": ["D58.2"]}
Chromosome 5q deletion is a chromosome abnormality that occurs when there is a missing copy of the genetic material located on the long arm (q) of chromosome 5. The severity of the condition and the signs and symptoms depend on the size and location of the deletion and which genes are involved. Features that often occur in people with chromosome 5q deletion include developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most cases are not inherited, but people can pass the deletion 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Chromosome 5q deletion	c3888961	3,390	gard	https://rarediseases.info.nih.gov/diseases/10840/chromosome-5q-deletion	2021-01-18T18:01:21	{"synonyms": ["Deletion 5q", "Monosomy 5q", "5q deletion", "5q monosomy", "Partial monosomy 5q"]}
Fibromyalgia is a common condition characterized by long-lasting (chronic) pain affecting many areas of the body. The pain is associated with tenderness that occurs with touch or pressure on the muscles, joints, or skin. Some affected individuals also report numbness, tingling, or a burning sensation (paresthesia) in the arms and legs. Other signs and symptoms of fibromyalgia include excessive tiredness (exhaustion); sleep problems, such as waking up feeling unrefreshed; and problems with memory or thinking clearly. People with fibromyalgia often report additional types of pain, including headaches, back and neck pain, sore throat, pain or clicking in the jaw (temporomandibular joint dysfunction), and stomach pain or digestive disorders such as irritable bowel syndrome. They have an increased likelihood of developing mood or psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder. However, many people with fibromyalgia do not have a mental health condition. The major signs and symptoms of fibromyalgia can occur by themselves or together with another chronic pain condition such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or systemic lupus erythematosus. ## Frequency Fibromyalgia occurs in an estimated 2 to 8 percent of the general population worldwide. Because its signs and symptoms are nonspecific and overlap with those of many other conditions, it can be challenging to diagnose. The condition seems to affect women more than men, and its prevalence increases with age. ## Causes Fibromyalgia is known to run in families, suggesting that genetic factors contribute to the risk of developing this disease. However, little is known for certain about the genetic basis of fibromyalgia. It is likely that variations in many genes, each with a small effect, combine to increase the risk of developing this condition. The signs and symptoms of fibromyalgia are related to the way the brain recognizes and interprets pain signals. People with fibromyalgia have an increased sensitivity to pain; they feel pain more acutely than others would in response to a given stimulus. Researchers describe this phenomenon as the "volume" of pain sensations being turned up too high (pain amplification). Studies of the genetics of fibromyalgia have focused on genes with roles in the way the brain processes pain. For example, several genes that may influence the condition are involved in the production and breakdown of certain chemical messengers called neurotransmitters. These chemicals relay signals between nerve cells that can increase or decrease the sensation of pain, a process known as pain modulation. Nongenetic (environmental) factors also play critical roles in a person's risk of developing fibromyalgia. The disorder can be triggered by infection or illness that would not otherwise cause chronic pain, injury, and other physical stress. Psychological and social factors such as a history of childhood abuse or neglect, exposure to war or other catastrophic events, and low job or life satisfaction have also been associated with an increased risk of fibromyalgia. Additionally, physical inactivity, obesity, and sleep disturbances seem to increase risk. However, many people who develop this condition do not have any recognized triggers or risk factors. It is likely that environmental conditions interact with genetic factors to determine the overall risk of developing this disorder. ### Learn more about the gene associated with Fibromyalgia * COMT Additional Information from NCBI Gene: * ADRB2 * HTR2A * SLC6A4 * TAAR1 ## Inheritance Pattern Fibromyalgia does not have a clear pattern of inheritance in families. Overall, the risk of developing this condition is about eight times higher for first-degree relatives of affected individuals (such as siblings or children) as compared to the general public. Many people with fibromyalgia also have relatives with headaches, irritable bowel syndrome, temporomandibular joint dysfunction, and other conditions that cause chronic pain. These disorders may cluster in families in part because they share some genetic risk factors with fibromyalgia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Fibromyalgia	c0016053	3,391	medlineplus	https://medlineplus.gov/genetics/condition/fibromyalgia/	2021-01-27T08:24:55	{"mesh": ["D005356"], "synonyms": []}
A mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities. Leigh syndrome Other namesjuvenile subacute necrotizing encephalomyelopathy, Leigh disease, infantile subacute necrotizing encephalomyelopathy, subacute necrotizing encephalomyelopathy (SNEM)[1] Detection of numerous ragged red fibers in a muscle biopsy SpecialtyNeurology Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951.[2] Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily.[3][4] ## Contents * 1 Signs and symptoms * 2 Genomics * 2.1 Mitochondrial DNA mutations * 2.2 Nuclear DNA mutations * 2.3 X-linked Leigh syndrome * 2.4 French Canadian Leigh syndrome * 3 Pathophysiology * 4 Diagnosis * 4.1 Clinical findings * 4.2 Differential diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 History * 9 See also * 10 References * 11 Further reading * 12 External links ## Signs and symptoms[edit] The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years;[1] however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis.[5] Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.[6] Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive.[1] Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.[5] As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements).[1] Slow saccades are also sometimes seen.[6] The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death;[1] asymmetric septal hypertrophy has also been associated with Leigh syndrome.[7] In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.[6] However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.[1] Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.[6] ## Genomics[edit] Two healthy mitochondria from mammalian lung tissue as shown by electron microscopy Mutations in mitochondrial DNA (mtDNA) and over 30 genes in nuclear DNA (gene SURF1[8] and some COX assembly factors) have been implicated in Leigh disease.[1] Disorders of oxidative phosphorylation, the process by which cells produce their main energy source of adenosine triphosphate (ATP), may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual. Four out of the five protein complexes involved in oxidative phosphorylation are most commonly disrupted in Leigh syndrome, either because of malformed protein or because of an error in the assembly of these complexes. Regardless of the genetic basis, it results in an inability of the complexes affected by the mutation to perform their role in oxidative phosphorylation. In the case of Leigh disease, crucial cells in the brain stem and basal ganglia are affected. This causes a chronic lack of energy in the cells, which leads to cell death and in turn, affects the central nervous system and inhibits motor functions. The heart and other muscles also require a lot of energy and are affected by cell death caused by chronic energy deficiencies in Leigh syndrome.[1] ### Mitochondrial DNA mutations[edit] Mitochondria are essential organelles in eukaryotic cells. Their function is to convert the potential energy of glucose, amino acids, and fatty acids into adenosine triphosphate (ATP) in a process called oxidative phosphorylation. Mitochondria carry their own DNA, called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of the enzymes essential to the production of ATP.[1] Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in MT-ATP6, a gene that codes for a protein in the last complex of the oxidative phosphorylation chain, ATP synthase, an enzyme that directly generates ATP. Without ATP synthase, the electron transport chain will not produce any ATP.[1] The most common MT-ATP6 mutation found with Leigh syndrome is a point mutation at nucleotide 8993 that changes a thymine to a guanine. This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells.[9] Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genes MT-ND2, MT-ND3, MT-ND5, MT-ND6 and MT-CO1.[7][10] Mitochondrial DNA is passed down matrilineally in a pattern called maternal inheritance — a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.[1] ### Nuclear DNA mutations[edit] The autosomal recessive pattern of inheritance seen in some cases of Leigh syndrome Nuclear DNA comprises most of the genome of an organism and in sexually reproducing organisms is inherited from both parents, in contrast to mitochondrial DNA's maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an autosomal recessive pattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant allele, can have an affected child if that child inherits the mutant allele from both parents.[1] 75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh disease. Mutations in a gene called SURF1 (surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria.[1] SURF1 is located on the long arm of chromosome 9.[11] Another nuclear DNA mutation that causes Leigh syndrome affects another protein complex in the mitochondria, pyruvate dehydrogenase, which is an enzyme in the Link reaction pathway.[1] Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.[6] Other nuclear genes associated with Leigh syndrome are located on chromosome 2 (BCS1L and NDUFA10); chromosome 5 (SDHA, NDUFS4, NDUFAF2, and NDUFA2); chromosome 8 (NDUFAF6), chromosome 10 (COX15); chromosome 11 (NDUFS3, NDUFS8, and FOXRED1); chromosome 12 (NDUFA9 and NDUFA12); and chromosome 19 (NDUFS7). Many of these genes affect the first oxidative phosphorylation complex.[7] ### X-linked Leigh syndrome[edit] The X-linked recessive pattern of inheritance seen occasionally in cases of Leigh syndrome. Leigh syndrome can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM 308930). The neurological features of Leigh syndrome caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency.[citation needed] X-linked recessive Leigh syndrome affects male children far more often than female children because they only have one copy of the X chromosome. Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.[1] ### French Canadian Leigh syndrome[edit] The type of Leigh syndrome found at a much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec is caused by a mutation in the LRPPRC gene, located on the small ('p') arm of chromosome 2.[7][12] Both compound heterozygosity and homozygous mutations have been observed in French Canadian Leigh syndrome. This subtype of the disease was first described in 1993 in 34 children from the region, all of whom had a severe deficiency in cytochrome c oxidase (COX), the fourth complex in the mitochondrial electron transport chain. Though the subunits of the protein found in affected cells were functional, they were not properly assembled. The deficiency was found to be almost complete in brain and liver tissues and substantial (approximately 50% of normal enzyme activity) in fibroblasts (connective tissue cells) and skeletal muscle. Kidney and heart tissues were found to not have a COX deficiency.[12] French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are developmentally delayed, have mildly dysmorphic facial features, including hypoplasia of the midface and wide nasal bridge, chronic metabolic acidosis, and hypotonia (decreased muscular strength). Other symptoms include tachypnea (unusually quick breathing rate), poor sucking ability, hypoglycemia (low blood sugar), and tremors. Severe, sudden metabolic acidosis is a common cause of mortality.[12] Estimates of the rate of genetic carriers in the Saguenay-Lac-Saint-Jean region range from 1 in 23 to 1 in 28; the number of children born with the disease has been estimated at 1 in 2063 to 1 in 2473 live births. Genealogic studies suggest that the responsible mutation was introduced to the region by early European settlers.[12] ## Pathophysiology[edit] The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal lesions in the brainstem, basal ganglia, cerebellum, and other regions of the brain. The lesions take on different forms, including areas of demyelination, spongiosis, gliosis, necrosis, and capillary proliferation.[7] Demyelination is the loss of the myelin sheath around the axons of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.[1] The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of pyruvate, which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into alanine via alanine aminotransferase or converted into lactic acid by lactate dehydrogenase; both of these substances can then build up in the body.[6] ## Diagnosis[edit] Leigh syndrome is suggested by clinical findings and confirmed with laboratory and genetic testing.[6] ### Clinical findings[edit] Dystonia, nystagmus, and problems with the autonomic nervous system suggest damage to the basal ganglia and brain stem potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such as hypertrichosis and neurologically caused deafness. Laboratory findings of lactic acidosis or acidemia and hyperalaninemia (elevated levels of alanine in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in the metabolic pathway.[6] ### Differential diagnosis[edit] Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include perinatal asphyxia, kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency, Wilson's disease, biotin-responsive basal ganglia disease, and some forms of encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia is not treated with phototherapy, the bilirubin can accumulate in the basal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.[6] ## Treatment[edit] Succinic acid has been studied, and shown effective for both Leigh syndrome, and MELAS syndrome.[13][14] A high-fat, low-carbohydrate diet may be followed if a gene on the X chromosome is implicated in an individual's Leigh syndrome. Thiamine (vitamin B1) may be given if pyruvate dehydrogenase deficiency is known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet with sodium bicarbonate (baking soda) or sodium citrate, but these substances do not treat the cause of Leigh syndrome. Dichloroacetate may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance.[5] Coenzyme Q10 supplements have been seen to improve symptoms in some cases.[7] Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.[15] In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA, performed a spindle transfer mitochondrial donation technique on a mother in Mexico who was at risk of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016. However, it is not yet certain if the technique is completely reliable and safe.[16] ## Prognosis[edit] Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.[5] ## Epidemiology[edit] Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.[1] ## History[edit] Leigh syndrome was first described by Denis Leigh in 1951[17] and distinguished from similar Wernicke's encephalopathy in 1954.[7] In 1968, the disease's link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and other electron transport chain proteins were not discovered until 1977.[6] ## See also[edit] * Joseph Maraachli case * Neuropathy, ataxia, and retinitis pigmentosa ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q "Leigh syndrome". Genetics Home Reference. National Institute of Health. 23 September 2013. Retrieved 16 October 2013. 2. ^ Noble, Peter (2018). "Denis Archibald Leigh". Psychiatric Bulletin. 22 (10): 648–9. doi:10.1192/pb.22.10.648. 3. ^ Murphy, Jerome V (1974). "Leigh Disease: Biochemical Characteristics of the Inhibitor". Archives of Neurology. 31 (4): 220–7. doi:10.1001/archneur.1974.00490400034002. 4. ^ Murphy, J. V; Craig, L (1975). "Leigh's disease: Significance of the biochemical changes in brain". Journal of Neurology, Neurosurgery, and Psychiatry. 38 (11): 1100–3. doi:10.1136/jnnp.38.11.1100. PMC 492163. PMID 1206418. 5. ^ a b c d "NINDS Leigh's Disease Information Page". National Institute of Neurological Diseases and Stroke. NIH. 16 December 2011. Archived from the original on 3 December 2013. Retrieved 25 November 2013. 6. ^ a b c d e f g h i j Baertling, F; Rodenburg, R. J; Schaper, J; Smeitink, J. A; Koopman, W. J. H; Mayatepek, E; Morava, E; Distelmaier, F (2013). "A guide to diagnosis and treatment of Leigh syndrome". Journal of Neurology, Neurosurgery & Psychiatry. 85 (3): 257–65. doi:10.1136/jnnp-2012-304426. PMID 23772060. S2CID 45323262. 7. ^ a b c d e f g "Leigh Syndrome". Online Mendelian Inheritance in Man. McKusick–Nathans Institute of Genetic Medicine. 13 March 2013. Retrieved 25 November 2013. 8. ^ Pronicki, M; Matyja, E; Piekutowska-Abramczuk, D; Szymanska-Debinska, T; Karkucinska-Wieckowska, A; Karczmarewicz, E; Grajkowska, W; Kmiec, T; Popowska, E; Sykut-Cegielska, J (2008). "Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease". Journal of Clinical Pathology. 61 (4): 460–6. doi:10.1136/jcp.2007.051060. PMC 2571978. PMID 17908801. 9. ^ "MT-ATP6". Genetics Home Reference. NIH. 19 November 2013. Retrieved 25 November 2013. 10. ^ Poole, Olivia V.; Everett, Chris M.; Gandhi, Sonia; Marino, Silvia; Bugiardini, Enrico; Woodward, Cathy; Lam, Amanda; Quinlivan, Ros; Hanna, Michael G.; Pitceathly, Robert D.S. (July 2019). "Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1". Mitochondrion. 47: 294–297. doi:10.1016/j.mito.2019.02.004. PMID 30743023. 11. ^ "SURF1". Genetics Home Reference. NIH. 19 November 2013. Retrieved 25 November 2013. 12. ^ a b c d "Leigh Syndrome, French Canadian type". Online Mendelian Inheritance in Man. Johns Hopkins University. 1 December 2011. Retrieved 25 December 2013. 13. ^ Ehinger, Johannes K; Piel, Sarah; Ford, Rhonan; Karlsson, Michael; Sjövall, Fredrik; Frostner, Eleonor Åsander; Morota, Saori; Taylor, Robert W; Turnbull, Doug M; Cornell, Clive; Moss, Steven J; Metzsch, Carsten; Hansson, Magnus J; Fliri, Hans; Elmér, Eskil (2016). "Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency". Nature Communications. 7: 12317. Bibcode:2016NatCo...712317E. doi:10.1038/ncomms12317. PMC 4980488. PMID 27502960. 14. ^ Oguro, Hiroaki; Iijima, Kenichi; Takahashi, Kazuo; Nagai, Atsushi; Bokura, Hirokazu; Yamaguchi, Shuhei; Kobayashi, Shotai (2004). "Successful Treatment with Succinate in a Patient with MELAS". Internal Medicine. 43 (5): 427–31. doi:10.2169/internalmedicine.43.427. PMID 15206559. 15. ^ "Archived copy". Archived from the original on 2013-08-19. Retrieved 2013-07-24.CS1 maint: archived copy as title (link) 16. ^ Roberts, Michelle (2016-09-27). "First 'three person baby' born using new method". BBC News. Retrieved 2016-09-28. 17. ^ Leigh, D (1951). "Subacute Necrotizing Encephalomyelopathy in an Infant". Journal of Neurology, Neurosurgery & Psychiatry. 14 (3): 216–21. doi:10.1136/jnnp.14.3.216. PMC 499520. PMID 14874135. ## Further reading[edit] * GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP * OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP * Leigh syndrome; Subacute necrotizing encephalopathy; Leigh's disease at NIH's Office of Rare Diseases * leighsdisease at NINDS * Maternally Inherited Leigh Syndrome at NIH's Office of Rare Diseases ## External links[edit] Classification D * ICD-10: G31.8 * ICD-9-CM: 330.8 * OMIM: 256000 * MeSH: D007888 * DiseasesDB: 30792 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Mitochondrial diseases Carbohydrate metabolism * PCD * PDHA Primarily nervous system * Leigh disease * LHON * NARP Myopathies * KSS * Mitochondrial encephalomyopathy * MELAS * MERRF * PEO No primary system * DAD * MNGIE * Pearson syndrome Chromosomal * OPA1 * Kjer's optic neuropathy * SARS2 * HUPRA syndrome * TIMM8A * Mohr–Tranebjærg syndrome see also mitochondrial proteins * v * t * e Disorders of citric acid cycle and electron transport chain Citric acid cycle * Pyruvate dehydrogenase deficiency * Fumarase deficiency Electron transport chain * Coenzyme Q10 deficiency * Björnstad syndrome * GRACILE syndrome * Leigh's disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Leigh syndrome	c0023264	3,392	wikipedia	https://en.wikipedia.org/wiki/Leigh_syndrome	2021-01-18T18:33:01	{"gard": ["6877"], "mesh": ["D007888"], "umls": ["C0023264"], "orphanet": ["506"], "wikidata": ["Q1815019"]}
A xanthochromistic and normal Argentine horned frog Xanthochromism (also called xanthochroism or xanthism) is an unusually yellow pigmentation in an animal. It is often associated with the lack of usual red pigmentation and its replacement with yellow. The cause is usually genetic but may also be related to the animal's diet. A Cornell University survey of unusual-looking birds visiting feeders reported that 4% of such birds were described as xanthochromistic (compared with 76% albinistic). The opposite of xanthochromism, a deficiency in or complete absence of yellow pigment, is known as axanthism. Birds exhibiting genetic xanthochromism, especially deliberately bred mutations of several species of parrot in aviculture, are termed "lutinos". Wild birds in which xanthochromism has been recorded include yellow wagtail, wood warbler, Cape May warbler, rose-breasted grosbeak, evening grosbeak, red-bellied woodpecker, scarlet tanager, northern cardinal, great spotted woodpecker, common tailorbird, crimson-breasted shrike, kakariki and kea. ## See also[edit] * Albinism in biology * Albinism * Albino and white squirrels * Amelanism * Dyschromia * Erythrism * Heterochromia iridum * Leucism * Melanism * Piebaldism * Carotenosis ## References[edit] * Cornell University Project Feeder Watch 2002-2003 Accessed 19 March 2007. * Helleiner CW (1979). "Xanthochroism in the Evening Grosbeak". Canadian Field-Naturalist. 93 (1): 66–7. * Isted, Deloris (1985). "A xanthochroistic male Purple Finch". Bulletin of the Oklahoma Ornithological Society. 18 (4): 31. * Schnell, Gary D; Caldwell, Larry D (1966). "Xanthochroism in a Cape May Warbler". Auk. 83 (4): 667–8. doi:10.2307/4083162. JSTOR 4083162. * Schwartz FJ (1978). "Xanthochromism in Epinephelus drummondhayi (Pisces: Serranidae) caught off North Carolina". Northeast Gulf Science. 2 (1): 62–4. doi:10.18785/negs.0201.06. ## External links[edit] Wikimedia Commons has media related to Xanthism. * Birders’ World Magazine, August 2003 * Strange birds at your feeder * Yellow-breasted Crimson-breasted Shrike This veterinary medicine–related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Xanthochromism	None	3,393	wikipedia	https://en.wikipedia.org/wiki/Xanthochromism	2021-01-18T18:48:35	{"wikidata": ["Q2597715"]}
Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal hardening of the skin and, sometimes, other organs. It is classified into two main forms: localized scleroderma and systemic sclerosis (SSc), the latter comprising three subsets; diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) and limited SSc (lSSc) (see these terms). ## Epidemiology The prevalence is estimated at around 1-9/100,000 for localized scleroderma, and 1/6,500 adults for systemic sclerosis. Women are predominantly affected (F/M sex ratio around 4:1). ## Clinical description Localized scleroderma is the cutaneous form of scleroderma characterized by fibrosis of the skin causing cutaneous plaques (morphea) or strips (linear scleroderma). Systemic sclerosis (SSc) is a generalized disorder characterized by fibrosis and vascular obliteration in the skin and organs, particularly, lungs, heart, and digestive tract. ## Etiology The exact cause of scleroderma is unknown. The disease originates from an autoimmune reaction which leads to localized overproduction of collagen. In some cases, the condition is associated with exposure to chemicals. Other suggested causes include genetic and infectious mechanisms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Scleroderma	c0011644	3,394	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=801	2021-01-23T17:22:00	{"mesh": ["D012594"], "umls": ["C0011644", "C0852007"]}
Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract.[1] It is a monogenetic disease caused by mutation in the IKBKG gene (IKKγ, also known as the NF-κB essential modulator, or NEMO). NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus. The link between IKBKG mutations and NEMO deficiency was identified in 1999. IKBKG is located on the X chromosome and is X-linked therefore this disease predominantly affects males, However females may be genetic carriers of certain types of mutations.[2] Other forms of the syndrome involving NEMO-related pathways can be passed on from parent to child in an autosomal dominant manner – this means that a child only has to inherit the faulty gene from one parent to develop the condition. This autosomal dominant type of NEMO deficiency syndrome can affect both boys and girls.[3] ## Contents * 1 Presentation * 1.1 Commonly Associated Diseases * 2 Diagnosis * 3 Treatment * 4 References ## Presentation[edit] ### Commonly Associated Diseases[edit] NEMO deficiency syndrome may present itself as Incontinentia pigmenti or Ectodermal dysplasia depending on the type of genetic mutation present, such as if the mutation results in the complete loss of gene function or a point mutation. Amorphic genetic mutations in the IKBKG gene, which result in the loss of gene function, typically present themselves as Incontinetia Pigmenti (IP).[4] Because loss of NEMO function is lethal, only heterozygous females or males with XXY karyotype or mosaicism for this gene survive and exhibit symptoms of Incontinetia Pigmenti, such as skin lesions and abnormalities in hair, teeth, and nails. There are a variety of mutations that may cause the symptoms of IP, however, they all involve the deletion of exons on the IKBKG gene.[5] Hypomorphic genetic mutations in the IKBKG gene, resulting in a partial loss of gene function, cause the onset of Anhidrotic ectodermal dysplasia with Immunodeficiency (EDA-IP).[6] The lack of NEMO results in a decreased levels of NF-κB transcription factor translocation and gene transcription, which in turn leads to a low level of immunoglobulin production. Because NF-κB translocation is unable to occur without proper NEMO function, the cell signaling response to immune mediators such as IL-1β, IL-18, and LPS are ineffective thus leading to a compromised immune response to various forms of bacterial infections. ## Diagnosis[edit] Originally NEMO deficiency syndrome was thought to be a combination of Ectodermal Dysplasia (ED) and a lack of immune function,[7] but is now understood to be more complex disease. NEMO Deficiency Syndrome may manifest itself in the form of several different diseases dependent upon mutations of the IKBKG gene such as Incontinentia pigmenti or Ectodermal dysplasia.[8] The clinical presentation of NEMO deficiency is determined by three main symptoms: 1. Susceptibility to pyogenic infections in the form of severe local inflammation 2. Susceptibility to mycobacterial infection 3. Symptoms of Ectodermal Dysplasia To determine whether or not patient has NEMO deficiency, an immunologic screen to test immune system response to antigen may be used although a genetic test is the only way to be certain as many individuals respond differently to the immunological tests. ## Treatment[edit] The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms. In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor.[3] ## References[edit] 1. ^ Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, McCune JM, Wara DW (2009). "Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome". Clinical Immunology (Orlando, Fla.). 132 (1): 124–31. doi:10.1016/j.clim.2009.03.514. PMC 2800791. PMID 19375390. 2. ^ NEMO deficiency syndrome information, Great Ormond Street Hospital for Children 3. ^ a b "NEMO deficiency syndrome". Retrieved 2017-01-16. 4. ^ Zhang, Qian; Lenardo, Michael; Baltimore, David (12 Jan 2017). "30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology". Cell. 168: 37–57. doi:10.1016/j.cell.2016.12.012. PMC 5268070. 5. ^ Fusco, F (May 2008). "Alterations of the IKBKG locus and diseases: An update and a report of 13 novel mutations". Human Mutation. 29 (5): 595–604. doi:10.1002/humu.20739. 6. ^ Zhang, Qian; Lenardo, Michael; Baltimore, David (2017). "30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology". Cell. 168: 37–57. doi:10.1016/j.cell.2016.12.012. PMC 5268070. 7. ^ "NEMO deficiency syndrome". Great Ormond Street Hospital for Children. July 2015. Retrieved January 5, 2019. 8. ^ Fusco, F (2015). "EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation". Int Rev Immunol. 34 (6): 445. doi:10.3109/08830185.2015.1055331. PMID 26269396. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NEMO deficiency syndrome	c2931839	3,395	wikipedia	https://en.wikipedia.org/wiki/NEMO_deficiency_syndrome	2021-01-18T18:28:42	{"gard": ["12915"], "mesh": ["C538399"], "umls": ["C2931839"], "wikidata": ["Q24885766"]}
Worsening of neurologic symptoms in multiple sclerosis Uhthoff's phenomenon SpecialtyNeurology Differential diagnosisdegeneration of condition of Multiple sclerosis Uhthoff's phenomenon (also known as Uhthoff's syndrome, Uhthoff's sign, and Uhthoff's symptom) is the worsening of neurologic symptoms in multiple sclerosis (MS) and other neurological, demyelinating conditions when the body gets overheated from hot weather, exercise, fever, or saunas and hot tubs. It is possibly due to the effect of increased temperature on nerve conduction.[1] With an increased body temperature, nerve impulses are either blocked or slowed in a damaged nerve but once the body temperature is normalized, signs and symptoms may improve or disappear.[2] ## Clinical significance[edit] Many patients with MS experience increased fatigue and other symptoms such as pain, concentration difficulties, and urinary urgency when exposed to heat.[2] As a result, many patients with MS tend to avoid saunas, warm baths, and other sources of heat or wear ice or evaporative cooling apparel in the form of vests, neck wraps, arm/wrist bands, and hats. Peripheral nerve studies have shown that even a 0.5 °C increase in body temperature can slow or block the conduction of nerve impulses in demyelinated nerves. With greater levels of demyelination, a smaller increase in temperature is needed to slow down the nerve impulse conduction. Exercising and performing activities of daily living can cause a significant increase in body temperature in individuals with MS, especially if their mechanical efficiency is poor due to the use of mobility aids, ataxia, weakness, and spasticity.[3] However, exercise has been shown to be helpful in managing MS symptoms, reducing the risk of comorbidities, and promoting overall wellness.[4] Taking advantage of the cooling properties of water may help attenuate the consequences of heat sensitivity. In a study done by White et al. (2000), exercise pre-cooling via lower body immersion in water of 16–17 °C for 30 minutes allowed heat sensitive individuals with MS to exercise in greater comfort and with fewer side effects by minimizing body temperature increases during exercise.[3] Hydrotherapy exercise in moderately cool water of 27–29 °C water can also be advantageous to individuals with MS. Temperatures lower than 27 °C are not recommended because of the increased risk of invoking spasticity.[4] ## History[edit] This phenomenon was first described by Wilhelm Uhthoff in 1890[5] as a temporary worsening of vision with exercise in patients with optic neuritis. Later research revealed the link between neurological signs such as visual loss and increased heat production and Uhthoff's belief that exercise was the etiology of visual loss was replaced by the conclusions of these later researchers stating that heat was the prime etiology.[6] ## References[edit] 1. ^ Davis SL, Frohman TC, Crandall CG, et al. (March 2008). "Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis". Neurology. 70 (13 Pt 2): 1098–106. doi:10.1212/01.wnl.0000291009.69226.4d. PMID 18287569. S2CID 24002003. 2. ^ a b Flensner, G.; Ek, A.C.; Soderhamn, O.; Landtblom, A.M. (2011). "Sensitivity to heat in MS patients: a factor strongly influencing symptomology-an explorative survey". BMC Neurol. 11: 27. doi:10.1186/1471-2377-11-27. PMC 3056752. PMID 21352533. 3. ^ a b White, A.T.; Wilson, T.E.; Davis, S.L.; Petajan, J.H. (2000). "Effect of precooling on physical performance in multiple sclerosis". Mult Scler. 6 (3): 176–180. doi:10.1177/135245850000600307. PMID 10871829. S2CID 41165079. 4. ^ a b White, L.J.; Dressendorfer, L.H. (2004). "Exercise and multiple sclerosis". Sports Med. 34 (15): 1077–1100. doi:10.2165/00007256-200434150-00005. PMID 15575796. S2CID 27787579. 5. ^ W. Uhthoff: Untersuchungen über die bei der multiplen Herdsklerose vorkommenden Augenstörungen. Archiv für Psychiatrie und Nervenkrankheiten, Berlin, 1890, 21: 55-116 and 303-410. 6. ^ Guthrie, T.C.; Nelson, D.A. (1995). "Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential". J Neurol Sci. 129 (1): 1–8. doi:10.1016/0022-510x(94)00248-m. PMID 7751837. S2CID 12555514. * v * t * e Multiple sclerosis and other demyelinating diseases of the central nervous system Signs and symptoms * Ataxia * Depression * Diplopia * Dysarthria * Dysphagia * Fatigue * Incontinence * Nystagmus * Optic neuritis * Pain * Uhthoff's phenomenon Investigations and diagnosis * Multiple sclerosis diagnosis * McDonald criteria * Poser criteria * Clinical * Clinically isolated syndrome * Expanded Disability Status Scale * Serological and CSF * Oligoclonal bands * Radiological * Radiologically isolated syndrome * Lesional demyelinations of the central nervous system * Dawson's fingers Approved[by whom?] treatment * Management of multiple sclerosis * Alemtuzumab * Cladribine * Dimethyl fumarate * Fingolimod * Glatiramer acetate * Interferon beta-1a * Interferon beta-1b * Mitoxantrone * Natalizumab * Ocrelizumab * Ozanimod * Siponimod * Teriflunomide Other treatments * Former * Daclizumab * Multiple sclerosis research Demyleinating diseases Autoimmune * Multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis Inflammatory * Acute disseminated encephalomyelitis * MOG antibody disease * Balo concentric sclerosis * Marburg acute multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis * Tumefactive multiple sclerosis * Experimental autoimmune encephalomyelitis Hereditary * Adrenoleukodystrophy * Alexander disease * Canavan disease * Krabbe disease * Metachromatic leukodystrophy * Pelizaeus–Merzbacher disease * Leukoencephalopathy with vanishing white matter * Megalencephalic leukoencephalopathy with subcortical cysts * CAMFAK syndrome Other * Central pontine myelinolysis * Marchiafava–Bignami disease * Mitochondrial DNA depletion syndrome Other * List of multiple sclerosis organizations * List of people with multiple sclerosis * Multiple sclerosis drug pipeline * Pathophysiology * v * t * e Symptoms and signs relating to the nervous system Neurological examination · Cranial nerve examination Central nervous system Head * Battle's sign * Kernig's sign * Macewen's sign * Myerson's sign * Stroop test * Hirano body Other * increased intracranial pressure * Cushing's triad * Lhermitte's sign * Charcot's neurologic triad Peripheral nervous system Reflexes Combination * Jendrassik maneuver Legs * Plantar reflex * Chaddock reflex * Oppenheim's sign * Westphal's sign Arms * Hoffmann's sign Other Arms * Froment's sign * carpal tunnel syndrome * Tinel sign * Phalen maneuver Legs * Gowers' sign * Hoover's sign * Lasègue's sign * Trendelenburg's sign Torso * Beevor's sign General * Pain stimulus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Uhthoff's phenomenon	c1610071	3,396	wikipedia	https://en.wikipedia.org/wiki/Uhthoff%27s_phenomenon	2021-01-18T18:35:03	{"umls": ["C1610071"], "wikidata": ["Q1066143"]}
Desmoplastic/nodular medulloblastoma is a histological variant of medulloblastoma (see this term), an embryonic malignancy, often located in one of the cerebellar hemispheres, occurring most frequently in adults and manifesting with symptoms such as vomiting and headache. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Desmoplastic/nodular medulloblastoma	c0751291	3,397	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251863	2021-01-23T18:44:54	{"mesh": ["D008527"], "omim": ["155255"], "umls": ["C0751291"], "icd-10": ["C71.6"]}
A number sign (#) is used with this entry because of evidence that fibular hypoplasia and complex brachydactyly is caused by homozygous or compound heterozygous mutation in the GDF5 gene (601146) on chromosome 20q11. Clinical Features Fibular hypoplasia and complex brachydactyly was probably first described by Du Pan (1924), who reported the isolated case of a boy with a complex type of brachydactyly associated with bilateral absence of the fibula. The same disorder was described by Grebe (1955) in a brother and sister from a first-cousin marriage. The sibs had shortening of various metacarpals, small carpals, trapezoid middle phalanx of the index finger, with radial deviation, almost complete absence of the fibula bilaterally, and tibiotarsal dislocation (Volkmann deformity). The toes were short and laterally deviated. Kohn et al. (1989) reported 3 sibs with short-limb dwarfism associated with bilateral absence of fibulae and severe abnormalities of all digits. There was also hypoplasia of the distal ulna leading to bowing of the radius. Hypoplasia or absence of proximal and middle phalanges resulted in deformed 'nubbin-like' fingers and toes similar to those seen in Grebe syndrome (200700). However, shortness of the limbs was much less marked than in the latter condition. Ahmad et al. (1990) described a highly inbred Pakistani kindred with at least 9 affected persons, providing strong support for autosomal recessive inheritance. The average inbreeding coefficient for the affected persons was significantly greater than that for unaffected persons in the pedigree, and consanguineous loops could account for all affected persons being homozygous for the same abnormal allele. Szczaluba et al. (2005) reported a Polish mother and daughter with Du Pan syndrome. The daughter showed symmetric shortening of the extremities, unequal brachydactyly with the thumbs most severely affected, equinovalgus deformity with medial displacement of the tibia at the ankle joint, absence of the fibulae, and small but well-formed nails. Psychomotor development was normal. The mother had mesomelic shortening of the extremities, brachydactyly, partial syndactyly of the fingers, equinovalgus deformity, and severe hypoplasia/dysplasia of the fibulae and short tubular bones. Douzgou et al. (2008) reported a 20-month-old boy with complex brachydactyly and mild proximal fibular hypoplasia. Hand plain films showed delayed ossification of the phalanges, apparently absent middle phalanges, hypoplastic metacarpals, and absent metacarpals and proximal phalanges of the first rays. There was also mild proximal hypoplasia of the fibula, without valgus deformity of the knee, instability of the proximal tibiofibular articulation, or anomalies of the femur. These findings supported a less severe involvement of the middle lower limb skeleton. Molecular analysis identified compound heterozygosity for 2 mutations in the GDF5 gene (601146.0018; 601146.0019). The father, who was heterozygous for 1 of the mutations, had features consistent with brachymesophalangy on radiographic studies of the hand. Molecular Genetics Because of similarities to the Hunter-Thompson (201250) and Grebe (200700) types of acromesomelic chondrodysplasia, Faiyaz-Ul-Haque et al. (2002) examined genomic DNA from a Pakistani family with Du Pan syndrome for mutations in the GDF5 gene and identified homozygosity for a missense mutation (601146.0005). In a mother and daughter with Du Pan syndrome, Szczaluba et al. (2005) identified heterozygosity for 3 mutations on the same allele of the GDF5 gene (601146.0012). The authors postulated that the 3 mutations had a synergistic cis-acting dominant-negative effect on gene expression, resulting in autosomal dominant inheritance of the disorder in this family. INHERITANCE \- Autosomal recessive SKELETAL Limbs \- Absent fibulae \- Displaced patella Hands \- Brachydactyly, complex \- Mild hand shortness \- Malaligned carpal bone \- Short metacarpals (especially first metacarpal) \- Hypoplastic phalanges (especially middle and proximal) Feet \- Talipes equinovalgus \- Ball-like toes \- Deformed tarsal bones \- Short metatarsals (especially first metatarsal) \- Absent-rudimentary phalanges SKIN, NAILS, & HAIR Nails \- Hypoplastic-absent toenails MISCELLANEOUS \- Allelic to Grebe syndrome ( 200700 ), brachydactyly type C ( 113100 ), and acromesomelic dysplasia, Hunter-Thompson type ( 201250 ) \- No phenotype in heterozygotes MOLECULAR BASIS \- Caused by mutations in the cartilage-derived morphogenetic protein-1 gene (CDMP1, 601146.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	FIBULAR HYPOPLASIA AND COMPLEX BRACHYDACTYLY	c1856738	3,398	omim	https://www.omim.org/entry/228900	2019-09-22T16:27:51	{"doid": ["0050790"], "mesh": ["C537931"], "omim": ["228900"], "orphanet": ["2639"], "synonyms": ["Alternative titles", "DU PAN SYNDROME"]}
Anal stricture or anal stenosis is a narrowing of the anal canal.[1] It can be caused by a number of surgical procedures including: hemorrhoid removal and following anorectal wart treatment.[2] ## References[edit] 1. ^ Ehrenpreis, Eli D. (2003). Anal and rectal diseases explained. London: Remedica Group. pp. 53. ISBN 9781901346671. 2. ^ Katdare, MV; Ricciardi, R (February 2010). "Anal stenosis". The Surgical clinics of North America. 90 (1): 137–45, Table of Contents. doi:10.1016/j.suc.2009.10.002. PMID 20109638. This medical treatment–related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Anal stricture	c0156183	3,399	wikipedia	https://en.wikipedia.org/wiki/Anal_stricture	2021-01-18T18:37:54	{"mesh": ["D000071056"], "umls": ["C0156183"], "wikidata": ["Q41091"]}

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