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Cousin syndrome is a rare syndrome characterized mainly by short stature at birth, unusual facial appearance and skeletal abnormalities involving the shoulder blades and hips. Intelligence may vary from normal to moderately delayed. Mutations in the TBX15 gene inherited in an autosomal recessive pattern have been suggested as the cause of this condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Cousin syndrome	c1850040	8,700	gard	https://rarediseases.info.nih.gov/diseases/1555/cousin-syndrome	2021-01-18T18:01:04	{"mesh": ["C535550"], "omim": ["260660"], "umls": ["C1850040"], "orphanet": ["93333"], "synonyms": ["Craniofacial dysmorphism, hypoplasia of scapula and pelvis and short stature", "Pelviscapular dysplasia"]}
Trisomy 2 mosaicism is a rare chromosome disorder characterized by having an extra copy of chromosome 2 in a proportion, but not all, of a person’s cells. Many cases of trisomy 2 mosaicism result in miscarriage during pregnancy. In infants born with trisomy 2 mosaicism, severity as well as signs and symptoms vary widely. Features of trisomy 2 mosaicism may include intrauterine growth restriction (IUGR), any of various birth defects, distinctive facial features, growth delay, developmental delays, and intellectual disabilities. However, children with trisomy 2 mosaicism with no significant medical problems have been reported (although long-term follow-up was not available). The severity and specific symptoms present generally depend on the level of mosaicism (the proportion of cells affected) and the location or type of affected cells in the body. Trisomy 2 mosaicism is not inherited. It is caused by a random error in cell division during early development of the embryo. When trisomy 2 mosaicism is detected during early pregnancy with chorionic villus sampling (CVS), the affected cells may be confined only to the placenta, and not present in the fetus. Amniocentesis is typically recommended to confirm this, and monitoring is still warranted due to an increased risk for intrauterine growth restriction, low amniotic fluid level (oligohydramnios), or other complications including stillbirth. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Trisomy 2 mosaicism	c4707010	8,701	gard	https://rarediseases.info.nih.gov/diseases/5331/trisomy-2-mosaicism	2021-01-18T17:57:17	{"orphanet": ["1723"], "synonyms": ["Mosaic trisomy 2", "Mosaic trisomy chromosome 2", "Trisomy 2 mosaicism"]}
Hemoglobin D disease(HbD) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin D, with no or mild clinical manifestations (splenomegaly, very mild 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hemoglobin D disease	c0272080	8,702	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90039	2021-01-23T18:19:10	{"umls": ["C0272080"], "icd-10": ["D58.2"]}
Cancer associated with asbestos Mesothelioma Other namesMalignant mesothelioma CT scan showing a left sided mesothelioma with an enlarged mediastinal lymph node SpecialtyOncology SymptomsShortness of breath, swollen abdomen, chest wall pain, cough, feeling tired, weight loss[1] ComplicationsFluid around the lung[1] Usual onsetGradual onset[2] Causes~ 40 years after exposure to asbestos[3] Risk factorsGenetics, infection with simian virus 40[3] Diagnostic methodMedical imaging, examining fluid produced by the cancer, tissue biopsy[2] PreventionDecreased asbestos exposure[4] TreatmentSurgery, radiation therapy, chemotherapy, pleurodesis[5] PrognosisFive year survival ~8% (US)[6] Frequency60,800 (affected during 2015)[7] Deaths32,400 (2015)[8] Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium).[9] The most common area affected is the lining of the lungs and chest wall.[1][3] Less commonly the lining of the abdomen and rarely the sac surrounding the heart,[10] or the sac surrounding the testis may be affected.[1][11] Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss.[1] These symptoms typically come on slowly.[2] More than 80% of mesothelioma cases are caused by exposure to asbestos.[3] The greater the exposure the greater the risk.[3] As of 2013, about 125 million people worldwide have been exposed to asbestos at work.[12] High rates of disease occur in people who mine asbestos, produce products from asbestos, work with asbestos products, live with asbestos workers, or work in buildings containing asbestos.[3] Asbestos exposure and the onset of cancer are generally separated by about 40 years.[3] Washing the clothing of someone who worked with asbestos also increases the risk.[12] Other risk factors include genetics and infection with the simian virus 40.[3] The diagnosis may be suspected based on chest X-ray and CT scan findings, and is confirmed by either examining fluid produced by the cancer or by a tissue biopsy of the cancer.[2] Prevention centers around reducing exposure to asbestos.[4] Treatment often includes surgery, radiation therapy, and chemotherapy.[5] A procedure known as pleurodesis, which involves using substances such as talc to scar together the pleura, may be used to prevent more fluid from building up around the lungs.[5] Chemotherapy often includes the medications cisplatin and pemetrexed.[2] The percentage of people that survive five years following diagnosis is on average 8% in the United States.[6] In 2015, about 60,800 people had mesothelioma, and 32,000 died from the disease.[7][8] Rates of mesothelioma vary in different areas of the world.[3] Rates are higher in Australia, the United Kingdom, and lower in Japan.[3] It occurs in about 3,000 people per year in the United States.[13] It occurs more often in males than females.[3] Rates of disease have increased since the 1950s.[3] Diagnosis typically occurs after the age of 65 and most deaths occur around 70 years old.[3] The disease was rare before the commercial use of asbestos.[3] ## Contents * 1 Signs and symptoms * 1.1 Lungs * 1.2 Abdomen * 1.3 Heart * 1.4 End stage * 2 Causes * 2.1 Asbestos * 2.1.1 Occupational * 2.1.2 Paraoccupational secondary exposure * 2.1.3 Asbestos in buildings * 2.2 Genetic disposition * 2.3 Erionite * 2.4 Other * 3 Pathophysiology * 3.1 Systemic * 3.2 Intracellular * 3.3 Immune system * 4 Diagnosis * 4.1 Imaging * 4.2 Biopsy * 4.3 Immunochemistry * 4.4 Subtypes * 4.5 Differential diagnosis * 4.6 Staging * 5 Prevention * 6 Screening * 7 Treatment * 7.1 Surgery * 7.2 Radiation * 7.3 Chemotherapy * 7.4 Immunotherapy * 7.5 Hyperthermic intrathoracic chemotherapy * 7.6 Multimodality therapy * 8 Prognosis * 9 Epidemiology * 9.1 UK * 10 History * 11 Society and culture * 11.1 Notable cases * 11.2 Legal issues * 11.2.1 History * 12 Research * 13 References * 14 External links ## Signs and symptoms[edit] ### Lungs[edit] Symptoms or signs of mesothelioma may not appear until 20 to 50 years (or more) after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma.[14] Mesothelioma that affects the pleura can cause these signs and symptoms:[14] * Chest wall pain * Pleural effusion, or fluid surrounding the lung * Shortness of breath - which could be due to a collapsed lung * Fatigue or anemia * Wheezing, hoarseness, or a cough * Blood in the sputum (fluid) coughed up (hemoptysis) In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread to other parts of the body. ### Abdomen[edit] The most common symptoms of peritoneal mesothelioma are abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other features may include weight loss, fever, night sweats, poor appetite, vomiting, constipation, and umbilical hernia.[15] If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.[citation needed] These symptoms may be caused by mesothelioma or by other, less serious conditions. Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:[citation needed] * Abdominal pain * Ascites, or an abnormal buildup of fluid in the abdomen * A mass in the abdomen * Problems with bowel function * Weight loss ### Heart[edit] Pericardial mesothelioma is not well characterized, but observed cases have included cardiac symptoms, specifically constrictive pericarditis, heart failure, pulmonary embolism, and cardiac tamponade. They have also included nonspecific symptoms, including substernal chest pain, orthopnea (shortness of breath when lying flat), and cough. These symptoms are caused by the tumor encasing or infiltrating the heart.[10] ### End stage[edit] In severe cases of the disease, the following signs and symptoms may be present:[7] * Blood clots in the veins, which may cause thrombophlebitis * Disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs * Jaundice, or yellowing of the eyes and skin * Low blood sugar * Pleural effusion * Pulmonary embolism, or blood clots in the arteries of the lungs * Severe ascites If a mesothelioma forms metastases, these most commonly involve the liver, adrenal gland, kidney, or other lung.[16] ## Causes[edit] Working with asbestos is the most common risk factor for mesothelioma.[17] However, mesothelioma has been reported in some individuals without any known exposure to asbestos. Tentative evidence also raises concern about carbon-fibre nanotubes.[18][19] ### Asbestos[edit] The incidence of mesothelioma has been found to be higher in populations living near naturally occurring asbestos. People can be exposed to naturally occurring asbestos in areas where mining or road construction is occurring, or when the asbestos-containing rock is naturally weathered. Another common route of exposure is through asbestos-containing soil, which is used to whitewash, plaster, and roof houses in Greece.[12] In central Cappadocia, Turkey, mesothelioma was causing 50% of all deaths in three small villages—Tuzköy, Karain, and Sarıhıdır. Initially, this was attributed to erionite. Environmental exposure to asbestos has caused mesothelioma in places other than Turkey, including Corsica, Greece, Cyprus, China, and California.[12][20][21] In the northern Greek mountain town of Metsovo, this exposure had resulted in mesothelioma incidence around 300 times more than expected in asbestos-free populations, and was associated with very frequent pleural calcification known as Metsovo lung.[22][23] The documented presence of asbestos fibers in water supplies and food products has fostered concerns about the possible impact of long-term and, as yet, unknown exposure of the general population to these fibers.[24] Exposure to talc is also a risk factor for mesothelioma; exposure can affect those who live near talc mines, work in talc mines, or work in talc mills.[25] In the United States, asbestos is considered the major cause of malignant mesothelioma[26] and has been considered "indisputably"[27] associated with the development of mesothelioma. Indeed, the relationship between asbestos and mesothelioma is so strong that many consider mesothelioma a "signal" or "sentinel" tumor.[28][29][30][31] A history of asbestos exposure exists in most cases. Pericardial mesothelioma may not be associated with asbestos exposure.[10] Asbestos was known in antiquity, but it was not mined and widely used commercially until the late 19th century. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not publicly known. However, an increased risk of developing mesothelioma was later found among naval personnel (e.g., Navy, Marine Corps, and Coast Guard), shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the official position of the U.S. Occupational Safety and Health Administration (OSHA) and the U.S. EPA is that protections and "permissible exposure limits" required by U.S. regulations, while adequate to prevent most asbestos-related non-malignant disease, are not adequate to prevent or protect against asbestos-related cancers such as mesothelioma.[32] Likewise, the British Government's Health and Safety Executive (HSE) states formally that any threshold for exposure to asbestos must be at a very low level and it is widely agreed that if any such threshold does exist at all, then it cannot currently be quantified. For practical purposes, therefore, HSE assumes that no such "safe" threshold exists. Others have noted as well that there is no evidence of a threshold level below which there is no risk of mesothelioma.[33] There appears to be a linear, dose–response relationship, with increasing dose producing increasing risk of disease.[34] Nevertheless, mesothelioma may be related to brief, low level or indirect exposures to asbestos.[27] The dose necessary for effect appears to be lower for asbestos-induced mesothelioma than for pulmonary asbestosis or lung cancer.[27] Again, there is no known safe level of exposure to asbestos as it relates to increased risk of mesothelioma. The time from first exposure to onset of the disease, is between 25 and 70 years.[35] It is virtually never less than fifteen years and peaks at 30–40 years.[27][36] The duration of exposure to asbestos causing mesothelioma can be short. For example, cases of mesothelioma have been documented with only 1–3 months of exposure.[37][38] #### Occupational[edit] Exposure to asbestos fibers has been recognized as an occupational health hazard since the early 20th century. Numerous epidemiological studies have associated occupational exposure to asbestos with the development of pleural plaques, diffuse pleural thickening, asbestosis, carcinoma of the lung and larynx, gastrointestinal tumors, and diffuse malignant mesothelioma of the pleura and peritoneum. Asbestos has been widely used in many industrial products, including cement, brake linings, gaskets, roof shingles, flooring products, textiles, and insulation.[39] Commercial asbestos mining at Wittenoom, Western Australia, took place from 1937 to 1966. The first case of mesothelioma in the town occurred in 1960. The second case was in 1969, and new cases began to appear more frequently thereafter. The lag time between initial exposure to asbestos and the development of mesothelioma varied from 12 years 9 months up to 58 years.[40] A cohort study of miners employed at the mine reported that 85 deaths attributable to mesothelioma had occurred by 1985. By 1994, 539 reported deaths due to mesothelioma had been reported in Western Australia.[citation needed] Occupational exposure to asbestos in the United States mainly occurs when people are maintaining buildings that already have asbestos. Approximately 1.3 million US workers are exposed to asbestos annually; in 2002, an estimated 44,000 miners were potentially exposed to asbestos.[25] #### Paraoccupational secondary exposure[edit] Family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos-related diseases.[11][41][42] This risk may be the result of exposure to asbestos dust brought home on the clothing and hair of asbestos workers via washing a worker's clothes or coming into contact with asbestos-contaminated work clothing.[12][25] To reduce the chance of exposing family members to asbestos fibres, asbestos workers are usually required to shower and change their clothing before leaving the workplace.[citation needed] #### Asbestos in buildings[edit] Many building materials used in both public and domestic premises prior to the banning of asbestos may contain asbestos. Those performing renovation works or DIY activities may expose themselves to asbestos dust. In the UK, use of chrysotile asbestos was banned at the end of 1999. Brown and blue asbestos were banned in the UK around 1985. Buildings built or renovated prior to these dates may contain asbestos materials.[citation needed] ### Genetic disposition[edit] In a recent research carried on white American population in 2012, it was found that people with a germline mutation in their BAP1 gene are at higher risk of developing mesothelioma and uveal melanoma.[43] ### Erionite[edit] Erionite is a zeolite mineral with similar properties to asbestos and is known to cause mesothelioma.[11] Detailed epidemiological investigation has shown that erionite causes mesothelioma mostly in families with a genetic predisposition.[12][20][21] Erionite is found in deposits in the Western United States, where it is used in gravel for road surfacing, and in Turkey, where it is used to construct homes. In Turkey, the United States, and Mexico, erionite has been associated with mesothelioma and has thus been designated a "known human carcinogen" by the US National Toxicology Program.[21] ### Other[edit] In rare cases, mesothelioma has also been associated with irradiation of the chest or abdomen, intrapleural thorium dioxide (thorotrast) as a contrast medium, and inhalation of other fibrous silicates, such as erionite or talc.[11][25] Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma.[25] This has been confirmed in animal studies,[44][45] but studies in humans are inconclusive.[44][46][47] ## Pathophysiology[edit] Diffuse pleural mesothelioma with extensive involvement of the pericardium. ### Systemic[edit] The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.[citation needed] Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers).[27] However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System.[48] Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localized lesions of accumulated asbestos fibers in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor.[citation needed] Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities (see next-but-one paragraph). However, complete in vitro transformation of normal human mesothelial cells to a malignant phenotype following exposure to asbestos fibers has not yet been achieved. In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.[citation needed] ### Intracellular[edit] Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.[citation needed] Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:[citation needed] * Neurofibromatosis type 2 at 22q12 * P16INK4A[49] * P14ARF Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:[citation needed] * Inactivation of tumor suppressor genes * Activation of oncogenes * Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region * Activation of DNA repair enzymes, which may be prone to error * Activation of telomerase * Prevention of apoptosis Several genes are commonly mutated in mesothelioma, and may be prognostic factors. These include epidermal growth factor receptor (EGFR) and C-Met, receptor tyrosine kinases which are overexpressed in many mesotheliomas. Some association has been found with EGFR and epithelioid histology but no clear association has been found between EGFR overexpression and overall survival. Expression of AXL receptor tyrosine kinase is a negative prognostic factor. Expression of PDGFRB is a positive prognostic factor.[50] In general, mesothelioma is characterized by loss of function in tumor suppressor genes, rather than by an overexpression or gain of function in oncogenes.[51] As an environmentally triggered malignancy, mesothelioma tumors have been found to be polyclonal in origin, by performing an X-inactivation based assay on epitheloid and biphasic tumors obtained from female patients.[52] These results suggest that an environmental factor, most likely asbestos exposure, may damage and transform a group of cells in the tissue, resulting in a population of tumor cells that are, albeit only slightly, genetically different.[53] ### Immune system[edit] Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic (chromosome-breaking) and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.[citation needed] Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.[citation needed] ## Diagnosis[edit] CXR demonstrating a mesothelioma CT scan of a patient with mesothelioma, coronal section (the section follows the plane that divides the body in a front and a back half). The mesothelioma is indicated by yellow arrows, the central pleural effusion (fluid collection) is marked with a yellow star. Red numbers: (1) right lung, (2) spine, (3) left lung, (4) ribs, (5) descending part of the aorta, (6) spleen, (7) left kidney, (8) right kidney, (9) liver. Micrograph of a pleural fluid cytopathology specimen showing mesothelioma. Diagnosis of mesothelioma can be suspected with imaging but is confirmed with biopsy. It must be clinically and histologically differentiated from other pleural and pulmonary malignancies, including reactive pleural disease, primary lung carcinoma, pleural metastases of other cancers, and other primary pleural cancers.[11] Primary pericardial mesothelioma is often diagnosed after it has metastasized to lymph nodes or the lungs.[10] Micrographs showing conventionally-stained mesothelioma in a core biopsy (higher magnifications on right). ### Imaging[edit] Diagnosing mesothelioma is often difficult because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma.[14] A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe.[10] For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g., tuberculosis, heart failure).[citation needed] However, with primary pericardial mesothelioma, pericardial fluid may not contain malignant cells and a tissue biopsy is more useful in diagnosis.[10] Using conventional cytology diagnosis of malignant mesothelioma is difficult, but immunohistochemistry has greatly enhanced the accuracy of cytology.[citation needed] ### Biopsy[edit] Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. Alternatively, the chest surgeon might directly open the chest (thoracotomy). If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, an open surgical procedure may be necessary.[citation needed] ### Immunochemistry[edit] Immunohistochemical studies play an important role for the pathologist in differentiating malignant mesothelioma from neoplastic mimics, such as breast or lung cancer that has metastasized to the pleura. There are numerous tests and panels available, but no single test is perfect for distinguishing mesothelioma from carcinoma or even benign versus malignant. The positive markers indicate that mesothelioma is present; if other markers are positive it may indicate another type of cancer, such as breast or lung adenocarcinoma. Calretinin is a particularly important marker in distinguishing mesothelioma from metastatic breast or lung cancer.[11] Typical immunohistochemistry results Positive Negative EMA (epithelial membrane antigen) in a membranous distribution CEA (carcinoembryonic antigen)[11] WT1 (Wilms' tumour 1)[11] B72.3 Calretinin[11] MOC-3 1 Mesothelin[11] CD15 Cytokeratin 5[11] Ber-EP4 HBME-1 (human mesothelial cell 1) TTF-1 (thyroid transcription factor-1)[11] Podoplanin (PDPN)[11] Claudin-4[11] Osteopontin[11] Epithelial cell adhesion molecule (EpCAM)[11] Estrogen receptor alpha[11] Mammaglobin[11] ### Subtypes[edit] There are three main histological subtypes of malignant mesothelioma: epithelioid, sarcomatous, and biphasic. Epithelioid and biphasic mesothelioma make up approximately 75-95% of mesotheliomas and have been well characterized histologically, whereas sarcomatous mesothelioma has not been studied extensively. Most mesotheliomas express high levels of cytokeratin 5 regardless of subtype.[11] Epithelioid mesothelioma is characterized by high levels of calretinin.[11] Sarcomatous mesothelioma does not express high levels of calretinin.[11] Other morphological subtypes have been described: * Desmoplastic * Clear cell * Deciduoid * Adenomatoid * Glandular * Mucohyaline * Cartilaginous and osseous metaplasia * Lymphohistiocytic ### Differential diagnosis[edit] * Metastatic adenocarcinoma * Pleural sarcoma * Synovial sarcoma * Thymoma * Metastatic clear cell renal cell carcinoma * Metastatic osteosarcoma ### Staging[edit] Staging of mesothelioma is based on the recommendation by the International Mesothelioma Interest Group.[54] TNM classification of the primary tumor, lymph node involvement, and distant metastasis is performed. Mesothelioma is staged Ia–IV (one-A to four) based on the TNM status.[54][55] ## Prevention[edit] Mesothelioma can be prevented in most cases by preventing exposure to asbestos. The US National Institute for Occupational Safety and Health maintains a recommended exposure limit of 0.1 asbestos fiber per cubic centimeter.[25] ## Screening[edit] There is no universally agreed protocol for screening people who have been exposed to asbestos. Screening tests might diagnose mesothelioma earlier than conventional methods thus improving the survival prospects for patients. The serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening.[56] Doctors have begun testing the Mesomark assay, which measures levels of soluble mesothelin-related proteins (SMRPs) released by mesothelioma cells.[57] ## Treatment[edit] Mesothelioma is generally resistant to radiation and chemotherapy treatment.[58] Long-term survival and cures are exceedingly rare.[11] Treatment of malignant mesothelioma at earlier stages has a better prognosis. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease. The histological subtype and the patient's age and health status also help predict prognosis. The epithelioid histology responds better to treatment and has a survival advantage over sarcomatoid histology.[59] The effectiveness of radiotherapy compared to chemotherapy or surgery for malignant pleural mesothelioma is not known.[60] ### Surgery[edit] Surgery, by itself, has proved disappointing. In one large series, the median survival with surgery (including extrapleural pneumonectomy) was only 11.7 months.[61] However, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008), or with one of the latter. A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.[citation needed] In localized pericardial mesothelioma, pericardectomy can be curative; when the tumor has metastasized, pericardectomy is a palliative care option. It is often not possible to remove the entire tumor.[10] ### Radiation[edit] For patients with localized disease, and who can tolerate a radical surgery, radiation can be given post-operatively as a consolidative treatment. The entire hemithorax is treated with radiation therapy, often given simultaneously with chemotherapy. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations. It can also induce severe side-effects, including fatal pneumonitis.[62] As part of a curative approach to mesothelioma, radiotherapy is commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.[citation needed] Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy, when given alone with curative intent, has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be beyond human tolerance.[citation needed] Radiotherapy is of some use in pericardial mesothelioma.[10] ### Chemotherapy[edit] Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomised and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name Alimta) chemotherapy in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive "curative" surgery.[63] This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the group of patients treated with cisplatin in the combination with pemetrexed and who also received supplementation with folate and vitamin B12. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B12 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhoea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration (FDA) approved pemetrexed for treatment of malignant pleural mesothelioma.[64] However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give.[citation needed] Cisplatin and pemetrexed together give patients a median survival of 12.1 months.[11] Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted but non-randomised data have shown lower response rates and high rates of haematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin.[65] Cisplatin in combination with premetrexed disodium, folic acid, and vitamin B12 may also improve survival for people who are responding to chemotherapy.[66] In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma after research conducted by a nationwide study by Duke University concluded an almost 50 point increase in remission rates.[citation needed] In pericardial mesothelioma, chemotherapy - typically adriamycin or cisplatin - is primarily used to shrink the tumor and is not curative.[10] In October 2020, the FDA approved the combination of nivolumab (Opdivo) with ipilimumab (Yervoy) for the first-line treatment of adults with malignant pleural mesothelioma (MPM) that cannot be removed by surgery.[64] Nivolumab and ipilimumab are both monoclonal antibodies that, when combined, decrease tumor growth by enhancing T-cell function.[64] The combination therapy was evaluated through a randomized, open-label trial in which participants who received nivolumab in combination with ipilimumab survived a median of 18.1 months while participants who underwent chemotherapy survived a median of 14.1 months.[64] ### Immunotherapy[edit] Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.[citation needed] ### Hyperthermic intrathoracic chemotherapy[edit] Hyperthermic intrathoracic chemotherapy is used in conjunction with surgery,[67] including in patients with malignant pleural mesothelioma.[68] The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48 °C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained. High concentrations of selected drugs are then administered into the pleural cavity. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.[citation needed] ### Multimodality therapy[edit] Multimodal therapy, which includes a combined approach of surgery, radiation or photodynamic therapy, and chemotherapy, is not suggested for routine practice for treating malignant pleural mesothelioma.[69] The effectiveness and safety of multimodal therapy is not clear (not enough research has been performed) and one clinical trial has suggested a possible increased risk of adverse effects.[69] Large series of examining multimodality treatment have only demonstrated modest improvement in survival (median survival 14.5 months and only 29.6% surviving 2 years).[61] Reducing the bulk of the tumor with cytoreductive surgery is key to extending survival. Two surgeries have been developed: extrapleural pneumonectomy and pleurectomy/decortication. The indications for performing these operations are unique. The choice of operation namely depends on the size of the patient's tumor. This is an important consideration because tumor volume has been identified as a prognostic factor in mesothelioma.[70] Pleurectomy/decortication spares the underlying lung and is performed in patients with early stage disease when the intention is to remove all gross visible tumor (macroscopic complete resection), not simply palliation.[71] Extrapleural pneumonectomy is a more extensive operation that involves resection of the parietal and visceral pleurae, underlying lung, ipsilateral (same side) diaphragm, and ipsilateral pericardium. This operation is indicated for a subset of patients with more advanced tumors, who can tolerate a pneumonectomy.[72] ## Prognosis[edit] Mesothelioma often has a poor prognosis. Typical survival despite surgery is between 12 and 21 months depending on the stage of disease at diagnosis with about 7.5% of people surviving for 5 years.[73] Women, young people, people with low-stage cancers, and people with epithelioid cancers have better prognoses.[11] Negative prognostic factors include sarcomatoid or biphasic histology, high platelet counts (above 400,000), age over 50 years, white blood cell counts above 15.5, low glucose levels in the pleural fluid, low albumin levels, and high fibrinogen levels. Several markers are under investigation as prognostic factors, including nuclear grade, and serum c-reactive protein. Long-term survival is rare.[50] Pericardial mesothelioma has a 10-month median survival time.[10] In peritoneal mesothelioma, high expression of WT-1 protein indicates a worse prognosis.[11] ## Epidemiology[edit] Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. The incidence rate varies from one country to another, from a low rate of less than 1 per 1,000,000 in Tunisia and Morocco, to the highest rate in Britain, Australia and Belgium: 30 per 1,000,000 per year.[74] For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1,000 per 1,000,000. Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades.[75] Worldwide incidence is estimated at 1-6 per 1,000,000.[11] Incidence of mesothelioma lags behind that of asbestosis due to the longer time it takes to develop; due to the cessation of asbestos use in developed countries, mesothelioma incidence is expected to decrease.[25] Incidence is expected to continue increasing in developing countries due to continuing use of asbestos.[11] Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age. Approximately one fifth to one third of all mesotheliomas are peritoneal.[citation needed] Less than 5% of mesotheliomas are pericardial. The prevalence of pericardial mesothelioma is less than 0.002%; it is more common in men than women. It typically occurs in a person's 50s-70s.[10][76] Between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States.[77] Between 1973 and 1984, the incidence of pleural mesothelioma among Caucasian males increased 300%. From 1980 to the late 1990s, the death rate from mesothelioma in the USA increased from 2,000 per year to 3,000, with men four times more likely to acquire it than women.[citation needed] More than 80% of mesotheliomas are caused by asbestos exposure.[11] The incidence of peritoneal mesothelioma is 0.5–3.0 per million per year in men, and 0.2–2.0 per million per year in women.[78] ### UK[edit] Mesothelioma accounts for less than 1% of all cancers diagnosed in the UK, (around 2,600 people were diagnosed with the disease in 2011), and it is the seventeenth most common cause of cancer death (around 2,400 people died in 2012).[79] ## History[edit] The connection between asbestos exposure and mesothelioma was discovered in the 1970s. In the United States, asbestos manufacture stopped in 2002. Asbestos exposure thus shifted from workers in asbestos textile mills, friction product manufacturing, cement pipe fabrication, and insulation manufacture and installation to maintenance workers in asbestos-containing buildings.[25] ## Society and culture[edit] ### Notable cases[edit] Mesothelioma, though rare, has had a number of notable patients: * Malcolm McLaren, musician and manager of the punk rock band the Sex Pistols, was diagnosed with peritoneal mesothelioma in October 2009 and died on 8 April 2010 in Switzerland.[80] * Steve McQueen, American actor, was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced. McQueen subsequently sought alternative treatments at clinics in Mexico. He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery. He may have been exposed to asbestos while serving with the U.S. Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or from its use as an insulating material in automobile racing suits (McQueen was an avid racing driver and fan).[81] * Mickie Most, record producer, died of peritoneal mesothelioma in May 2003; however, it has been questioned whether this was due to asbestos exposure.[82] * Warren Zevon, American musician, was diagnosed with pleural mesothelioma in 2002, and died roughly a year later. It is believed that this was caused through childhood exposure to asbestos insulation in the attic of his father's shop.[83] * David Martin, Australian sailor and politician, died on 10 August 1990 of pleural mesothelioma. It is believed that this was caused by his exposure to asbestos on military ships during his career in the Royal Australian Navy.[84] * Paul Kraus, diagnosed in 1997, is considered the longest currently living (as of 2017) mesothelioma survivor in the world.[85] Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould, a well-regarded paleontologist, was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote "The Median Isn't the Message",[86] in which he argued that statistics such as median survival are useful abstractions, not destiny. Gould lived for another 20 years, eventually succumbing to cancer not linked to his mesothelioma. ### Legal issues[edit] Main article: Asbestos and the law Some people who were exposed to asbestos have collected damages for an asbestos-related disease, including mesothelioma. Compensation via asbestos funds or class action lawsuits is an important issue in law practices regarding mesothelioma.[citation needed] The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars.[87] The amounts and method of allocating compensation have been the source of many court cases, reaching up to the United States Supreme Court, and government attempts at resolution of existing and future cases. However, to date, the US Congress has not stepped in and there are no federal laws governing asbestos compensation.[88] In 2013, the "Furthering Asbestos Claim Transparency (FACT) Act of 2013" passed the US House of representatives and was sent to the US Senate, where it was referred to the Senate Judiciary Committee.[89] As the Senate did not vote on it before the end of the 113th Congress, it died in committee. It was revived in the 114th Congress, where it has not yet been brought before the House for a vote.[90] #### History[edit] The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. In 1960, an article published by Wagner et al. was seminal in establishing mesothelioma as a disease arising from exposure to asbestos.[91] The article referred to over 30 case studies of people who had suffered from mesothelioma in South Africa. Some exposures were transient and some were mine workers. Before the use of advanced microscopy techniques, malignant mesothelioma was often diagnosed as a variant form of lung cancer.[92] In 1962, McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker.[93] The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.[citation needed] In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds. In 1965, an article in the British Journal of Industrial Medicine established that people who lived in the neighbourhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.[citation needed] Despite proof that the dust associated with asbestos mining and milling causes asbestos-related disease, mining began at Wittenoom in 1943 and continued until 1966. In 1974, the first public warnings of the dangers of blue asbestos were published in a cover story called "Is this Killer in Your Home?" in Australia's Bulletin magazine. In 1978, the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, "The Health Hazard at Wittenoom", containing the results of air sampling and an appraisal of worldwide medical information.[citation needed] By 1979, the first writs for negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.[citation needed] In Leeds, England the Armley asbestos disaster involved several court cases against Turner & Newall where local residents who contracted mesothelioma demanded compensation because of the asbestos pollution from the company's factory. One notable case was that of June Hancock, who contracted the disease in 1993 and died in 1997.[94] ## Research[edit] See also: Mesothelioma Applied Research Foundation The WT-1 protein is overexpressed in mesothelioma and is being researched as a potential target for drugs.[11] There are two high-confidence miRNAs that can potentially serve as biomarkers of asbestos exposure and malignant mesothelioma. Validation studies are needed to assess their relevance.[citation needed] ## References[edit] 1. ^ a b c d e "Malignant Mesothelioma Treatment–Patient Version (PDQ®)". NCI. September 4, 2015. Archived from the original on 5 April 2016. Retrieved 3 April 2016. 2. ^ a b c d e Kondola, S; Manners, D; Nowak, AK (12 February 2016). "Malignant pleural mesothelioma: an update on diagnosis and treatment options". Therapeutic Advances in Respiratory Disease. 10 (3): 275–88. doi:10.1177/1753465816628800. PMC 5933604. PMID 26873306. 3. ^ a b c d e f g h i j k l m n Robinson, BM (November 2012). 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This article includes information from a public domain U.S. National Cancer Institute fact sheet. ## External links[edit] Wikinews has news related to: Asbestos Wikibooks has a book on the topic of: Radiation Oncology/Lung/Mesothelioma * Mesothelioma at Curlie Classification D * ICD-10: C45 * ICD-9-CM: 163 * ICD-O: M9050/3-9055 * OMIM: 156240 * MeSH: D008654 * DiseasesDB: 8074 External resources * MedlinePlus: 000115 * eMedicine: med/1457 * 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 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claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Mesothelioma	c0025500	8,703	wikipedia	https://en.wikipedia.org/wiki/Mesothelioma	2021-01-18T18:51:47	{"gard": ["7026"], "mesh": ["D008654"], "umls": ["C0025500"], "wikidata": ["Q1077603"]}
## Clinical Features Hegab and Al-Mutawa (1996) reported a large Jordanian family in which 2 sisters married to cousins had a total of 3 children (1 male and 2 females) with congenital alacrima (but no achalasia). The lacrimal glands were present, the lacrimal puncta were patent and apparently normal, but no tear production could be elicited with tensilon or neostigmine. Inheritance Autosomal recessive inheritance of isolated congenital alacrima was proposed in the family reported by Hegab and Al-Mutawa (1996). See 103420 for an autosomal dominant form of congenital alacrima. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Punctate corneal epithelial erosions \- Photophobia \- Alacrima - hypolacrimation, severe \- Normal lacrimal puncta ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	ALACRIMA, CONGENITAL, AUTOSOMAL RECESSIVE	c1863199	8,704	omim	https://www.omim.org/entry/601549	2019-09-22T16:14:37	{"mesh": ["C566307"], "omim": ["601549"], "orphanet": ["91416"]}
A number sign (#) is used with this entry because of evidence that psychomotor retardation, epilepsy, and craniofacial dysmorphism (PMRED) is caused by homozygous mutation in the SNIP1 gene (608241) on chromosome 1p34. Clinical Features Puffenberger et al. (2012) reported 3 Amish patients, including 2 brothers, with severe psychomotor retardation, intractable seizures, dysmorphic features, and a 'lumpy' skull surface. Patients were hypotonic and had poor feeding in the neonatal period. They had severe developmental delay with an inability to speak or walk independently. All developed focal or generalized intractable seizures by age 6 months associated with multifocal spike-wave discharges on EEG. Seizures were manifest as dystonic posturing, drop attacks, myoclonic jerks, or generalized tonic-clonic events. Dysmorphic features evolved over time and included a bulbous nose, wide mouth and tongue, broad jaw, short hands, short tapered fingers, and broad thumbs. Other features included hypotonia, strabismus, slow horizontal nystagmus, and weak or absent tendon reflexes. Brain MRI showed ventriculomegaly, thin corpus callosum, white matter abnormalities, and an undulating or 'lumpy' skull surface. The cortical ribbon followed the irregular skull contour. Other variable physical anomalies included subglottic stenosis, aortic stenosis, bicuspid aortic valve, umbilical hernia, and hydrocele. Inheritance The transmission pattern of psychomotor retardation, epilepsy, and craniofacial dysmorphism in the Amish families reported by Puffenberger et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics By homozygosity mapping followed by exome sequencing of Amish patients with severe psychomotor retardation, intractable seizures, and craniofacial dysmorphism, Puffenberger et al. (2012) identified a homozygous mutation in the SNIP1 gene (608241.0001). Six heterozygous carriers of this mutation were found among 203 Old Order Amish controls, yielding a population-specific allele frequency of 1.48%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Broad jaw Eyes \- Strabismus \- Horizontal nystagmus Nose \- Bulbous nose Mouth \- Wide mouth \- Large tongue CARDIOVASCULAR Heart \- Aortic stenosis (variable) \- Bicuspid aortic valve (variable) RESPIRATORY Larynx \- Subglottic stenosis (variable) ABDOMEN External Features \- Umbilical hernia Gastrointestinal \- Poor feeding (neonatal period) SKELETAL Skull \- Lumpy skull surface Hands \- Short hands \- Short, tapered fingers \- Broad thumbs MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Lack of independent ambulation \- Lack of speech development \- Hyporeflexia \- Ventriculomegaly \- Thin corpus callosum \- Irregular cortical ribbon \- White matter abnormalities \- Hypomyelination \- Multifocal intractable seizures \- Abnormal EEG MISCELLANEOUS \- Three Amish patients have been reported (as of February 2012) MOLECULAR BASIS \- Caused by mutation in the SMAD nuclear interacting protein-1 gene (SNIP1, 608241.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	PSYCHOMOTOR RETARDATION, EPILEPSY, AND CRANIOFACIAL DYSMORPHISM	c3281055	8,705	omim	https://www.omim.org/entry/614501	2019-09-22T15:55:04	{"omim": ["614501"]}
Absence of tibia is a rare birth defect that is characterized by deficiency of the tibia (the shinbone) with other bones of the lower leg relatively intact. The condition may affect one or both legs. Some cases are isolated birth defects, while others are associated with a variety of skeletal and other malformations. It can also be a part of a recognized syndrome such as Werner's syndrome, tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome, and CHARGE syndrome. The underlying cause is generally unknown. Although most isolated cases occur sporadically in people with no family history of the condition, absence of the tibia can rarely affect more than one family member. Treatment varies based on the severity of the condition, but generally involves surgery (i.e. amputation or reconstructive surgery with a prosthesis adapted to growth). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Absence of Tibia	c0265633	8,706	gard	https://rarediseases.info.nih.gov/diseases/8707/absence-of-tibia	2021-01-18T18:02:23	{"mesh": ["C535563"], "omim": ["275220"], "orphanet": ["93322"], "synonyms": ["Bilateral absence of the tibia", "Tibial hemimelia", "Tibia, absence of"]}
A number sign (#) is used with this entry because of evidence that X-linked mental retardation-104 (MRX104) is caused by mutation in the FRMPD4 gene (300838) on chromosome Xp22. Clinical Features Hu et al. (2016) reported a large family (P58) in which 5 males had mild to severe intellectual disability with variable seizures, poor or absent speech, and behavioral problems. They also reported an unrelated patient (L87) who presented at age 17 years with significant developmental delay, absence of speech, and autism spectrum disorder. Piard et al. (2018) reported follow-up of the patients reported by Hu et al. (2016) and identified 4 additional male patients from 2 additional unrelated families. Including the previous report, there were 10 affected males from 4 unrelated families with patients ranging from 4 to 66 years of age. All patients had global developmental delay with variably impaired intellectual development. Acquisition of walking was mildly delayed (by 30 months at the latest), and speech was also delayed, although several patients were unable to speak in their teens. Some patients had behavioral abnormalities, including autism spectrum disorder, hyperactivity, and aggression. Less common neurologic findings included hypotonia, spasticity, hyperreflexia, ataxia, and tremor. Two brothers had ophthalmic findings, including strabismus, nystagmus, myopia, and optic atrophy with no eye contact (in 1 of them), and another unrelated boy had strabismus and no eye contact. One patient in the large previously reported family had onset of seizures at age 19 years, whereas 2 sibs in another family had onset of focal seizures in the first years of life. Brain imaging, performed in a few patients, showed nonspecific and variable abnormalities, such as thin corpus callosum, cortical atrophy, and delayed myelination. A few patients had dysmorphic features, such as high forehead, retrognathia, dysplastic ears, frontal hair upsweep, broad nasal bridge, high-arched palate, and mild hand anomalies, but there was no distinctive facial gestalt. In 1 family, a female mutation carrier was noted to be mildly affected. Inheritance The transmission pattern of MRX104 in the family reported by Hu et al. (2016) was consistent with X-linked recessive inheritance. Molecular Genetics In 5 affected males from a family (P58) with MRX104, Hu et al. (2016) identified a hemizygous truncating mutation in the FRMPD4 gene (300838.0001). An unrelated male patient (L87) with MRX104 was found to carry a de novo hemizygous missense mutation in the FRMPD4 gene (R415W; 300838.0002). The mutations were found by X-chromosome exome sequencing of 405 probands with X-linked intellectual disability. Functional studies of the variants were not performed. In affected members of 2 unrelated families with MRX104, Piard et al. (2018) identified hemizygous mutations in the FRMPD4 gene (300838.0003 and 300838.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Including the previous report (Hu et al., 2016), there was 1 frameshift mutation, 1 nonsense mutation, 1 deletion of a coding exon, and 1 missense mutation. Piard et al. (2018) noted that the frameshift mutation previously reported by Hu et al. (2016) (300838.0001) predicts a truncated protein that lacks the C-terminal HOMER binding domain and the PDZ binding domain. In vitro functional expression studies in HEK293 cells showed that the mutation disrupted FRMPD4 binding with PSD95 and HOMER1. When transfected into rat hippocampal cells, the mutated protein failed to increase spine density and caused abnormal spine morphology, consistent with a loss of function. Functional studies of the other variants and studies of patient cells were not performed. The authors speculated that FRMPD4 mutations likely also disrupt the proper assembly of the FRMPD4 protein complex that regulates certain glutamate receptors. Both mechanisms may contribute to cognitive dysfunction via a loss-of-function effect. Animal Model Piard et al. (2018) found that Frmpd4-null mice demonstrated deficits in hippocampal-based spatial learning and memory compared to controls. INHERITANCE \- X-linked HEAD & NECK Face \- Dysmorphic features, nonspecific (in some patients) \- High forehead \- Retrognathia Ears \- Dysplastic ears Eyes \- Ophthalmic abnormalities (in some patients) \- Nystagmus \- Strabismus \- Poor eye contact \- Optic atrophy Nose \- Broad nasal bridge Mouth \- High-arched palate SKIN, NAILS, & HAIR Hair \- Frontal upsweep NEUROLOGIC Central Nervous System \- Developmental delay \- Delayed walking, mild \- Intellectual disability \- Poor or absent speech \- Seizures (in some patients) \- Ataxia \- Tremor \- Spasticity \- Hyperreflexia \- Nonspecific brain imaging abnormalities \- Thin corpus callosum \- Delayed myelination \- Cortical atrophy Behavioral Psychiatric Manifestations \- Behavioral abnormalities \- Autistic features \- Aggression \- Hyperactivity MISCELLANEOUS \- Onset in infancy \- Variable features \- Carrier females may be mildly affected MOLECULAR BASIS \- Caused by mutation in the FERM and PDZ domains-containing protein 4 gene (FRMPD4, 300838.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	MENTAL RETARDATION, X-LINKED 104	c2931498	8,707	omim	https://www.omim.org/entry/300983	2019-09-22T16:19:02	{"mesh": ["C567906"], "omim": ["300983"], "orphanet": ["777"]}
A rare, genetic, primary bone dysplasia with increased bone density disorder characterized by bone abnormalities, including metaphyseal plaques, osteopathia striata, marked cranial sclerosis, and sclerosis of the ribs and long bones, as well as macrocephaly, cleft palate, hearing loss, developmental delay, and facial dysmorphism (hypertelorism, prominent forehead, wide nasal bridge). Hypotonia, tracheo-/laryngomalacia, and astigmatic myopia are also associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Mixed sclerosing bone dystrophy with extra-skeletal manifestations	None	8,708	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324364	2021-01-23T17:16:44	{"icd-10": ["M85.8"]}
For a phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). Clinical Features Levin and Surana (1991) described holoprosencephaly in association with an interstitial deletion of chromosome 14q11.1-q13. Parental karyotypes were normal. The white female, born to nonconsanguineous young parents after an uncomplicated pregnancy, showed hypotelorism, lack of nasal bridge, flattened nasal tip with no visible septum, wide midline cleft of lip and hard palate, and ptosis of the left upper eyelid. Axial CT scan of the head was interpreted as showing semilobar holoprosencephaly. The infant died at 8 days of age. Kamnasaran et al. (2005) reported 6 patients with HPE and interstitial deletions on proximal chromosome 14q: 1 had alobar HPE and 5 had lobar HPE. Other findings included microcephaly, cebocephaly, underdeveloped pituitary gland, hypothyroidism, micrognathia, depressed nasal bridge, iris coloboma, hypertelorism, midface hypoplasia, bilateral cleft lip, respiratory distress, congenital heart defects, and developmental delay. Cytogenetics Kamnasaran et al. (2005) reported 6 patients with HPE and interstitial deletions on proximal chromosome 14q, 5 of which were of paternal origin and 1 of maternal origin. Mapping Kamnasaran et al. (2005) defined a locus for holoprosencephaly (HPE8) on chromosome 14q13 between markers D14S49 and AFM205XG5, an estimated 2.82-Mb interval, by mapping deletion intervals of affected subjects with proximal chromosome 14q interstitial deletions. Using the deletion intervals of 2 patients with no HPE signs (under the assumption of complete penetrance), the critical region was reduced to an estimated 1.78-Mb interval between markers D14S49 and D14S1014. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	HOLOPROSENCEPHALY 8	c0079541	8,709	omim	https://www.omim.org/entry/609408	2019-09-22T16:06:04	{"doid": ["0110879"], "mesh": ["D016142"], "omim": ["609408"], "orphanet": ["2162"], "genereviews": ["NBK1530"]}
A number sign (#) is used with this entry because of evidence that susceptibility to attention deficit-hyperactivity disorder (ADHD) can be caused by mutation in the TPH2 gene (607478). For a phenotypic description and a discussion of genetic heterogeneity of attention deficit-hyperactivity disorder, see 143465. Clinical Features McKinney et al. (2008) reported a Norwegian woman with ADHD and a history of major depression. Her daughter also had ADHD. Both reported an excellent response to stimulant medication. Both patients had normal developmental histories. Mapping Walitza et al. (2005) investigated the effect of polymorphic variants in the TPH2 gene, which maps to chromosome 12q, in 225 children with ADHD in 103 families. Three SNPs in and downstream of the transcriptional control region were assessed using the pedigree disequilibrium test. Preferential transmissions were detected for 2 of the SNPs (rs4570625, p = 0.049; rs11178997, p = 0.034). Haplotype analysis revealed a trend of association between these 2 SNPs and ADHD (p = 0.064). Molecular Genetics In a Norwegian mother and daughter with ADHD, McKinney et al. (2008) identified a heterozygous mutation in the TPH2 gene (R303W; 143465.0002). In vitro functional expression studies showed that the mutant protein had less than 5% residual enzyme activity and decreased solubility, compatible with a folding defect or increased hydrophobicity of the mutant protein. McKinney et al. (2008) concluded that a loss-of-function TPH2 mutation leads to reduced serotonin synthesis, which may result in increased susceptibility to ADHD and possibly other psychiatric disorders. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	ATTENTION DEFICIT-HYPERACTIVITY DISORDER, SUSCEPTIBILITY TO, 7	c2751802	8,710	omim	https://www.omim.org/entry/613003	2019-09-22T16:00:06	{"omim": ["613003"], "synonyms": ["Alternative titles", "ADHD7"]}
Micrograph showing hypertrophic decidual vasculopathy, the histomorphologic correlate of gestational hypertension. H&E stain. In pathology, hypertrophic decidual vasculopathy, abbreviated HDV, is the histomorphologic correlate of gestational hypertension, as may be seen in intrauterine growth restriction (IUGR)[1] and HELLP syndrome. The name of the condition describes its appearance under the microscope; the smooth muscle of the decidual (or maternal) blood vessels is hypertrophic, i.e. the muscle part of the blood vessels feeding the placenta is larger due to cellular enlargement. ## Morphologic features[edit] The morphologic features of mild and moderate HDV include:[1] * Perivascular inflammatory cells, * +/-Vascular thrombosis, * Smooth muscle hypertrophy, and * Endothelial hyperplasia. Severe HDV is characterized by: * Atherosis - foamy macrophages within vascular wall, and * Fibrinoid necrosis of vessel wall (amorphous eosinophilic vessel wall). ## See also[edit] * Fetal thrombotic vasculopathy * Gestational diabetes * Placenta * Pregnancy ## References[edit] 1. ^ a b Roberts, DJ.; Post, MD. (Dec 2008). "The placenta in pre-eclampsia and intrauterine growth restriction". J Clin Pathol. 61 (12): 1254–60. doi:10.1136/jcp.2008.055236. PMID 18641412. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hypertrophic decidual vasculopathy	None	8,711	wikipedia	https://en.wikipedia.org/wiki/Hypertrophic_decidual_vasculopathy	2021-01-18T18:43:16	{"wikidata": ["Q12466983"]}
A number sign (#) is used with this entry because primary hyperoxaluria type III (HP3) is caused by homozygous or compound heterozygous mutation in the DHDPSL gene (613597) on chromosome 10q24. Description Primary hyperoxaluria is an autosomal recessive disorder of glyoxylate metabolism that results in excessive endogenous oxalate synthesis and the formation of calcium oxalate kidney stones. Progressive renal inflammation and interstitial fibrosis from advanced nephrocalcinosis, recurrent urolithiasis, and urinary tract infections can cause reduced renal function, systemic oxalate deposition, and end-stage renal failure. Compared to hyperoxaluria type I (HP1; 259900) and type II (HP2; 260000), HP3 appears to be the least severe, with good preservation of kidney function in most patients. The typical clinical characteristic is early onset of recurrent urolithiasis, but less active stone formation later (summary by Wang et al., 2015). For a discussion of genetic heterogeneity of primary hyperoxaluria, see HP1 (259900). Clinical Features Wang et al. (2015) reported a 27-month-old Chinese boy with primary hyperoxaluria type III. Age of onset was 10 months when he presented with bilateral renal calculi, multiple bladder stones, and upper ureteral calculi. Clinical features included early onset of nephrolithiasis, abnormal increase in urinary excretion levels of oxalate and calcium, and decreased level of citrate. At age 27 months, his renal function was normal. M'dimegh et al. (2017) identified 3 unrelated Tunisian patients, who ranged in age from 2 to 8 years, with primary hyperoxaluria type III. All 3 patients were born to consanguineous parents. The median age of onset of clinical symptoms was 3.93 years, with a range of 1.5 to 5.5 years. All patients had normal renal function at diagnosis. Two of the families had a positive family history for urolithiasis. All patients presented with urolithiasis, but only one had nephrocalcinosis. Urine crystal analysis, performed in 2 cases, revealed monohydrated calcium oxalate. One patient displayed impaired renal function at follow-up. Mapping Belostotsky et al. (2010) performed high-density SNP array analysis in 15 patients with non-HP1/non-HP2 calcium oxalate nephrolithiasis and 24 unaffected relatives from 8 unrelated families. Using a strategy of 'heterozygosity mapping' followed by reconstruction of haplotypes, they identified a 6.1-Mb critical region on chromosome 10 containing 19 genes. Molecular Genetics In affected members of 9 unrelated families with non-HP1/non-HP2 calcium oxalate nephrolithiasis mapping to chromosome 10, Belostotsky et al. (2010) analyzed the candidate gene DHDPSL and identified homozygosity or compound heterozygosity for 6 different mutations (613597.0001-613597.0006, respectively). The unaffected parents were all heterozygous for 1 of the mutations, respectively. In a 27-month-old Chinese boy with primary hyperoxaluria in whom mutations in the AGXT (604285) and GRHPR (604296) genes had been excluded, Wang et al. (2015) identified compound heterozygous mutations in the HOGA1 gene (613597.0007 and 613597.0008). The parents were each heterozygous for one of the mutations. In 3 unrelated boys, born to consanguineous Tunisian parents, with primary hyperoxaluria, who did not have mutations in the AGXT or GRHPR genes, M'dimegh et al. (2017) identified mutations in the HOGA1 gene: 2 boys were homozygous for a P190L and a G287V (613597.0002) mutation, respectively, and the other boy was heterozygous for the G287V mutation. Two of the families had a positive family history for recurrent urolithiasis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	HYPEROXALURIA, PRIMARY, TYPE III	c0020500	8,712	omim	https://www.omim.org/entry/613616	2019-09-22T15:58:06	{"doid": ["2977"], "mesh": ["D006959"], "omim": ["613616"], "orphanet": ["93600", "416"], "synonyms": [], "genereviews": ["NBK316514"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (December 2015) This article may be expanded with text translated from the corresponding article in French. (May 2012) Click [show] for important translation instructions. * View a machine-translated version of the French article. * Machine translation like DeepL or Google Translate is a useful starting point for translations, but translators must revise errors as necessary and confirm that the translation is accurate, rather than simply copy-pasting machine-translated text into the English Wikipedia. * Do not translate text that appears unreliable or low-quality. If possible, verify the text with references provided in the foreign-language article. * You must provide copyright attribution in the edit summary accompanying your translation by providing an interlanguage link to the source of your translation. A model attribution edit summary `Content in this edit is translated from the existing French Wikipedia article at [[:fr:Malnutrition au Tibet]]; see its history for attribution.` * You should also add the template `{{Translated\|fr\|Malnutrition au Tibet}}` to the talk page. * For more guidance, see Wikipedia:Translation. Malnutrition is an important health concern in Tibet. According to a study conducted in 1994/1995 in eleven districts of Tibet, malnutrition affected more than half of the children from 1–7 years old. The major cause was poverty.[1] ## See also[edit] * Health in China ## References[edit] 1. ^ Cesar Chelala (July 28, 2001). "Malnutrition plagues Tibet's children". Japan Times. Retrieved May 14, 2012. "QUOTE: "In 1996, the Western Consortium for Public Health, a private U.S.-based organization, said 60 percent of the children studied fell drastically below accepted international growth reference values and concluded that the height of Tibetan children was a matter of grave concern. Their data indicated that the children’s shortness was a result of nutritional deficiencies — chronic malnutrition during the first three years of life — rather than the consequence of genetics or altitude, as had been previously suggested."" [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Malnutrition in Tibet	None	8,713	wikipedia	https://en.wikipedia.org/wiki/Malnutrition_in_Tibet	2021-01-18T18:41:21	{"wikidata": ["Q3282269"]}
A number sign (#) is used with this entry because Snyder-Robinson mental retardation syndrome (MRXSSR) is caused by mutation in the spermine synthase gene (SMS; 300105) on chromosome Xp22. Description Snyder-Robinson mental retardation syndrome is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthic speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia (summary by Zhang et al., 2013). Clinical Features Snyder and Robinson (1969) reported a family in which affected males had a form of nonspecific X-linked mental retardation with hypotonia and unsteady gait. Eleven males in 4 generations were affected. Arena et al. (1992, 1996) reevaluated the family, defining the disorder as a specific syndrome with the following features: mild to moderate mental retardation; asthenic body build (marfanoid habitus); diminished muscle bulk; osteoporosis; kyphoscoliosis; long, thin face; slight facial asymmetry with a prominent lower lip; nasal voice; high, narrow, or cleft palate; and long, thin fingers and toes. Carrier females were clinically normal. Arena et al. (1996) redefined the entity as an X-linked mental retardation syndrome. In a follow-up of the same family, Cason et al. (2003) reported that some affected males had an unsteady gait, nonspecific movement disorder, and seizures. Two of 4 affected males had an abnormal EEG. De Alencastro et al. (2008) reported a second family with genetically- confirmed Snyder-Robinson syndrome (300105.0002). At age 12 years, the proband had profound mental retardation, seizures, no speech development, and was unable to stand alone or walk. He had short stature and mild facial dysmorphism, with mild hypertelorism, exophthalmia, short philtrum, thickened lower lip, slight high-arched palate, mandibular prognathism, and ears with prominent antihelices and hypoplastic lobules. Other features included high myopia, pectus carinatum, cryptorchidism, severe kyphoscoliosis, camptodactyly without arachnodactyly, and muscular hypotonia. Kesler et al. (2009) performed brain MRI studies on 2 affected males with Snyder-Robinson syndrome reported by Cason et al. (2003), at ages 13 and 39 years, respectively. IQ measurements were 36 and 54, respectively. Both had dysmorphic facial features; the younger patient had myoclonic seizures. Total brain volumes of both patients were somewhat enlarged and affected gray, white, and CSF volumes equally. The younger patient had disproportionately decreased cerebellar volume, and both had disproportionately decreased hippocampal and red nucleus volumes. Kesler et al. (2009) postulated that spermine deficiency may result in an imbalance between cell growth and pruning mechanisms during neurodevelopment. Becerra-Solano et al. (2009) reported 2 adult Mexican brothers with Snyder-Robinson syndrome. Clinical features included mental retardation, multiple childhood fractures associated with decreased bone density, thin body habitus with poor muscle bulk and long thin limbs, pectus excavatum with widely-spaced nipples, and kyphoscoliosis. Dysmorphic facial features included brachycephaly, asymmetric facies, slanted upper palpebral fissures, sparse eyebrows, synophrys, right palpebral ptosis, high nasal bridge, bulbous nasal tip, anteverted nares, smooth philtrum, prominent lower lip, high palate, overcrowded teeth, asymmetric ears, and short webbed neck. Both also had areas of patchy skin hyperpigmentation. Family history was notable for a spontaneous abortion in the mother during the first trimester. Zhang et al. (2013) reported a family in which 4 males in 3 generations had Snyder-Robinson syndrome. The proband was reported in detail: he had delayed psychomotor development, delayed language, IQ of 74, thin build, low-set ears, small mouth, kyphoscoliosis, and long fingers and toes. He did not have facial asymmetry, or abnormal gait or other neurologic symptoms. He had good social interaction and attended a special school. His maternal uncle also went to a special school and worked in a sheltered environment. Zhang et al. (2013) noted that the phenotype in these patients was relatively mild compared to that reported in other patients with this disorder. Peron et al. (2013) reported a boy from Italy with Snyder-Robinson syndrome characterized by a thin habitus with decreased muscle mass, unsteady gait, osteoporosis, kyphoscoliosis, dysmorphic facial features, cognitive impairment, and nasal speech. In addition to features typically seen in Snyder-Robinson syndrome, the patient also had an ectopic right kidney and early onset of epilepsy. Seizure activity was first observed in the first year of life and he was diagnosed with atypical West syndrome; at age 6 years, he developed myoclonus and focal motor seizures. The finding of a mutation in the SMS gene (see MOLECULAR GENETICS) confirmed the diagnosis of MRXSSR. Mapping By linkage analysis of 17 members of an affected family, Arena et al. (1996) found a maximum lod score of 4.7 at markers DXS41 and DXS989 on Xp21.3-p22.12, distal to the 3-prime end of the DMD gene (300377). Molecular Genetics In affected members of the family originally reported by Snyder and Robinson (1969), Cason et al. (2003) identified a mutation in the SMS gene (300105.0001). In 2 Mexican brothers with Snyder-Robinson syndrome, Becerra-Solano et al. (2009) identified a mutation in the SMS gene (V132G; 300105.0003). Zhang et al. (2013) reported a patient and his uncle with a mild form of Snyder-Robinson syndrome who carried a missense mutation in the SMS gene (Y328C; 300105.0004). In a boy from Italy with Snyder-Robinson syndrome who had originally been diagnosed with West syndrome, Peron et al. (2013) identified a missense mutation in the SMS gene (300105.0005). In the patient's lymphoblastoid cells, no spermine synthase activity above baseline was detected, and the spermine/spermidine ratio was abnormal, consistent with Snyder-Robinson syndrome. The patient's mother was heterozygous for the mutation, and X-inactivation analysis showed mild skewing. INHERITANCE \- X-linked recessive GROWTH Height \- Tall stature \- Short stature Other \- Thin body build HEAD & NECK Face \- Facial asymmetry \- Prognathism \- Short philtrum Ears \- Asymmetric dysplastic ears Eyes \- High myopia \- Hypertelorism, mild \- Slanted palpebral fissures Mouth \- Prominent lower lip \- Small upper lip \- High, narrow palate \- Cleft palate \- Bifid uvula Teeth \- Overcrowded teeth Neck \- Short, webbed neck CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum \- Pectus carinatum Breasts \- Widely spaced nipples GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Osteoporosis \- Multiple fractures Spine \- Kyphoscoliosis Hands \- Long, thin hands \- Long, hyperextensible fingers Feet \- Long halluces \- Clubfoot MUSCLE, SOFT TISSUES \- Decreased muscle mass NEUROLOGIC Central Nervous System \- Mental retardation (males) \- Hypotonia \- Wide-based gait \- Seizures VOICE \- Nasal speech \- Dysarthric speech MISCELLANEOUS \- Variable phenotype \- Carrier females are normal MOLECULAR BASIS \- Caused by mutation in the spermine synthase gene (SMS, 300105.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	MENTAL RETARDATION, X-LINKED, SYNDROMIC, SNYDER-ROBINSON TYPE	c0796160	8,714	omim	https://www.omim.org/entry/309583	2019-09-22T16:17:43	{"doid": ["0060802"], "mesh": ["C536678"], "omim": ["309583"], "orphanet": ["3063"], "synonyms": ["Alternative titles", "SNYDER-ROBINSON MENTAL RETARDATION SYNDROME"], "genereviews": ["NBK144284"]}
Disease of the brain or spinal cord This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (March 2020) Central nervous system disease Central nervous system in yellow (brain and spinal cord) SpecialtyPsychiatry, Neurology, Neurosurgery Central nervous system diseases, also known as central nervous system disorders, are a group of neurological disorders that affect the structure or function of the brain or spinal cord, which collectively form the central nervous system (CNS).[1][2][3] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Trauma * 2.2 Infections * 2.3 Degeneration * 2.4 Structural defects * 2.5 CNS Tumors * 2.6 Autoimmune disorders * 2.7 Stroke * 3 Functions * 3.1 Spinal cord * 3.2 Brain * 4 Diagnosis * 4.1 Types of CNS disorders * 4.1.1 Addiction * 4.1.2 Arachnoid cysts * 4.1.3 Attention deficit/hyperactivity disorder (ADHD) * 4.1.4 Autism * 4.1.5 Bipolar disorder * 4.1.6 Catalepsy * 4.1.7 Depression * 4.1.8 Encephalitis * 4.1.9 Epilepsy/Seizures * 4.1.10 Infection * 4.1.11 Locked-in syndrome * 4.1.12 Meningitis * 4.1.13 Migraine * 4.1.14 Multiple sclerosis * 4.1.15 Myelopathy * 4.1.16 Neurodegenerative disorders * 4.1.16.1 Alzheimer’s * 4.1.16.2 Huntington's disease * 4.1.16.3 Parkinson's * 4.1.17 Tourette's * 5 Treatments * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Every disease has different signs and symptoms. Some of them are persistent headache; pain in the face, back, arms, or legs; an inability to concentrate; loss of feeling; memory loss; loss of muscle strength; tremors; seizures; increased reflexes, spasticity, tics; paralysis; and slurred speech. One should seek medical attention if affected by these. ## Causes[edit] ### Trauma[edit] Main article: Traumatic brain injury Any type of traumatic brain injury (TBI) or injury done to the spinal cord can result in a wide spectrum of disabilities in a person. Depending on the section of the brain or spinal cord that suffers the trauma, the outcome may be anticipated. ### Infections[edit] Main article: List of central nervous system infections Infectious diseases are transmitted in several ways. Some of these infections may affect the brain or spinal cord directly. Generally, an infection is a disease that is caused by the invasion of a microorganism or virus. ### Degeneration[edit] Degenerative spinal disorders involve a loss of function in the spine. Pressure on the spinal cord and nerves may be associated with herniation or disc displacement. Brain degeneration also causes central nervous system diseases (i.e. Alzheimer's, Parkinson's, and Huntington's diseases). Studies have shown that obese people may have severe degeneration in the brain[dubious – discuss] due to loss of tissue affecting cognition.[4][citation needed] ### Structural defects[edit] Common structural defects include birth defects,[5] anencephaly, hypospadias, and spina bifida. Children born with structural defects may have malformed limbs, heart problems, and facial abnormalities. Defects in the formation of the cerebral cortex include microgyria, polymicrogyria, bilateral frontoparietal polymicrogyria, and pachygyria. ### CNS Tumors[edit] A tumor is an abnormal growth of body tissue. In the beginning, tumors can be noncancerous, but if they become malignant, they are cancerous. In general, they appear when there is a problem with cellular division. Problems with the body's immune system can lead to tumors. ### Autoimmune disorders[edit] An autoimmune disorder is a condition where in the immune system attacks and destroys healthy body tissue. This is caused by a loss of tolerance to proteins in the body, resulting in immune cells recognising these as 'foreign' and directing an immune response against them. ### Stroke[edit] Main article: Stroke A stroke is an interruption of the blood supply to the brain. Approximately every 40 seconds, someone in the US has a stroke.[6] This can happen when a blood vessel is blocked by a blood clot or when a blood vessel ruptures, causing blood to leak to the brain. If the brain cannot get enough oxygen and blood, brain cells can die, leading to permanent damage. ## Functions[edit] ### Spinal cord[edit] Main article: Spinal cord The spinal cord transmits sensory reception from the peripheral nervous system.[7] It also conducts motor information to the body's skeletal muscles, cardiac muscles, smooth muscles, and glands. There are 31 pairs of spinal nerves along the spinal cord, all of which consist of both sensory and motor neurons.[7] The spinal cord is protected by vertebrae and connects the peripheral nervous system to the brain, and it acts as a "minor" coordinating center. ### Brain[edit] Main article: Human brain The brain serves as the organic basis of cognition and exerts centralized control over the other organs of the body. The brain is protected by the skull; however, if the brain is damaged, significant impairments in cognition and physiological function or death may occur. ## Diagnosis[edit] ### Types of CNS disorders[edit] This section is missing information about a number of brain disorders[3][8] that not currently listed here. Please expand the section to include this information. Further details may exist on the talk page. (July 2016) #### Addiction[edit] Main article: Addiction Addiction is a disorder of the brain's reward system which arises through transcriptional and epigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., morphine, cocaine, sexual intercourse, gambling, etc.).[9][10][11][12] #### Arachnoid cysts[edit] Main article: Arachnoid cysts Arachnoid cysts are cerebrospinal fluid covered by arachnoidal cells that may develop on the brain or spinal cord.[13] They are a congenital disorder, and in some cases may not show symptoms. However, if there is a large cyst, symptoms may include headache, seizures, ataxia (lack of muscle control), hemiparesis, and several others. Macrocephaly and ADHD are common among children, while presenile dementia, hydrocephalus (an abnormality of the dynamics of the cerebrospinal fluid), and urinary incontinence are symptoms for elderly patients (65 and older). #### Attention deficit/hyperactivity disorder (ADHD)[edit] Main article: Attention deficit-hyperactivity disorder ADHD is an organic disorder of the nervous system.[14][15][16][17] ADHD, which in severe cases can be debilitating,[18] has symptoms thought to be caused by structural as well as biochemical imbalances in the brain; in particular, low levels of the neurotransmitters dopamine and norepinephrine,[19] which are responsible for controlling and maintaining attention and movement. Many people with ADHD continue to have symptoms well into adulthood.[20] Also of note is an increased risk of the development of Dementia with Lewy bodies, or (DLB), and a direct genetic association of Attention deficit disorder to Parkinson's disease[21][22] two progressive, and serious, neurological diseases whose symptoms often occur in people over age 65.[20][23][24][25] #### Autism[edit] Main article: Autism Autism is a neurodevelopmental disorder that is characterized by restricted and repetitive patterns of behavior and persistent deficits in social interaction and communication.[8] #### Bipolar disorder[edit] Main article: Bipolar disorder Bipolar disorder is a serious illness of the nervous system.[26] Symptoms can include both signs of major depression and mania. Mood swings from the highs of mania to the lows of deep depression usually occurs over several weeks to months. New research suggests that bipolar disorder is actually a neurological disease genetically related to Parkinson's disease[27] #### Catalepsy[edit] Main article: Catalepsy Catalepsy is a nervous disorder characterized by immobility and muscular rigidity, along with a decreased sensitivity to pain. Catalepsy is considered a symptom of serious diseases of the nervous system (e.g., Parkinson's disease, Epilepsy, etc.) rather than a disease by itself. Cataleptic fits can range in duration from several minutes to weeks. Catalepsy often responds to Benzodiazepines (e.g., Lorazepam) in pill and I.V. form.[28] #### Depression[edit] Main article: Major depressive disorder Major depressive disorder, otherwise known as depression, is a disorder that is characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and by a loss of interest or pleasure in normally enjoyable activities. #### Encephalitis[edit] Main article: Encephalitis Encephalitis is an inflammation of the brain. It is usually caused by a foreign substance or a viral infection. Symptoms of this disease include headache, neck pain, drowsiness, nausea, and fever. If caused by the West Nile virus,[29] it may be lethal to humans, as well as birds and horses. #### Epilepsy/Seizures[edit] Main article: Epilepsy Epilepsy is an unpredictable, serious, and potentially fatal disorder of the nervous system, thought to be the result of faulty electrical activity in the brain. Epileptic seizures result from abnormal, excessive, or hypersynchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing countries. Epilepsy becomes more common as people age. Onset of new cases occurs most frequently in infants and the elderly. Epileptic seizures may occur in recovering patients as a consequence of brain surgery.[30] #### Infection[edit] For a more comprehensive list, see List of infections of the central nervous system. A number of different pathogens (i.e., certain viruses, bacteria, protozoa, fungi, and prions) can cause infections that adversely affect the brain or spinal cord. #### Locked-in syndrome[edit] A medical condition, Locked-in syndrome usually resulting from a stroke that damages part of the brainstem, in which the body and most of the facial muscles are paralysed but consciousness remains and the ability to perform certain eye movements is preserved. #### Meningitis[edit] Main article: Meningitis Meningitis is an inflammation of the meninges (membranes) of the brain and spinal cord. It is most often caused by a bacterial or viral infection. Fever, vomiting, and a stiff neck are all symptoms of meningitis. #### Migraine[edit] Main article: Migraine A chronic, often debilitating neurological disorder characterized by recurrent moderate to severe headaches, often in association with a number of autonomic nervous system symptoms. #### Multiple sclerosis[edit] Main article: Multiple sclerosis Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, meaning that the myelin sheath of neurons is damaged. Symptoms of MS include visual and sensation problems, muscle weakness, numbness and tingling all over, muscle spasms, poor coordination, and depression. Also, patients with MS have reported extreme fatigue and dizziness, tremors, and bladder leakage. #### Myelopathy[edit] Main article: Myelopathy Myelopathy is an injury to the spinal cord due to severe compression that may result from trauma, congenital stenosis, degenerative disease or disc herniation. The spinal cord is a group of nerves housed inside the spine that runs almost its entire length. #### Neurodegenerative disorders[edit] This section is empty. You can help by adding to it. (July 2019) ##### Alzheimer’s[edit] Main article: Alzheimer's disease Alzheimer's is a neurodegenerative disease typically found in people over the age of 65 years. Worldwide, approximately 24 million people have dementia; 60% of these cases are due to Alzheimer's. The ultimate cause is unknown. The clinical sign of Alzheimer's is progressive cognition deterioration. ##### Huntington's disease[edit] Main article: Huntington's disease Huntington's disease is a degenerative neurological disorder that is inherited. Degeneration of neuronal cells occurs throughout the brain, especially in the striatum. There is a progressive decline that results in abnormal movements.[31] Statistics show that Huntington's disease may affect 10 per 100,000 people of Western European descent. ##### Parkinson's[edit] Main article: Parkinson's disease Parkinson's disease, or PD, is a progressive illness of the nervous system. Caused by the death of dopamine-producing brain cells that affect motor skills and speech. Symptoms may include bradykinesia (slow physical movement), muscle rigidity, and tremors. Behavior, thinking, sensation disorders, and the sometimes co-morbid skin condition Seborrheic dermatitis are just some of PD's numerous nonmotor symptoms. Parkinson's disease, Attention deficit/hyperactivity disorder (ADHD) and Bi-polar disorder, all appear to have some connection to one another, as all three nervous system disorders involve lower than normal levels of the brain chemical dopamine (In ADHD, Parkinson's, and the depressive phase of Bi-polar disorder.) or too much dopamine (in Mania or Manic states of Bi-polar disorder) in different areas of the brain:[27][32][33][34] #### Tourette's[edit] Main article: Tourette's syndrome Tourette's syndrome is an inherited neurological disorder. Early onset may be during childhood, and it is characterized by physical and verbal tics. Tourette's often also includes symptoms of both OCD and ADHD indicating a link between the three disorders. The exact cause of Tourette's, other than genetic factors, is unknown. ## Treatments[edit] There is a wide range of treatments for central nervous system diseases. These can range from surgery to neural rehabilitation or prescribed medications. ## See also[edit] * Neurodegenerative disease * List of central nervous system infections ## References[edit] 1. ^ "Nervous System Diseases". Healthinsite.gov.au. Retrieved 2013-10-30. 2. ^ Central Nervous System Diseases at the US National Library of Medicine Medical Subject Headings (MeSH) 3. ^ a b Cacabelos R, Torrellas C, Fernández-Novoa L, López-Muñoz F (2016). "Histamine and Immune Biomarkers in CNS Disorders". Mediators Inflamm. 2016: 1924603. doi:10.1155/2016/1924603. PMC 4846752. PMID 27190492. 4. ^ https://www.livescience.com/10582-obese-people-severe-brain-degeneration.html 5. ^ "Birth Defects". Kidshealth.org. Retrieved 2013-10-30. 6. ^ "Stroke". Hearthealthywomen.org. Archived from the original on 2013-06-24. Retrieved 2013-10-30. 7. ^ a b "Organization of the Nervous System". Users.rcn.com. Retrieved 2013-10-30. 8. ^ a b Lipton JO, Sahin M (October 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC 4223653. PMID 25374355. 9. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. doi:10.31887/DCNS.2013.15.4/enestler. PMC 3898681. PMID 24459410. 10. ^ Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. 11. ^ Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 12. ^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. 13. ^ "How the Brain Works". Arachnoidcyst.org. Archived from the original on 2011-09-30. Retrieved 2013-10-30. 14. ^ "Brain Studies Show ADHD Is Real Disease - ABC News". Abcnews.go.com. Retrieved 2013-10-30. 15. ^ "ADHD Study: General Information". Genome.gov. Retrieved 2013-10-30. 16. ^ "MNT - ADHD Is A Genetic Neurodevelopmental Disorder, Scientists Reveal". Medicalnewstoday.com. doi:10.1016/S0140-6736 (inactive 2021-01-17). Retrieved 2013-10-30. Cite journal requires `\|journal=` (help)CS1 maint: DOI inactive as of January 2021 (link) 17. ^ "Social Security Disability Ssi And Adhd, Attention Deficit Hyperactivity Disorder". Ssdrc.com. Retrieved 2013-10-30. 18. ^ "112.00-MentalDisorders-Childhood". Ssa.gov. 2013-05-31. Retrieved 2013-10-30. 19. ^ "What Is ADHD? Attention Deficit Hyperactivity Disorder: What You Need to Know". Webmd.com. 2008-09-18. Retrieved 2013-10-30. 20. ^ a b "Adult ADHD (attention-deficit/hyperactivity disorder)". MayoClinic.com. 2013-03-07. Retrieved 2013-10-30. 21. ^ "Parkinsonism, ADHD: Common Genetic Link?". 2014-07-04. 22. ^ Golimstok, A.; Rojas, J. I.; Romano, M.; Zurru, M. C.; Doctorovich, D.; Cristiano, E. (2011-02-06). "Previous adult attention-deficit and hyperactivity disorder symptoms and risk of dementia with Lewy bodies: A case-control study". European Journal of Neurology. 18 (1): 78–84. doi:10.1111/j.1468-1331.2010.03064.x. PMID 20491888. S2CID 3914739. Lay summary. 23. ^ "Dementia With Lewy Bodies Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". Ninds.nih.gov. 2013-06-06. Retrieved 2013-10-30. 24. ^ Puschmann A, Bhidayasiri R, Weiner WJ (2012). "Synucleinopathies from bench to bedside". Parkinsonism Relat Disord. 18 Suppl 1: S24-7. doi:10.1016/S1353-8020(11)70010-4. PMID 22166445. 25. ^ Hansen, Freja H.; Skjørringe, Tina; Yasmeen, Saiqa; Arends, Natascha V.; Sahai, Michelle A.; Erreger, Kevin; Andreassen, Thorvald F.; Holy, Marion; Hamilton, Peter J.; Neergheen, Viruna; Karlsborg, Merete; Newman, Amy H.; Pope, Simon; Heales, Simon J.R.; Friberg, Lars; Law, Ian; Pinborg, Lars H.; Sitte, Harald H.; Loland, Claus; Shi, Lei; Weinstein, Harel; Galli, Aurelio; Hjermind, Lena E.; Møller, Lisbeth B.; Gether, Ulrik (2014). "Missense dopamine transporter mutations associate with adult parkinsonism and ADHD". Journal of Clinical Investigation. 124 (7): 3107–3120. doi:10.1172/JCI73778. PMC 4071392. PMID 24911152. 26. ^ "NIMH » Bipolar Disorder". 27. ^ a b Engmann, Birk (2011). "Bipolar Affective Disorder and Parkinson's Disease". Case Reports in Medicine. 2011: 1–3. doi:10.1155/2011/154165. PMC 3226531. PMID 22162696. 28. ^ "What is Catalepsy? (with pictures)". wiseGEEK. 29. ^ "West Nile Virus". Medicinenet.com. Retrieved 2013-10-30. 30. ^ "How Serious Are Seizures?". Epilepsy.com. Retrieved 2013-10-30. 31. ^ "Huntington's Disease". Hdsa.org. Archived from the original on 2013-11-01. Retrieved 2013-10-30. 32. ^ ADHD and Parkinson's \| LIVESTRONG.COM 33. ^ Walitza S, Melfsen S, Herhaus G, Scheuerpflug P, Warnke A, Müller T, Lange KW, Gerlach M (2007). "Association of Parkinson's disease with symptoms of attention deficit hyperactivity disorder in childhood". J Neural Transm Suppl (72): 311–5. doi:10.1007/978-3-211-73574-9_38. ISBN 978-3-211-73573-2. PMID 17982908. 34. ^ "Movement disorders in young people related to ADHD". ## External links[edit] Classification D * MeSH: D002493 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Central nervous system disease	c0007682	8,715	wikipedia	https://en.wikipedia.org/wiki/Central_nervous_system_disease	2021-01-18T19:04:49	{"mesh": ["D002493"], "umls": ["C4021765", "C0007682"], "wikidata": ["Q5062122"]}
Postpericardiotomy syndrome SpecialtyCardiology/immunology Postpericardiotomy syndrome (PPS) is a medical syndrome referring to an immune phenomenon that occurs days to months (usually 1–6 weeks[1]) after surgical incision of the pericardium (membranes encapsulating the human heart).[2] PPS can also be caused after a trauma, a puncture of the cardiac or pleural structures (such as a bullet or stab wound), after percutaneous coronary intervention (such as stent placement after a myocardial infarction or heart attack), or due to pacemaker or pacemaker wire placement.[1] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Pathogenesis * 3 Diagnosis * 4 Treatment * 4.1 Colchicine * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] The typical signs of post-pericardiotomy syndrome include fever, pleuritis (with possible pleural effusion), pericarditis (with possible pericardial effusion), occasional but rare pulmonary infiltrates, and fatigue.[1][2] Cough, pleuritic or retrosternal chest pain, joint pain and decreased oxygen saturation can also be seen in some cases.[1] Other signs include arthritis, together with petechiae on the skin and palate.[3]:827 ### Complications[edit] Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Beck's triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death. ## Pathogenesis[edit] The cause is believed to be an autoimmune response against damaged cardiac tissue. This is supported by excellent response to immunosuppressive (steroid) therapy.[4] This condition is a febrile illness caused by immune attack of the pleura and the pericardium. Possible cell mediated immunity led by Helper T-cells and Cytotoxic T-cells is postulated to be important in the pathogenesis of this condition.[1] There is also possibility of anti-cardiac antibodies created idiopathically, or due to concurrent cross-reactivity of the antibodies produced against viral antigens, however the latter assumption is not fool-proof or completely reliable due to conflicting studies.[1] ## Diagnosis[edit] A chest X-ray might depict pleural effusion, pulmonary infiltration, or pericardial effusion.[2] During medical doctor examination, a pericardial friction rub can be auscultated indicating pericarditis. Auscultation of the lungs can show crackles indicating pulmonary infiltration, and there can be retrosternal/pleuritic chest pain worse on inspiration (breathing in). Patient can also depict sweating (diaphoresis) and agitation or anxiety. ## Treatment[edit] ### Colchicine[edit] Colchicine has been used effectively to prevent pericarditis, and inflammation that follows surgery of the pericardium.[5] Although no current drug on the market prevents post-pericardiotomy syndrome, colchicine seems to provide an effective and safe way to treat pericarditis by reducing inflammation.[6] Colchicine is a natural product extracted from plants, and is a secondary metabolite (an organic compound not directly related to growth and development in an organism).[5] Colchicine interferes with the inflammatory process by altering several important steps in the pathway. Microtubules are structural components of the cytoskeleton that lengthen and shrink for important cell functions. Colchicine binds to β- tubulin and forms tubulin-colchicine complexes.,[5][6] These complexes interfere with microtubule formation microtubules. Low doses of colchicine can inhibit the formation of microtubules, while high doses depolymerize or break down a polymer to a monomer.[7] Therefore, any process involving cytoskeleton change, including mitosis and motility of white blood cells, are highly impacted. Microtubule disruption decrease neutrophil adhesion, an important step for inflammation.[7] Neutrophils are recruited to the target location of inflammation via signals from the endothelium where they adhere and play a role in the inflammatory response. Colchicine diminishes neutrophil adhesion by decreasing expression of selectins, a family of cell adhesion molecules.[7] In addition, colchicine prevents the movement and secretion of intercellular granules, substances, proinflammatory enzymes from neutrophils, thus making a significant impact on inflammatory processes within the body.[6] The high concentration of colchicine in neutrophils, sixteen times greater compared the plasma levels, can account for the positive therapeutic effects.[6] Many mediators are altered to assist neutrophils during inflammation, including the monokine tumor necrosis factor-alpha (TNFα).[8] Cytokines help stimulate the acute phase reaction in response to inflammation. Colchicine inhibits macrophage production of TNFα, leading to the interference between TNFα and neutrophil interaction.[8] There are many more effects of colchicine that are currently under research, and some aspects of this metabolite are not fully understood. There was great hope that Colchicine could be a primary preventive measure in treating Post-Pericardiotomy Syndrome due to its anti-inflammatory effects.[6] In the COPPS-2 trial, however, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. Thus colchicine is not likely going to be the ideal way to prevent this problem.[9] ## Epidemiology[edit] More common in children and often common in patients receiving cardiac operations that involves opening the pericardium.[1] CABG surgery is a common culprit. ## See also[edit] * Skin lesion * Dressler syndrome ## References[edit] 1. ^ a b c d e f g M. Silvana Horenstein (April 30, 2009). "Postpericardiotomy syndrome". eMedicine from WebMD. Cite journal requires `\|journal=` (help) 2. ^ a b c Marc. E. Kaminsky; Rodan B.; Osborn D.; Chen J.; Sealy W.; Putman C. "Postcardiotomy syndrome" (PDF). American Journal of Roentgenology. Cite journal requires `\|journal=` (help)[permanent dead link] 3. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 4. ^ Heffner, John (2010). Pleural Effusions Following Cardiac surgery. UpToDate. 5. ^ a b c Eur Heart, J. (2009). Colchicine for pericarditis: hype or hope? Oxford Journal. Vol 30. 532-539. 6. ^ a b c d e Eur Heart, J. (2010) Colchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multiculture, randomized, double-blind, placebo controlled trial. Oxford Journal. Vol 31. 2749-2754. 7. ^ a b c Spyridon Deftereos, S., Giannopoulos, G., Papoutsidakis, N., Panagopoulou, V., Kossyvakis, C., Raisakis, K., Stefanadis, C. (2013). Colchicine and the heart. Journal of the American College of Cardiology. Vol 62(20), 1817-1825. 8. ^ a b Molad, Y. (2002). Update on Colchicine and Its Mechanism of Action. Current Rheumatology Reports. Vol 4. 252-256. 9. ^ Imazio M, Brucato A, Ferrazzi P, Pullara A, Adler Y, Barosi A, Caforio AL, Cemin R, Chirillo F, Comoglio C, Cugola D, Cumetti D, Dyrda O, Ferrua S, Finkelstein Y, Flocco R, Gandino A, Hoit B, Innocente F, Maestroni S, Musumeci F, Oh J, Pergolini A, Polizzi V, Ristic A, Simon C, Spodick DH, Tarzia V, Trimboli S, Valenti A, Belli R, Gaita F (2014). "Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation. The COPPS-2 Randomized Clinical Trial" (PDF). JAMA. 312 (10): 1016–1023. doi:10.1001/jama.2014.11026. hdl:2434/634839. PMID 25172965. ## External links[edit] Classification D * ICD-10: I97.0 * ICD-9-CM: 429.4 * MeSH: D011185 * SNOMED CT: 278536002 External resources * eMedicine: article/891471 * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Postpericardiotomy syndrome	c0032805	8,716	wikipedia	https://en.wikipedia.org/wiki/Postpericardiotomy_syndrome	2021-01-18T19:04:01	{"mesh": ["D011185"], "umls": ["C0032805"], "icd-9": ["429.4"], "icd-10": ["I97.0"], "wikidata": ["Q7234096"]}
Coma blister SpecialtyDermatology Coma blisters are a cutaneous condition characterized by tense bullae at sites of maximal pressure.[1] ## See also[edit] * Friction blister * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. * v * t * e General wounds and injuries Abrasions * Abrasion * Avulsion Blisters * Blood blister * Coma blister * Delayed blister * Edema blister * Fracture blister * Friction blister * Sucking blister Bruises * Hematoma/Ecchymosis * Battle's sign * Raccoon eyes * Black eye * Subungual hematoma * Cullen's sign * Grey Turner's sign * Retroperitoneal hemorrhage Animal bites * Insect bite * Spider bite * Snakebite Other: * Ballistic trauma * Stab wound * Blunt trauma/superficial/closed * Penetrating trauma/open * Aerosol burn * Burn/Corrosion/Chemical burn * Frostbite * Occupational injuries * Traumatic amputation By region * Hand injury * Head injury * Chest trauma * Abdominal trauma This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Coma blister	c2747865	8,717	wikipedia	https://en.wikipedia.org/wiki/Coma_blister	2021-01-18T18:41:31	{"umls": ["C2747865"], "wikidata": ["Q5150468"]}
Dental avulsion SpecialtyDentistry Dental avulsion is the complete displacement of a tooth from its socket in alveolar bone owing to trauma.[1] The treatment for permanent teeth consists of replantation, immediately if possible. Deciduous teeth should not be replanted due to the risk of damaging the permanent tooth germ. Immediate replantation ensures the best possible prognosis but is not always possible since more serious injuries may be present. Studies have shown that teeth that are protected in a physiologically ideal media can be replanted within 15 minutes to one hour after the accident with good prognosis. The success of delayed replantation depends on the vitality of the cells remaining on the root surface. In normal conditions, a tooth is connected to the socket by means of the periodontal ligament. When a tooth is knocked out, that ligament stretches and splits in half.[2] Maintaining the vitality of the cells that remain attached to the root surface is the key to success following replantation. Years ago, it was thought that the key to maintaining root cell vitality was keeping the knocked-out tooth wet,[3] thus giving rise to storage media recommendations such as water, the mouth and milk. Recent research has shown that one of the key elements for maintaining vitality is storing the tooth in an environment that closely resembles the original socket environment. This environment is one that has the proper osmolality (cell pressure), pH, nutritional metabolites and glucose. There are scientifically designed storage media that provide this environment. These storage media are now available in retail products. Use of devices that incorporate the ideal storage media and protective apparatuses have increased the success rate of replanted knocked-out teeth to over 90% when used within sixty minutes of the accident. ## Contents * 1 Prevention * 2 Risk factors * 3 Management * 3.1 Initial assessment * 3.2 Re-implantation * 3.3 Biologic basis for success of replantation following avulsion * 3.4 Prevention of cell crushing * 3.5 Maintenance of normal cell metabolism * 3.6 Storage media * 4 Prognosis * 5 Epidemiology * 6 History * 7 Archaeology * 8 See also * 9 References * 10 External links ## Prevention[edit] Main article: Mouthguard In contact sports, such as rugby, and even in non-contact sports, such as basketball, there is significant risk of dental injury.[4] The best method for the prevention of knocked-out teeth is the use of helmets and mouth protectors (mouthguards).[5] Custom-made mouth protectors, as opposed to ill-fitting, over-the-counter mouth protectors offer the best protection.[4] Mouth protectors can be very inexpensive, however, the compliance rate for their use is poor.[6][7] Studies have shown that, even when mandated, athletes and other high risk individuals often will not use them.[8] Also, even with their use, mouth guards can be knocked-out, leaving the user unprotected. ## Risk factors[edit] * Postnormal occlusion * An over-jet exceeding 4 mm * Short upper lip * Incompetent lips * Mouth breathing[9] ## Management[edit] This section contains content that is written like an advertisement. Please help improve it by removing promotional content and inappropriate external links, and by adding encyclopedic content written from a neutral point of view. (January 2018) (Learn how and when to remove this template message) Dental avulsion is a real dental emergency in which prompt management (within 20–40 minutes of injury) affects the prognosis of the tooth.[10] The avulsed permanent tooth should be gently but well rinsed with saline, with care taken not to damage the surface of the root which may have living periodontal fiber and cells. Once the tooth and mouth are clean an attempt can be made to re-plant in its original socket within the alveolar bone and later splinted by a dentist for several weeks.[11] Failure to re-plant the avulsed tooth within the first 40 minutes after the injury may result in a less favorable prognosis for the tooth.[11] If the tooth cannot be immediately replaced in its socket, follow the directions for Treatment of knocked-out (avulsed) teeth and cold milk or saliva and take it to an emergency room or a dentist. If the mouth is sore or injured, cleansing of the wound may be necessary, along with stitches, local anesthesia, and an update of tetanus immunization if the mouth was contaminated with soil. Management of injured primary teeth differs from management of permanent teeth; avulsed primary tooth should not be re-planted (to avoid damage to the permanent dental crypt).[12] Although some dentists advise that the best treatment for an avulsed tooth is immediate replantation,[13][14] for a variety of reasons this can be difficult for the non-professional person. The teeth are often covered with debris. This debris must be washed off with a physiological solution and not scrubbed. Often multiple teeth are knocked-out and the person will not know which socket an individual tooth belongs to. The injured victim may have other more serious injuries that require more immediate attention or injuries such as a severely lacerated bleeding lip or gum that prevent easy visualization of the socket. Pain may be severe and the person may resist replantation of the teeth. People may, in light of infectious diseases (e.g. HIV), fear handling the teeth or touching the blood associated with them. If immediate replantation is not possible, the teeth should be placed in an appropriate storage solution and brought to a dentist who can then replant them. The dentist will clean the socket, wash the teeth if necessary, and replant them into their sockets. He will splint them to non-knocked-out teeth for a maximum of two weeks for teeth with normal alveolar process and bone support. Properly handled, even replantation of periodontally compromised permanent teeth in older patients under good maintenance have been reported, with splinting extending for over 4 weeks due to the reduced support structure for the root due to periodontal disease.[15] One week to ten days after the replantation, the dental pulps of the replanted teeth should be removed and a root canal treatment completed within two months. In addition, as recommended in all dental traumas good oral hygiene with 0.12% chlorhexidine gluconate mouthwash, a soft and cold diet, and avoidance of smoking for several days may provide a favorable condition for periodontal ligaments regeneration.[10] ### Initial assessment[edit] When a patient arrives at the Dentist they should be seen quickly and with urgency. If the tooth has not been placed in a suitable storage medium, the Dentist should do this immediately. A thorough extra oral and intra-oral examination should be performed. The clinician should consider the age of the patient, the history of the injury and that it is in line with clinical findings. If there is concern about non-accidental injury, then safeguarding procedures should be followed.[16] ### Re-implantation[edit] Prior to the beginning of the procedure, a local anesthetic should be administered to both the palatal/lingual tissues to minimize discomfort. Gentle Irrigation with a saline solution should be performed as this removes any clots within the socket, which could prevent the proper re-positioning of the tooth into its original position. The tooth should always be handled via the enamel on the crown, not the root! Wash the root surface with saline, be careful not to scrub the root surface, as this may crush the delicate cells. Any stubborn debris can be removed by 'gently dabbing with gauze soaked in saline'. The tooth may then be gently placed back into the socket.[17] Soaking is the practice of soaking the tooth in an active medicament before re-implantation.[18][needs update] It has been shown that soaking the avulsed tooth in an immune-modulating drug prior to re-implantation can increase periodontal healing and tooth survival, compared to a saline control.[19] ### Biologic basis for success of replantation following avulsion[edit] Every tooth is connected to its surrounding bone by the periodontal ligament. The tooth receives its nourishment through this ligament. When a tooth is knocked-out, this ligament is stretched and splits in half; half stays on the tooth root and half stays on the socket wall. If these two halves can be kept alive, the tooth can be replanted and the halves of the ligament will reattach and the tooth will remain vital. The half that stays on the socket wall, since it remains connected to the bone blood supply, is naturally kept alive. However, the ligament cells that remain on the tooth root lose their blood and nutrition supply and must be artificially maintained. They must be protected from two potentially destructive processes: cell crushing and loss of normal cell metabolism.[2] All treatment between the time of the accident and the ultimate replantation must be focused on preventing these two possibilities. ### Prevention of cell crushing[edit] When teeth are knocked-out, they end up on an artificial surface: the floor, the ground or material such as carpeting. If the surface is hard, the tooth root cells will be traumatized. Since the cells remaining on the tooth root are very delicate, additional trauma to the tooth root cells must be avoided so as to avoid more tooth root cell crushing. This damage can occur while picking the tooth up and/or during transportation to the dentist. When a tooth is picked up, it should always be grasped by the enamel on the crown.[13][14][20] Finger pressure on the tooth root cells will cause cell crushing. Any attempt to clean off any debris should be avoided. Debris should always be washed off gently with, at the very least, a physiologic saline. Even with the use of a physiologic saline, the “scrubbing” of the tooth root to remove debris must be avoided.[2] When placed in a physiologic solution, the tooth should be gently agitated to permit the cleansing of the tooth root. At the same time that this agitation occurs, the bumping of the tooth root against a hard surface such as glass, plastic or even cardboard must also be avoided.[2] For the same reasons, the method in which the knocked-out teeth are transported must be carefully selected.[2] Placing the knocked-out teeth in transporting vehicles such as tissues and handkerchiefs can be damaging and transporting them in glass or cardboard containers can also be potentially damaging to the cells. In addition to the potential damage that the hard surface can cause, glass containers have the added possibility of breakage or leakage of the physiologic storage fluid. If the glass container does not have a tightly fitting top, then during the transportation, the physiologic storage solution can spill out and the teeth can fall, once again, on the floor and, at the same time, be out of a physiologic environment. ### Maintenance of normal cell metabolism[edit] Normally metabolizing tooth root cells have an internal cell pressure (osmolality) of 280-300 mOs and a pH of 7.2.[21] When there is an uninterrupted blood supply, all of the metabolites (calcium, phosphate, potassium) and glucose that the cells require are provided. When the tooth is knocked-out, this normal blood supply is cut off and within 15 minutes[20] most of the stored metabolites have been depleted and the cells will begin to die. Within one to two hours, enough cells will die that rejection of the tooth by the body at a later time is the usual outcome.[22][23][24][25] The method by which the body rejects the replanted tooth is a process called “replacement root resorption”.[5] During this process, the tooth root cells become necrotic (dead) and will activate the immunologic mechanism of the body to attempt to remove this necrotic layer and literally eats away the tooth root. This is called “root resorption” It is a slow, but non-painful, process that is sometimes not observed by x-rays for years. Once this process starts, it is irreversible and the tooth will eventually fall out. In growing children, this can cause bone development problems because the replacement resorption (also termed ankylosis) attaches the tooth firmly to the jaw bone and stops normal tooth eruption and impedes normal jaw growth.[citation needed] Research has shown that the critical factor for reduction of the death of the tooth root cells and the subsequent root replacement resorption following reimplantation of knocked-out teeth is maintenance of normal cell physiology and metabolism of the cells left on the tooth root while the tooth is out of the socket.[2] In order to maintain this normalcy, the environment in which the teeth are stored must supply the optimum internal cell pressure, cell nutrients and pH.[21] ### Storage media[edit] There are many storage media available for knocked-out tooth storage. The most often recommended are: saliva, physiologic saline, milk and pH balanced cell preserving fluids. Water and ice have been shown to damage the tooth root cells, and as such, avulsed teeth should never be stored in them.[21] The osmolality and pH of water and ice is very low (7-17mOs) compared to normal cell pressure (280 mOs). When a knocked-out tooth is placed in water, the cells attempt to equalize with the surrounding environment, the cell fluid tries to move to the outside pressure environment and burst. Water with table salt in it is damaging to the knocked out teeth. Saliva, that is placing the tooth under the accident victim’s tongue or in the cheek, has been recommended. Saliva, as a storage media, causes twice damage as water. Its osmolality is very low, causing bursting of the tooth root cells, but additionally, because saliva is filled with its normal flora of microorganisms, it will severely infect the tooth root cells. When the tooth is replanted, not only will the cells be necrotic but they will also infect the bone socket.[2] Physiologic saline has a fairly compatible osmolality and will not cause cell swelling but it lacks the metabolites and glucose necessary for maintenance of normal cell metabolism.[21] Milk has been also recommended as a storage medium for avulsed teeth.[21] Its advantage is the high availability of fresh whole milk. Only whole milk can be used for tooth preservation. Skim milk and heavy cream do not have the correct fluid pressure and will cause damage to the root cells. Milk has no observed regenerative properties for cells on knocked out teeth. It was discovered 30 years ago that milk was less damaging to knocked out teeth than water or saliva. It was recommended because it has a compatible osmolality (fluid pressure) to tooth root cells and it is thought to be readily available. However, like physiologic saline, milk lacks the necessary metabolites and glucose necessary to maintain normal cell metabolism of the tooth root cells.[21] The cells on knocked-out tooth roots in milk do not die immediately but are unable to replicate (mitosis) and so are less able to reform new cells when replanted. The most optimum storage media that are available have been shown to be pH balanced cell preserving solutions.[21][26][27] The best known and most extensively tested is called Hank’s Balanced Salt Solution (HBSS).[21][26][28][29][30] It has all of the metabolites such as Ca, phosphate ions, K+ and glucose that are necessary to maintain normal cell metabolism for long periods of time.[21] HBSS has been extensively tested in dental and medical research for the past twenty years. This research has shown that 90% of cells stored in HBSS for 24 hours maintain their normal viability and after four days, still have 70%viable.[26] In research studies, extracted dog’s teeth that have been placed in HBSS for four days can still be replanted with little signs of resorption.[26] Hank's Balanced Salt Solution is found in a Save-A-Tooth, a storage device for the storage, preservation, and regeneration of tooth root cells. HBSS also has been shown to be capable of replacing lost cell metabolites.[28] Since a cell that has been cut off from its blood supply depletes its stored metabolites after fifteen minutes, a tooth that has been extra-oral for one hour has less vital cells to reconnect with the bone ligament cells. Some studies in dental research have shown that knocked out teeth that have been dry for up to one hour will have less resorption if they are soaked in a HBSS for 30 minutes prior to replantation. In these studies, dog’s teeth were extracted and left dry for 30, 45 and 60 minutes and then soaked in HBSS for 30 minutes and then reimplanted.[28] These teeth showed 50% less replacement resorption following reimplantation. It has also been shown that keeping the teeth cold while in the HBSS does not affect success. Many other types of storage liquids have been tested such as powdered milk, Enfamil, Gatorade, and contact lens solution. All of them have been shown to either be ineffective or damaging to avulsed tooth. ## Prognosis[edit] Despite the treatment provided, dental avulsion carries one of the poorest outcomes with 73-96% of the replanted teeth eventually being lost.[31] There are three main factors which significantly influence the prognosis of the tooth. These include: * The extent of damage to the periodontal ligament (PDL) at the time of injury * The storage conditions of the avulsed tooth * The duration prior to replantation [32][33][34] Dental trauma varies widely in complexity and usually there is little that lay people or professionals (excluding dentists) can do.[35] However, avulsion is the one type of traumatic dental injury where lay people can play a critical role in determining the prognosis of the tooth.[35] The tooth has the best prognosis if it is replanted within 15 minutes of the accident [20] but also has an excellent prognosis if it has been stored in an optimal storage medium within one hour of the accident.[36] PDL healing is the primary outcome measure when assessing interventions for tooth avulsion.[37] When the healing of the PDL is unfavourable it means that there is no longer protection for the root from the surrounding alveolar bone. The bone that surrounds the tooth is continually undergoing physiological remodelling. Over time, the root is gradually replaced by bone,[38] which leads to the loss of tooth root and so the crown of the tooth fractures.[37] The results of replanting permanent incisor teeth can be divided into short, medium and long term survival of the tooth.[37] If the tooth is replanted it acts in the short term to maintain space, maintain bone and provide good to excellent aesthetics.[37] If unfavourable healing has occurred, the tooth can last into the medium term on 2-10+ years[32] depending on the speed of bone turnover.[38][33] Long-term survival of the tooth only happens when favourable healing of the periodontal ligament has occurred. If this happens the tooth can be estimated to survive as long as any other tooth[37] ## Epidemiology[edit] Research has shown that more than five million teeth are knocked-out each year in the United States.[39] Dental avulsion is a type of dental trauma and the prevalence of dental trauma is estimated at 17.5% and can vary due to the geographical area.[40] Although dental trauma is relatively low, dental avulsion is the fourth most prevalent type of dental trauma.[41] Dental avulsion is more prevalent in males than females. Males are three times more likely to suffer from dental avulsion than females.[41] Up to 25% of school-aged children and military trainees and fighters experience some kind of dental trauma each year.[1][2] The incidence of dental avulsion in school aged children ranges from 0.5 to 16% of all dental trauma. Many of these teeth are knocked-out during school activities or sporting events such as contact sports, football, basketball, and hockey. It is important for anyone whom is related, working, or witnessing sports that they be educated on this subject matter. Being educated could aid in minimizing injuries that could do further harm to the victim. Being informed and spreading awareness of dental avulsion in the state of knowledge, treatment, and prevention could make an impact.[42] ## History[edit] The first reported cases of knocked-out teeth being replanted was by Pare in 1593. In 1706, Pierre Fauchard also reported replanting knocked out teeth. Wigoper in 1933 used a cast gold splint to hold reimplanted teeth in place. In 1959, Lenstrup and Skieller[43] declared that the success rate of replanted knocked out teeth should be considered a temporary procedure because the success rate of less than 10% was so poor. In 1966[36][44] in a retrospective study, Andresen theorized that 90% of avulsed teeth could be successfully retained if they were replanted within the first 30 minutes of the accident. In 1974, Cvek[45] showed that removal of the dental pulp following reimplantation was necessary to prevent resorption of the tooth root. In 1974, Cvek[45] showed that storage of knocked out teeth in saline could improve the success of replanted teeth. In 1977, Lindskog et al.[46] showed that the key to retention of the knocked-out teeth was to maintain the vitality of the periodontal ligament. In 1980, Blomlof[21] showed the storing the periodontal ligament cells in a biocompatible medium could extend the extra oral time to four hours or more. He found that the best storage medium was a medical research fluid called Hank’s Balanced Solution. In this study, it was serendipitously discovered that milk could also maintain cell viability for two hours. In 1981, Andreasen[22][23][24] showed that crushing of cells on the tooth root could cause death of the cells and lead to resorption and reduction in prognosis. In 1983, Matsson et al.[28] showed that soaking in Hank’s Balanced Solution for thirty minutes prior to reimplantation could revitalize extracted dog’s teeth that were dry for 60 minutes. In 1989,[47] a systematic storage device was developed to optimally store and preserve knocked out teeth. In 1992, Trope et al.[26] showed that extracted dog’s teeth could be stored in Hank’s Balanced Solution for up to 96 hours and still maintain significant vitality. In this study, milk was only able to maintain vitality for two hours. ## Archaeology[edit] In ancient times, ritual dental avulsion was widespread among different cultures around the world. For example, it was common during the Early Holocene (from around 11,500 BP up to 5,000 BP) in North Africa, and was occasionally observed in the Natufian culture (14,000 to 11,500 BP).[48] Such tooth avulsion was the intentional removal of one or more teeth, which was done for ritual or aesthetic reasons. It was also used to denote group affiliation. Typically the maxillary incisors were the teeth most often selected for removal. This practice is still common in parts of Africa.[49] ## See also[edit] * Medicine portal * Dental emergency * Dental trauma ## References[edit] 1. ^ a b Zadik Y, Levin L (February 2009). "Oral and facial trauma among paratroopers in the Israel Defense Forces". Dental Traumatology. 25 (1): 100–2. doi:10.1111/j.1600-9657.2008.00719.x. PMID 19208020. 2. ^ a b c d e f g h Krasner P, Rankow HJ (May 1995). "New philosophy for the treatment of avulsed teeth". Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 79 (5): 616–23. doi:10.1016/S1079-2104(05)80105-2. PMID 7600227. 3. ^ Andreasen JO (1970). "Etiology and pathogenesis of traumatic dental injuries. A clinical study of 1,298 cases". Scandinavian Journal of Dental Research. 78 (4): 329–42. doi:10.1111/j.1600-0722.1970.tb02080.x. 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PMID 3860382. 47. ^ Krasner PR, Rankow HJ, Ehrenreich A (April 1989). "Apparatus for storing and transporting traumatically avulsed teeth". Compendium (Newtown, Pa.). 10 (4): 232–4, 237–8. PMID 2605601. 48. ^ Arkadiusz Sołtysiak, Hojjat Darabi, Human remains from Ali Kosh, Iran, 2017. Bioarchaeology of the Near East, 11:76–83 (2017) Short fieldwork report. 49. ^ Pinchi, Vilma; Barbieri, Patrizia; Pradella, Francesco; Focardi, Martina; Bartolini, Viola; Norelli, Gian-Aristide (2015). "Dental Ritual Mutilations and Forensic Odontologist Practice: a Review of the Literature". Acta Stomatologica Croatica. 49 (1): 3–13. doi:10.15644/asc49/1/1. ISSN 0001-7019. PMC 4945341. PMID 27688380. ## External links[edit] Classification D * ICD-10: S03.2 * MeSH: D014084 * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Dental avulsion	c0040443	8,718	wikipedia	https://en.wikipedia.org/wiki/Dental_avulsion	2021-01-18T18:49:55	{"mesh": ["D014084"], "icd-10": ["S03.2"], "wikidata": ["Q2422102"]}
Sprengel deformity is a congenital condition characterized by abnormal development and elevation of the shoulder blade (scapula). Severity can range considerably from being almost invisible when covered with clothes, to the shoulder being elevated over 5 centimeters, with neck webbing. Signs and symptoms may include a lump in the back of the base of the neck and limited movement in the shoulder or arm. The condition may also be associated with other skeletal (bone or cartilage) or muscular abnormalities. Sprengel deformity typically occurs sporadically for no apparent reason but autosomal dominant inheritance has been reported. It is caused by an interruption of normal development and movement of the scapula during early fetal growth (probably between the 9th and 12th weeks of gestation). Treatment often includes physical therapy, but severe cases may require surgery to improve cosmetic appearance and scapular function. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Sprengel deformity	c0152438	8,719	gard	https://rarediseases.info.nih.gov/diseases/7693/sprengel-deformity	2021-01-18T17:57:31	{"mesh": ["C535802"], "omim": ["184400"], "umls": ["C0152438"], "orphanet": ["3181"], "synonyms": ["Congenital upward displacement of the scapula", "High scapula", "Sprengel's shoulder", "Congenital elevation of the scapula", "Sprengel's deformity"]}
A number sign (#) is used with this entry because short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is caused by homozygous mutation in the GSC gene (138890) on chromosome 14q32. Description Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (summary by Parry et al., 2013). Clinical Features Lemire et al. (1998) described a 9-year-old girl, the daughter of consanguineous Mennonite parents, who had a seemingly unique multiple congenital anomaly syndrome consisting of short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities. The skeletal defects consisted of bilateral humeral hypoplasia, delayed ossification of the pubic rami, and previously unreported humeroscapular synostosis. Either autosomal recessive inheritance or new autosomal dominant mutation was considered plausible. The child was the youngest of 6 children. The face was round with somewhat broad forehead, deep-set eyes, downslanting palpebral fissures, micrognathia, and small mouth with prominent incisors. The ears showed a simple, dysplastic pinnae with atretic ear canals. Ter Heide et al. (2002) described a child with auditory canal atresia and scapulohumeral synostosis who had previously been reported by Schrander-Stumpel et al. (1998). The girl was the fifth child of first-cousin Afghan parents and was noted to have simply formed external ears with bilateral auditory canal atresia, short humeri, and clubfeet. Her external genitalia were hypoplastic and ventrally displaced with the urethra ending within the vagina. She also had severe mandibular hypoplasia, proximally implanted thumbs, delayed ossification of the pubic rami, and dysplastic hips. Chromosomal studies and mental development were normal. Parry et al. (2013) reported 2 unrelated patients with SAMS. A 6-year-old boy, born of consanguineous Pakistani parents, presented at birth with respiratory insufficiency and poor feeding resulting from craniofacial abnormalities, including high-arched palate, malar hypoplasia, and severe micrognathia. He had rhizomelic shortening of the upper limbs with reduced elbow mobility, proximally placed thumbs, talipes equinovarus, cryptorchidism, and bilateral external auditory canal atresia causing hearing loss. Dysmorphic facial features included scaphocephaly with prominent forehead, slightly downslanting palpebral fissures, short upturned nose, preauricular pits, simple pinnae, and small mouth. Radiographic studies showed left humeroscapular synostosis, dislocated hips, and delayed ossification of the pelvis. The second child was born of consanguineous Bangladeshi parents. At birth, he was noted to have contractures of all limbs, rhizomelic skeletal abnormalities, talipes equinovarus, microphthalmia, micrognathia, external auditory canal atresia with conductive hearing loss, and no testes or scrotal sac. He also had feeding difficulties. Radiographic studies showed scapulohumeral synostosis, mild scapula hypoplasia, and markedly abnormal pelvic ossification, including small iliac bones, narrow sacrosciatic notches, dislocated hips, an absence of the ischial bodies, deficient medial acetabular walls, and an absence of pubic bones. Inheritance Consanguinity in the family reported by ter Heide et al. (2002) suggested autosomal recessive inheritance. Molecular Genetics In 3 unrelated patients with SAMS, including the patient previously reported by Lemire et al. (1998), Parry et al. (2013) identified homozygous truncating mutations in the GSC gene (138890.0001-138890.0003). The first mutation was found by whole-exome sequencing. A fourth patient with SAMS, previously reported by ter Heide et al. (2002), was found to carry a homozygous 306-kb deletion of chromosome 14q32.13 encompassing the entire GSC gene. The mutations segregated with the disorder in family members available for study. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Face \- Malar hypoplasia \- Micrognathia \- Mandibular hypoplasia Ears \- Atretic external auditory canal \- Abnormal middle ear ossicles \- Hearing loss, conductive \- Preauricular pits \- Dysplastic pinnae Eyes \- Deep-set eyes \- Hypotelorism \- Downslanting palpebral fissures Mouth \- Small mouth \- High-arched palate CHEST Ribs Sternum Clavicles & Scapulae \- Humero-scapulo synostosis \- Scapular hypoplasia \- Shortening of the clavicles ABDOMEN Gastrointestinal \- Feeding difficulties GENITOURINARY External Genitalia (Male) \- Lack of testes \- Lack of scrotal sac Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Contractures Skull \- Mandibular hypoplasia Pelvis \- Delayed ossification of pubic rami \- Hip dislocation \- Narrow sacrosciatic notches \- Absence of pubic bones Limbs \- Rhizomelic shortening \- Bilateral humeral hypoplasia \- Radial head dislocation Feet \- Clubfoot NEUROLOGIC Central Nervous System \- Normal intelligence MISCELLANEOUS \- Onset at birth MOLECULAR BASIS \- Caused by mutation in the goosecoid homeobox gene (GSC, 138890.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	SHORT STATURE, AUDITORY CANAL ATRESIA, MANDIBULAR HYPOPLASIA, AND SKELETAL ABNORMALITIES	c1865361	8,720	omim	https://www.omim.org/entry/602471	2019-09-22T16:13:41	{"mesh": ["C566544"], "omim": ["602471"], "orphanet": ["397623"]}
Early-onset autosomal dominant Alzheimer disease (EOAD) is a progressive dementia with reduction of cognitive functions. EOAD presents the same phenotype as sporadic Alzheimer disease (AD) but has an early age of onset, usually before 60 years old. ## Epidemiology EOAD represents less than 1% of all cases of AD. ## Clinical description Initial findings of EOAD are mainly disorders of episodic memory or changes in behavior. The patient is often anosognosic and the diagnosis is therefore carried out with the help of a family member. Neurological signs that can be associated with EOAD are spastic paraparesis, intracerebral hemorrhages, seizures, extrapyramidal syndrome and exceptionally cerebellar ataxia. ## Etiology EOAD is the consequence of either PSEN1 mutations (69%), APP mutations (13%), or APP duplication (7,5%), and exceptionally of PSEN2 mutations (2%). These mutations result in an incompletely understood cascade of events resulting in neuronal death, synapse loss, and the formation of neurofibrillary tangles and senile plaques. ## Diagnostic methods EOAD is diagnosed using the clinical criteria of the NINCDS-ADRDA(McKahnn, 1984). Brain imaging can be normal. Lumbar puncture for measurement of cerebrospinal fluid tau and amyloid may be useful (tau and phosphorylated tau are often elevated and amyloid is usually low). Age of onset before 60 years suggests an EOAD and needs a pedigree. ## Differential diagnosis Differential diagnosis includes depression and other young dementias such as frontotemporal dementia, Lewy body dementia and Huntington disease (see these terms). ## Genetic counseling Genetic counseling should be offered to the families. ## Management and treatment Management is symptomatic and includes the use of cholinesterase inhibitors and partial N-methyl-D-aspartate antagonists. Psychotrops may also be useful. ## Prognosis The disease is progressive; patients have deterioration in their behavior, cognition, and ability to perform activities of daily living. At an advanced stage, patients are confined to bed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Early-onset autosomal dominant Alzheimer disease	c0276496	8,721	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1020	2021-01-23T19:06:23	{"gard": ["12798", "632"], "mesh": ["D000544"], "omim": ["104300", "104310", "602096", "605055", "605526", "606187", "606889", "607116", "607822", "609636", "609790", "611073", "611152", "611154", "611155"], "umls": ["C0276496"], "icd-10": ["G30.0"], "synonyms": ["EOFAD", "Early-onset familial autosomal dominant Alzheimer disease", "Familial Alzheimer disease"]}
Junctional epidermolysis bullosa with pyloric atresia is a severe subtype of junctional epidermolysis bullosa (JEB, see this term) characterized by generalized blistering at birth and congenital atresia of the pylorus and rarely of other portions of the gastrointestinal tract. ## Epidemiology Prevalence is unknown. More than 100 cases have been reported worldwide. ## Clinical description Skin manifestations include severe blistering, atrophic scarring, and nail dystrophy. Congenital absence of skin (aplasia cutis congenita) is present in approximately 20% of cases, and ear anomalies are also relatively common. The manifestations of pyloric atresia include vomiting, abdomen distension, and an absence of stools. Patients present oral cavity involvement and enamel hypoplasia. Other extracutaneous manifestations include involvement of the respiratory, gastrointestinal and genitourinary tracts. In particular, genitourinary malformations and acquired genitourinary abnormalities (polypoid bladder wall lesions, hemorrhagic cystitis, urethral strictures) are relatively frequent and characteristic. Growth delay and anemia, secondary to the extensive cutaneous and mucosal lesions, are common. Polyhydramnios, secondary to pyloric atresia, is usually present in pregnancies with an affected fetus. Some patients with an identical presentation have been found to have intraepidermal rather than intra-lamina lucida blister formation, necessitating their inclusion under the rarer subtypes of EB simplex rather than under junctional EB. ## Etiology The condition is caused by mutations in either of the genes encoding the two subunits of alpha6-beta4 integrin, ITGA6 (2q31.1) and ITGB4 (17q11-qter). ## Diagnostic methods Diagnosis in neonates is suspected based on clinical findings of skin fragility and gastric outlet obstruction. In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone by immunofluorescence antigen mapping and/or transmission electron microscopy, a negative or highly reduced immunofluorescence staining for integrin alpha6beta4 is typical of JEB-PA. Genetic testing is possible but is not necessary to confirm the diagnosis. ## Antenatal diagnosis For pregnancies at risk, genetic testing for prenatal diagnosis is required if the disease-causing mutations have been identified in the family. ## Genetic counseling The condition follows an autosomal recessive pattern of inheritance. ## Management and treatment Pyloric atresia must be corrected surgically. ## Prognosis JEB-PA leads in most cases to early death. Prognosis depends predominantly on the prompt surgical correction of pyloric atresia. Among patients in whom this is successful, a minority show mild skin involvement or a gradual improvement of blistering lesions and survive until adulthood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Junctional epidermolysis bullosa-pyloric atresia syndrome	c1856934	8,722	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79403	2021-01-23T18:49:48	{"gard": ["9694"], "mesh": ["C535377"], "omim": ["226730"], "umls": ["C1856934"], "icd-10": ["Q81.8"], "synonyms": ["Carmi syndrome", "JEB-PA"]}
Urinary retention Other namesIschuria, bladder failure, bladder obstruction Urinary retention with greatly enlarged bladder as seen by CT scan. SpecialtyEmergency medicine, urology SymptomsSudden onset: Inability to urinate, low abdominal pain[1] Long term: Frequent urination, loss of bladder control, urinary tract infection[1] TypesAcute, chronic[1] CausesBlockage of the urethra, nerve problems, certain medications, weak bladder muscles[1] Diagnostic methodAmount of urine in the bladder post urination[1] TreatmentCatheter, urethral dilation, urethral stents, surgery[1] MedicationAlpha blockers such as terazosin, 5α-reductase inhibitors such as finasteride[1] Frequency6 per 1,000 per year (males > 40 years old)[1] Urinary retention is an inability to completely empty the bladder.[1] Onset can be sudden or gradual.[1] When of sudden onset, symptoms include an inability to urinate and lower abdominal pain.[1] When of gradual onset, symptoms may include loss of bladder control, mild lower abdominal pain, and a weak urine stream.[1] Those with long-term problems are at risk of urinary tract infections.[1] Causes include blockage of the urethra, nerve problems, certain medications, and weak bladder muscles.[1] Blockage can be caused by benign prostatic hyperplasia (BPH), urethral strictures, bladder stones, a cystocele, constipation, or tumors.[1] Nerve problems can occur from diabetes, trauma, spinal cord problems, stroke, or heavy metal poisoning.[1] Medications that can cause problems include anticholinergics, antihistamines, tricyclic antidepressants, decongestants, cyclobenzaprine, diazepam, NSAIDs, amphetamines, and opioids.[1] Diagnosis is typically based on measuring the amount of urine in the bladder after urinating.[1] Treatment is typically with a catheter either through the urethra or lower abdomen.[1][2] Other treatments may include medication to decrease the size of the prostate, urethral dilation, a urethral stent, or surgery.[1] Males are more often affected than females.[1] In males over the age of 40 about 6 per 1,000 are affected a year.[1] Among males over 80 this increases 30%.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Bladder * 2.2 Prostate * 2.3 Postoperative * 2.4 Chronic * 2.5 Other * 3 Diagnosis * 4 Complications * 5 Treatment * 5.1 Medication * 5.2 Catheter * 5.3 Surgery * 5.4 Sitting voiding position * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Onset can be sudden or gradual.[1] When of sudden onset, symptoms include an inability to urinate and lower abdominal pain.[1] When of gradual onset, symptoms may include loss of bladder control, mild lower abdominal pain, and a weak urine stream.[1] Those with long-term problems are at risk of urinary tract infections.[1] ## Causes[edit] ### Bladder[edit] * Detrusor sphincter dyssynergia * Neurogenic bladder (commonly spinal cord damage, pelvic splanchic nerve damage, cauda equina syndrome, pontine micturition or storage center lesions, demyelinating diseases or Parkinson's disease) * Iatrogenic (caused by medical treatment/procedure) scarring of the bladder neck (commonly from removal of indwelling catheters or cystoscopy operations) * Damage to the bladder ### Prostate[edit] * Benign prostatic hyperplasia (BPH) * Prostate cancer and other pelvic malignancies * Prostatitis Penile urethra: * Congenital urethral valves * Phimosis or pinhole meatus * Circumcision * Obstruction in the urethra, for example a stricture (usually caused either by injury or STD), a metastasis or a precipitated pseudogout crystal in the urine * STD lesions (gonorrhoea causes numerous strictures, leading to a "rosary bead" appearance, whereas chlamydia usually causes a single stricture) * Emasculation ### Postoperative[edit] Risk factors include * Age: Older people may have degeneration of neural pathways involved with bladder function and it can lead to an increased risk of postoperative urinary retention.[3] The risk of postoperative urinary retention increases up to 2.11 fold for people older than 60 years.[3] * Medications: Anticholinergics and medications with anticholinergic properties, alpha-adrenergic agonists, opiates, nonsteroidal anti-inflammatories (NSAIDs), calcium-channel blockers and beta-adrenergic agonists, may increase the risk.[3] * Anesthesia: General anesthetics during surgery may cause bladder atony by acting as a smooth muscle relaxant.[3] General anesthetics can directly interfere with autonomic regulation of detrusor tone and predispose people to bladder overdistention and subsequent retention.[3] Spinal anesthesia results in a blockade of the micturition reflex.[3] Spinal anesthesia shows a higher risk of postoperative urinary retention compared to general anesthesia.[3] * Benign prostatic hyperplasia: Men with benign prostatic hyperplasia are at an increased risk of acute urinary retention.[3] * Surgery related: Operative times longer than 2 hours may lead to an increased risk of postoperative urinary retention 3-fold.[3] ### Chronic[edit] Chronic urinary retention that is due to bladder blockage which can either be as a result of muscle damage or neurological damage.[4] If the retention is due to neurological damage, there is a disconnect between the brain to muscle communication, which can make it impossible to completely empty the bladder.[4] If the retention is due to muscle damage, it is likely that the muscles are not able to contract enough to completely empty the bladder.[4] The most common cause of chronic urinary retention is BPH.[1] BPH is a result of the ongoing process of testosterone being converted to dihydrotestosterone which stimulates prostate growth.[5] Over a person's lifetime, the prostate experiences constant growth due to the conversion of testosterone to dihydrotestosterone.[5] This can cause the prostate to push on the urethra and block it, which can lead to urinary retention.[5] ### Other[edit] * Tethered spinal cord syndrome * Psychogenic causes (psychosocial stresses, fear associated with urination, paruresis ("shy bladder syndrome")- in extreme cases, urinary retention can result) * Consumption of some psychoactive substances, mainly stimulants, such as MDMA and amphetamine. * Use of NSAIDs or drugs with anticholinergic properties. * Stones or metastases can theoretically appear anywhere along the urinary tract, but vary in frequency depending on anatomy * Muscarinic antagonist such as atropine and scopolamine * Malfunctioning artificial urinary sphincter ## Diagnosis[edit] As seen on axial CT Ultrasonography showing a trabeculated wall, seen as small irregularities mainly at left (superior part). This is strongly associated with urinary retention.[6] Analysis of urine flow may aid in establishing the type of micturition (urination) abnormality. Common findings, determined by ultrasound of the bladder, include a slow rate of flow, intermittent flow, and a large amount of urine retained in the bladder after urination. A normal test result should be 20-25 mL/s peak flow rate. A post-void residual urine greater than 50 ml is a significant amount of urine and increases the potential for recurring urinary tract infections. In adults older than 60 years, 50-100 ml of residual urine may remain after each voiding because of the decreased contractility of the detrusor muscle.[4] In chronic retention, ultrasound of the bladder may show massive increase in bladder capacity (normal capacity is 400-600 ml). Non-neurogenic chronic urinary retention does not have a standardized definition; however, urine volumes >300mL can be used as an informal indicator.[4] Diagnosis of urinary retention is conducted over a period of 6 months, with 2 separate measurements of urine volume 6 months apart. Measurements should have a PVR (post-void residual) volume of >300mL.[4] Determining the serum prostate-specific antigen (PSA) may help diagnose or rule out prostate cancer, though this is also raised in BPH and prostatitis. A TRUS biopsy of the prostate (trans-rectal ultra-sound guided) can distinguish between these prostate conditions. Serum urea and creatinine determinations may be necessary to rule out backflow kidney damage. Cystoscopy may be needed to explore the urinary passage and rule out blockages. In acute cases of urinary retention where associated symptoms in the lumbar spine are present such as pain, numbness (saddle anesthesia), parasthesias, decreased anal sphincter tone, or altered deep tendon reflexes, an MRI of the lumbar spine should be considered to further assess cauda equina syndrome. ## Complications[edit] Play media The urinary bag of a person with post obstructive diuresis Urinary retention often occurs without warning. It is basically the inability to pass urine. In some people, the disorder starts gradually but in others it may appear suddenly. Acute urinary retention is a medical emergency and requires prompt treatment. The pain can be excruciating when urine is not able to flow out. Moreover, one can develop severe sweating, chest pain, anxiety and high blood pressure. Other patients may develop a shock-like condition and may require admission to a hospital. Serious complications of untreated urinary retention include bladder damage and chronic kidney failure.[7] Urinary retention is a disorder treated in a hospital, and the quicker one seeks treatment, the fewer the complications. In the longer term, obstruction of the urinary tract may cause: * Bladder stones * Atrophy of the detrusor muscle (atonic bladder is an extreme form) * Hydronephrosis (congestion of the kidneys) * Hypertrophy of the detrusor muscle (the muscle that squeezes the bladder to empty it during urination) * Diverticula (formation of pouches) in the bladder wall (which can lead to stones and infection) ## Treatment[edit] In acute urinary retention, urinary catheterization, placement of a prostatic stent, or suprapubic cystostomy relieves the retention. In the longer term, treatment depends on the cause. BPH may respond to alpha blocker and 5-alpha-reductase inhibitor therapy, or surgically with prostatectomy or transurethral resection of the prostate (TURP). Use of alpha-blockers can provide relief of urinary retention following de-catheterization for both men and women.[8][9] In case, if catheter can't be negotiated, suprapubic puncture can be done with lumbar puncture needle. ### Medication[edit] Some people with BPH are treated with medications. These include tamsulosin to relax smooth muscles in the bladder neck, and finasteride and dutasteride to decrease prostate enlargement. The drugs only work for mild cases of BPH but also have mild side effects. Some of the medications decrease libido and may cause dizziness, fatigue and lightheadedness. ### Catheter[edit] Acute urinary retention is treated by placement of a urinary catheter (small thin flexible tube) into the bladder. This can be either an intermittent catheter or a Foley catheter that is placed with a small inflatable bulb that holds the catheter in place. Intermittent catheterization can be done by a health care professional or by the person themselves (clean intermittent self catheterization). Intermittent catheterization performed at the hospital is a sterile technique. Patients can be taught to use a self catheterization technique in one simple demonstration,[10] and that reduces the rate of infection from long-term Foley catheters. Self catheterization requires doing the procedure periodically during the day, the frequency depending on fluid intake and bladder capacity. If fluid intake/outflow is around 1.5 litres per day, this would typically be performed roughly three times per day, i.e. roughly every six to eight hours during the day, more frequently when fluid intake is higher and/or bladder capacity lower. For acute urinary retention, treatment requires urgent placement of a urinary catheter. A permanent urinary catheter may cause discomfort and pain that can last several days. Older people with ongoing problems may require continued intermittent self catheterization (CISC). CISC has a lower infection risk compared to catheterization techniques that stay within the body.[10] Challenges with CISC include compliance issues as some people may not be able to place the catheter themselves.[11] ### Surgery[edit] The chronic form of urinary retention may require some type of surgical procedure. While both procedures are relatively safe, complications can occur. In most patients with benign prostate hyperplasia (BPH), a procedure known as transurethral resection of the prostate (TURP) may be performed to relieve bladder obstruction.[12] Surgical complications from TURP include a bladder infection, bleeding from the prostate, scar formation, inability to hold urine, and inability to have an erection. The majority of these complications are short lived, and most individuals recover fully within 6–12 months.[13] ### Sitting voiding position[edit] A meta-analysis on the influence of voiding position on urodynamics in males with lower urinary tract symptoms (LUTS) showed that in the sitting position, the residual urine in the bladder was significantly reduced, the maximum urinary flow was increased, and the voiding time was decreased. For healthy males, no influence was found on these parameters, meaning that they can urinate in either position.[14] ## Epidemiology[edit] Urinary retention is a common disorder in elderly males. The most common cause of urinary retention is BPH. This disorder starts around age 50 and symptoms may appear after 10–15 years. BPH is a progressive disorder and narrows the neck of the bladder leading to urinary retention. By the age of 70, almost 10 percent of males have some degree of BPH and 33% have it by the eighth decade of life. While BPH rarely causes sudden urinary retention, the condition can become acute in the presence of certain medications (blood pressure pills, anti histamines, antiparkinson medications), after spinal anaesthesia or stroke. In young males, the most common cause of urinary retention is infection of the prostate (acute prostatitis). The infection is acquired during sexual intercourse and presents with low back pain, penile discharge, low grade fever and an inability to pass urine. The exact numbers of individuals with acute prostatitis is unknown, because many do not seek treatment. In the US, at least 1-3 percent of males under the age of 40 develop urinary difficulty as a result of acute prostatitis. Most physicians and other health care professionals are aware of these disorders. Worldwide, both BPH and acute prostatitis have been found in males of all races and ethnic backgrounds. Cancers of the urinary tract can cause urinary obstruction but the process is more gradual. Cancer of the bladder, prostate or ureters can gradually obstruct urine output. Cancers often present with blood in the urine, weight loss, lower back pain or gradual distension in the flanks.[15] Urinary retention in females is uncommon, occurring 1 in 100,000 every year, with a female-to-male incidence rate of 1:13. It is usually transient. The causes of UR in women can be multi-factorial, and can be postoperative and postpartum. Prompt urethral catheterization usually resolves the problem.[16] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab "Urinary Retention". National Institute of Diabetes and Digestive and Kidney Diseases. Aug 2014. Archived from the original on 4 October 2017. Retrieved 24 October 2017. 2. ^ Sliwinski, A; D'Arcy, FT; Sultana, R; Lawrentschuk, N (April 2016). "Acute urinary retention and the difficult catheterization: current emergency management". European Journal of Emergency Medicine. 23 (2): 80–8. doi:10.1097/MEJ.0000000000000334. PMID 26479738. 3. ^ a b c d e f g h i Kowalik, Urszula; Plante, Mark K. (June 2016). "Urinary Retention in Surgical Patients". The Surgical Clinics of North America. 96 (3): 453–467. doi:10.1016/j.suc.2016.02.004. ISSN 1558-3171. PMID 27261788. 4. ^ a b c d e f Stoffel, JT (September 2017). "Non-neurogenic Chronic Urinary Retention: What Are We Treating?". Current Urology Reports. 18 (9): 74. doi:10.1007/s11934-017-0719-2. PMID 28730405. 5. ^ a b c Herati, AS; Kohn, TP; Butler, PR; Lipshultz, LI (June 2017). "Effects of Testosterone on Benign and Malignant Conditions of the Prostate". Current Sexual Health Reports. 9 (2): 65–73. doi:10.1007/s11930-017-0104-7. PMC 5648355. PMID 29056882. 6. ^ Page 306 in:Sam D. Graham, Thomas E. Keane, James Francis Glenn (2010). Glenn's Urologic Surgery. Lippincott Williams & Wilkins. ISBN 9780781791410.CS1 maint: multiple names: authors list (link) 7. ^ General information on urinary retention Archived 2010-02-20 at the Wayback Machine 2010-02-10 8. ^ Fisher, Euan; Subramonian, Kesavapillai; Omar, Muhammad Imran (2014-06-10). "The role of alpha blockers prior to removal of urethral catheter for acute urinary retention in men". The Cochrane Database of Systematic Reviews (6): CD006744. doi:10.1002/14651858.CD006744.pub3. ISSN 1469-493X. PMID 24913721. 9. ^ Drake, MarcusJ; Mevcha, Amit (2010-04-01). "Etiology and management of urinary retention in women". Indian Journal of Urology. 26 (2): 230–5. doi:10.4103/0970-1591.65396. PMC 2938548. PMID 20877602. 10. ^ a b "Clean Intermittent Self-Catheterization". Archived from the original on 2017-07-16. 11. ^ Seth, Jai H.; Haslam, Collette; Panicker, Jalesh N. (2014). "Ensuring patient adherence to clean intermittent self-catheterization". Patient Preference and Adherence. 8: 191–198. doi:10.2147/PPA.S49060. ISSN 1177-889X. PMC 3928402. PMID 24611001. 12. ^ eMedicine Health. "Inability to urinate" Archived 2010-03-05 at the Wayback Machine 2010-02-10. 13. ^ National kidney and urologic diseases information clearinghouse. "Urinary retention overview" Archived 2010-01-29 at the Wayback Machine 2010-02-10. 14. ^ Phillips, Robert S.; de Jong, Ype; Pinckaers, Johannes Henricus Francisca Maria; ten Brinck, Robin Marco; Lycklama à Nijeholt, Augustinus Aizo Beent; Dekkers, Olaf Matthijs (2014). "Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis". PLoS ONE. 9 (7): e101320. doi:10.1371/journal.pone.0101320. PMC 4106761. PMID 25051345. 15. ^ Urologic Emergencies Archived 2010-03-10 at the Wayback Machine Urology Channel portal. 2010-02-10 16. ^ Özveren, B; Keskin, S (2016). "Presentation and prognosis of female acute urinary retention: Analysis of an unusual clinical condition in outpatients". Urology Annals. 8 (4): 444–448. doi:10.4103/0974-7796.192111. PMC 5100150. PMID 28057989. ## External links[edit] Classification D * ICD-10: R33 * ICD-9-CM: 788.2 * MeSH: D016055 * DiseasesDB: 13582 External resources * Patient UK: Urinary retention * v * t * e Symptoms and signs relating to the urinary system Pain * Dysuria * Renal colic * Costovertebral angle tenderness * Vesical tenesmus Control * Urinary incontinence * Enuresis * Diurnal enuresis * Giggling * Nocturnal enuresis * Post-void dribbling * Stress * Urge * Overflow * Urinary retention Volume * Oliguria * Anuria * Polyuria Other * Lower urinary tract symptoms * Nocturia * urgency * frequency * Extravasation of urine * Uremia Eponymous * Addis count * Brewer infarcts * Lloyd's sign * Mathe's sign [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Urinary retention	c0080274	8,723	wikipedia	https://en.wikipedia.org/wiki/Urinary_retention	2021-01-18T19:06:41	{"mesh": ["D016055"], "umls": ["C0080274"], "icd-9": ["788.2"], "icd-10": ["R33"], "wikidata": ["Q1366695"]}
Carpenter et al. (1987) described a boy who at age 3 complained of severe leg pains and was found to have periosteal new bone formation in several bones, increased intracranial pressure with splayed cranial sutures, and hypercalcemia. An erythematous, exfoliative rash, alopecia totalis, liver disease, and ascites ensued. He died of renal failure associated with severe coagulopathy, pneumonia, and sepsis. The main source of extra vitamin A was thought to be a chicken liver spread. This had been ingested also by the younger brother who likewise had recurrent otitis media from an early age and later developed leg pain and nausea with papilledema. A marked restriction of vitamin A was inadequate in controlling recurrent and severe disease. For that reason, 2-hydroxypropyl-beta-cyclodextrin was used in an attempt to increase urinary excretion of vitamin A. Because both parents and a sister had similar intake of vitamin A, unusual intolerance of vitamin A was suspected on a genetic basis in the 2 brothers. The family was of European-Jewish extraction; the parents were not related. Schurr et al. (1983) described a similar case in a patient of European-Jewish extraction and likewise postulated heritable variability in vitamin A tolerance. Skel \- Leg pain \- Periosteal new bone formation GU \- Renal failure Lab \- Hypercalcemia Skin \- Erythematous, exfoliative rash \- Alopecia totalis HEENT \- Increased intracranial pressure \- Splayed cranial sutures \- Papilledema Inheritance \- Autosomal recessive GI \- Nausea \- Liver disease \- Ascites Heme \- Coagulopathy ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	HYPERVITAMINOSIS A, SUSCEPTIBILITY TO	c1855883	8,724	omim	https://www.omim.org/entry/240150	2019-09-22T16:26:40	{"omim": ["240150"]}
SC(1) is a component of saliva demonstrated immunoelectrophoretically. The precise mechanism of genetic control has not been determined although the importance of genetic factors has been demonstrated (Niswander et al., 1964) by family data and twin studies. Environmental influences seem rather strong. The component is lacking from serum. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	SC(1) TRAIT OF SALIVA	c1867022	8,725	omim	https://www.omim.org/entry/181200	2019-09-22T16:35:01	{"omim": ["181200"]}
Peripheral artery disease Other namesPeripheral vascular disease (PVD), peripheral artery occlusive disease, peripheral obliterative arteriopathy An arterial insufficiency ulcer in a person with severe peripheral artery disease[1] SpecialtyInterventional radiology, vascular surgery SymptomsLeg pain when walking which resolves with rest, skin ulcers, bluish skin, cold skin[2][3] ComplicationsInfection, amputation[4] CausesAtherosclerosis, artery spasm[5][6] Risk factorsCigarette smoking, diabetes, high blood pressure, high blood cholesterol.[4][7] Diagnostic methodAnkle-brachial index < 0.90, duplex ultrasonography, angiography[8][9] TreatmentStopping smoking, supervised exercise therapy, surgery[10][11][12] MedicationStatins, ACE inhibitors, cilostazol[12] Frequency155 million (2015)[13] Deaths52,500 (2015)[14] Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain.[5][15] When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular disease.[4] Peripheral artery disease most commonly affects the legs, but other arteries may also be involved – such as those of the arms, neck, or kidneys.[4][16] The classic symptom is leg pain when walking which resolves with rest, known as intermittent claudication.[2] Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg.[3] Complications may include an infection or tissue death which may require amputation; coronary artery disease, or stroke.[4] Up to 50% of people with PAD do not have symptoms.[2] The greatest risk factor for PAD is cigarette smoking.[4] Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol.[7][17] The most common underlying mechanism of peripheral artery disease is atherosclerosis, especially in individuals over 40 years old.[6][18] Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis.[5][17] PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm.[9] Duplex ultrasonography and angiography may also be used.[8] Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.[9] It is unclear if screening for peripheral artery disease in people without symptoms is useful as it has not been properly studied.[19][20][18] In those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy improve outcomes.[11][12] Medications, including statins, ACE inhibitors, and cilostazol may also help.[12][21] Aspirin does not appear to help those with mild disease but is usually recommended in those with more significant disease due to the increased risk of heart attacks.[18][22][23] Anticoagulants such as warfarin are not typically of benefit.[24] Procedures used to treat the disease include bypass grafting, angioplasty, and atherectomy.[10] In 2015, about 155 million people had PAD worldwide.[13] It becomes more common with age.[25] In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds.[7] In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90.[7] PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected.[7] In 2015 PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.[14][26] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Risk factors * 2.2 High risk populations * 3 Mechanism * 4 Diagnosis * 4.1 Classification * 4.2 Screening * 5 Treatment * 5.1 Lifestyle * 5.2 Medication * 5.3 Revascularization * 5.4 Guidelines * 6 Prognosis * 7 Epidemiology * 8 Research * 9 References * 10 External links ## Signs and symptoms[edit] Peripheral arterial disease resulting in necrosis of multiple toes[27] The signs and symptoms of peripheral artery disease are based on the part of the body that is affected. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms.[17] The most common presenting symptom is intermittent claudication, which causes pain and severe cramping when walking or exercising. The pain is usually located in the calf muscles of the affected leg and relieved by rest. This occurs because during exercise the muscles of the leg need more oxygen and in an unaffected leg, the arteries would be able to increase the amount of blood and therefore oxygen going to the exercised leg. However, when there is a narrowing, the artery is unable to meet the increased demand for oxygen by the muscles. In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction to blood flow in the artery is compromised to the point where the blood is unable to maintain oxygenation of tissue at rest.[17] This can lead to pain at rest, feeling of cold, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss, arterial insufficiency ulcers, erectile dysfunction, and gangrene.[28] People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications are irreversible. ## Causes[edit] ### Risk factors[edit] The illustration shows how PAD can affect arteries in the legs. Figure A shows a normal artery with normal blood flow. The inset image shows a cross-section of the normal artery. Figure B shows an artery with plaque buildup that is partially blocking blood flow. The inset image shows a cross-section of the narrowed artery. Factors contributing to increased risk of PAD are the same as those for atherosclerosis.[29][30] These include age, sex, and ethnicity.[31] PAD is two times as common in males as females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio.[citation needed] * Smoking – tobacco use in any form is the single greatest risk factor of peripheral artery disease internationally. Smokers have up to a 10-fold increase in risk of PAD in a dose-response relationship.[30] Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease.[32] Greater than 80%-90% of patients with lower extremity peripheral arterial disease are current or former smokers.[33] The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.[34][35] * High blood sugar – Diabetes mellitus is shown to increase risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries.[36][37][38] The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.[39] * High blood cholesterol – Dyslipidemia, which is an abnormally high level of cholesterol or fat in the blood.[31] Dyslipidemia is caused by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels have been correlated with accelerated peripheral artery disease. Management of Dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.[40] * High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.[41] * Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A.[42] Individuals with increased levels of homocysteine in their blood have a 2-fold risk of peripheral artery disease.[31] While there are genetics leading to risk factors for peripheral artery disease, including diabetes and high blood pressure; there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.[31] ### High risk populations[edit] Peripheral arterial disease is more common in these populations:[35][43] * All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain * All people aged 65 years and over regardless of risk factor status * All people between 50 and 69 and who have a cardiovascular risk factor (particularly diabetes or smoking) * Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia) * Individuals with an abnormal lower extremity pulse examination * Those with known atherosclerotic coronary, carotid, or renal artery disease * All people with a Framingham risk score of 10%–20% * All people who have previously experienced chest pain ## Mechanism[edit] Illustration of how the buildup of lipids cause a blockage of blood flow to the portion of the artery below the narrowing. As previously mentioned, the most common cause of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis.[17] Atherosclerosis is a narrowing of the arteries caused by lipid or fat build up and calcium deposition in the wall of the affected arteries. The most commonly affected site occurs at arterial branch points, because there is an increase in turbulence and stress on the artery at these areas where the artery branches to supply distant structures. Disease of distant structures, including feet and toes, are usually caused by diabetes and seen in the elderly population. Additional mechanisms of peripheral artery disease including arterial spasm, thrombosis, and fibromuscular dysplasia.[17] The mechanism of arterial spasm is still being studied, but it can occur secondary to trauma.[44] The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Similar to atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, occurs usually due stasis or trauma.[44] Damage to the lining of the blood vessel begins the process of clot formation. The blood clot ultimately creates a narrowing in the artery preventing adequate blood flow and oxygen to the tissue further down. ## Diagnosis[edit] Measuring the ankle-brachial index Diagnosing or identifying peripheral artery disease requires history of symptoms and a physical exam followed by confirmatory testing.[18] In the setting of symptoms consistent with peripheral artery disease a physician will then examine an individual for specific exam findings. Abnormal physical exam findings can lead a health care provider to consider a specific diagnosis.[17] However, in order to confirm a diagnosis, confirmatory testing is required.[18] These findings are associated with peripheral artery disease:[17] * Decreased or absent pulses * Muscle atrophy or wasting * Noticeable blueness of the affected limb * Decreased temperature (coolness) in affected limb when compared to the other * Thickened nails * Smooth or shiny skin and hair loss * Buerger's test can check for pallor when the affected limb is in an elevated position. The limb is then moved from elevated to sitting position and is checked for redness, which is called reactive hyperemia. Buerger's test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to. If peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI).[18] The ABI is a simple, non-invasive test, which measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected. An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if an ABI is less than 0.40. These categories can provide insight into the disease course.[35] Furthermore, ABI values of 0.91 to 0.99 are considered borderline and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives and thus, such results merit further investigation and higher-level studies.[45] Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within a two-year period.[46] In individuals with suspected PAD with normal ABIs can undergo exercise testing of ABI. A baseline ABI is obtained prior to exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.[35][43] If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and extent of atherosclerosis. Other imaging can be performed by angiography,[29] where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography. Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis and lower extremities in one sitting.[47][48] ### Classification[edit] Gangrene of three toes resulting from peripheral artery disease The two most commonly used methods to classify peripheral artery disease are the Fontaine and the Rutherford systems of classification.[49] The Fontaine stages, were introduced by René Fontaine in 1954 to define severity of chronic limb ischemia:[43][49][50] * Stage I: asymptomatic * Stage IIa: intermittent claudication after walking a distance of more than 200 meters * Stage IIb: intermittent claudication after walking a distance of less than 200 meters * Stage III: rest pain * Stage IV: ulcers or gangrene of the limb The Rutherford classification was created by the Society for Vascular Surgery and International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):[43][51] * Grade 0, Category 0: asymptomatic * Grade I, Category 1: mild claudication * Grade I, Category 2: moderate claudication * Grade I, Category 3: severe claudication * Grade II, Category 4: rest pain * Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot * Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene Moderate to severe PAD classified by Fontaine's stages III to IV or Rutherford's categories 4 to 5, presents limb threat (risk of limb loss) in the form of critical limb ischemia.[52] Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot Infection" (WIfI).[53] This classification system, published in 2013 was created to account for the demographic changes that have occurred over the past forty years including increased incidence of high blood sugar and evolving techniques and ability for revascularization. This system was created on the basis of ischemia and angiographic disease patterns not being the sole determinants of amputation risk.[54] The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 on the presence of ulceration and/or gangrene and ischemia.[53] * Grade 0: no ulcer, no gangrene * Grade 1: small, shallow ulcer; no gangrene * Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes * Grade 3: extensive, full-thickness ulcer; gangrene extending to forefoot or midfoot Ischemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.[53] * Grade 0: ABI 0.8 or higher, ankle * Grade 1: arterial brachial index 0.6 to 0.79, ankle pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg * Grade 2: ABI 0.4–0.59, ankle pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg The TASC (and TASC II) classification suggested PAD treatment is based on the severity of disease seen on angiogram.[43] ### Screening[edit] It is not clear if screening for disease in the general population is useful as it has not been properly studied.[19] This includes screening with the ankle-brachial index.[55] Testing for coronary artery disease or carotid artery disease is of unclear benefit.[18] While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms.[18] In people with symptomatic PAD screening by ultrasound for AAA is not unreasonable.[18] ## Treatment[edit] Depending on the severity of the disease, these steps can be taken, according to these guidelines:[56] ### Lifestyle[edit] * Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease) * Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week[29]) has been reviewed as another treatment with a number of positive outcomes, including reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD. ### Medication[edit] * Management of diabetes * Management of hypertension * Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, can help with disease progression, and address the other cardiovascular risks that the affected person is likely to have. According to guidelines, taking aspirin or clopidogrel is recommended to reduce MI, stroke, and other causes of vascular death in people with symptomatic peripheral artery disease.[18] The effectiveness of both aspirin and clopidogrel, to reduce risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.[57] Cilostazol can improve symptoms in some.[21] Pentoxifylline is of unclear benefit.[58] Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.[21] Treatment with other drugs or vitamins are unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".[56] ### Revascularization[edit] After a trial of the best medical treatment outline above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss such as wound and infection severity.[54] * 3D Medical Animation still shot depicting the Vascular Bypass Grafting Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits.[59] Patency rates following angioplasty are highest for iliac arteries, and decrease with arteries towards the toes. Other criteria that affect outcome following revascularization are length of lesion and number of lesions.[60][61] There does not appear to be long term advantages or sustained benefit to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.[62] * Atherectomy, in which the plaque is scraped off of the inside of the vessel wall (albeit with no better results than angioplasty).[63] * Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable. * When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness. * Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism. ### Guidelines[edit] A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines.[35] For chronic limb threatening ischemia the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years, or who have an autogenous vein, bypass surgery is recommended.[64] ## Prognosis[edit] Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology";[65] prognosis is correlated with the severity of the PAD as measured by an ABI.[65] Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".[65] The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication.[56] Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".[65] ## Epidemiology[edit] The prevalence of PAD in the general population is 12–14%, affecting up to 20% of those over 70;[65] 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation.[citation needed] Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment. In people aged 40 years and older in the United States in 2000, rates of PAD was 4.3%.[66] Rates were 14.5% people aged 70 years or over. Within age groups, rates were generally higher in women than men. Non-Hispanic blacks had a rates of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%)in Mexican Americans.[66] The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four- to five-fold higher risk of heart attack or stroke. The Diabetes Control and Complications Trial, and the U.K. Prospective Diabetes Study trials, in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries.[67] ## Research[edit] Research is being done on therapies to prevent progression of PAD.[68] In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.[69] Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD.[70] The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints.[71] As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial, and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.[72][73] In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for treatment of PAD, including the advanced stage of critical limb ischemia.[74][75] ## References[edit] 1. ^ Moore, Jonathan (September 1, 2008). "Creating the Ideal Microcosm for Rapid Incorporation of Bioengineered Alternative Tissues Using An Advanced Hydrogel Impregnated Gauze Dressing: A Case Series". The Foot & Ankle Journal. doi:10.3827/faoj.2008.0109.0002. 2. ^ a b c Violi, F; Basili, S; Berger, JS; Hiatt, WR (2012). Antiplatelet therapy in peripheral artery disease. Handbook of Experimental Pharmacology. 210. pp. 547–63. doi:10.1007/978-3-642-29423-5_22. ISBN 978-3-642-29422-8. PMID 22918746. 3. ^ a b "What Are the Signs and Symptoms of Peripheral Arterial Disease?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 26, 2015. 4. ^ a b c d e f "What Is Peripheral Arterial Disease?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 25, 2015. 5. ^ a b c "What Is Peripheral Vascular Disease?" (PDF). American Heart Association (heart.org). 2012. Archived (PDF) from the original on April 12, 2015. Retrieved February 26, 2015. 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"2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary". Circulation. 135 (12): e686–e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332. Classification D * ICD-10: I73.9 * ICD-9-CM: 443.9 * MeSH: D016491 * DiseasesDB: 31142 External resources * MedlinePlus: 000170 * eMedicine: med/391 emerg/862 * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Peripheral artery disease	c1704436	8,726	wikipedia	https://en.wikipedia.org/wiki/Peripheral_artery_disease	2021-01-18T18:56:37	{"mesh": ["D058729"], "umls": ["C1704436"], "icd-10": ["I73.9"], "wikidata": ["Q378681"]}
Sulfonamide hypersensitivity syndrome Sulfonamide hypersensitivity syndrome is similar to anticonvulsant hypersensitivity syndrome, but the onset is often sooner in the treatment course, generally after 7–14 days of therapy.[1]:118–9 It is considered immune-mediated.[2] ## See also[edit] * 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 0721629210. 2. ^ Cribb AE, Pohl LR, Spielberg SP, Leeder JS (August 1997). "Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins". J. Pharmacol. Exp. Ther. 282 (2): 1064–71. PMID 9262376. ## External links[edit] Classification D * ICD-10: Y40 * ICD-9-CM: E930.8 * v * t * e Adverse drug reactions Antibiotics * Penicillin drug reaction * Sulfonamide hypersensitivity syndrome * Urticarial erythema multiforme * Adverse effects of fluoroquinolones * Red man syndrome * Jarisch–Herxheimer reaction Hormones * Steroid acne * Steroid folliculitis Chemotherapy * Chemotherapy-induced acral erythema * Chemotherapy-induced hyperpigmentation * Scleroderma-like reaction to taxanes * Hydroxyurea dermopathy * Exudative hyponychial dermatitis Anticoagulants * Anticoagulant-induced skin necrosis * Warfarin necrosis * Vitamin K reaction * Texier's disease Immunologics * Adverse reaction to biologic agents * Leukotriene receptor antagonist-associated Churg–Strauss syndrome * Methotrexate-induced papular eruption * Adverse reaction to cytokines Other drugs * Anticonvulsant hypersensitivity syndrome * Allopurinol hypersensitivity syndrome * Vaccine adverse event * Eczema vaccinatum * Bromoderma * Halogenoderma * Iododerma General Skin and body membranes * Acute generalized exanthematous pustulosis * Bullous drug reaction * Drug-induced acne * Drug-induced angioedema * Drug-related gingival hyperplasia * Drug-induced lichenoid reaction * Drug-induced lupus erythematosus * Drug-induced nail changes * Drug-induced pigmentation * Drug-induced urticaria * Stevens–Johnson syndrome * Injection site reaction * Linear IgA bullous dermatosis * Toxic epidermal necrolysis * HIV disease-related drug reaction * Photosensitive drug reaction Other * Drug-induced pseudolymphoma * Fixed drug reaction * Serum sickness-like reaction This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Sulfonamide hypersensitivity syndrome	None	8,727	wikipedia	https://en.wikipedia.org/wiki/Sulfonamide_hypersensitivity_syndrome	2021-01-18T19:04:04	{"icd-9": ["E930.8"], "icd-10": ["Y40"], "wikidata": ["Q7636209"]}
Lung Infarction Other namesPulmonary infarction Pulmonary infarcts found on autopsy SpecialtyPulmonology, cardiology Lung infarction occurs when an artery to the lung becomes blocked and part of the lung dies.[1] It is most often caused by pulmonary embolism. Because of the dual blood supply to the lungs from both the bronchial circulation and the pulmonary circulation, this tissue is more resistant to infarction. An occlusion of the bronchial circulation does not cause infarction, but it can still occur in pulmonary embolism when the pulmonary circulation is blocked and the bronchial circulation cannot fully compensate for it.[2] * CT scan of a lung infarction because of chronic pulmonary embolism (white arrow). The infarcted area (black arrow) has a reverse halo sign. ## References[edit] 1. ^ Philip T. Cagle (2008). Color atlas and text of pulmonary pathology (2 ed.). Philadelphia: Lippincott Williams & Wilkins. p. 291. ISBN 9780781782081. 2. ^ Thomas H. McConnell (2007). The Nature of Disease: Pathology for the Health Professions. Lippincott Williams & Wilkins. pp. 81–. ISBN 978-0-7817-5317-3. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx * MeSH: D054060 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Lung infarction	c0034074	8,728	wikipedia	https://en.wikipedia.org/wiki/Lung_infarction	2021-01-18T18:43:39	{"mesh": ["D054060"], "icd-9": ["415.19"], "wikidata": ["Q13538850"]}
A rare juvenile idiopathic inflammatory myopathy characterized by the association of inflammatory myositis (manifesting with acral erythema, progressive weakness of the limbs, pain, general fatigue, moodiness or crankiness) with clinical and/or laboratory features of other autoimmune diseases (e.g. systemic lupus erythematosus, localized scleroderma, diabetes). Cardiac involvement has been reported in some patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Juvenile overlap myositis	c4707728	8,729	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329894	2021-01-23T18:18:12	{"icd-10": ["M33.0"]}
## Summary ### Clinical characteristics. Most individuals with Canavan disease have the neonatal/infantile form. Although such infants appear normal early in life, by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed. Most children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals. ### Diagnosis/testing. The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine and/or with biallelic pathogenic variants in ASPA identified by molecular genetic testing. ### Management. Treatment of manifestations: * Neonatal/infantile Canavan disease. Treatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway. Hospice care is a resource used by the families of the individuals affected by the disease. Physical therapy minimizes contractures and maximizes motor abilities and seating posture; special education programs enhance communication skills. Seizures are treated with antiepileptic drugs. Gastrostomy may be needed to maintain adequate food intake and hydration when swallowing difficulties exist. * Mild/juvenile Canavan disease. May require speech therapy or tutoring but no special medical care. Surveillance: * Neonatal/infantile Canavan disease. Follow up every six months to evaluate developmental status and evidence of any new problems. * Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist or a developmental pediatrician is indicated. ### Genetic counseling. Canavan disease is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a pathogenic variant in ASPA has a 25% chance of resulting in a child with Canavan disease, a 50% chance of resulting in a child who is an asymptomatic carrier, and a 25% chance of resulting in a child who is unaffected and not a carrier. Carrier testing is available on a population basis for individuals of Ashkenazi Jewish heritage. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible when the pathogenic variants in the family are known. ## Diagnosis ### Suggestive Findings Canavan disease should be suspected in individuals with * The triad of hypotonia, head lag, and macrocephaly after age three to five months * Poor visual following and difficulties with suck and swallow * Developmental delays (with regression in infantile form and without regression in mild/juvenile form) * Leukodystrophy on neuroimaging (generalized in infantile form and localized to basal ganglia in mild/juvenile form) * Elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (GC-MS) ### Establishing the Diagnosis The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (see Note) and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing (see Table 1). Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with neonatal/infantile (severe) Canavan disease, elevated concentration of NAA in urine is sufficient for diagnosis of affected individuals [Michals & Matalon 2011]. (2) Canavan disease is associated with decreased aspartoacylase enzyme activity; individuals with severe Canavan disease may have unmeasurable enzyme activity, and carriers (heterozygotes) may have enzyme activity ~50% of normal. Aspartoacylase enzyme activity may not be reliable in the diagnosis of Canavan disease because enzyme activity fluctuates with culture conditions; therefore, measurement of the urinary concentration of NAA is the preferred diagnostic method [Matalon et al 1993]. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Canavan disease is broad, infants with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild/juvenile Canavan disease phenotype indistinguishable from many other inherited disorders with developmental delay are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing. Sequence analysis of ASPA detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Targeted analysis for the pathogenic variants p.Glu285Ala, p.Tyr231Ter, and p.Ala305Glu can be performed first in individuals of Ashkenazi Jewish ancestry. Targeted analysis for the pathogenic variant p.Ala305Glu can be performed first in individuals of non-Ashkenazi Jewish ancestry. Note: This targeted testing is most appropriate when (1) biochemical testing indicates a diagnosis of Canavan disease or (2) the individual is of Ashkenazi Jewish ancestry. A multigene panel that includes ASPA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Note: Follow-up urinary NAA or enzyme testing may help to interpret sequencing results if a variant of unknown significance is identified. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Canavan Disease View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method ASPATargeted testing 3p.Glu285Ala, p.Tyr231TerAshkenazi Jewish: 98% 4 Non-Ashkenazi Jewish: 3% 4 p.Ala305GluAshkenazi Jewish: 1% 5 Non-Ashkenazi Jewish: 30%-60% 5 Sequence analysis 6~99% 7 Gene-targeted deletion/duplication analysis 89 reported 9 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Various molecular methods may be used to detect targeted variants. 4\. Michals & Matalon [2011] 5\. Kaul et al [1994b], Elpeleg & Shaag [1999] 6\. 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. 7\. Kaul et al [1994b], Elpeleg & Shaag [1999], Olsen et al [2002], Zeng et al [2002], Michals & Matalon [2011] 8\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 9\. Shaag et al [1995], Elpeleg & Shaag [1999], Zeng et al [2006], Caliebe et al [2010], Cozzolino et al [2011] ## Clinical Characteristics ### Clinical Description Canavan disease is a neurodegenerative disorder associated with spongy degeneration of the white matter of the brain. Typical presentation is in the first several months of life, although a later presentation is also recognized. #### Neonatal/Infantile (Severe) Canavan Disease Presentation. Most individuals with Canavan disease have the neonatal/infantile form. Such infants appear normal early in life, but by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent. Hypotonia is an early finding associated with poor head control. * Inability to support the head is a constant feature of this disorder. * With age, hypotonia gives way to spasticity. Macrocephaly. In early infancy the head circumference may be normal or in some cases remain at the upper limit of normal. However, in the majority of individuals, the head circumference increases after age six months and by the first year is above the 90th percentile. Developmental delay becomes more obvious with increasing age: * Children are especially delayed in their motor skills and are not able to sit, stand, walk, or talk. * They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position. Vision and hearing. Early in life there is a decreased ability to fix and follow. Optic atrophy usually develops in the second year of life. Hearing is usually not impaired. Progression. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some of the children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy. Prognosis. Most individuals with Canavan disease die in the first decade of life. However, with improved medical and nursing care a larger number of children survive beyond the first decade. #### Mild/Juvenile Canavan Disease Presentation. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed [Matalon & Michals Matalon 2015]. Most of the children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals [Tacke et al 2005, Delaney et al 2015]. #### Neuroimaging Neonatal/infantile (severe) Canavan disease. CT or MRI performed in infancy may be interpreted as normal [Matalon & Michals-Matalon 2000]. Diffuse, symmetric white matter changes are observed in the subcortical areas and in the cerebral cortex; involvement of the cerebellum and brain stem is less marked [Matalon et al 1995]. Magnetic resonance spectrometry (MRS) to detect N-acetylaspartic acid has been reported as the best method for the diagnosis of Canavan disease in infants, even with normal serum and urine N-acetylaspartic acid levels [Karimzadeh et al 2014]. Mild/juvenile Canavan disease. Brain MRI does not show general white matter changes, although increased signal intensities in the basal ganglia have been reported [Surendran et al 2003, Yalcinkaya et al 2005, Michals & Matalon 2011]. #### Neuropathology In neonatal/infantile Canavan disease subcortical spongy degeneration is observed. Electron microscopy (EM) reveals swollen astrocytes and distorted mitochondria. ### Genotype-Phenotype Correlations Neonatal/infantile (severe) Canavan disease is associated with complete loss of ASPA enzyme activity. The common p.Tyr231Ter, p.Glu285Ala, and p.Ala305Glu pathogenic variants in the homozygous or compound heterozygous (with each other) state are associated with neonatal/infantile disease [Matalon & Michals-Matalon 1998]. Mild/juvenile Canavan disease is associated with at least one "mild" pathogenic variant (p.Tyr288Cys, p.Arg71His, or p.Pro257Arg) with residual ASPA enzyme activity. Individuals are usually heterozygous with one mild variant and one severe variant [Surendran et al 2003, Yalcinkaya et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011]. ### Nomenclature Other names for neonatal/infantile (severe) Canavan disease that are no longer in use: * Spongy degeneration of the brain (see also Differential Diagnosis) * Van Bogaert and Bertrand disease ### Prevalence While Canavan disease occurs in all ethnic groups, most reported individuals are of Ashkenazi Jewish origin. Carrier frequency has varied from 1:40 to 1:82 in the Ashkenazi Jewish population depending on the source of samples [Kronn et al 1995, Matalon et al 1995, Fares et al 2008]. The carrier rate in non-Jews is not known; however, it is assumed to be much lower than the carrier rate in the Ashkenazi Jewish population. ## Differential Diagnosis ### Table 2. Disorders to Consider in the Differential Diagnosis of Canavan Disease View in own window DisorderGene(s)MOIClinical Features of This Disorder Overlapping w/Canavan diseaseDistinguishing from Canavan disease Alexander diseaseGFAPAD * Neurodegenerative disorder of infancy * Normal or large head * Marked frontal predominance of white matter changes * Rostrocaudal progression of myelin loss on serial imaging studies Tay-Sachs diseaseHEXAAR * Neurodegenerative disorder of infancy * Normal or large head * Increased startle response * Cherry-red spot of the macula of the retina Metachromatic leukodystrophyARSAAR * Neurodegenerative disorder of infancy * Normal or large head Late-infantile onset (age <30 mos) after a period of apparently normal development Glutaric acidemia type 1GCDHAR * Neurodegenerative disorder of infancy * Normal or large head Progressive movement disorder Leigh syndrome (see also Mitochondrial Disorders Overview)mtDNAmt ARSpongy degeneration of the brainDecompensation (often w/elevated lactate levels in blood &/or CSF) during an intercurrent illness is typically associated w/psychomotor retardation or regression. Glycine encephalopathy (nonketotic hyperglycinemia)AMT GCSH GLDCARSpongy degeneration of the brain * Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks. * Apnea * Profound intellectual disability * Intractable seizures Viral encephalitisNANASpongy degeneration of the brainHistory of viral infection in a previously typical individual AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; NA = not applicable; XL = X-linked Mild/juvenile Canavan disease may be misdiagnosed as a mitochondrial disorder (see Mitochondrial Disorders Overview). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Canavan disease, the following evaluations are recommended if they have not already been completed. Neonatal/infantile (severe) form * Brain MRI and MRI spectroscopy * Neurologic evaluation * Developmental assessment * Ophthalmologic assessment * Nutritional assessment Juvenile/mild form * Neurologic evaluation * Developmental assessment * Ophthalmologic assessment All Canavan disease. Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Neonatal/infantile Canavan disease * Treatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway. * Hospice care is a resource used by the families of the individuals affected by the disease. * Children benefit from: * Physical therapy to minimize contractures and optimize abilities and seating posture, * Other therapies to enhance communication skills (especially in those with a more gradual clinical course), and * Early intervention and special education programs. * Seizures may be treated with antiepileptic drugs. * A feeding gastrostomy may be required to maintain adequate intake and hydration in the presence of swallowing difficulties. * Botox® injections may be used to relieve spasticity. Mild/juvenile Canavan disease. Individuals may require speech therapy or tutoring but require no special medical care. ### Prevention of Secondary Complications Neonatal/infantile Canavan disease * Contractures and decubiti need to be prevented by exercise and position changes. * Feeding difficulties and seizures increase the risk of aspiration, which can be reduced with use of a G-tube for feeding. ### Surveillance Neonatal/infantile Canavan disease. Follow up at six-month intervals by a pediatric neurologist to evaluate developmental status and evidence of any new problems is suggested. Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist (or a developmental pediatrician) is indicated. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Canavan Disease	c0206307	8,730	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1234/	2021-01-18T21:36:36	{"mesh": ["D017825"], "synonyms": ["ASPA Deficiency", "Aspartoacylase Deficiency"]}
Combined immunodeficiency due to partial RAG1 deficiency is a form of combined T and B cell immunodeficiency (CID; see this term) characterized by severe and persistent cytomegalovirus (CMV) infection and autoimmune cytopenia. ## Epidemiology Prevalence is unknown. To date, 9 cases have been reported. ## Clinical description Patients present before the age of one year with severe disseminated CMV infection, which can manifest with fever and splenomegaly, and recurrent and severe co-infections including sepsis and pneumonitis. Autoimmune cytopenia also occurs and can include autoimmune hemolytic anemia (see these terms) or neutropenia. ## Etiology SCID due to partial RAG1 deficiency is caused by hypomorphic mutation in the RAG1 gene (11p13). This results in oligoclonal expansion of T cell receptor (TCR) gamma-delta T cells and TCR alpha-beta T cell lymphopenia, although total lymphocyte counts are normal, in combination with CMV infection and autoimmunity. ## Diagnostic methods Diagnosis is based on clinical evaluation, immunological investigation, including lymphocyte subset phenotyping, lymphocyte proliferation to mitogen stimulation, immunoglobulin levels and antibody response to vaccine antigens, and genetic confirmation. ## Differential diagnosis Differential diagnoses include other combined immunodeficiencies. ## Antenatal diagnosis Prenatal diagnosis can be performed in families where there is a family history and in which the genetic mutation has been identified. ## Genetic counseling Transmission is autosomal recessive. ## Management and treatment Treatment involves antiviral treatment and management of recurrent infections. Bone marrow transplant has been attempted but may result in graft versus host disease (GVHD; see this term) associated with reactivation of CMV disease. Patients should be treated in centers with experience of transplanting complex primary immunodeficiencies. ## Prognosis The majority of patients reported to date have died within the first few years 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Combined immunodeficiency due to partial RAG1 deficiency	c1835931	8,731	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231154	2021-01-23T17:43:57	{"mesh": ["C563691"], "omim": ["609889"], "umls": ["C1835931"], "icd-10": ["D81.8"], "synonyms": ["CID due to partial RAG1 deficiency", "CID with expansion of gamma delta T cells", "Combined immunodeficiency with expansion of gamma delta T cells"]}
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: "Renpenning's syndrome" – news · newspapers · books · scholar · JSTOR (September 2010) (Learn how and when to remove this template message) Renpenning's syndrome Renpenning's syndrome is inherited in an X-linked recessive manner. SpecialtyMedical genetics Renpenning's syndrome is a neurodevelopmental disorder recognised in males that causes intellectual disability, mild growth retardation with examples in the testes and head, and a somewhat short stature. The condition only affects males, starting at birth. ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 See also * 8 References * 9 External links ## Presentation[edit] People with Renpenning's typically begin learning language at an ordinary pace, but by the age of 3–4 they experience a regression in mental and physical development, such as mild low muscle tone resulting in elongated faces and rapid loss in the normal growth of the head (microcephaly). Small testes and short stature are also known to commonly occur. ## Genetics[edit] It is associated with mutations in the PQBP1 gene.[1] The gene product is a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. The gene itself is located on the short arm of the X chromosome (Xp11.23). The most common mutations causing this condition occur in exon 4. ## Diagnosis[edit] This diagnosis may be suspected on clinical grounds but should be confirmed by sequencing the PQBP1 gene. ## Treatment[edit] There is no specific or curative treatment for this condition at present. Management is supportive ## Epidemiology[edit] This condition normally only occurs in males but a case in a female has been reported.[2] ## History[edit] This condition was first characterized in 1962.[3] and later described by Hans Renpenning in 1963 after he documented these traits on many children in one family alone. ## See also[edit] * Lujan-Fryns syndrome * Fragile x syndrome ## References[edit] 1. ^ Martínez-Garay I, Tomás M, Oltra S, et al. (January 2007). "A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation". Eur. J. Hum. Genet. 15 (1): 29–34. doi:10.1038/sj.ejhg.5201717. PMID 17033686. 2. ^ Cho RY, Peñaherrera MS, Du Souich C, Huang L, Mwenifumbo J, Nelson TN, Elliott AM, Adam S, Eydoux P, Yang GX, Chijiwa C, Van Allen MI, Friedman JM, Robinson WP, Lehman A (2019) Renpenning syndrome in a female. Am J Med Genet A 3. ^ RENPENNING H, GERRARD JW, ZALESKI WA, TABATA T (November 1962). "Familial sex-linked mental retardation". Can Med Assoc J. 87: 954–6. PMC 1849750. PMID 13981686. ## External links[edit] Classification D * OMIM: 309500 * MeSH: C537761 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Renpenning's syndrome	c0796135	8,732	wikipedia	https://en.wikipedia.org/wiki/Renpenning%27s_syndrome	2021-01-18T19:05:16	{"mesh": ["C537761"], "umls": ["C0796135"], "orphanet": ["3242"], "wikidata": ["Q7313459"]}
Familial hypobetalipoproteinemia (FHBL) is a disorder that impairs the body's ability to absorb and transport fats, causing low levels of cholesterol in the blood. The severity of the condition varies widely. Mildly affected people may have no signs or symptoms. Many affected people develop an abnormal buildup of fats in the liver (called hepatic steatosis, or fatty liver). In severe cases, this may progress to cirrhosis. Some people also have digestive problems in childhood, resulting in failure to thrive. FHBL is usually caused by mutations in the APOB gene. In a few cases, it may be caused by mutations in other genes, or the cause may be unknown. It is inherited in an autosomal codominant manner; a mutation in one copy of the APOB gene can cause the condition, but changes in both copies of the gene cause more severe symptoms. Management may include reducing fat in the diet and vitamin E supplementation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Familial hypobetalipoproteinemia	c1862596	8,733	gard	https://rarediseases.info.nih.gov/diseases/2876/familial-hypobetalipoproteinemia	2021-01-18T18:00:34	{"mesh": ["C566267"], "omim": ["615558"], "umls": ["C1862596"], "orphanet": ["426"], "synonyms": ["Hypobetalipoproteinemia, familial", "FHBL"]}
This article is about a malady of the brain. For other uses, see SCA (disambiguation). Spinocerebellar ataxia Other namesSpinocerebellar atrophy or Spinocerebellar degeneration Cerebellum (in blue) of the human brain SpecialtyNeurology Spinocerebellar ataxia (SCA) is a progressive, degenerative,[1] genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Classification * 4 Treatment * 4.1 Medication * 4.2 N-Acetyl-Leucine * 4.3 Rehabilitation * 5 References * 6 Further reading * 7 External links ## Signs and symptoms[edit] Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. A review of different clinical features among SCA subtypes was recently published describing the frequency of non-cerebellar features, like parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures, among others.[3] As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum,[4] loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms. The symptoms of an ataxia vary with the specific type and with the individual patient. In many cases a person with ataxia retains full mental capacity but progressively loses physical control.[citation needed] ## Cause[edit] The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.[citation needed] * Many types of autosomal dominant cerebellar ataxias for which specific genetic information is available are now known. Synonyms for autosomal-dominant cerebellar ataxias (ADCA) used prior to the current understanding of the molecular genetics were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration." (Spinocerebellar degeneration is a rare inherited neurological disorder of the central nervous system characterized by the slow degeneration of certain areas of the brain. There are three forms of spinocerebellar degeneration: Types 1, 2, 3. Symptoms begin during adulthood.)[citation needed] * There are five typical autosomal-recessive disorders in which ataxia is a prominent feature: Friedreich ataxia, ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA), spastic ataxia. Disorder subdivisions: Friedreich's ataxia, Spinocerebellar ataxia, Ataxia telangiectasia, Vasomotor ataxia, Vestibulocerebellar, Ataxiadynamia, Ataxiophemia, Olivopontocerebellar atrophy, and Charcot-Marie-Tooth disease.[citation needed] * There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele. This falls under the category of genetic anticipation.[5] Several types of SCA are characterized by repeat expansion of the trinucleotide sequence CAG in DNA that encodes a polyglutamine repeat tract in protein. The expansion of CAG repeats over successive generations appears to be due to slipped strand mispairing during DNA replication or DNA repair.[6] * There are numerous types of autosomal-dominant cerebellar ataxias * There are five typical autosomal recessive disorders in which ataxia is a prominent feature ## Diagnosis[edit] ### Classification[edit] A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade genetic testing has allowed precise identification of dozens of different SCAs and more tests are being added each year.[7] In 2008, a genetic ataxia blood test developed to test for 12 types of SCA, Friedreich's ataxia, and several others. However, since not every SCA has been genetically identified some SCAs are still diagnosed by neurological examination, which may include a physical exam, family history, MRI scanning of the brain and spine, and spinal tap.[8] Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e., ataxin-1, ataxin-3, etc.) contains a large number of repeats of glutamine residues, termed a polyQ sequence or a "CAG trinucleotide repeat" disease for either the one-letter designation or codon for glutamine respectively. The threshold for symptoms in most forms of SCA is around 35, though for SCA3 it extends beyond 50. Most polyglutamine diseases are dominant due to the interactions of resulting polyQ tail.[citation needed] The first ataxia gene was identified in 1993 and called "Spinocerebellar ataxia type 1" (SCA1); later genes were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 29 different gene mutations that have been found.[citation needed] The following is a list of some of the many types of Spinocerebellar ataxia. SCA Type Average Onset (Range in Years) Average Duration (Range in Years) What the patient experiences Common origin Problems with DNA SCA1[9] (ATXN1) 4th decade (<10 to >60) 15 years (10–35) Hypermetric saccades, slow saccades, upper motor neuron (note: saccades relates to eye movement) CAG repeat, 6p (Ataxin 1) SCA2[10] (ATXN2) 3rd–4th decade (<10 to >60) 10 years (1–30) Diminished velocity saccades areflexia (absence of neurologic reflexes) Cuba CAG repeat, 12q SCA3[11] (MJD) (ATXN3) 4th decade (10–70) 10 years (1–20) Also called Machado-Joseph disease (MJD)[12] Gaze-evoked nystagmus (a rapid, involuntary, oscillatory motion of the eyeball) upper motor neuron slow saccades Azores (Portugal) CAG repeat, 14q SCA4 (PLEKHG4) 4th–7th decade (19–72) Decades areflexia (absence of neurologic reflexes) Chromosome 16q SCA5 (SPTBN2) 3rd–4th decade (10–68) >25 years Pure cerebellar Chromosome 11 SCA6[13] (CACNA1A) 5th–6th decade (19–71) >25 years Downbeating nystagmus, positional vertigo Symptoms can appear for the first time as late as 65 years old. CAG repeat, 19p Calcium channel gene SCA7[14] (ATXN7) 3rd–4th decade (0.5–60) 20 years (1–45; early onset correlates with shorter duration) Macular degeneration, upper motor neuron, slow saccades CAG repeat, 3p (Ataxin 7) SCA8[15] (IOSCA) 39 yrs (18–65) Normal lifespan Horizontal nystagmus (a rapid, involuntary, oscillatory motion of the eyeball), instability, lack of coordination CTG repeat,[16] 13q SCA10[17] (ATXN10) 36 years 9 years ataxia, seizures Mexico Chromosome 22q linked pentanucleotide repeat SCA11 (TTBK2) 30 yrs (15–70) Normal lifespan Mild, remain ambulatory (able to walk about on one's own) 15q SCA12[18] (PPP2R2B) 33 yrs (8–55) Head and hand tremor, akinesia (loss of normal motor function, resulting in impaired muscle movement) CAG repeat, 5q SCA13 (KCNC3) Childhood or adulthood depending on mutation Depending on KCNC3 (a kind of gene) Mental retardation 19q SCA14[19] (PRKCG) 28 yrs (12–42) Decades (1–30) Myoclonus (a sudden twitching of muscles or parts of muscles, without any rhythm or pattern, occurring in various brain disorders) 19q SCA16 (ITPR1) 39 yrs (20–66) 1–40 years Head and hand tremor 8q SCA17 (TBP) CAG repeat, 6q (TATA-binding protein) SCA19, SCA22 (KCND3[20]) Mild cerebellar syndrome, dysarthria SCA25 1.5–39 yrs Unknown ataxia with sensory neuropathy, vomiting and gastrointestinal pain. 2p SCA27[21] (FGF14[20]) 15–20 yrs Unknown ataxia with poor cognition, dyskinesias and tremor. FGF14 13q34 SCA35 40–48 years Unknown gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses, reduced proprioception and hyperreflexia China transglutaminase 6 (TGM6) located at chromosome 20p13 Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29. Four X-linked types have been described ( 302500, 302600, 301790, 301840), but only the first of these has so far been tied to a gene (SCAX1). Name OMIM RareDiseases Other Anemia, sideroblastic spinocerebellar ataxia; Pagon Bird Detter syndrome 301310 Disease ID 668 at NIH's Office of Rare Diseases Friedreich's ataxia; Spinocerebellar ataxia, Friedreich 229300 Disease ID 6468 at NIH's Office of Rare Diseases Infantile onset Spinocerebellar ataxia 605361 Disease ID 4062 at NIH's Office of Rare Diseases Spinocerebellar ataxia 1 164400 Disease ID 4071 at NIH's Office of Rare Diseases Spinocerebellar ataxia 2 183090 Disease ID 4072 at NIH's Office of Rare Diseases Spinocerebellar ataxia 3; Machado Joseph disease 109150 Disease ID 6801 at NIH's Office of Rare Diseases Spinocerebellar ataxia 4 600223 Disease ID 9970 at NIH's Office of Rare Diseases Spinocerebellar ataxia 5 600224 Disease ID 4953 at NIH's Office of Rare Diseases Spinocerebellar ataxia 7 164500 Disease ID 4955 at NIH's Office of Rare Diseases Spinocerebellar ataxia 8 603680 Disease ID 4956 at NIH's Office of Rare Diseases Spinocerebellar ataxia 13 605259 Disease ID 9611 at NIH's Office of Rare Diseases Spinocerebellar ataxia 18 607458 Disease ID 9976 at NIH's Office of Rare Diseases Spinocerebellar ataxia 19 607346 Disease ID 9969 at NIH's Office of Rare Diseases Spinocerebellar ataxia 20 608687 Disease ID 9997 at NIH's Office of Rare Diseases Spinocerebellar ataxia 21 607454 Disease ID 9999 at NIH's Office of Rare Diseases Spinocerebellar ataxia 23 610245 Disease ID 9950 at NIH's Office of Rare Diseases Spinocerebellar ataxia 25 608703 Disease ID 9996 at NIH's Office of Rare Diseases Spinocerebellar ataxia 26 609306 Disease ID 9995 at NIH's Office of Rare Diseases Spinocerebellar ataxia 28 610246 Disease ID 9951 at NIH's Office of Rare Diseases Spinocerebellar ataxia 30 117360 Disease ID 9975 at NIH's Office of Rare Diseases Spinocerebellar ataxia 35 613908 Disease ID at NIH's Office of Rare Diseases Spinocerebellar ataxia amyotrophy deafness syndrome Disease ID 2451 at NIH's Office of Rare Diseases ORPHA:2074 at Orphanet Spinocerebellar ataxia, autosomal recessive 1 606002 Disease ID 4949 at NIH's Office of Rare Diseases Spinocerebellar ataxia, autosomal recessive 3 271250 Disease ID 9971 at NIH's Office of Rare Diseases Spinocerebellar ataxia, autosomal recessive 4 607317 Disease ID 4952 at NIH's Office of Rare Diseases Spinocerebellar ataxia, autosomal recessive 5 606937 Disease ID 9977 at NIH's Office of Rare Diseases Spinocerebellar ataxia, autosomal recessive 6 608029 Disease ID 4954 at NIH's Office of Rare Diseases Spinocerebellar ataxia, autosomal recessive 21 - mutation in SCYL1 Online Mendelian Inheritance in Man (OMIM): 616719 ORPHA:466794 Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 607250 Disease ID 10000 at NIH's Office of Rare Diseases Spinocerebellar ataxia, X-linked, 2 302600 Disease ID 9978 at NIH's Office of Rare Diseases Spinocerebellar ataxia, X-linked, 3 301790 Disease ID 9981 at NIH's Office of Rare Diseases Spinocerebellar ataxia, X-linked, 4 301840 Disease ID 9980 at NIH's Office of Rare Diseases ## Treatment[edit] ### Medication[edit] There is no cure for spinocerebellar ataxia, which is currently considered to be a progressive and irreversible disease, although not all types cause equally severe disability.[22] In general, treatments are directed towards alleviating symptoms, not the disease itself. Many patients with hereditary or idiopathic forms of ataxia have other symptoms in addition to ataxia. Medications or other therapies might be appropriate for some of these symptoms, which could include tremor, stiffness, depression, spasticity, and sleep disorders, among others. Both onset of initial symptoms and duration of disease are variable. If the disease is caused by a polyglutamine trinucleotide repeat CAG expansion, a longer expansion may lead to an earlier onset and a more radical progression of clinical symptoms. Typically, a person afflicted with this disease will eventually be unable to perform daily tasks (ADLs).[23] However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent.[24] Researchers are exploring multiple avenues for a cure including RNAi and the use of Stem Cells and several other avenues.[25] On January 18, 2017 BioBlast Pharma announced completion of Phase 2a clinical trials of their medication, Trehalose, in the treatment of SCA3. BioBlast has received FDA Fast Track status and Orphan Drug status for their treatment. The information provided by BioBlast in their research indicates that they hope this treatment may prove efficacious in other SCA treatments that have similar pathology related to PolyA and PolyQ diseases.[26][27] In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades.[28] Her research began in the mid-1990s and progressed to work with mouse models about a decade later and most recently has moved to a study with non-human primates. The results from her most recent research "are supportive of clinical application of this gene therapy".[29] Finally, another gene transfer technology discovered in 2011 has also been shown by Dr. Davidson to hold great promise and offers yet another avenue to a potential future cure.[30] ### N-Acetyl-Leucine[edit] N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).[31] N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA)[32] and the European Medicines Agency (EMA)[33] for the treatment of various genetic diseases, including Spinocerebellar Ataxias. N-Acetyl-Leucine has also been granted Orphan Drug Designations in the US and EU for the related inherited cerebellar ataxia Ataxia-Telangiectasia U.S. Food & Drug Administration (FDA)[34] and the European Medicines Agency (EMA).[35] Published case series studies have demonstrated the effects of acute treatment with N-Acetyl-Leucine for the treatment of inherited cerebellar ataxias, including Spinocerebellar Ataxias.[36][37] These studies further demonstrated that the treatment is well tolerated, with a good safety profile.[citation needed] A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, Ataxia-Telangiectasia, began in 2019.[38] IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C[39] and GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).[40] Future opportunities to develop N-Acetyl-Leucine include Lewy Body Dementia,[41]Amyotrophic lateral sclerosis, Restless Leg Syndrome, Multiple Sclerosis, and Migraine[42] ### Rehabilitation[edit] Physical therapists can assist patients in maintaining their level of independence through therapeutic exercise programmes. One recent research report demonstrated a gain of 2 SARA points (Scale for the Assessment and Rating of Ataxia) from physical therapy.[43] In general, physical therapy emphasises postural balance and gait training for ataxia patients.[44] General conditioning such as range-of-motion exercises and muscle strengthening would also be included in therapeutic exercise programmes. Research showed that spinocerebellar ataxia 2 (SCA2) patients [45] with a mild stage of the disease gained significant improvement in static balance and neurological indices after six months of a physical therapy exercise training program.[46] Occupational therapists may assist patients with incoordination or ataxia issues through the use of adaptive devices. Such devices may include a cane, crutches, walker, or wheelchair for those with impaired gait. Other devices are available to assist with writing, feeding, and self care if hand and arm coordination are impaired. A randomised clinical trial revealed that an intensive rehabilitation program with physical and occupational therapies for patients with degenerative cerebellar diseases can significantly improve functional gains in ataxia, gait, and activities of daily living. Some level of improvement was shown to be maintained 24 weeks post-treatment.[47] Speech language pathologists may use both behavioral intervention strategies as well as augmentative and alternative communication devices to help patients with impaired speech.[citation needed] ## References[edit] 1. ^ "spinocerebellar ataxia" at Dorland's Medical Dictionary 2. ^ http://www.ninds.nih.gov/disorders/ataxia/ataxia.htm[full citation needed] 3. ^ Rossi, M; Perez-Lloret, S; Doldan, L; Cerquetti, D; Balej, J; Millar Vernetti, P; Hawkes, H; Cammarota, A; Merello, M (2014). "Autosomal dominant cerebellar ataxias: A systematic review of clinical features". European Journal of Neurology. 21 (4): 607–15. doi:10.1111/ene.12350. PMID 24765663. 4. ^ "Spinocerebellar ataxia". Genes and Disease [Internet]. Bethesda MD: National Center for Biotechnology Information. 1998. NBK22234. — Gives a concise description of SCA, along with a picture of shrunken degenerated cerebellum. 5. ^ Khristich AN, Mirkin SM (March 2020). "On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability". J. Biol. Chem. 295 (13): 4134–4170. doi:10.1074/jbc.REV119.007678. PMC 7105313. PMID 32060097. 6. ^ Usdin K, House NC, Freudenreich CH (2015). "Repeat instability during DNA repair: Insights from model systems". Crit. Rev. Biochem. Mol. Biol. 50 (2): 142–67. doi:10.3109/10409238.2014.999192. PMC 4454471. PMID 25608779. 7. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2015-07-27. Retrieved 2017-01-25.CS1 maint: archived copy as title (link) 8. ^ www.ataxia.org[full citation needed] 9. ^ sca1 at NIH/UW GeneTests 10. ^ sca2 at NIH/UW GeneTests 11. ^ sca3 at NIH/UW GeneTests 12. ^ machado_joseph at NINDS 13. ^ sca6 at NIH/UW GeneTests 14. ^ sca7 at NIH/UW GeneTests 15. ^ sca8 at NIH/UW GeneTests 16. ^ Mosemiller, A.K.; Dalton, J.C.; Day, J.W.; Ranum, L.P.W. (2003). "Molecular genetics of spinocerebellar ataxia type 8 (SCA8)". Cytogenetic and Genome Research. 100 (1–4): 175–83. doi:10.1159/000072852. PMID 14526178. S2CID 2292926. 17. ^ sca10 at NIH/UW GeneTests 18. ^ sca12 at NIH/UW GeneTests 19. ^ sca14 at NIH/UW GeneTests 20. ^ a b Perlman, Susan L. (2016). Evaluation and Management of Ataxic Disorders: An Overview for Physicians. Minneapolis: National Ataxia Foundation. p. 6. ISBN 978-0-943218-14-4. LCCN 2007923539. 21. ^ Online Mendelian Inheritance in Man (OMIM): 609307 22. ^ Jiang, Bingcheng; Glover, J.N. Mark; Weinfeld, Michael (2016). "Neurological disorders associated with DNA strand-break processing enzymes". Mechanisms of Ageing and Development. 161 (Pt A): 130–140. doi:10.1016/j.mad.2016.07.009. ISSN 0047-6374. PMC 5266678. PMID 27470939. 23. ^ Cruts, Marc; Engelborghs, Sebastiaan; van der Zee, Julie; Van Broeckhoven, Christine (1993). "C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Stephens, Karen; Amemiya, Anne (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 25577942. 24. ^ Synofzik, Matthis; Ilg, Winfried (2014). "Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames". BioMed Research International. 2014: 583507. doi:10.1155/2014/583507. PMC 4022207. PMID 24877117. 25. ^ "Archived copy". Archived from the original on 2016-11-19. Retrieved 2017-01-26.CS1 maint: archived copy as title (link) 26. ^ "Bioblast Announces Phase 2a Results of Trehalose in Patients with Spinocerebellar Ataxia Type 3 (SCA3)". Investors Hub. Retrieved 14 October 2017. 27. ^ "The Orphan Genetic Disease Company: Bioblast Pharma Ltd. June 2016" (PDF). Bioblast Pharma Ltd. Retrieved 14 October 2017. 28. ^ Veritas, Gene (17 August 2013). "RNA Interference for Treating Huntington's Disease: An Interview with Dr. Beverly Davidson". Vimeo. Retrieved 14 October 2017. 29. ^ Keiser, M. S.; Kordower, J. H.; Gonzalez-Alegre, P; Davidson, B. L. (2015). "Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy". Brain. 138 (12): 3555–3566. doi:10.1093/brain/awv292. PMC 4840549. PMID 26490326. 30. ^ http://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(1[dead link] 31. ^ "IntraBio". Retrieved 2019-08-01. 32. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01. 33. ^ FRANCISCO, Estela Miranda (2018-12-20). "EU/3/18/2059". European Medicines Agency. Retrieved 2019-08-01. 34. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01. 35. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01. 36. ^ Cross, Jo (April 2006). "MEDLINE, PubMed, PubMed Central, and the NLM". Editors' Bulletin. 2 (1): 1–5. doi:10.1080/17521740701702115. ISSN 1752-1742. 37. ^ Schniepp, Roman; Strupp, Michael; Wuehr, Max; Jahn, Klaus; Dieterich, Marianne; Brandt, Thomas; Feil, Katharina (2016). "Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series". Cerebellum & Ataxias. 3: 8. doi:10.1186/s40673-016-0046-2. ISSN 2053-8871. PMC 4828858. PMID 27073690. 38. ^ "N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-08-01. 39. ^ "N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-08-01. 40. ^ "N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-08-01. 41. ^ "IntraBio". Retrieved 2019-08-01. 42. ^ Strupp, Michael; Bayer, Otmar; Feil, Katharina; Straube, Andreas (2019-02-01). "Prophylactic treatment of migraine with and without aura with acetyl-dl-leucine: a case series". Journal of Neurology. 266 (2): 525–529. doi:10.1007/s00415-018-9155-6. ISSN 1432-1459. PMID 30547273. S2CID 56148131. 43. ^ Synofzik, Matthis; Ilg, Winfried (3 April 2018). "Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames". BioMed Research International. 2014: 583507. doi:10.1155/2014/583507. PMC 4022207. PMID 24877117. 44. ^ Marsden, J.; Harris, C. (2011). "Cerebellar ataxia: Pathophysiology and rehabilitation". Clinical Rehabilitation. 25 (3): 195–216. doi:10.1177/0269215510382495. PMID 21321055. S2CID 40374830. 45. ^ "SCA2 information sheet from www.ataxia.org" (PDF). Archived from the original (PDF) on 2012-07-12. Retrieved 2012-05-10. 46. ^ Trujillo-Martín, M.Mar; Serrano-Aguilar, Pedro; Monton-Álvarez, Fernando; Carrillo-Fumero, Romen (2009). "Effectiveness and safety of treatments for degenerative ataxias: A systematic review". Movement Disorders. 24 (8): 1111–24. doi:10.1002/mds.22564. PMID 19412936. 47. ^ Miyai, I.; Ito, M.; Hattori, N.; Mihara, M.; Hatakenaka, M.; Yagura, H.; Sobue, G.; Nishizawa, M.; Cerebellar Ataxia Rehabilitation Trialists Collaboration (2011). "Cerebellar Ataxia Rehabilitation Trial in Degenerative Cerebellar Diseases". Neurorehabilitation and Neural Repair. 26 (5): 515–22. doi:10.1177/1545968311425918. PMID 22140200. S2CID 23764699. ## Further reading[edit] * Bird, Thomas D (23 January 2014). Hereditary Ataxia Overview. University of Washington, Seattle. PMID 20301317. NBK1138. In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle. * Moreira, Maria-Ceu; Koenig, Michel (December 8, 2011). Ataxia with Oculomotor Apraxia Type 2. University of Washington, Seattle. PMID 20301333. NBK1154. In GeneReviews * Pulst, Stefan-M (1 March 2012). Spinocerebellar Ataxia Type 13. University of Washington, Seattle. PMID 20301404. NBK1225. In GeneReviews * Brussino, Alessandro; Brusco, Alfredo; Dürr, Alexandra (7 February 2013). Spinocerebellar Ataxia Type 28. University of Washington, Seattle. PMID 21595125. NBK54582. In GeneReviews * Online Mendelian Inheritance in Man (OMIM): Spinocerebellar Ataxia, Autosomal Recessive 1; SCAR1 - 606002 * Online Mendelian Inheritance in Man (OMIM): Senataxin; SETX - 608465 ## External links[edit] * ataxia at NINDS * msa at NINDS * opca_doc at NINDS * MedlinePlus Encyclopedia: Olivopontocerebellar atrophy * Spinocerebellar ataxia 27 at NIH's Office of Rare Diseases * Spinocerebellar ataxia dysmorphism at NIH's Office of Rare Diseases Classification D * ICD-10: G11.1 * ICD-9-CM: 334 * OMIM: 164400 * MeSH: D020754 * DiseasesDB: 12339 * 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 Non-Mendelian inheritance: anticipation Trinucleotide Polyglutamine (PolyQ), CAG * Dentatorubral-pallidoluysian atrophy * Huntington's disease * Kennedy disease * Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease) Non-polyglutamine * CGG (Fragile X syndrome) * GAA (Friedreich's ataxia) * CTG (Myotonic dystrophy type 1) * CTG (Spinocerebellar ataxia 8) * CAG (Spinocerebellar ataxia 12) Tetranucleotide * CCTG (Myotonic dystrophy type 2) Pentanucleotide * ATTCT (Spinocerebellar ataxia 10) * v * t * e Inherited disorders of trafficking / vesicular transport proteins Vesicle formation Lysosome/Melanosome: * HPS1–HPS7 * Hermansky–Pudlak syndrome * LYST * Chédiak–Higashi syndrome COPII: * SEC23A * Cranio-lenticulo-sutural dysplasia * COG7 * CDOG IIE APC: * AP1S2 * X-linked intellectual disability * AP3B1 * Hermansky–Pudlak syndrome 2 * AP4M1 * CPSQ3 Rab * ARL6 * BBS3 * RAB27A * Griscelli syndrome 2 * CHM * Choroideremia * MLPH * Griscelli syndrome 3 Cytoskeleton Myosin: * MYO5A * Griscelli syndrome 1 Microtubule: * SPG4 * Hereditary spastic paraplegia 4 Kinesin: * KIF5A * Hereditary spastic paraplegia 10 Spectrin: * SPTBN2 * Spinocerebellar ataxia 5 Vesicle fusion Synaptic vesicle: * SNAP29 * CEDNIK syndrome * STX11 * Hemophagocytic lymphohistiocytosis 4 Caveolae: * CAV1 * Congenital generalized lipodystrophy 3 * CAV3 * Limb-girdle muscular dystrophy 2B, Long QT syndrome 9 Vacuolar protein sorting: * VPS33B * ARC syndrome * VPS13B * Cohen syndrome * DYSF * Distal muscular dystrophy See also vesicular transport proteins Authority control * NDL: 01033493 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Spinocerebellar ataxia	c0029534	8,734	wikipedia	https://en.wikipedia.org/wiki/Spinocerebellar_ataxia	2021-01-18T19:06:23	{"gard": ["10748"], "mesh": ["D020754"], "umls": ["C0029534"], "icd-10": ["G11.1"], "orphanet": ["99"], "wikidata": ["Q899726"]}
## Summary ### Clinical characteristics. PAFAH1B1-associated lissencephaly includes Miller-Dieker syndrome (MDS), isolated lissencephaly sequence (ILS), and (rarely) subcortical band heterotopia (SBH). Lissencephaly and SBH are cortical malformations caused by deficient neuronal migration during embryogenesis. Lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). SBH refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. MDS is characterized by lissencephaly, typical facial features, and severe neurologic abnormalities. ILS is characterized by lissencephaly and its direct sequelae: developmental delay, intellectual disability, and seizures. ### Diagnosis/testing. MDS is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include PAFAH1B1 (formerly LIS1) and YWHAE, and intervening genes. ILS is caused by smaller submicroscopic deletions of PAFAH1B1; intragenic deletions or duplications of PAFAH1B1; or sequence variants of PAFAH1B1. ### Management. Treatment of manifestations: Poor feeding may require nasogastric tube feedings in newborns and later placement of a gastrostomy tube. Seizures require prompt and aggressive management based on the specific seizure type and frequency; response to treatment is similar to that in children with seizures due to other causes. Surveillance: Whenever any unusual spells or any developmental regression is noted, a child neurology consultation should be performed and EEG considered. ### Genetic counseling. Approximately 80% of individuals with MDS have a de novo deletion involving 17p13.3 and approximately 20% have inherited a deletion from a parent who carries a balanced chromosome rearrangement. If neither parent has a structural chromosome rearrangement detectable by high-resolution chromosome analysis, the risk to sibs is negligible. If a parent has a balanced structural chromosome rearrangement, the risk to sibs for MDS depends on the specific rearrangement. Although germline mosaicism in a parent could lead to familial recurrence of ILS, all PAFAH1B1 intragenic pathogenic variants reported to date have been de novo; thus, the risk to sibs for ILS is negligible if neither parent has mosaicism for the PAFAH1B1 pathogenic variant present in the proband. Prenatal testing for pregnancies at increased risk for MDS is possible if the familial chromosome rearrangement is known. ## Diagnosis ### Clinical Diagnosis Together, lissencephaly and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis [Barkovich et al 1991, Norman et al 1995]. The term lissencephaly refers to a "smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria). #### MRI Findings Lissencephaly * Cerebral gyri are absent or abnormally broad. * The cerebral cortex is abnormally thick (12-20 mm; normal: 3-4 mm) [Barkovich et al 1991]. * Associated findings in the most common ("classic") form of lissencephaly include: * Enlarged lateral ventricles, especially posteriorly * Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened) * Cavum septi pellucidi et vergae * Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few Subcortical band heterotopia (SBH) * A subcortical band of heterotopic gray matter, present just beneath the cortex, is separated from it by a thin zone of normal white matter [Barkovich et al 1994]. SBH is most often symmetric, but may be asymmetric. * In PAFAH1B1-associated SBH, the subcortical bands are restricted to the parietal and occipital lobes (diffuse or frontal predominant SBH are associated with mutation of DCX (see DCX-Related Disorders). * The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present. Lissencephaly and SBH are graded by anterior-posterior gradient and severity (Table 1 and Figure 1). When the lissencephaly or SBH is more severe posteriorly, it is referred to as a posterior to anterior (p>a) gradient. When more severe anteriorly, it is referred to as an anterior to posterior (a>p) gradient. PAFAH1B1 abnormalities give rise to diffuse or p>a gradients, whereas abnormalities of DCX generally give rise to diffuse or a>p gradients [Pilz et al 1998a, Dobyns et al 1999]. #### Figure 1. Brain MRIs of lissencephaly, ranging from grade 1 (the most severe) to grade 6 (subcortical band heterotopia, the least severe). (P) indicates posterior; (A) indicates anterior. Lissencephaly that is more severe posteriorly than anteriorly (best observed (more...) ### Table 1. Grading System for Classic Lissencephaly and SBH View in own window GradientGrade of Severity 1a=p 1Complete agyria 2p>a or 2a>pDiffuse agyria with a few undulations at the frontal or occipital poles 3p>a or 3a>pMixed agyria and pachygyria 4p>a or 4a>pDiffuse pachygyria, or mixed pachygyria and normal or simplified gyri 5a>p 2Mixed pachygyria and subcortical band heterotopia 6p>a or 6a>pSubcortical band heterotopia only 1\. With severe grade 1 lissencephaly, it is difficult to determine if a gradient is present. 2\. The reverse (5p>a) has not been observed. #### Histologic Findings Classic lissencephaly. The cortex is abnormally thick and poorly organized with four apparent layers consisting of the following [Crome 1956, Forman et al 2005]: * Poorly defined marginal zone with increased cellularity * Superficial cortical gray zone with diffusely scattered neurons * Relatively neuron-sparse zone * Deep cortical gray zone with neurons often oriented in columns. Neurons may be oriented with dendrites extending toward the pial surface or inverted, extending toward the ventricle. SBH. The architecture of the cortex has not been studied in individuals with PAFAH1B1 pathogenic variants (see DCX-Related Disorders) ### Testing Chromosome analysis * High-resolution chromosome studies at the 450-band level or higher identify cytogenetically visible deletions or other structural rearrangements of 17p13.3 in approximately 70% of individuals with Miller-Dieker syndrome (MDS), but not in individuals with isolated lissencephaly sequence (ILS) or SBH [Dobyns et al 1991]. * Rarely, individuals with ILS have a balanced reciprocal translocation disrupting PAFAH1B1. * Rarely, individuals with posterior-predominant SBH have mosaic deletions of 17p13.3 visible on cytogenetic analysis. #### Molecular Genetic Testing Gene. Abnormalities of PAFAH1B1 (LIS1)* cause isolated PAFAH1B1-associated lissencephaly/SBH [Pilz et al 1998b, Pilz et al 1999, Fogli et al 1999, Cardoso et al 2000, Cardoso et al 2002, Sicca et al 2003, Saillour et al 2009]. * Note: PAFAH1B1 is the official gene designation; however, the former gene designation (LIS1) is still in common use in medical genetics. Clinical testing. Abnormalities of PAFAH1B1 range from single-nucleotide variants to contiguous gene deletions. Clinical testing for PAFAH1B1 is available for the detection of these various abnormalities. ### Table 2. Molecular Genetic Testing Used in PAFAH1B1-Related Lissencephaly/SBH View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2 MDS 3ILSSBH PAFAH1B1Deletion / duplication analysis 4See footnotes 5, 6100%~54%4 individuals 7 See footnote 80~68% 9Not described Sequence analysis 1o0~32% 117 individuals 12 Data from Pilz et al [1998a], Pilz et al [1998b], Pilz et al [1999], Cardoso et al [2002], D’Agostino et al [2002], Cardoso et al [2003], Sicca et al [2003], Mei et al [2008], Haverfield et al [2009] 1\. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. 2\. Does not take into account individuals with pathogenic variants in DCX, TUBA1A, or other lissencephaly-associated genes, and those in whom no pathogenic variants have been identified. 3\. As currently defined, MDS is associated with deletions that include both PAFAH1B1 and YWHAE (a region of about 1.3 Mb harboring many genes) in 17p13.3 [Pilz et al 1998a, Cardoso et al 2003]. 4\. Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), targeted array CGH and chromosomal microarray (CMA) that includes this gene/chromosome segment. 5\. Detecting deletions of PAFAH1B1 and adjacent genes/regions. 6\. Chromosomal microarray analysis as well as FISH testing can be performed using a probe containing PAFAH1B1 (e.g., PAC95H6). Chromosomal microarray analysis will detect microdeletions/contiguous gene deletions that involve PAFAH1B1, and may detect partial deletions of PAFAH1B1 depending on the size of the deletion and probe density of the array. FISH analysis will detect microdeletions/contiguous gene deletions that involve the entire gene but will not detect partial deletions of PAFAH1B1. 7\. Mosaic deletions of 17p13.3 involving PAFAH1B1 have been observed in four individuals with SBH [WB Dobyns, personal communication]. 8\. Quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and targeted array CGH may be used to detect partial deletions of PAFAH1B1 that may be intragenic and may affect single or multiple exons, the promoter, or the 5’ untranslated region. 9\. Intragenic deletions and duplications of PAFAH1B1 that range in size from a single exon to multiple exons to the entire gene are present in approximately 14% of individuals with PAFAH1B1-related ILS [Mei et al 2008, Haverfield et al 2009]. 10\. 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. 11\. Germline PAFAH1B1 pathogenic variants are present in approximately 32% of individuals with PAFAH1B1-related ILS. Rarely, mosaic pathogenic variants have been identified. 12\. On occasion, PAFAH1B1 pathogenic variants are identified in individuals with SBH. To date, pathogenic variants have been identified in seven individuals: four who had mosaic pathogenic variants and three with apparent germline pathogenic variants [Pilz et al 1999; D’Agostino et al 2002; Sicca et al 2003; Uyanik et al 2007; Mineyko et al 2010; Pagnamenta et al 2012; WB Dobyns & S Das, personal communication]. Issues with interpretation of test results * Normal results of FISH analysis using a PAFAH1B1-derived probe such as PAC95H6 do not exclude the presence of the following: * A submicroscopic deletion of 17p13 that includes partial deletions of PAFAH1B1. Partial deletions of PAFAH1B1 may affect single or multiple exons, the promoter or the 5’ untranslated region (UTR). * An intragenic pathogenic variant in PAFAH1B1 * Normal results of chromosomal microarray analysis do not exclude the presence of PAFAH1B1 intragenic deletions or duplications that affect single or multiple exons. Targeted deletion/duplication analysis that contains probes to PAFAH1B1 can detect smaller PAFAH1B1 intragenic deletions/duplications. ### Testing Strategy #### Probands with Isolated Lissencephaly Sequential single-gene testing. One strategy for the diagnosis of an individual suspected of having lissencephaly with a p>a gradient or lissencephaly with an unknown or uncertain gradient is sequential single-gene testing. * Deletion/duplication analysis that detects all large deletions involving PAFAH1B1 as well as small exon deletions and duplications not detected by sequence analysis should be performed first. * If no deletion or duplication involving PAFAH1B1 is identified, sequence analysis of PAFAH1B1 should be considered next. Lissencephaly with a p>a gradient * If no pathogenic variant in PAFAH1B1 is identified by deletion/duplication or sequence analysis, molecular genetic testing of the following genes may be considered next: DCX, DYNC1H1, KIF2A, TUBA1A (codon R402) and TUBG1 (see Differential Diagnosis). * Chromosome analysis. Only two individuals with balanced reciprocal translocations disrupting PAFAH1B1 have been observed (<1%); both had the ILS phenotype. Lissencephaly with an unknown or uncertain gradient * If no pathogenic variant in PAFAH1B1 is identified by deletion/duplication or sequence analysis, molecular genetic testing of the following genes may be considered next: DCX, ACTB, ACTG1, DYNC1H1, KIF2A, RELN, TUBA1A (codon R402), TUBG1 and VLDLR (see Differential Diagnosis). Multigene panel. An alternative to single-gene molecular genetic testing is a panel in which a number of genes that lead to lissencephaly (see Differential Diagnosis) are represented. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual also varies. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Lissencephaly with an a>p gradient (see Differential Diagnosis) * Perform sequence analysis of DCX, ACTB, ACTG1, PAFAH1B1, RELN and VLDLR. While DCX is the most indicated in this category and can be sequenced first, the other genes can result in an overlapping phenotype. Note: PAFAH1B1 abnormalities are generally not associated with an a>p gradient but when severe can be difficult to differentiate. #### Probands with SBH Sequential single-gene testing. One strategy for the diagnosis of an individual suspected of having SBH is sequential single-gene testing. * Sequence analysis of DCX should be considered first, as this detects pathogenic variants in up to 80% of females [des Portes et al 1998, Gleeson et al 1999, Matsumoto et al 2001] and 30% of males [D’Agostino et al 2002]. * If no pathogenic variant is detected in DCX through sequence analysis, deletion/duplication analysis should be considered next. Deletion/duplication analysis of DCX detects intragenic deletions in approximately 5%-9% of females [Mei et al 2007, Haverfield et al 2009]. * If no pathogenic variants are detected in DCX, sequence analysis of PAFAH1B1 may be considered. * If no pathogenic variants are identified, FISH testing using a PAFAH1B1-derived probe may be considered. Multigene panel. An alternative to single-gene molecular genetic testing is a panel in which a number of genes that lead to SBH (see Differential Diagnosis) are represented. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual also varies. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ## Clinical Characteristics ### Clinical Description The phenotypes associated with mutation of PAFAH1B1 comprise a spectrum of severity that can be separated into Miller-Dieker syndrome (MDS), posterior predominant ILS (or isolated lissencephaly) and, on rare occasion, posterior predominant subcortical band heterotopia (SBH). MDS consists of severe lissencephaly (grade 1-2) (see Table 1 and Figure 1), characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities [Dobyns et al 1991, Cardoso et al 2003]. The facial changes consist of high and prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip with downturned vermilion border, and small jaw (Figure 2). Other malformations seen on occasion include omphalocele and congenital heart defects. #### Figure 2. Two children with Miller-Dieker syndrome showing typical facial features Photographs obtained with consent of the families. ILS consists of more variable lissencephaly (grades 2-4) (see Table 1 and Figure 1), minor facial changes, rare malformations outside of the brain, and similar neurologic and developmental handicaps as in MDS [Dobyns et al 1992]. In both MDS and ILS, the pregnancy may be complicated by polyhydramnios. Affected newborns may appear normal or may have mild to moderate hypotonia, poor feeding, and transient elevations in bilirubin likely related to feeding difficulties [Dobyns et al 1991, Dobyns et al 1992]. At birth, the occipitofrontal circumference (OFC) is typically normal (between the mean and 2 SD below the mean). However, postnatal head growth is slow; most children develop microcephaly by age one year. Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia including poor head control. Some have difficulty with feeding. Children with lissencephaly have epileptic encephalopathies that typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike and wave pattern on EEG. Overall, seizures occur in more than 90% of children with lissencephaly with onset usually before age six months. Approximately 80% have infantile spasms, although the EEG does not always show the typical hypsarrhythmia pattern. The onset of infantile spasms may be associated with a decline in function. After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures [Guerrini 2005], complex partial seizures, atypical absences, and atonic and myoclonic seizures. Some children with lissencephaly have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [Quirk et al 1993]. The developmental prognosis is poor for all children with MDS and for the majority with isolated lissencephaly. Even with good seizure control, the best developmental level achieved by children with MDS or isolated lissencephaly (excluding the few with partial lissencephaly) is the equivalent of about age three to five months. This may include brief visual tracking, rolling over, limited creeping, and very rarely, sitting. With poor seizure control, children with lissencephaly may function at or below the level of a newborn. A few individuals with less severe (grade 4) lissencephaly, especially partial posterior lissencephaly or pachygyria, have a better developmental outcome [Leventer et al 2001]. During the first years, neurologic examination typically demonstrates brief visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent, although hypotonia remains. Rarely, affected individuals develop moderate spastic quadriplegia and scoliosis. Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons. Children with lissencephaly have poor control of their airway, which predisposes to aspiration pneumonia, the most common terminal event. The prognosis differs somewhat between MDS and isolated lissencephaly. In MDS, death occurs within the first two years in many children, and only a few reach age ten years. The oldest known individual with MDS died at age 17 years. In isolated lissencephaly, approximately 50% live to age ten years, and very few reach age 20 years. The oldest known individual lived to age 30 years. These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly). In general, life expectancy is related to the severity of the lissencephaly on neuroimaging [de Wit et al 2011]. Seven individuals with SBH associated with PAFAH1B1 pathogenic variants have been reported/identified, three with germline pathogenic variants and four with mosaic pathogenic variants [Pilz et al 1999; D’Agostino et al 2002; Sicca et al 2003; Uyanik et al 2007; Mineyko et al 2010; Pagnamenta et al 2012; WB Dobyns & S Das, unpublished review]. Two other unreported individuals have had mosaic deletions of chromosome 17p13.3 [WB Dobyns, personal observation]. SBH is characterized by normal facial appearance, epilepsy, and intellectual disability. Four of the seven individuals with PAFAH1B1-related SBH had frequent seizures. One had an IQ of 107 at age seven years that declined to 60 by age 13 years, most likely as a result of severe seizures; one had an IQ of approximately 60; one had severe intellectual disability; two had global developmental delay. In general individuals with SBH live into adult life. No reliable data regarding life span exist; it is likely to be shortened in those with severe intellectual disability, intractable epilepsy, or both. ### Genotype-Phenotype Correlations MDS. The most severely affected individuals with MDS have large cytogenetically visible deletions of 17p13.3 and unbalanced chromosome rearrangements associated with duplication of another chromosome segment. The next-most severe abnormality is deletion of 17p13.3 that includes both PAFAH1B1 and YWHAE [Cardoso et al 2003], the latter located telomeric to PAFAH1B1 in the MDS chromosome region. ILS. Smaller deletions, including intragenic deletions and duplications of PAFAH1B1, cause ILS that is less severe than MDS, ranging in severity from grade 2 to 4. * Most individuals with a telomeric deletion including the 5’ end of PAFAH1B1 have grade 2 to 3 lissencephaly. * Most individuals with a deletion of the 3’ end of PAFAH1B1 have grade 3 to 4 lissencephaly [Chong et al 1997; unpublished data]. * The vast majority of individuals with intragenic deletions and duplications of PAFAH1B1 have grade 3 lissencephaly [Haverfield et al 2009]. Intragenic pathogenic variants in PAFAH1B1 usually result in ILS grade 3 or 4. In general: * Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in PAFAH1B1 [Cardoso et al 2000, Leventer et al 2001, Cardoso et al 2002]. * Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than the similar variants that occur in other downstream regions of the gene [Cardoso et al 2000, Cardoso et al 2002]. Note: These generalizations notwithstanding, severity of the phenotype does not always appear to correspond to location and type of pathogenic variant, as a more severe phenotype has been observed in some individuals with pathogenic missense variants and more severe grades (2 and 3) of lissencephaly have been observed in individuals with truncation/deletion variants in the coiled-coil domain toward the 3’ end of PAFAH1B1 [Uyanik et al 2007]. SBH. Two PAFAH1B1 pathogenic missense variants, one frameshift variant, and somatic mosaicism for a PAFAH1B1 missense, nonsense, in-frame, and splice site variant have been identified in seven individuals with a milder phenotype of SBH [Pilz et al 1999; D’Agostino et al 2002; Sicca et al 2003; Uyanik et al 2007; Mineyko et al 2010; Pagnamenta et al 2012; WB Dobyns & S Das, unpublished review]. Somatic mosaicism for a PAFAH1B1 deletion also results in the milder phenotype SBH (seen in two individuals [WB Dobyns, unpublished observation]). ### Prevalence Classic lissencephaly is rare. Birth prevalence is estimated to range from 11.7 to 40 per million births [personal communication with Metropolitan Atlanta Congenital Defects Program Personnel, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, 2002]. Even the latter is likely to be an underestimate as the CDC program ascertains only hospitalized children in the first several years of life. ## Differential Diagnosis The greatest difficulty in diagnosis of lissencephaly and subcortical band heterotopia (SBH) is recognizing the malformation. Several types of lissencephaly have been described, although they have overlapping features (Table 3). The most common are classic lissencephaly (including SBH) and cobblestone complex. ### Table 3. Types of Lissencephaly View in own window TypeDescriptionGenesInheritance Pattern Classic lissencephalyVery thick cortex (15-20 mm), normal corpus callosum, & cerebellar vermis (or mild hypoplasia)PAFAH1B1AD DCXX-linked TUBA1AAD Lissencephaly with cerebellar hypoplasia, tubulin typeDiffuse or posterior predominant lissencephaly w/moderate to severe cerebellar hypoplasiaTUBA1AAD TUBB2B Lissencephaly with cerebellar hypoplasia, reelinopathy typeMild frontal lissencephaly w/severe cerebellar hypoplasiaRELNAR VLDLR Cobblestone cortical malformation (lissencephaly)Pebbled brain surface, moderately thick 5-10 mm cortex (unless thinned by hydrocephalus), diffuse or patchy white matter abnormality, brain stem & cerebellar hypoplasiaFKTNAR FKRP LARGE POMGnT1 POMT1 POMT2 ADGRG1 (GPR56) Lissencephaly with agenesis of the corpus callosumLissencephaly w/total or severe partial agenesis of the corpus callosumARXX-linked MicrolissencephalyBirth OFC -3 SD or small, thick cortexNANA AD = autosomal dominant AR = autosomal recessive NA = not applicable OFC = occipital frontal circumference Several different cortical malformations that are sometimes mistaken for lissencephaly have been described, including severe congenital microcephaly with reduced number of gyri, cobblestone malformations as seen in Walker-Warburg and other syndromes, polymicrogyria, and polymicrogyria-like variants associated with pathogenic variants of tubulin genes. This leads to incorrect diagnosis, counseling, and testing. Clinical features can help distinguish children who have lissencephaly from those who have other brain malformations. Children with lissencephaly usually have normal or slightly small OFC at birth (> -3 SD) and diffuse hypotonia except for mildly increased tone at the wrists and ankles. Children with severe congenital (i.e., primary) microcephaly and gyral abnormalities have smaller birth OFC (≤ -3 SD) and may be hypotonic or spastic. Infants with polymicrogyria, especially when the frontal lobes are involved, frequently have spastic quadriparesis. The differential diagnosis of classic lissencephaly includes the PAFAH1B1-related malformations, DCX-related malformations, TUBA1A-related malformations and the rare Baraitser-Winter syndrome (BWS) [Dobyns et al 1991, Dobyns et al 1992, Pilz et al 1998a, Pilz et al 1998b, Dobyns et al 1999, Matsumoto et al 2001, Ross et al 2001, Rossi et al 2003, Poirier et al 2007]. These disorders are distinguished by mode of inheritance, grade and gradient of lissencephaly or SBH (Table 1), presence of other congenital anomalies, and results of molecular genetic testing. * Classic lissencephaly associated with deletions or intragenic pathogenic variants in PAFAH1B1 is more common than classic lissencephaly associated with pathogenic variants in DCX, located on the X chromosome [Pilz et al 1998b], and classic lissencephaly associated with pathogenic variants in TUBA1A codon Arg402. * SBH in females associated with pathogenic variants in DCX is far more common than SBH in females with PAFAH1B1 pathogenic variants [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003]. * PAFAH1B1-related malformations are characterized by a p>a gradient (see Table 1). DCX-related malformations are associated with an a>p gradient [Pilz et al 1998b, Dobyns et al 1999]. However, in severe classic lissencephaly or SBH the gradient may be difficult to discern. * TUBA1A-related malformations, like PAFAH1B1-related malformations, are characterized by a p>a gradient. The lissencephaly phenotype associated with PAFAH1B1 and TUBA1A Arg402 pathogenic variants may be indistinguishable. Pathogenic variants elsewhere in TUBA1A result in a spectrum of malformations that vary from polymicrogyria-like cortical malformation with cerebellar hypoplasia and callosal dysgenesis to the most severe forms of lissencephaly with cerebellar hypoplasia (also called 2-layer lissencephaly) [Poirier et al 2007, Kumar et al 2010, Cushion et al 2013]. * Baraitser-Winter syndrome is characterized by: lissencephaly with an a>p gradient similar to that of DCX-related malformations; trigonocephaly; shallow orbits; ptosis; and colobomas of the iris, choroid, or both [Ramer et al 1995, Rossi et al 2003]. Lissencephaly with agenesis of the corpus callosum is typically associated with pathogenic variants in ARX. The XLAG (X-linked lissencephaly with abnormal genitalia) phenotype in severely affected individuals with a 46,XY karyotype differs significantly from the phenotype associated with pathogenic variants in either PAFAH1B1 or DCX. XLAG is characterized by congenital or postnatal microcephaly, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and abnormal genitalia [Kato & Dobyns 2003, Kato et al 2004]. The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy) differ clinically in a number of ways, including the frequent presence of hydrocephalus and cerebellar hypoplasia, multiple different eye anomalies, and congenital muscular dystrophy manifest by hypotonia and elevated serum creatine kinase concentrations. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PAFAH1B1-associated lissencephaly/ subcortical band heterotopia (SBH), the following are recommended: * Evaluation of: * Growth * Feeding and nutrition * Respiratory status * Development * Seizures * Clinical genetics consultation MRI should be interpreted carefully to provide as much prognostic information as possible. Note: Although most affected individuals have severe to profound intellectual disability, a minority have less extensive lissencephaly that results in only moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is not usually sufficient to allow this. ### Treatment of Manifestations Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" (DNR) orders, in the event of severe illnesses. Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life. But they often worsen again with intercurrent illnesses and with advancing age and size. At least 50% of children with PAFAH1B1-related lissencephaly (but not SBH) eventually have a gastrostomy tube placed for feeding. A large majority of children with lissencephaly have seizures, including frequent infantile spasms, which can be difficult to control. Management of seizures in children with ILS or SBH is based on the specific seizure type and frequency. In general, seizures should be treated promptly and aggressively by specialists, as poor seizure control frequently results in decline in function and health. Specifically, poor seizure control worsens feeding and increases the likelihood that a gastrostomy tube will be needed, and increases the risk for pneumonia. ### Surveillance Whenever any unusual spells or any developmental regression is noted, a child neurology consultation should be performed, and EEG considered. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia	None	8,735	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK5189/	2021-01-18T21:06:23	{"synonyms": ["LIS1-Associated Lissencephaly/Subcortical Band Heterotopia"]}
Glutaric acidemia type 2 Other namesMultiple acyl-CoA dehydrogenase deficiency (MADD)[1] Glutaric acid SpecialtyMedical genetics Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis. ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Genetics[edit] Glutaric acidemia type 2 has an autosomal recessive pattern of inheritance. Mutations in the ETFA, ETFB, and ETFDH genes cause glutaric acidemia type II. Mutations in these genes result in a deficiency in one of two enzymes that normally work together in the mitochondria, which are the energy-producing centers of cells. The ETFA and ETFB genes encode two subunits of the enzyme electron transfer flavoprotein, while the ETFDH gene encodes the enzyme electron transfer flavoprotein dehydrogenase. When one of these enzymes is defective or missing, the mitochondria cannot function normally, partially broken-down proteins and fats accumulate in the cells and damage them; this damage leads to the signs and symptoms of glutaric acidemia type II.[1] This condition is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – are needed to inherit the disorder. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the defective gene, but do not show signs and symptoms of the disorder themselves. ## Diagnosis[edit] Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes, and vomiting. There may also be enlargement of the liver, heart failure, and a characteristic odor resembling that of sweaty feet. Some infants with glutaric acidemia type 2 have birth defects, including multiple fluid-filled growths in the kidneys (polycystic kidneys). Glutaric acidemia type 2 is a very rare disorder. Its precise incidence is unknown. It has been reported in several different ethnic groups. ## Treatment[edit] It is important for patients with MADD to strictly avoid fasting to prevent hypoglycemia and crises of metabolic acidosis;[2][3] for this reason, infants and small children should eat frequent meals.[3] Patients with MADD can experience life-threatening metabolic crises precipitated by common childhood illnesses or other stresses on the body,[3] so avoidance of such stresses is critical.[2] Patients may be advised to follow a diet low in fat and protein and high in carbohydrates, particularly in severe cases.[2][3] Depending on the subtype, riboflavin[3] (100-400 mg/day),[2] coenzyme Q10 (CoQ10),[2] L-carnitine,[3] or glycine[3] supplements may be used to help restore energy production. Some small, uncontrolled studies[4][5][6] have reported that racemic salts of beta-hydroxybutyrate were helpful in patients with moderately severe disease; further research is needed.[2] ## See also[edit] * Glutaric acidemia type 1 ## References[edit] 1. ^ a b "Glutaric acidemia type II". Genetics Home Reference. U.S. Department of Health & Human Services. Retrieved 20 August 2018. 2. ^ a b c d e f "Multiple acyl-CoA dehydrogenase deficiency". Orphanet. INSERM and the European Commission. Retrieved 30 August 2018. 3. ^ a b c d e f g "Glutaric acidemia type II". Genetic and Rare Diseases Information Center (GARD). National Institutes of Health National Center for Advancing Translational Sciences. Retrieved 30 August 2018. 4. ^ Gautschi M, Weisstanner C, Slotboom J, Nava E, Zürcher T, Nuoffer JM (January 2015). "Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy". Pediatr Res. 77 (1): 91–8. doi:10.1038/pr.2014.154. PMID 25289702. 5. ^ Van Rijt WJ, Heiner-Fokkema MR, du Marchie Sarvaas GJ, Waterham HR, Blokpoel RG, van Spronsen FJ, Derks TG (October 2014). "Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD". Pediatrics. 134 (4): e1224-8. doi:10.1542/peds.2013-4254. PMID 25246622. Retrieved 30 August 2018. 6. ^ Van Hove JL, Grünewald S, Jaeken J, Demaerel P, Declercq PE, Bourdoux P, Niezen-Koning K, Deanfeld JE, Leonard JV (26 April 2003). "D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD)". The Lancet. 361 (9367): 1433–5. doi:10.1016/S0140-6736(03)13105-4. PMID 12727399. This article incorporates public domain text from The U.S. National Library of Medicine ## External links[edit] Classification D * ICD-10: E72.3 * ICD-9-CM: 277.85 * OMIM: 231680 * MeSH: D054069 * DiseasesDB: 29816 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria * v * t * e Inborn error of lipid metabolism: fatty-acid metabolism disorders Synthesis * Biotinidase deficiency (BTD) Degradation Acyl transport * Carnitine * CPT1 * CPT2 * CDSP * CACTD * Adrenoleukodystrophy (ALD) Beta oxidation General * Acyl CoA dehydrogenase * Short-chain SCADD * Medium-chain MCADD * Long-chain 3-hydroxy LCHAD * Very long-chain VLCADD * Mitochondrial trifunctional protein deficiency (MTPD): Acute fatty liver of pregnancy Unsaturated * 2,4 Dienoyl-CoA reductase deficiency (DECRD) Odd chain * Propionic acidemia (PCC deficiency) Other * 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (HADHD) * Glutaric acidemia type 2 (MADD) To acetyl-CoA * Malonic aciduria (MCD) Aldehyde * Sjögren–Larsson syndrome (SLS) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Glutaric acidemia type 2	c3278155	8,736	wikipedia	https://en.wikipedia.org/wiki/Glutaric_acidemia_type_2	2021-01-18T18:34:03	{"gard": ["6523"], "mesh": ["D054069"], "umls": ["C3278155", "C3278154", "C2931346", "C3278156"], "icd-9": ["277.85"], "orphanet": ["26791"], "wikidata": ["Q1403045"]}
POEMS syndrome is a paraneoplastic syndrome characterized by polyradiculoneuropathy (P), organomegaly (O), endocrinopathy (E), clonal plasma cell disorder (M), and skin changes (S). Other features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis, and elevated VEGF levels. ## Epidemiology Exact prevalence and incidence rates are not known. The only estimates are from Japan. In this country, prevalence has been reported to be about 1/330,000. Male predilection has been reported (2.5:1). ## Clinical description The average age of onset is in the 5th or 6th decade. The disease covers a wide clinical spectrum depending on the systems involved. Neuropathy is the primary manifestation and is usually peripheral, ascending, and symmetrical with distal weakness and paresthesia. It is both sensory and motor and may cause pain, hyperesthesia, and areflexia. A clonal plasma cell disorder (PCD) is the second major feature. Organomegaly mainly includes hepatomegaly, splenomegaly, and/or lymphadenopathy (Castleman disease; see this term). Various and extensive endocrine disorders may be found causing hypogonadism, thyroid abnormalities, adrenal insufficiency, and/or erectile dysfunction and gynecomastia in men. The skin is commonly affected with development of hyperpigmentation, hemangiomas, hypertrichosis, leukonychia or nail clubbing, sclerodermoid changes, lipodystrophy, and flushing. The main ocular manifestation is papilledema. Extravascular overload mainly manifests as peripheral edema, and sometimes as pleural effusion, ascites, and pericardial effusions. An increased risk of arterial and/or venous thrombosis is reported (up to 20% of patients). Disease severity depends on the systems involved and the course is chronic. Some patients have a mild presentation while others have debilitating disease. 25% have respiratory manifestations including restrictive lung disease, pulmonary hypertension, and respiratory muscle weakness. ## Etiology The pathogenesis has not been clearly elucidated. Vascular endothelial growth factor (VEGF) appears to play a significant role in this plasma cell disorder. ## Diagnostic methods All of the clinical features are not required for diagnosis. Patients with three of the major criteria necessarily including polyradiculoneuropathy and clonal PCD (plus possibly Castleman, sclerotic bone lesions, VEGF elevation), plus at least one minor criterion can be diagnosed with POEMS. Minor criteria are organomegaly, endocrinopathy, papilledema, extravascular overload, and skin changes. Patient with POEMS features who do not have both peripheral neuropathy and PCD are considered as having the Castleman disease variant of POEMS. Radiographic assessment of bones, elevated VEGF, and bone marrow biopsy aid in confirming the diagnosis. VEGF levels correlate with disease activity. ## Differential diagnosis The main differential diagnoses are chronic inflammatory demyelinating polyneuropathy, AL amyloidosis and Guillain-Barré syndrome (see these terms). Monoclonal gammopathy of undetermined significance (MGUS) and should also be considered. ## Management and treatment Patients with dominant sclerotic plasmacytoma are treated with radiotherapy. Radiation is also used in patients with diffuse sclerotic lesions or disseminated bone marrow involvement. Some patients progress after radiation therapy and require systemic treatment. Alkylators are the main treatment, along with lenalidomide and to a lesser extent thalidomide and bortezomib. High-dose chemotherapy with peripheral blood stem cell transplant may be successful. Supportive care should also be provided (orthotics, physical therapy, and continuous positive airway pressure (CPAP)). ## Prognosis The prognosis is generally good if diagnosis is early and appropriate treatment is provided. Causes of death include progressive anasarca, thrombosis, and inanition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	POEMS syndrome	c0085404	8,737	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2905	2021-01-23T17:54:58	{"gard": ["7411"], "mesh": ["D016878"], "umls": ["C0085404", "C1510415"], "icd-10": ["D47.7"], "synonyms": ["Crow-Fukase syndrome", "Osteosclerotic myeloma", "PEP syndrome", "Polyneuropathy-endocrinopathy-plasma cell dyscrasia syndrome", "Takatsuki syndrome"]}
Diabetic foot ulcer Neuropathic diabetic foot ulcer Causesdiabetes Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot. Wound healing is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepwise repair of lost extracellular matrix (ECM) that forms the largest component of the dermal skin layer.[1] But in some cases, certain disorders or physiological insult disturbs the wound healing process. Diabetes mellitus is one such metabolic disorder that impedes the normal steps of the wound healing process. Many studies show a prolonged inflammatory phase in diabetic wounds, which causes a delay in the formation of mature granulation tissue and a parallel reduction in wound tensile strength.[2] Treatment of diabetic foot ulcers should include: blood sugar control, removal of dead tissue from the wound, wound dressings, and removing pressure from the wound through techniques such as total contact casting. Surgery in some cases may improve outcomes.[3] Hyperbaric oxygen therapy may also help but is expensive.[3] It occurs in 15% of people with diabetes,[4] and precedes 84% of all diabetes-related lower-leg amputations.[5] ## Contents * 1 Risk factors * 2 Pathophysiology * 2.1 Extracellular matrix * 2.2 Altered metabolism * 2.3 Biomechanics * 3 Diagnosis * 3.1 Classification * 4 Prevention * 4.1 Footwear * 5 Treatment * 5.1 Antibiotics * 5.2 Wound dressings * 5.3 Total contact casting * 5.4 Hyperbaric oxygen * 5.5 Negative pressure wound therapy * 5.6 Other treatments * 6 Epidemiology * 7 Research * 8 References * 9 External links ## Risk factors[edit] Risk factors implicated in the development of diabetic foot ulcers are infection, older age,[6] diabetic neuropathy,[7] peripheral vascular disease, cigarette smoking, poor glycemic control, previous foot ulcerations[7] or amputations,[5] and ischemia of small and large blood vessels.[8][9] Prior history of foot disease, foot deformities that produce abnormally high forces of pressure, callus at pressure areas[7] renal failure, oedema, impaired ability to look after personal care (e.g. visual impairment) are further risk factors for diabetic foot ulcer.[6][5] People with diabetes often develop diabetic neuropathy due to several metabolic and neurovascular factors. Peripheral neuropathy causes loss of pain or feeling in the toes, feet, legs and arms due to distal nerve damage and low blood flow. Blisters and sores appear on numb areas of the feet and legs such as metatarso-phalangeal joints, heel region and as a result pressure or injury goes unnoticed and eventually become portal of entry for bacteria and infection. ## Pathophysiology[edit] ### Extracellular matrix[edit] Extra cellular matrix (or "ECM") is the external structural framework that cells attach to in multicellular organisms. The dermis lies below the epidermis, and these two layers are collectively known as the skin. Dermal skin is primarily a combination of fibroblasts growing in this matrix. The specific species of ECM of connective tissues often differ chemically, but collagen generally forms the bulk of the structure. Through the interaction of a cell with its extracellular matrix (transmitted through the anchoring molecules classed as integrins) there forms a continuous association between the cell interior, cell membrane and its extracellular matrix components that helps drive various cellular events in a regulated fashion.[10] Wound healing is a localized event involving the reaction of cells to the damage sustained. The cells break down damaged ECM and replace it, generally increasing in number to react to the harm. The process is activated, though perhaps not exclusively, by cells responding to fragments of damaged ECM, and the repairs are made by reassembling the matrix by cells growing on and through it. Because of this extracellular matrix is often considered as a 'conductor of the wound healing symphony'.[11] In the Inflammatory phase, neutrophils and macrophages recruit and activate fibroblasts which in subsequent granulation phase migrate into the wound, laying down new collagen of the subtypes I and III. In the initial events of wound healing, collagen III predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional tensile strength to the healing tissue.[12][13] It is evident from the known collagen assembly that the tensile strength is basically due to fibrillar arrangement of collagen molecules, which self-assemble into microfibrils in a longitudinal as well as lateral manner producing extra strength and stability to the collagen assembly.[13][14] Metabolically altered collagen is known to be highly inflexible and prone to break down, particularly over pressure areas. Fibronectin is the major glycoprotein secreted by fibroblasts during initial synthesis of extracellular matrix proteins. It serves important functions, being a chemo-attractant for macrophages, fibroblasts and endothelial cells. The basement membrane that separates the epidermis from the dermal layer and the endothelial basement membrane mainly contains collagen IV that forms a sheet and binds to other extra cellular matrix molecules like laminin and proteoglycans. In addition to collagen IV, the epidermal and endothelial basement membrane also contains laminin, perlecan and nidogen.[13][14] Hyaluronic acid, a pure glycosaminoglycan component, is found in high amounts in damaged or growing tissues. It stimulates cytokine production by macrophages and thus promotes angiogenesis. In normal skin chondroitin sulfate proteoglycan is mainly found in the basement membrane, but in healing wounds they are up-regulated throughout the granulation tissue especially during the second week of wound repair where they provide a temporary matrix with highly hydrative capacity.[15] Binding of growth factors is clearly an important role of perlecan in wound healing and angiogenesis. Poor wound healing in diabetes mellitus may be related to perlecan expression. High levels of glucose can decrease perlecan expression in some cells, probably through transcriptional and post-transcriptional modification.[15][16] Wound healing phases especially, granulation, re-epithelization and remodelling exhibit controlled turnover of extracellular matrix components. ### Altered metabolism[edit] Diabetes mellitus is a metabolic disorder and hence the defects observed in diabetic wound healing are thought to be the result of altered protein and lipid metabolism and thereby abnormal granulation tissue formation.[17] Increased glucose levels in the body end up in uncontrolled covalent bonding of aldose sugars to a protein or lipid without any normal glycosylation enzymes.[18] These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called advanced glycation endproducts (AGEs) or Amadori products. Formation of AGEs occurs on extracellular matrix proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen, vitronectin, and laminin through AGE-AGE intermolecular covalent bonds or cross-linking.[18][19][20] AGE cross-linking on type I collagen and elastin results in increased stiffness. AGEs are also known to increase synthesis of type III collagen that forms the granulation tissue. AGEs on laminin result in reduced binding to type IV collagen in the basement membrane, reduced polymer elongation and reduced binding of heparan sulfate proteoglycan.[18] Impaired NO synthesis Nitric oxide is known as an important stimulator of cell proliferation, maturation and differentiation. Thus, nitric oxide increases fibroblast proliferation and thereby collagen production in wound healing. Also, L-arginine and nitric oxide are required for proper cross linking of collagen fibers, via proline, to minimize scarring and maximize the tensile strength of healed tissue.[21] Endothelial cell specific nitric oxide synthase (EcNOS) is activated by the pulsatile flow of blood through vessels. Nitric oxide produced by EcNOS, maintains the diameter of blood vessels and proper blood flow to tissues. In addition to this, nitric oxide also regulates angiogenesis, which plays a major role in wound healing.[22] Thus, diabetic patients exhibit reduced ability to generate nitric oxide from L-arginine. Reasons that have been postulated in the literature include accumulation of nitric oxide synthase inhibitor due to high glucose associated kidney dysfunction and reduced production of nitric oxide synthase due to ketoacidosis observed in diabetic patients and pH dependent nature of nitric oxide synthase.[18][23] Structural and functional changes in fibroblasts Diabetic ulcer fibroblasts show various morphological differences compared to fibroblasts from age matched controls. Diabetic ulcer fibroblasts are usually large and widely spread in the culture flask compared to the spindle shaped morphology of the fibroblasts in age-matched controls. They often show dilated endoplasmic reticulum, numerous vesicular bodies and lack of microtubular structure in transmission electron microscopy study. Therefore, interpretation of these observations would be that in spite of high protein production and protein turnover in diabetic ulcer fibroblasts, vesicles containing secretory proteins could not travel along the microtubules to release the products outside.[24][25] Fibroblasts from diabetic ulcer exhibit proliferative impairment that probably contributes to a decreased production of extracellular matrix proteins and delayed wound contraction and impaired wound healing.[24] Increased matrix metalloproteinases (MMP) activity In order for a wound to heal, extracellular matrix not only needs to be laid down but also must be able to undergo degradation and remodeling to form a mature tissue with appropriate tensile strength.[26] Proteases, namely matrix metalloproteinases are known to degrade almost all the extracellular matrix components. They are known to be involved in fibroblast and keratinocyte migration, tissue re-organization, inflammation and remodeling of the wounded tissue.[2][26] Due to persistently high concentrations of pro-inflammatory cytokines in diabetic ulcers, MMP activity is known to increase by 30 fold when compared to acute wound healing.[27] MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers.[2][28] Balance in the MMP activity is usually achieved by tissue inhibitor of metalloproteinases (TIMP). Rather than absolute concentrations of either two, it is the ratio of MMP and TIMP that maintains the proteolytic balance and this ratio is found to be disturbed in diabetic ulcer.[29][30] In spite of these findings, the exact mechanism responsible for increased MMP activity in diabetes is not known yet. One possible line of thought considers Transforming growth factor beta (TGF-β) as an active player. Most MMP genes have TGF-β inhibitory element in their promoter regions and thus TGF–β regulates the expression of both MMP and their inhibitor TIMP.[31] In addition to the importance of cell-cell and cell-matrix interactions, all phases of wound healing are controlled by a wide variety of different growth factors and cytokines. To mention precisely, growth factors promote switching of early inflammatory phase to the granulation tissue formation. Decrease in growth factors responsible for tissue repair such as TGF-β is documented in diabetic wounds. Thus, reduced levels of TGFβ in diabetes cases lower down the effect of inhibitory regulatory effect on MMP genes and thus cause MMPs to over express.[4][32][33] ### Biomechanics[edit] Complications in the diabetic foot and foot-ankle complex are wider and more destructive than expected, and may compromise structure and function of several systems: vascular, nervous, somatosensory, musculoskeletal. Thus, a deeper comprehension of the alteration of gait and foot biomechanics in the diabetic foot is of great interest, and may play a role in the design and onset of preventive as well as therapeutic actions. Briefly, the effect of diabetes on the main structures of the foot-ankle complex can be summarised as: * effects on skin: skin – and the soft tissues immediately underneath the skin – undergo greater compression and shear loading than usual, thus explaining the onset of tissue damage so deeply correlated to traumatic ulceration processes. Besides this, skin of the diabetic foot suffers from loss of autonomic nervous control and consequently reduced hydration, making it less elastic and thus more vulnerable to the action of increased mechanical stress; * effects on tendons and ligaments: protein glycosylation and the resulting collagen abnormalities lead to greater transversal section – i.e. thickening – of tendons and ligaments and a greater coefficient of elasticity. Particularly impacted by this process are Plantar Fascia and Achilles Tendon. Both causes lead to an increased stiffness of those structures; * effects on cartilage: similar to what happens to tendons and ligaments, cartilage changes its composition mainly due to the modification of collagen fibers. This increases its stiffness and decreases the range of motion of all joints in the foot and ankle. * effects on muscles: Diabetes mellitus causes severe damage to nerve conduction, thus causing a worsening in the management of the related muscle fibers. As a consequence, both intrinsic and extrinsic muscles of the foot-ankle complex are damaged in structure (reduction of muscle volume) and function (reduction of muscle strength); * effects on peripheral sensory system: impaired nerve conduction has a dramatic effect on the peripheral sensory system, since it leads to loss of protective sensation under the sole of the foot. This exposes the diabetic foot to thermal or mechanical trauma, and to the late detection of infection processes or tissue breakdown; * effects on foot morphology (deformities): due to most of the above alterations, a significant imbalance of peripheral musculature and soft tissue occur in the foot which seriously alters its morphology and determines the onset of foot deformities. Most common deformities of the diabetic foot are represented by a high longitudinal arch (rigid cavus foot), hammer toes and hallux valgus. A completely different morphologic degeneration is represented by neuropathic arthropathy, whose analysis is not part of this discussion.[34][35][36][37][38] ## Diagnosis[edit] Assessment of diabetic foot ulcer includes identifying risk factors such as diabetic peripheral neuropathy, noting that 50 percent of people are asymptomatic, and ruling out other causes of peripheral neuropathy such as alcohol abuse and spinal injury.[6] The location of the ulcer, its size, shape, depth and whether the tissue is granulating or sloughy needs to be considered. Further considerations include whether there is malodour, condition of the border of the wound and palpable bone and sinus formation should be investigated. Signs of infection require to be considered such as development of grey or yellow tissue, purulent discharge, unpleasant smell, sinus, undermined edges and exposure of bone or tendon.[39] Identification of diabetic foot in medical databases, such as commercial claims and prescription data, is complicated by the lack of a specific ICD-9 code for diabetic foot and variation in coding practices. The following codes indicate ulcer of the lower limb or foot: * 707.1 Ulcer of lower limbs, except pressure ulcer * 707.14 Ulcer of heel and midfoot * 707.15 Ulcer of other part of foot * 707.19 Ulcer of other part of lower limb One or more codes, in combination with a current or prior diagnosis of diabetes may be sufficient to conclude diabetic foot: * 250.0 Diabetes Mellitus * 250.8 Diabetes with other specified manifestations ### Classification[edit] Diabetic foot ulcer is a complication of diabetes. Diabetic foot ulcers are classified as either neuropathic, neuroischaemic or ischaemic.[39] Doctors also use the Wagner Grades to describe the severity of an ulcer. The purpose of the Wagner Grades is to allow specialists to better monitor and treat diabetic foot ulcers. This grading system classifies Diabetic foot ulcers using numbers, from 0 to 5. Wagner Grades 0 through 5 are as follows: * 0\. No diabetic foot ulcer is present, but there is a high risk of developing one. * 1\. A surface ulcer involves full skin thickness, but does not yet involve the underlying tissues. * 2\. A deep ulcer penetrates past the surface, down to the ligaments and muscle. There is no abscess or bone involved yet. * 3\. A deep ulcer occurs with inflammation of subcutaneous connective tissue or an abscess. This can include infections in the muscle, tendon, joint, and/or bone. * 4\. The tissue around the area of the ulcer (limited to the toes and forefoot) has begun to decay. This condition is called gangrene. * 5\. Gangrene has spread from the localized area of the ulcer to become extensive. This involves the whole foot. [40] ## Prevention[edit] Steps to prevent diabetic foot ulcers include frequent review by a foot specialist and multidisciplinary team,[7] good foot hygiene, diabetic socks[41] and shoes, as well as avoiding injury. Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions.[42] There is no high quality researches that evaluate complex intervention of combining two or more preventive strategies in preventing diabetic foot ulcer.[43] ### Footwear[edit] The evidence for special footwear to prevent foot ulcers is poor.[37] Clinical Evidence reviewed the topic and concluded "Individuals with significant foot deformities should be considered for referral and assessment for customised shoes that can accommodate the altered foot anatomy. In the absence of significant deformities, high quality well fitting non-prescription footwear seems to be a reasonable option".[44] National Institute for Health and Clinical Excellence concluded that for people at "high risk of foot ulcers (neuropathy or absent pulses plus deformity or skin changes or previous ulcer" that "specialist footwear and insoles" should be provided.[45] People with loss of feeling in their feet should inspect their feet on a daily basis, to ensure that there are no wounds starting to develop.[46][47] They should not walk around barefoot, but use proper footwear at all times. ## Treatment[edit] Foot ulcers in diabetes require multidisciplinary assessment, usually by diabetes nurse specialist, a tissue viability nurse,[39] podiatrists, diabetes specialists and surgeons. An aim to improve glycaemic control, if poor, forms part of the management, to slow disease progression.[6] Individuals who have sausage shaped toes, a positive 'probe to bone' test, evidence suggesting osteomyelitis, suspected charcot neuroarthropathy, or those whose ulcers do not improve within 4 weeks of standard care and where there is evidence that exudate is of synovial membrane in origin. When osteomyelitis is suspected to be involved in the foot ulcer, but not evidenced on an x-ray, an MRI scan should be obtained.[39] With regards to infected foot ulcers, the presence of microorganisms is not in itself enough to determine whether an infection is present. Signs such as inflammation and purulence are the best indicators of an active infection. The most common organism causing infection is staphylococcus.[5] The treatment consists of debridement, appropriate bandages, managing peripheral arterial disease and appropriate use of antibiotics[5] (against pseudomonas aeruginosa, staphylococcus, streptococcus and anaerobe strains), and arterial revascularisation. ### Antibiotics[edit] The length of antibiotic courses depend on the severity of the infection and whether bone infection is involved but can range from 1 week to 6 weeks or more. Current recommendations are that antibiotics are only used when there is evidence of infection and continued until there is evidence that the infection has cleared, instead of evidence of ulcer healing. Choice of antibiotic depends on common local bacterial strains known to infect ulcers. Microbiological swabs are believed to be of limited value in identifying causative strain.[6] Microbiological investigation is of value in cases of osteomyelitis.[39] Most ulcer infections involve multiple microorganisms.[5] There is limited safety and efficacy data of topical antibiotics in treating diabetic foot ulcers.[48] ### Wound dressings[edit] There are many types of dressings used to treat diabetic foot ulcers such as absorptive fillers, hydrogel dressings, and hydrocolloids.[49] There is no good evidence that one type of dressing is better than another for diabetic foot ulcers.[50] In selecting dressings for chronic non healing wounds it is recommended that the cost of the product be taken into account.[51] Hydrogel dressings may have shown a slight advantage over standard dressings, but the quality of the research is of concern.[52][53] Dressings and creams containing silver have not been properly studied[54] nor have alginate dressings.[55] Biologically active bandages that combine hydrogel and hydrocolloid traits are available, however more research needs to be conducted as to the efficacy of this option over others.[49] ### Total contact casting[edit] Total contact casting (TCC) is a specially designed cast designed to take weight of the foot (off-loading) in patients with DFUs. Reducing pressure on the wound by taking weight of the foot has proven to be very effective in DFU treatment. DFUs are a major factor leading to lower leg amputations among the diabetic population in the US with 85% of amputations in diabetics being preceded by a DFU.[56] Furthermore, the 5 year post-amputation mortality rate among diabetics is estimated at around 45% for those suffering from neuropathic DFUs.[56] TCC has been used for off-loading DFUs in the US since the mid-1960s and is regarded by many practitioners as the “reference standard” for off-loading the bottom surface (sole) of the foot.[57] TCC helps patients to maintain their quality of life. By encasing the patient’s complete foot — including the toes and lower leg — in a specialist cast to redistribute weight and pressure from the foot to the lower leg during everyday movements, patients can remain mobile.[58] The manner in which TCC redistributes pressure protects the wound, letting damaged tissue regenerate and heal.[59] TCC also keeps the ankle from rotating during walking, which helps prevent shearing and twisting forces that can further damage the wound.[60] Effective off loading is a key treatment modality for DFUs, particularly those where there is damage to the nerves in the feet (peripheral neuropathy). Along with infection management and vascular assessment, TCC is vital aspect to effectively managing DFUs.[60] TCC is the most effective and reliable method for off-loading DFUs.[61][62][63] A 2013 meta-analysis by the Cochrane Collaboration compared the effectiveness of non-removable pressure relieving interventions, such as casts, with therapeutic shoes, dressings, removable pressure relieving orthotic devices, and surgical interventions. Non-removable pressure relieving interventions, including non-removable casts with an Achilles tendon lengthening component, were found to be more effective at healing foot ulcers related to diabetes that therapeutic shoes and other pressure relieving approaches.[64] ### Hyperbaric oxygen[edit] In 2015, a Cochrane review concluded that for people with diabetic foot ulcers, hyperbaric oxygen therapy reduced the risk of amputation and may improve the healing at 6 weeks.[65] However, there was no benefit at one year and the quality of the reviewed trials was inadequate to draw strong conclusions.[65] ### Negative pressure wound therapy[edit] Main article: Negative pressure wound therapy This treatment uses vacuum to remove excess fluid and cellular waste that usually prolong the inflammatory phase of wound healing. Despite a straightforward mechanism of action, results of negative pressure wound therapy studies have been inconsistent. Research needs to be carried out to optimize the parameters of pressure intensity, treatment intervals and exact timing to start negative pressure therapy in the course of chronic wound healing.[66] There is low-certainty evidence that negative pressure wound therapy would improve wound healing in diabetic foot ulcers.[67] ### Other treatments[edit] Ozone therapy – there is only limited and poor-quality information available regarding the effectiveness of ozone therapy for treating foot ulcers in people with diabetes.[68] Growth factors \- there is some low-quality evidence that growth factors may increase the likelihood that diabetic foot ulcers will heal completely.[69] Continuous diffusion of oxygen (CDO) - CDO delivers continuous oxygen to an occluded, moist wound site at much lower flow rates of 3–12 mL/h for 24 h 7 days a week for up to several weeks or months, depending on the wound status.[70] Phototherapy \- there is very weak evidence to suggest that people with foot ulcers due to diabetes may have improved healing.[71] There is no evidence to suggest that phototherapy improves the quality of life for people with foot ulcers caused by diabetes.[71] Sucrose-octasulfate impregnated dressing is recommended by the International Working Group on the Diabetic Foot Ulcer (IWGDF)[72] for the treatment of non-infected, neuro-ischaemic diabetic foot ulcers that do not show an improvement with a standard of care regimen[73] Autologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care is also recommended by IWGDF[74] However, there is only low quality evidence that such treatment is effective in treating diabetic foot ulcer.[75] There is limited evidence that granulocyte colony-stimulating factor may not hasten the resolution of diabetic foot ulcer infection. However, it may reduce the need for surgical interventions such as amputations and hospitalizations.[76] It is unknown that whether intensive or conventional blood glucose control is better for diabetic foot ulcer healing.[77] A 2020 Cochrane systematic review evaluated the effects of nutritional supplements or special diets on healing foot ulcers in people with diabetes. The review authors concluded that it's uncertain whether or not nutritional interventions have an effect on foot ulcer healing and that more research is needed to answer this question.[78] Skin grafting and tissue replacements can help to improve the healing of diabetic foot ulcer.[79] ## Epidemiology[edit] Approximately 15 percent of people with diabetes experience foot ulcers,[4] and approximately 84 percent of lower limb amputations have a history of ulceration with only approximately half of amputees surviving for more than 2 years. 56 percent of individuals with foot ulcers who do not have an amputations survive for 5 years. Foot ulcers and amputations significantly reduce the quality of life. Approximately 8.8 percent of hospital admissions of diabetic patients are for foot related problems, and such hospital admissions are about 13 days longer than for diabetics without foot related admissions.[5] Approximately 35 to 40 percent of ulcers recur within 3 years and up to 70 percent recur within 5 years. Diabetic foot disease is the leading cause of non-traumatic lower limb amputations.[6] ## Research[edit] Stem cell therapy may represent a treatment for promoting healing of diabetic foot ulcers.[80][81] Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of nonpathogenic bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.[82] The recent advances in epigenetic modifications, with special focus on aberrant macrophage polarisation is giving increasing evidences that epigenetic modifications might play a vital role in changing the treatment of diabetic foot ulcer in the near future.[83] ## References[edit] 1. ^ Nomikos Iakovos N, et al. (2006). "Protective and Damaging Aspects of Healing: A Review". Wounds. 18 (7): 177–185. 2. ^ a b c McLennan S, et al. (2006). "Molecular aspects of wound healing" (PDF). Primary Intention. 14 (1): 8–13. Archived from the original (PDF) on 2010-05-24. Retrieved 2009-05-28. 3. ^ a b Yazdanpanah L, Nasiri M, Adarvishi S (February 2015). "Literature review on the management of diabetic foot ulcer". 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Journal of the American Podiatric Medical Association. 104 (6): 555–67. doi:10.7547/8750-7315-104.6.555. PMID 25514266. 61. ^ Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB (June 2001). "Off-loading the diabetic foot wound: a randomized clinical trial". Diabetes Care. 24 (6): 1019–22. doi:10.2337/diacare.24.6.1019. PMID 11375363. 62. ^ Lavery LA, Vela SA, Lavery DC, Quebedeaux TL (August 1996). "Reducing dynamic foot pressures in high-risk diabetic subjects with foot ulcerations. A comparison of treatments". Diabetes Care. 19 (8): 818–21. doi:10.2337/diacare.19.8.818. PMID 8842597. S2CID 24007485. 63. ^ Lewis J, Lipp A (January 2013). "Pressure-relieving interventions for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews (1): CD002302. doi:10.1002/14651858.CD002302.pub2. PMID 23440787. 64. ^ Lewis, Jane; Lipp, Allyson (2013-01-31). "Pressure-relieving interventions for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews (1): CD002302. doi:10.1002/14651858.CD002302.pub2. ISSN 1469-493X. PMID 23440787. 65. ^ a b Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S (June 2015). "Hyperbaric oxygen therapy for chronic wounds" (PDF). The Cochrane Database of Systematic Reviews (6): CD004123. doi:10.1002/14651858.CD004123.pub4. PMC 7055586. PMID 26106870. 66. ^ Armstrong DG, Lavery LA, Abu-Rumman P, Espensen EH, Vazquez JR, Nixon BP, Boulton AJ (April 2002). "Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot". Ostomy/Wound Management. 48 (4): 64–8. PMID 11993062. 67. ^ Liu Z, Dumville JC, Hinchliffe RJ, Cullum N, Game F, Stubbs N, et al. (Cochrane Wounds Group) (October 2018). "Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus". The Cochrane Database of Systematic Reviews. 10: CD010318. doi:10.1002/14651858.CD010318.pub3. PMC 6517143. PMID 30328611. 68. ^ Liu J, Zhang P, Tian J, Li L, Li J, Tian JH, Yang K (October 2015). "Ozone therapy for treating foot ulcers in people with diabetes". The Cochrane Database of Systematic Reviews. 10 (10): CD008474. doi:10.1002/14651858.CD008474.pub2. PMID 26505864. 69. ^ Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J (October 2015). "Growth factors for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews. 10 (10): CD008548. doi:10.1002/14651858.CD008548.pub2. PMID 26509249. 70. ^ Jiang H, Ochoa M, Jain V, Ziaie B (2018-08-28). "A laser-customizable insole for selective topical oxygen delivery to diabetic foot ulcers". MRS Communications. 8 (3): 1184–1190. doi:10.1557/mrc.2018.181. 71. ^ a b Wang HT, Yuan JQ, Zhang B, Dong ML, Mao C, Hu D (June 2017). "Phototherapy for treating foot ulcers in people with diabetes". The Cochrane Database of Systematic Reviews. 6: CD011979. doi:10.1002/14651858.CD011979.pub2. PMC 6481843. PMID 28657134. 72. ^ "Wound healing interventions guideline". IWGDF Guidelines. 2019-05-25. Retrieved 2020-05-15. 73. ^ Edmonds M, Lázaro-Martínez JL, Alfayate-García JM, Martini J, Petit JM, Rayman G, et al. (March 2018). "Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial". The Lancet. Diabetes & Endocrinology. 6 (3): 186–196. doi:10.1016/S2213-8587(17)30438-2. PMID 29275068. 74. ^ Game F, Jeffcoate W, Tarnow L, Jacobsen JL, Whitham DJ, Harrison EF, et al. (November 2018). "LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial". The Lancet. Diabetes & Endocrinology. 6 (11): 870–878. doi:10.1016/S2213-8587(18)30240-7. PMID 30243803. 75. ^ Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L, et al. (Cochrane Wounds Group) (May 2016). "Autologous platelet-rich plasma for treating chronic wounds". The Cochrane Database of Systematic Reviews (5): CD006899. doi:10.1002/14651858.CD006899.pub3. PMID 27223580. 76. ^ Cruciani M, Lipsky BA, Mengoli C, de Lalla F, et al. (Cochrane Wounds Group) (August 2013). "Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections". The Cochrane Database of Systematic Reviews (8): CD006810. doi:10.1002/14651858.CD006810.pub3. PMID 23955465. 77. ^ Fernando ME, Seneviratne RM, Tan YM, Lazzarini PA, Sangla KS, Cunningham M, et al. (Cochrane Wounds Group) (January 2016). "Intensive versus conventional glycaemic control for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews (1): CD010764. doi:10.1002/14651858.CD010764.pub2. hdl:1893/24156. PMID 26758576. 78. ^ Moore ZE, Corcoran MA, Patton D (July 2020). "Nutritional interventions for treating foot ulcers in people with diabetes". The Cochrane Database of Systematic Reviews. 7: CD011378. doi:10.1002/14651858.cd011378.pub2. PMC 7388930. PMID 32677037. 79. ^ Santema TB, Poyck PP, Ubbink DT, et al. (Cochrane Wounds Group) (February 2016). "Skin grafting and tissue replacement for treating foot ulcers in people with diabetes". The Cochrane Database of Systematic Reviews. 2: CD011255. doi:10.1002/14651858.CD011255.pub2. PMC 6464524. PMID 26866804. 80. ^ Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W (April 2012). "The role of stem cells in the treatment of diabetic foot ulcers". Diabetes Research and Clinical Practice. 96 (1): 1–9. doi:10.1016/j.diabres.2011.10.032. PMID 22142631. 81. ^ Di Rocco G, Gentile A, Antonini A, Ceradini F, Wu JC, Capogrossi MC, Toietta G (December 2010). "Enhanced healing of diabetic wounds by topical administration of adipose tissue-derived stromal cells overexpressing stromal-derived factor-1: biodistribution and engraftment analysis by bioluminescent imaging". Stem Cells International. 2011: 304562. doi:10.4061/2011/304562. PMC 3014681. PMID 21234108. 82. ^ Lavigne JP, Sotto A, Dunyach-Remy C, Lipsky BA (January 2015). "New Molecular Techniques to Study the Skin Microbiota of Diabetic Foot Ulcers". Advances in Wound Care. 4 (1): 38–49. doi:10.1089/wound.2014.0532. PMC 4281861. PMID 25566413. 83. ^ Basu Mallik S, Jayashree BS, Shenoy RR (May 2018). "Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds". Journal of Diabetes and Its Complications. 32 (5): 524–530. doi:10.1016/j.jdiacomp.2018.01.015. PMID 29530315. ## External links[edit] Classification D External resources * eMedicine: article/460282 * v * t * e Diabetes Types * Type 1 * Type 2 * LADA * Gestational diabetes * Diabetes and pregnancy * Prediabetes * Impaired fasting glucose * Impaired glucose tolerance * Insulin resistance * KPD * MODY * Neonatal * Transient * Permanent * Type 3c (pancreatogenic) * Type 3 Blood tests * Blood sugar level * Glycosylated hemoglobin * Glucose tolerance test * Postprandial glucose test * Fructosamine * Glucose test * C-peptide * Noninvasive glucose monitor * Insulin tolerance test Management * Diabetic diet * Anti-diabetic drugs * Insulin therapy * intensive * conventional * pulsatile * Cure * Embryonic stem cells * Artificial pancreas * Other * Gastric bypass surgery Complications * Diabetic comas * Hypoglycemia * Ketoacidosis * Hyperosmolar hyperglycemic state * Diabetic foot * ulcer * Neuropathic arthropathy * Organs in diabetes * Blood vessels * Muscle * Kidney * Nerves * Retina * Heart * Diabetic skin disease * Diabetic dermopathy * Diabetic bulla * Diabetic cheiroarthropathy * Neuropathic ulcer * Hyperglycemia * Hypoglycemia Other * Glossary of diabetes * History of diabetes * Notable people with type 1 diabetes [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Diabetic foot ulcer	c1456868	8,738	wikipedia	https://en.wikipedia.org/wiki/Diabetic_foot_ulcer	2021-01-18T18:43:01	{"mesh": ["D017719"], "wikidata": ["Q52859"]}
A number sign (#) is used with this entry because of evidence that 3M syndrome-2 (3M2) is caused by homozygous or compound heterozygous mutation in the OBSL1 gene (610991) on chromosome 2q35. Description 3M syndrome-2 (3M2) is characterized by low birth weight and short stature, relative macrocephaly, lumbar hyperlordosis, and prominent heels. Dysmorphic facial features include triangular face with frontal bossing and midface hypoplasia, anteverted nares with fleshy nasal tip, and full fleshy lips (Hanson et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (273750). Clinical Features Temtamy et al. (2006) reported 2 Egyptian brothers and an unrelated Egyptian boy who exhibited the characteristic features and radiologic findings of 3M syndrome, including low birth weight, short stature, malar hypoplasia, anteverted nostrils with a fleshy nasal tip, long philtrum, pointed full chin, short broad neck, broad chest with transverse grooves of the anterior thorax, and hyperlordosis. Oral examination revealed prominent premaxilla, hypoplastic maxilla, thick patulous lips, high-arched palate, median fissured tongue, delayed eruption of teeth with enamel hypocalcification, and malocclusion. Radiographic studies showed slender long bones and ribs, a narrow pelvis, and foreshortened vertebral bodies. Hanson et al. (2009) studied probands from 10 families with the 3M syndrome phenotype in which direct DNA sequencing failed to detect mutations in the CUL7 gene (609577), including an Egyptian family with 2 affected brothers originally reported by Temtamy et al. (2006). All patients had short stature, prominent heels, and a distinctive facial appearance with anteverted nares, fleshy tipped nose, frontal bossing, midface hypoplasia, and prominent heels, and were phenotypically indistinguishable from those with 3M syndrome-1. Demir et al. (2013) described a 16.5-year-old Turkish boy, born of first-cousin parents, who had low birth weight, short stature, delayed bone age, slender long bones, lumbar lordosis, tall/foreshortened lumbar vertebrae, and prominent heels, who also exhibited facial dysmorphism consistent with 3M syndrome. Growth hormone treatment was instituted but discontinued due to inadequate height gain (3 cm) at the end of 1 year. Keskin et al. (2017) reported a 16-month-old Turkish girl who had prenatal growth retardation with severe short stature and lumbar lordosis, as well as triangular face, long philtrum, fleshy nose tip, prominent mouth and lips, and pointed chin, suggesting 3M syndrome. Growth hormone treatment resulted in a 7-cm gain in height over a 6-month period. Inheritance Temtamy et al. (2006) reported 2 brothers and an unrelated boy with 3M syndrome, all offspring of healthy first-cousin Egyptian parents, consistent with an autosomal recessive pattern of inheritance. Molecular Genetics By genomewide linkage analysis, followed by candidate gene sequencing of 10 unrelated families with 3M syndrome-2, including the Egyptian family with 2 affected brothers originally reported by Temtamy et al. (2006), Hanson et al. (2009) identified homozygous or compound heterozygous mutations in the OBSL1 gene (see, e.g., 610991.0001-610991.0005) in affected individuals. All of the mutations were truncating mutations within the first 6 exons of the gene and affected all known isoforms, resulting in complete loss of OBSL1. Thus, 3M syndrome-2 represents the null phenotype of human OBSL1. Knockdown of OBSL1 via siRNAs in HEK cells led to a decrease in CUL7 levels, suggesting a role for OBSL1 in the maintenance of normal levels of CUL7. These findings suggested that the 2 proteins work in the same pathway that affects cell proliferation and human growth. In a 16.5-year-old Turkish boy with 3M syndrome, who was negative for mutation in the CUL7 gene, Demir et al. (2013) identified homozygosity for a frameshift mutation in the OBSL1 gene (610991.0006). In a 16-month-old Turkish girl with 3M syndrome, Keskin et al. (2017) identified homozygosity for the most prevalent mutation in the OBSL1 gene, a 1-bp duplication (610991.0001). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Low birth weight HEAD & NECK Head \- Relative macrocephaly \- Dolichocephaly Face \- Triangular face \- Frontal bossing \- Midface hypoplasia \- Long philtrum \- Pointed chin Ears \- Prominent ears Nose \- Anteverted nares \- Fleshy tip of nose \- Low nasal bridge Mouth \- Full fleshy lips \- High-arched palate \- Median fissured tongue (in some patients) \- Partial ankyloglossia (rare) \- Bifid tip of tongue (rare) Teeth \- Delayed eruption \- Enamel hypocalcification \- Malocclusion Neck \- Short neck CHEST External Features \- Short thorax \- Square shoulders \- Pectus deformity \- Transverse chest groove Ribs Sternum Clavicles & Scapulae \- Thin ribs \- Winged scapulae SKELETAL \- Delayed bone age (rare) Skull \- Relative macrocephaly \- Dolichocephaly Spine \- Hyperlordosis \- Tall lumbar vertebrae Pelvis \- Small narrow pelvis Limbs \- Slender long bones Hands \- Short fifth fingers \- Fifth-finger clinodactyly Feet \- Prominent heels MISCELLANEOUS \- Facial dysmorphism becomes less prominent with age MOLECULAR BASIS \- Caused by mutation in the obscurin-like 1 gene (OBSL1, 610991.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	THREE M SYNDROME 2	c1851996	8,739	omim	https://www.omim.org/entry/612921	2019-09-22T16:00:21	{"doid": ["0060241"], "mesh": ["C535725"], "omim": ["612921"], "orphanet": ["2616"], "synonyms": ["Alternative titles", "3M SYNDROME 2"], "genereviews": ["NBK1481"]}
Soff et al. (1981) studied 2 families with combined deficiency of factors IX and XI. In the first family, 2 sisters had lower levels of factor IX than their mildly affected brother--findings inconsistent with X-linked recessive hemophilia B. In the second family, an 8-year-old boy with Down syndrome had factor IX levels (29-45%) higher than observed in hemophilia B. The authors were uncertain of the mode of inheritance but favored autosomal dominance. No other reported cases are known and the mechanism of the combined deficiency is unclear. Lab \- Combined factor IX and XI deficiency Inheritance \- ? Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	FACTOR IX AND FACTOR XI, COMBINED DEFICIENCY OF	c1851374	8,740	omim	https://www.omim.org/entry/134540	2019-09-22T16:41:14	{"mesh": ["C565022"], "omim": ["134540"], "synonyms": ["Alternative titles", "FAMILIAL MULTIPLE COAGULATION FACTOR DEFICIENCY VI", "MULTIPLE COAGULATION FACTOR DEFICIENCY VI"]}
Autonomic Nervous System Autonomic neuropathy SpecialtyNeurology Autonomic neuropathy (AN or AAN) is a form of polyneuropathy that affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system), affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen, and pelvis outside the spinal cord. They have connections with the spinal cord and ultimately the brain, however. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most—but not all—cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy. Autonomic neuropathy is one cause of malfunction of the autonomic nervous system (referred to as dysautonomia), but not the only one; some conditions affecting the brain or spinal cord also may cause autonomic dysfunction, such as multiple system atrophy, and therefore, may cause similar symptoms to autonomic neuropathy. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 4.1 Neurogenic Bladder * 5 References * 6 External links ## Signs and symptoms[edit] The signs and symptoms of autonomic neuropathy include the following:[citation needed] * Urinary bladder conditions: urinary incontinence or urinary retention which happens due to the uncoordinated contraction of the bladder. Neurogenic bladder is a broad term used to describe this dysfunction.[1] * Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhea, constipation * Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion * Respiratory system: impairments in the signals associated with regulation of breathing and gas exchange (central sleep apnea, hypopnea, bradypnea).[2] * Nervous system: pupillary defect, exaggerated hippus, dizziness or lightheadedness. * Other areas: hypoglycemia unawareness, genital impotence, sweat disturbances, sicca (dryness). * Absence of signs of cerebellar dysfunction or parkinsonian symptoms as the presence of either would indicate the more serious disease of multiple system atrophy. ## Causes[edit] Many health conditions can cause autonomic neuropathy. Some common causes of autonomic neuropathy include: * Diabetes, which is the most common cause of autonomic neuropathy, can gradually cause nerve damage throughout the body. * Injury to nerves caused by surgery or radiation to the neck. * Treatment with certain medications, including some drugs used in cancer chemotherapy. * Abnormal protein buildup in organs (amyloidosis), which affects the organs and the nervous system. * Neurodegenerative diseases including Parkinson's disease and “Parkinson’s Plus diseases” including multiple system atrophy and Lewy body dementia, and multiple sclerosis * Autonomic neuropathy may also be caused by an abnormal attack by the immune system (autoimmune autonomic ganglionopathy), sometimes as part of a paraneoplastic syndrome which can occur even when cancer has not yet been diagnosed. * Certain infectious diseases. Some viruses and bacteria, such as botulism, Lyme disease and HIV, can cause autonomic neuropathy. * Inherited disorders. Certain hereditary disorders can cause autonomic neuropathy. * Autoimmune diseases, in which the immune system attacks and damages parts of the body, including the nerves. Examples include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis and celiac disease. Guillain–Barré syndrome is an autoimmune disease that happens rapidly and can affect autonomic nerves. ## Diagnosis[edit] This section is empty. You can help by adding to it. (February 2017) ## Treatment[edit] ### Neurogenic Bladder[edit] Depending on the symptoms and severity of the dysfunction, the doctor might suggest one of the following treatments[3][4] * Behavioral changes: such as reducing water intake, kegel exercises, biofeedback training * Clean intermittent catheterization: insertion of a foley catheter to remove the urine every few hours and prevent retention, done in a sterile manner. * Pharmacological therapy, which includes anticholinergic drugs which reduce the contraction of the bladder * Botox injections into the bladder * Surgical treatment: Urinary diversion, Artificial Urinary Sphincter, Urethral sling, or insertion of electrical devices adjacent to the bladder to stimulate its contraction. ## References[edit] 1. ^ "Neurogenic Bladder: Overview, Neuroanatomy, Physiology and Pathophysiology". 2019-12-05. Cite journal requires `\|journal=` (help) 2. ^ Vinik, AI; Erbas, T (2013). "Diabetic autonomic neuropathy". Handbook of Clinical Neurology. 117: 279–94. doi:10.1016/b978-0-444-53491-0.00022-5. ISBN 9780444534910. PMID 24095132. 3. ^ "Neurogenic Bladder Management and Treatment". Cleveland Clinic. Retrieved 2020-03-08. 4. ^ Urology, Weill Cornell (2017-11-16). "Neurogenic Bladder - Treatment Options". Weill Cornell Medicine: Department of Urology - New York. Retrieved 2020-03-08. ## External links[edit] Classification D * MeSH: D001342 * SNOMED CT: 277879009 External resources * MedlinePlus: 000776 * eMedicine: article/1173756 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Autonomic neuropathy	c0259749	8,741	wikipedia	https://en.wikipedia.org/wiki/Autonomic_neuropathy	2021-01-18T18:46:02	{"mesh": ["D001342"], "umls": ["C0259749"], "wikidata": ["Q18554095"]}
A number sign (#) is used with this entry because of evidence that mitochondrial complex III deficiency nuclear type 5 (MC3DN5) is caused by homozygous mutation in the UQCRC2 gene (191329) on chromosome 16p12. For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000). Clinical Features Miyake et al. (2013) reported 3 affected individuals from a large consanguineous Mexican kindred with mitochondrial complex III deficiency nuclear type 5. The patients had neonatal onset of severe metabolic acidosis associated with hyperammonemia and hypoglycemia. Physical signs included tachypnea and poor sucking. Two of the patients showed normal growth and development by early childhood despite multiple episodes of metabolic decompensation, usually associated with illness. The third patient had a similar disease course but showed mild development delay at age 18 months. Complex III activity in one of the patient's cells was decreased to 50% of normal, whereas complex I activity was increased and complex IV activity was normal. Patients cells also showed severely decreased levels of complex III assembly and decreased levels of the supercomplex formed from complexes I, III, and IV. Gaignard et al. (2017) reported a 9-year-old boy, born of presumably unrelated French Canadian parents, with onset of a multisystem mitochondrial disorder in the first days of life. As a neonate, he had poor feeding, lactic acidosis, hypoglycemia, and hepatocellular dysfunction with coagulation abnormalities and abnormal liver enzymes. During the first year of life, he had several episodes of metabolic decompensation triggered by infections and manifest as hypoglycemia, lactic acidosis, increased plasma alanine and proline, mildly increased ammonia, abnormal urinary organic acids, ketosis, and evidence of mitochondrial dysfunction. At age 2.5 years, he had slight liver enlargement with facial dysmorphism and epicanthus, but normal neurologic, cardiac, muscular, and psychomotor functions. At age 9, he had mild learning difficulties and frequent episodes of vomiting and sleepiness with acute hepatocellular deficiency, cytolysis, and increased serum lactate without bleeding. He always recovered without sequelae with intravenous hydration; laboratory tests were normal between episodes. Patient fibroblasts showed significantly decreased levels and activities of complex III as well as complex I. Inheritance The transmission pattern of MC3DN5 in the family reported by Miyake et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 affected individuals from a large consanguineous Mexican kindred with mitochondrial complex III deficiency nuclear type 5, Miyake et al. (2013) identified a homozygous mutation in the UQCRC2 gene (R183W; 191329.0001). Structural analysis indicated that the substitution would disrupt the hydrophobic core at the interface of the UQCRC2-containing complex, resulting in destabilization of complex III. In vitro studies showed the mutant protein localized properly to the mitochondria but had decreased expression compared to wildtype, suggesting protein instability. In a boy of French Canadian descent with MC3DN5, Gaignard et al. (2017) identified homozygosity for the R183W mutation in the UQCRC2 gene. The mutation, which was found by targeted resequencing of nuclear genes involved in mitochondrial defects and confirmed by Sanger sequencing, segregated with the disorder in the family. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Liver dysfunction, episodic \- Abnormal liver enzymes NEUROLOGIC Central Nervous System \- Cognitive impairment, mild (1 patient) METABOLIC FEATURES \- Metabolic acidosis LABORATORY ABNORMALITIES \- Hyperammonemia \- Hypoglycemia \- Increased serum lactate \- Increased serum pyruvate \- Decreased mitochondrial complex III levels and activity in fibroblasts MISCELLANEOUS \- Onset in the neonatal period \- Episodic metabolic decompensation usually associated with illness \- Four patients from 2 unrelated families have been reported (last curated August 2017) MOLECULAR BASIS \- Caused by mutation in the ubiquinol-cytochrome c reductase core protein II gene (UQCRC2, 191329.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 5	c3554608	8,742	omim	https://www.omim.org/entry/615160	2019-09-22T15:53:00	{"doid": ["0080114"], "omim": ["615160"], "orphanet": ["1460"], "synonyms": ["Isolated CoQ-cytochrome C reductase deficiency", "Isolated coenzyme Q-cytochrome C reductase deficiency", "Isolated mitochondrial respiratory chain complex III deficiency", "Isolated ubiquinone-cytochrome C reductase deficiency"]}
A number sign (#) is used with this entry because of evidence that neonatal-onset chronic diarrhea-9 (DIAR9) is caused by homozygous mutation in the WNT2B gene (601968) on chromosome 1p13. Description Diarrhea-9 is a form of neonatal-onset chronic diarrhea characterized by an osmotic diarrhea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption (O'Connell et al., 2018). For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700). Clinical Features O'Connell et al. (2018) reported a Kuwaiti brother and sister and a Vietnamese boy who had neonatal-onset intractable severe diarrhea with multiple voluminous stools per day, resulting in failure to thrive and requiring parenteral nutrition. The diarrhea was osmotic and not substrate specific, with significant fat malabsorption. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon, with oxyntic atrophy in the stomach and partial villous atrophy in the duodenum, as well as a paucity of crypts and abnormal crypt architecture. Molecular Genetics By whole-exome sequencing in a Kuwaiti brother and sister with neonatal-onset chronic diarrhea, who were negative for mutation in known chronic diarrhea-associated genes, O'Connell et al. (2018) identified homozygosity for a nonsense mutation in the WNT2B gene (R69X; 601968.0001) that segregated with disease in the family. In a similarly affected Vietnamese boy, they identified homozygosity for another nonsense mutation in WNT2B (R105X; 601968.0002). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive ABDOMEN Gastrointestinal \- Diarrhea, chronic severe \- Inflammatory changes in intestinal tract, chronic \- Oxyntic atrophy in the stomach \- Partial villous atrophy in the duodenum \- Reduced number of crypts \- Abnormal crypt architecture LABORATORY ABNORMALITIES \- Elevated fecal fat \- Elevated fecal lactoferrin MISCELLANEOUS \- Neonatal onset of symptoms MOLECULAR BASIS \- Caused by mutation in the wingless-type MMTV integration site family, member-2B gene (WNT2B, 601968.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	DIARRHEA 9	None	8,743	omim	https://www.omim.org/entry/618168	2019-09-22T15:43:18	{"omim": ["618168"]}
Entry of materials into the larynx (voice box) and lower respiratory tract This article relies largely or entirely on a single source. Relevant discussion may be found on the talk page. Please help improve this article by introducing citations to additional sources. Find sources: "Pulmonary aspiration" – news · newspapers · books · scholar · JSTOR (June 2010) Pulmonary aspiration Upper gastrointestinal series at the level of the esophagus, showing pulmonary aspiration of the radiocontrast agent SpecialtyPulmonology Pulmonary aspiration is the entry of material such as pharyngeal secretions, food or drink, or stomach contents from the oropharynx or gastrointestinal tract, into the larynx (voice box) and lower respiratory tract, the portions of the respiratory system from the trachea (windpipe) to the lungs. A person may inhale the material, or it may be delivered into the tracheobronchial tree during positive pressure ventilation. When pulmonary aspiration occurs during eating and drinking, the aspirated material is often colloquially referred to as "going down the wrong pipe." Consequences of pulmonary aspiration range from no injury at all, to chemical pneumonitis or pneumonia, to death within minutes from asphyxiation. These consequences depend on the volume, chemical composition, particle size, and presence of infectious agents in the aspirated material, and on the underlying health status of the person. In healthy people, aspiration of small quantities of material is common and rarely results in disease or injury. People with significant underlying disease or injury are at greater risk for developing respiratory complications following pulmonary aspiration, especially hospitalized patients, because of certain factors such as depressed level of consciousness and impaired airway defenses (gag reflex and respiratory tract antimicrobial defense system). The lumen of the right main bronchus is more vertical and slightly wider than that of the left, so aspirated material is more likely to end up in this bronchus or one of its subsequent bifurcations. About 3.6 million cases of pulmonary aspiration or foreign body in the airway occurred in 2013.[1] ## Contents * 1 Presentation * 1.1 Consequences * 1.1.1 Particle-related * 1.1.2 Acid-related * 1.1.3 Bacterial * 1.1.4 Death * 2 Risk factors * 3 Prevention * 4 See also * 5 References * 6 Further reading * 7 External links ## Presentation[edit] ### Consequences[edit] Aspiration pneumonia #### Particle-related[edit] Pulmonary aspiration of particulate matter may result in acute airway obstruction which may rapidly lead to death from arterial hypoxemia.[2] #### Acid-related[edit] Pulmonary aspiration of acidic material (such as stomach acid) may produce an immediate primary injury caused by the chemical reaction of acid with lung parenchyma, and a later secondary injury as a result of the subsequent inflammatory response.[2] #### Bacterial[edit] Pulmonary aspiration may be followed by bacterial pneumonia. Community-acquired aspiration pneumonia is usually caused by anaerobic bacteria, whereas hospital-acquired aspiration pneumonia is more often caused by mixed flora, including both aerobic and anaerobic bacteria.[2] #### Death[edit] Histopathology of aspiration, taken from an autopsy, showing plant-like cells in a bronchiole. However, alveoli were clear, indicating a finding secondary to cardiopulmonary resuscitation rather than a primary cause of death. Pulmonary aspiration resulting in pneumonia, in some patients, particularly those with physical limitations, can be fatal. ## Risk factors[edit] Upper respiratory tract (pharynx and larynx) and lower respiratory tract (trachea, bronchi, and lung) Risk factors for pulmonary aspiration include conditions which depress the level of consciousness (such as traumatic brain injury, alcohol intoxication, drug overdose, and general anesthesia).[3] A decreased gag reflex, upper esophageal sphincter and lower esophageal sphincter tone, gastroesophageal reflux, full stomach, as well as obesity, stroke, and pregnancy can all increase the risk of aspiration in the semiconscious.[citation needed] Tracheal intubation or presence of a gastric tube (for example, a feeding tube) may also increase the risk.[4] ## Prevention[edit] The lungs are normally protected against aspiration by a series of protective reflexes such as coughing and swallowing. Significant aspiration can only occur if the protective reflexes are absent or severely diminished (in neurological disease, coma, drug overdose, sedation or general anesthesia). In intensive care, sitting patients up reduces the risk of pulmonary aspiration and ventilator-associated pneumonia. Measures to prevent aspiration depend on the situation and the patient. In patients at imminent risk of aspiration, tracheal intubation by a trained health professional provides the best protection. A simpler intervention that can be implemented is to lay the patient on their side in the recovery position (as taught in first aid and CPR classes), so that any vomitus produced by the patient will drain out their mouth instead of back down their pharynx. Some anesthetists will use sodium citrate to neutralize the stomach's low pH and metoclopramide or domperidone (pro-kinetic agents) to empty the stomach. People with chronic neurological disorders, for example, after a stroke, are less likely to aspirate thickened fluids on an instrumental swallowing assessment. However, this does not necessarily translate into reduced risk of pneumonia in real life eating and drinking.[5] Also, pharyngeal residue is more common with very thickened fluids: this may subsequently be aspirated and lead to a more severe pneumonia.[6] The location of abscesses caused by aspiration depends on the position one is in. If one is sitting or standing up, the aspirate ends up in the posterior basal segment of the right lower lobe. If one is on one's back, it goes to the superior segment of the right lower lobe. If one is lying on the right side, it goes to the posterior segment of the right upper lobe, or the posterior basal segment of the right upper lobe. If one is lying on the left, it goes to the lingula. ## See also[edit] * Drowning * Mendelson's syndrome * Salt water aspiration syndrome * Choking * Pharyngeal aspiration ## References[edit] 1. ^ Vos, Theo; Barber, Ryan M; Bell, Brad; Bertozzi-Villa, Amelia; Biryukov, Stan; Bolliger, Ian; Charlson, Fiona; Davis, Adrian; Degenhardt, Louisa; Dicker, Daniel; Duan, Leilei; Erskine, Holly; Feigin, Valery L; Ferrari, Alize J; Fitzmaurice, Christina; Fleming, Thomas; Graetz, Nicholas; Guinovart, Caterina; Haagsma, Juanita; Hansen, Gillian M; Hanson, Sarah Wulf; Heuton, Kyle R; Higashi, Hideki; Kassebaum, Nicholas; Kyu, Hmwe; Laurie, Evan; Liang, Xiofeng; Lofgren, Katherine; Lozano, Rafael; et al. (2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013". The Lancet. 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509. PMID 26063472. 2. ^ a b c Engelhardt, T.; Webster, N. R. (1999). "Pulmonary aspiration of gastric contents in anaesthesia". British Journal of Anaesthesia. 83 (3): 453–60. doi:10.1093/bja/83.3.453. PMID 10655918. 3. ^ Huxley, Eliot J.; Viroslav, Jose; Gray, William R.; Pierce, Alan K. (1978). "Pharyngeal aspiration in normal adults and patients with depressed consciousness". The American Journal of Medicine. 64 (4): 564–8. doi:10.1016/0002-9343(78)90574-0. PMID 645722. 4. ^ Gomes, Guilherme F.; Pisani, Julio C.; MacEdo, Evaldo D.; Campos, Antonio C. (2003). "The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia". Current Opinion in Clinical Nutrition and Metabolic Care. 6 (3): 327–33. doi:10.1097/01.mco.0000068970.34812.8b. PMID 12690267. 5. ^ O'Keeffe ST. (July 2018). Use of modified diets to prevent aspiration in oropharyngeal dysphagia: is current practice justified? BMC Geriatrics. 2018;18:167 https://doi.org/10.1186/s12877-018-0839-7 6. ^ Robbins J, Gensler G, Hind J, Logemann JA, Lindblad AS, Brandt D, et al. Comparison of 2 interventions for fluid aspiration on pneumonia incidence: a randomised trial. Ann Intern Med. 2008;148:509–18. ## Further reading[edit] * Levy, D M (2006). "Pre-operative fasting—60 years on from Mendelson". Continuing Education in Anaesthesia, Critical Care & Pain. 6 (6): 215–8. doi:10.1093/bjaceaccp/mkl048. * Mendelson, C. L. (1946). "The aspiration of stomach contents into the lungs during obstetric anesthesia". American Journal of Obstetrics and Gynecology. 52 (2): 191–205. doi:10.1016/S0002-9378(16)39829-5. PMID 20993766. ## External links[edit] Classification D * ICD-10: J69, J95.4 O29.0, O74.0 O89.0, P24 T17.3–T17.9W78–W80 * ICD-9-CM: 668.0, 997.3 * MeSH: D053120 * DiseasesDB: 979 * Atlas of Pathology * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Pulmonary aspiration	c1720922	8,744	wikipedia	https://en.wikipedia.org/wiki/Pulmonary_aspiration	2021-01-18T18:39:16	{"mesh": ["D053120"], "icd-9": ["668.0", "997.3"], "icd-10": ["O74.0", "J95.4", "O89.0", "T17.3", "O29.0", "T17.9"], "wikidata": ["Q737510"]}
This article is about the medical condition. For the video game, see Metal Gear Solid V: The Phantom Pain. Phantom pain SpecialtyNeurology Phantom pain is a perception that an individual experiences relating to a limb or an organ that is not physically part of the body. Limb loss is a result of either removal by amputation or congenital limb deficiency.[1] However, phantom limb sensations can also occur following nerve avulsion or spinal cord injury. Sensations are recorded most frequently following the amputation of an arm or a leg, but may also occur following the removal of a breast, tooth, or an internal organ. Phantom limb pain is the feeling of pain in an absent limb or a portion of a limb. The pain sensation varies from individual to individual. Phantom limb sensation is any sensory phenomenon (except pain) which is felt at an absent limb or a portion of the limb. It has been known that at least 80% of amputees experience phantom sensations at some time of their lives. Some experience some level of this phantom pain and feeling in the missing limb for the rest of their lives. The term "phantom limb" was first coined by American neurologist Silas Weir Mitchell in 1871.[2] Mitchell described that "thousands of spirit limbs were haunting as many good soldiers, every now and then tormenting them".[3] However, in 1551, French military surgeon Ambroise Paré recorded the first documentation of phantom limb pain when he reported that, "For the patients, long after the amputation is made, say that they still feel pain in the amputated part".[3] ## Contents * 1 Signs and symptoms * 1.1 Types * 2 Pathophysiology * 2.1 Peripheral mechanisms * 2.2 Spinal mechanisms * 2.3 Central mechanisms * 2.3.1 The neuromatrix * 3 Management * 3.1 Mirror therapy * 3.2 Medication * 3.3 Deep-brain stimulation * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Phantom pain involves the sensation of pain in a part of the body that has been removed. Symptoms include: Onset within the first few days of amputation. Comes and goes or is continuous. Often affects the part of the limb farthest from the body, such as the foot of an amputated leg. May be described as shooting, stabbing, boring, squeezing, throbbing or burning. Sometimes feels as if the phantom part is forced into an uncomfortable position. May be triggered by pressure on the remaining part of the limb or emotional stress.[4] ### Types[edit] There are various types of sensations that may be felt: * Sensations related to the phantom limb's posture, length and volume e.g. feeling that the phantom limb is behaving just like a normal limb like sitting with the knee bent or feeling that the phantom limb is as heavy as the other limb. Sometimes, an amputee will experience a sensation called telescoping, the feeling that the phantom limb is gradually shortening over time. * Sensations of movement (e.g. feeling that the phantom foot is moving). * Sensations of touch, temperature, pressure and itchiness. Many amputees report of feeling heat, tingling, itchiness, and pain. ## Pathophysiology[edit] The neurological basis and mechanisms for phantom limb pain are all derived from experimental theories and observations. Little is known about the true mechanism causing phantom pains, and many theories highly overlap. Historically, phantom pains were thought to originate from neuromas located at the stump tip. Traumatic neuromas, or non-tumor nerve injuries, often arise from surgeries and result from the abnormal growth of injured nerve fibers. Although stump neuromas contribute to phantom pains, they are not the sole cause. This is because patients with congenital limb deficiency can sometimes, although rarely, experience phantom pains. This suggests that there is a central representation of the limb responsible for painful sensations.[5] Currently, theories are based on altered neurological pathways and cortical reorganization. ### Peripheral mechanisms[edit] Neuromas formed from injured nerve endings at the stump site are able to fire abnormal action potentials, and were historically thought to be the main cause of phantom limb pain. Although neuromas are able to contribute to phantom pain, pain is not completely eliminated when peripheral nerves are treated with conduction blocking agents.[5] Physical stimulation of neuromas can increase C fiber activity, thus increasing phantom pain, but pain still persists once the neuromas have ceased firing action potentials. The peripheral nervous system is thought to have at most a modulation effect on phantom limb pain.[3] ### Spinal mechanisms[edit] In addition to peripheral mechanisms, spinal mechanisms are thought to have an influencing role in phantom pains. Peripheral nerve injury can lead to the degeneration of C fibers in the dorsal horn of the spinal cord, and terminating A fibers may subsequently branch into the same lamina.[3] If this occurs, A fiber inputs could be reported as noxious stimuli. Substance P, involved in the transmission of pain signals, is usually expressed by Aδ and C fibers, but following peripheral nerve damage, substance P is expressed by Aβ fibers.[3] This leads to hyperexcitability of the spinal cord, which usually occurs only in the presence of noxious stimuli. Because patients with complete spinal cord injury have experienced phantom pains, there must be an underlying central mechanism responsible for the generation of phantom pains. ### Central mechanisms[edit] Under ordinary circumstances, the genetically determined circuitry in the brain remains largely stable throughout life. It was thought, until about 30 years ago, that no new neural circuits could be formed in the adult mammalian brain.[5] Recently, functional MRI studies in amputees have shown that almost all patients have experienced motor cortical remapping.[6] The majority of motor reorganization has occurred as a downward shift of the hand area of the cortex onto the area of face representation, especially the lips. Sometimes there is a side shift of the hand motor cortex to the ipsilateral cortex.[5] In patients with phantom limb pain, the reorganization was great enough to cause a change in cortical lip representation into the hand areas only during lip movements.[5] It has also been found that there is a high correlation between the magnitude of phantom limb pain and the extent to which the shift of the cortical representation of the mouth into the hand area in motor and somatosensory cortical reorganization has occurred.[7] Additionally, as phantom pains in upper extremity amputees increased, there was a higher degree of medial shift of the facial motor representation.[7] There are multiple theories that try to explain how cortical remapping occurs in amputees, but none have been supported to a great extent. #### The neuromatrix[edit] The neuromatrix theory proposes that there is an extensive network connecting the thalamus and the cortex, and the cortex and the limbic system.[3] It is a theory that extends beyond body schema theory and incorporates the conscious awareness of oneself. This theory proposes that conscious awareness and the perception of self are generated in the brain via patterns of input that can be modified by different perceptual inputs.[1] The network is genetically predetermined, and is modified throughout one’s lifetime by various sensory inputs to create a neurosignature. It is the neurosignature of a specific body part that determines how it is consciously perceived.[3] The input systems contributing to the neurosignature are primarily the somatosensory, limbic, and thalamocortical systems. The neuromatrix theory aims to explain how certain activities associated with pain lead to the conscious perception of phantom pain. The persistence of the neurosignature, even after limb amputation, may be the cause of phantom sensations and pain. Phantom pain may arise from abnormal reorganization in the neuromatrix to a pre-existing pain state.[8] Opposition to the neuromatrix theory exists largely because it fails to explain why relief from phantom sensations rarely eliminates phantom pains. It also does not address how sensations can spontaneously end and how some amputees do not experience phantom sensations at all.[3] In addition, a major limitation of the neuromatrix theory is that it too broadly accounts for various aspects of phantom limb perception. It is also likely that it is too difficult to be tested empirically, especially when testing painless phantom sensations.[1] ## Management[edit] Various methods have been used to treat phantom limb pain. Doctors may prescribe medications to reduce the pain. Some antidepressants or antiepileptics have been shown to have a beneficial effect on reducing phantom limb pain. Often physical methods such as light massage, electrical stimulation, and hot and cold therapy have been used with variable results. There are many different treatment options for phantom limb pain that are actively being researched. Most treatments do not take into account the mechanisms underlying phantom pains, and are therefore ineffective. However, there are a few treatment options that have been shown to alleviate pain in some patients, but these treatment options usually have a success rate less than 30%.[3] It is important to note that this rate of success does not exceed the placebo effect. It is also important to note that because the degree of cortical reorganization is proportional to phantom limb pains, any perturbations to the amputated regions may increase pain perception.[3] ### Mirror therapy[edit] Ramachandran (right) with his original mirror box Mirror box therapy allows for illusions of movement and touch in a phantom limb by inducing somatosensory and motor pathway coupling between the phantom and real limb.[1] Many patients experience pain as a result of a clenched phantom limb, and because phantom limbs are not under voluntary control, unclenching becomes impossible.[9] This theory proposes that the phantom limb feels paralyzed because there is no feedback from the phantom back to the brain to inform it otherwise. Vilayanur S. Ramachandran believes that if the brain received visual feedback that the limb had moved, then the phantom limb would become unparalyzed.[9] Although the use of mirror therapy has been shown to be effective in some cases there is still no widely accepted theory of how it works. According to 2017 paper that reviewed a wide range of studies of mirror therapy, "Research evidence suggests that a course of treatment (four weeks) of mirror therapy may reduce chronic pain. Contraindications and side effects are few. The mechanism of action of mirror therapy remains uncertain, with reintegration of motor and sensory systems, restored body image and control over fear-avoidance likely to influence outcome. The evidence for clinical efficacy of mirror therapy is encouraging, but not yet definitive. Nevertheless, mirror therapy is inexpensive, safe and easy for the patient to self-administer."[10] Little research was published on MT before 2009, and much of the research since then has been of low quality.[11] Out of 115 publications between 2012 and 2017 about using mirror therapy to treat phantom limb pain, a 2018 review, found only 15 studies whose scientific results should be considered. From these 15 studies, the reviewers concluded that "MT seems to be effective in relieving PLP, reducing the intensity and duration of daily pain episodes. It is a valid, simple, and inexpensive treatment for PLP."[12] ### Medication[edit] Pharmacological techniques are often continued in conjunction with other treatment options. Doses of pain medications needed often drop substantially when combined with other techniques, but rarely are discontinued completely. Tricyclic antidepressants, such as amitriptyline, and sodium channel blockers, mainly carbamazepine, are often used to relieve chronic pain, and recently have been used in an attempt to reduce phantom pains. Pain relief may also be achieved through use of opioids, ketamine, calcitonin, and lidocaine.[3] ### Deep-brain stimulation[edit] Deep brain stimulation is a surgical technique used to alleviate patients from phantom limb pain. Prior to surgery, patients undergo functional brain imaging techniques such as PET scans and functional MRI to determine an appropriate trajectory of where pain is originating. Surgery is then carried out under local anesthetic, because patient feedback during the operation is needed. In the study conducted by Bittar et al., a radiofrequency electrode with four contact points was placed on the brain. Once the electrode was in place, the contact locations were altered slightly according to where the patient felt the greatest relief from pain. Once the location of maximal relief was determined, the electrode was implanted and secured to the skull. After the primary surgery, a secondary surgery under general anesthesia was conducted. A subcutaneous pulse generator was implanted into a pectoral pocket below the clavicle to stimulate the electrode.[3] It was found that all three patients studied had gained satisfactory pain relief from the deep brain stimulation. Pain had not been completely eliminated, but the intensity had been reduced by over 50% and the burning component had completely vanished.[3] ## Epidemiology[edit] Phantom limb pain and phantom limb sensations are linked, but must be differentiated from one another. While phantom limb sensations are experienced by those with congenital limb deficiency, spinal cord injury, and amputation, phantom limb pain occurs almost exclusively as a result of amputation.[13] Almost immediately following the amputation of a limb, 90–98% of patients report experiencing a phantom sensation. Nearly 75% of individuals experience the phantom as soon as anesthesia wears off, and the remaining 25% of patients experience phantoms within a few days or weeks.[5] Of those experiencing innocuous sensations, a majority of patients also report distinct painful sensations. Age and gender have not been shown to affect the onset or duration of phantom limb pain. Although it has not been fully explored, one investigation of lower limb amputation observed that as stump length decreased, there was a greater incidence of moderate and severe phantom pain.[3] ## See also[edit] * Phantom limb * Phantom eye syndrome ## References[edit] 1. ^ a b c d Giummarra, M. J.; Gibson, S. J.; Georgiou-Karistianis, N.; Bradshaw, J. L. (2007). "Central mechanisms in phantom limb perception: The past, present and future". Brain Research Reviews. 54 (1): 219–232. doi:10.1016/j.brainresrev.2007.01.009. PMID 17500095. S2CID 42209339. 2. ^ Halligan, P. W. (2002). "Phantom limbs: The body in mind". Cognitive Neuropsychiatry. 7 (3): 251–269. doi:10.1080/13546800244000111. PMID 16571541. S2CID 31375410. 3. ^ a b c d e f g h i j k l m n Bittar, R. G.; Otero, S.; Carter, H.; Aziz, T. Z. (2005). "Deep brain stimulation for phantom limb pain". Journal of Clinical Neuroscience. 12 (4): 399–404. doi:10.1016/j.jocn.2004.07.013. PMID 15925769. S2CID 42653229. 4. ^ "Phantom Pain". Mayo Clinic. Retrieved 26 September 2018. 5. ^ a b c d e f Ramachandran, V. S.; Hirstein, W. (1998). "The perception of phantom limbs. The D. O. Hebb lecture". Brain : A Journal of Neurology. 121 (9): 1603–1630. doi:10.1093/brain/121.9.1603. PMID 9762952. 6. ^ Cruz, V. T.; Nunes, B.; Reis, A. M.; Pereira, J. R. (2003). "Cortical remapping in amputees and dysmelic patients: A functional MRI study". NeuroRehabilitation. 18 (4): 299–305. doi:10.3233/NRE-2003-18404. PMID 14757926. 7. ^ a b Karl, A.; Birbaumer, N.; Lutzenberger, W.; Cohen, L. G.; Flor, H. (2001). "Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain". The Journal of Neuroscience. 21 (10): 3609–3618. doi:10.1523/JNEUROSCI.21-10-03609.2001. PMC 6762494. PMID 11331390. 8. ^ Melzack, R. (1992). "Phantom limbs". Scientific American. 266 (4): 120–126. Bibcode:1992SciAm.266d.120M. doi:10.1038/scientificamerican0492-120. PMID 1566028. 9. ^ a b Ramachandran, V. S.; Rogers-Ramachandran, D. (1996). "Synaesthesia in Phantom Limbs Induced with Mirrors". Proceedings of the Royal Society B: Biological Sciences. 263 (1369): 377–386. Bibcode:1996RSPSB.263..377R. doi:10.1098/rspb.1996.0058. PMID 8637922. S2CID 4819370. 10. ^ Mirror therapy: A potential intervention for pain management, Wittkopf,Johnson,2017 Nov;63(11):[1] 11. ^ Jessie, Barbin; Seetha, Vanessa (2016). "The effects of mirror therapy on pain and motor control of phantom limb in amputees: A systematic review". Annals of Physical and Rehabilitation Medicine. 59 (4): 270–275. doi:10.1016/j.rehab.2016.04.001. PMID 27256539. "Up to the 26th November 2015, 85 articles were retrieved on the Medline, Cochrane and Embase databases with using the keywords phantom limb and mirror therapy. It was noted that from 2009, the number of articles increased markedly (Fig. 1), showing increased interest in MT following amputation." 12. ^ Campo-Prieto, P; Rodríguez-Fuentes, G (November 14, 2018). "Effectiveness of mirror therapy in phantom limb pain: A literature review". Neurologia. doi:10.1016/j.nrl.2018.08.003. PMID 30447854. "It is a valid, simple, and inexpensive treatment for PLP. The methodological quality of most publications in this field is very limited, highlighting the need for additional, high-quality studies to develop clinical protocols that could maximise the benefits of MT for patients with PLP." 13. ^ Kooijman, C. M.; Dijkstra, P. U.; Geertzen, J. H.; Elzinga, A.; Van Der Schans, C. P. (2000). "Phantom pain and phantom sensations in upper limb amputees: An epidemiological study". Pain. 87 (1): 33–41. doi:10.1016/S0304-3959(00)00264-5. PMID 10863043. S2CID 7565030. ## External links[edit] Classification D * ICD-10: G54.6 * ICD-9-CM: 353.6 * DiseasesDB: 29431 * MacLachlan, Malcolm; McDonald, Dympna; Waloch, Justine (2004), "Mirror Treatment of Lower Limb Phantom Pain: A Case Study", Disability and Rehabilitation, 26 (14/15): 901–904, doi:10.1080/09638280410001708913, PMID 15497919, S2CID 36325980 * Richardson, Cliff; Glenn, Sheila; Horgan, Maureen; Nurmikko, Turo (October 2007), "A Prospective Study of Factors Associated with the Presence of Phantom Limb Pain Six Months After Major Lower Limb Amputation in Patients with Peripheral Vascular Disease", The Journal of Pain, 8 (10): 793–801, doi:10.1016/j.jpain.2007.05.007, PMID 17631056 * Targeted Muscle Reinnervation * v * t * e Pain By region/system Head and neck * Headache * Neck * Odynophagia (swallowing) * Toothache Respiratory system * Sore throat * Pleurodynia Musculoskeletal * Arthralgia (joint) * Bone pain * Myalgia (muscle) * Acute * Delayed-onset Neurologic * Neuralgia * Pain asymbolia * Pain disorder * Paroxysmal extreme pain disorder * Allodynia * Chronic pain * Hyperalgesia * Hypoalgesia * Hyperpathia * Phantom pain * Referred pain * Congenital insensitivity to pain * congenital insensitivity to pain with anhidrosis * congenital insensitivity to pain with partial anhidrosis Other * Pelvic pain * Proctalgia * Back * Low back pain Measurement and testing * Pain scale * Cold pressor test * Dolorimeter * Grimace scale (animals) * Hot plate test * Tail flick test * Visual analogue scale Pathophysiology * Nociception * Anterolateral system * Posteromarginal nucleus * Substance P Management * Analgesia * Anesthesia * Cordotomy * Pain eradication Related concepts * Pain threshold * Pain tolerance * Suffering * SOCRATES * Philosophy of pain * Cancer pain * Drug-seeking behavior [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Phantom pain	c3495442	8,745	wikipedia	https://en.wikipedia.org/wiki/Phantom_pain	2021-01-18T18:44:57	{"umls": ["C3495442"], "icd-9": ["353.6"], "wikidata": ["Q1202906"]}
Human pneumocystosis is caused by an infectious agent, which (after recent nomenclature and taxonomy revisions) is now classed as the fungus Pneumocystis jiroveci. The prevalence is unknown. Pneumocystis jiroveci is an opportunistic infectious agent, developing in immunosuppressed patients. It is an air-borne infection, localised to the lungs. However, extrapulmonary involvement is seen in AIDS patients. The disease manifests progressively with coughing, respiratory problems (dyspnea) and fever, followed by acute respiratory insufficiency and death within a few weeks in untreated cases. The most reliable diagnostic method is bronchoalveolar lavage. The treatment of choice is cotrimoxazole. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Pneumocystosis	c1535939	8,746	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=723	2021-01-23T17:05:23	{"gard": ["4386"], "mesh": ["D011020"], "umls": ["C1535939"], "icd-10": ["B59+", "J17.3*"]}
For a phenotypic description and a discussion of genetic heterogeneity of attention deficit-hyperactivity disorder, see 143465. Clinical Features Rommelse et al. (2008) cited 10 neuropsychologic cognitive and motor measures that had been shown to be candidate ADHD phenotypes: stop task, shifting attentional set, time test, visuo-spatial sequencing, digit span, pursuit, tracking, tapping, baseline speed, and motor timing (timing of motor output). Mapping In genomewide linkage analyses in a Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 unaffected sibs, Rommelse et al. (2008) used 8 neuropsychologic cognitive and motor measures that had been shown to be candidate ADHD phenotypes (those with heritabilities greater than 0.2) as quantitative traits. They also used an overall component score of neuropsychologic functioning. A total of 5,407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. They found a significant genomewide linkage signal for motor timing on chromosome 2q21.1, with a lod score of 3.944 at SNP rs985162. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	ATTENTION DEFICIT-HYPERACTIVITY DISORDER, SUSCEPTIBILITY TO, 5	c2676741	8,747	omim	https://www.omim.org/entry/612311	2019-09-22T16:01:50	{"omim": ["612311"], "synonyms": ["Alternative titles", "ADHD5", "MOTOR TIMING QUANTITATIVE TRAIT LOCUS"]}
A rare skin disease characterized most typically by targetoid papules with concentric color variation symmetrically distributed on the extensor surfaces of the extremities, accompanied by mucosal involvement (in particular the oral mucosa) in the form of initial erythema with edema, progressing to superficial erosions with pseudomembrane formation. Grouping of lesions around the elbows and knees and edema of the nail folds may also be observed. The condition is commonly proceeded by prodromal symptoms of malaise, fever, and myalgias, and is usually self-limiting, although recurrent disease is seen in a subset of patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Erythema multiforme major	c3241919	8,748	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=502499	2021-01-23T18:37:51	{"synonyms": ["Erythema exsudativum multiforme majus", "Erythema multiforme majus"]}
A number sign (#) is used with this entry because vitamin D-dependent rickets type 1B, due to a defect in vitamin D 25-hydroxylation, is caused by mutation in the CYP2R1 gene (608713) on chromosome 11p15. For a general phenotypic description and discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700). Clinical Features Casella et al. (1994) described 2 brothers of Nigerian descent who had rickets at a young age despite a history of adequate vitamin D intake. The patient had bone abnormalities of the legs appearing between 2 and 7 years of age. Before treatment, he had low normal serum calcium levels, low serum phosphate levels, elevated serum alkaline phosphatase levels, normal serum levels of 1-alpha,25-dihydroxyvitamin D, and low 25-hydroxyvitamin D. Treatment with vitamin D2 in pharmacologic doses resulted in resolution of the biochemical abnormalities and radiographic deformities. High levels of vitamin D2 were required to maintain normal concentrations of 25-hydroxyvitamin D in the serum even though vitamin D absorption was normal. The unique biochemical profile enabled exclusion of other causes of vitamin D-dependent rickets could be excluded (e.g., VDDR1A and VDDR2A, 277440). Cheng et al. (2004) noted that the scarcity of cases of 25-hydroxylase deficiency may reflect genetic polymorphisms that allow alternate pathways to function in some individuals. It may be significant that the patient studied by Cheng et al. (2004) was Nigerian. Individuals with dark skin require exposure to sunlight for longer periods of time to generate requisite levels of vitamin D3 as compared with those of less skin pigmentation and thus may be more sensitive to impaired synthesis of the vitamin. Molecular Genetics In one of the patients described by Casella et al. (1994), Cheng et al. (2004) identified a homozygous mutation in the CYP2R1 gene (608713.0001). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive \- Poor growth \- Growth retardation HEAD & NECK Head \- Frontal bossing CHEST Ribs Sternum Clavicles & Scapulae \- Enlargement and bulging of the costochondral junction \- Deformed rib cage SKELETAL \- Rickets \- Increased fractures \- Bone pain \- Sparse bone trabeculae \- Thin bony cortex Skull \- Widened cranial sutures \- Posterior flattening of the skull Limbs \- Delayed opacification of the epiphyses \- Widened, distorted epiphyses \- 'Bulging' epiphyses \- Frayed, irregular metaphyses \- Lower limb deformities \- Bowing of the legs \- Curvatures of the femur, tibia, fibula \- Enlargement of the wrists \- Enlargement of the ankles MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness \- Difficulty in walking \- Difficulty in standing LABORATORY ABNORMALITIES \- Low-to-normal serum calcium \- Hypophosphatemia \- Increased alkaline phosphatase \- Normal serum 1,25-dihydroxyvitamin D3 \- Decreased serum 25-hydroxyvitamin D MISCELLANEOUS \- Onset in infancy \- Good response to vitamin D treatment MOLECULAR BASIS \- Caused by mutations in the vitamin D 25-hydroxylase gene (CYP2R1, 608713.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1B	c0268689	8,749	omim	https://www.omim.org/entry/600081	2019-09-22T16:16:43	{"doid": ["10609"], "mesh": ["C562688"], "omim": ["600081"], "orphanet": ["289157"], "synonyms": ["Alternative titles", "VITAMIN D-DEPENDENT RICKETS, TYPE 1B", "25-HYDROXYVITAMIN D3 DEFICIENCY, SELECTIVE", "PSEUDOVITAMIN D3 DEFICIENCY RICKETS DUE TO 25-HYDROXYLASE DEFICIENCY"]}
Hypertensive retinopathy Hypertensive retinopathy with AV nicking and mild vascular tortuosity SpecialtySynonyms = Latin: Fundus hypertonicus Hypertensive retinopathy is damage to the retina and retinal circulation due to high blood pressure (i.e. hypertension). ## Contents * 1 Signs and symptoms * 1.1 Signs * 2 Pathophysiology * 3 Diagnosis * 3.1 Differential Diagnoses * 3.2 Keith Wagener Barker (KWB) Grades * 4 Management * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] Most patients with hypertensive retinopathy have no symptoms. However, some may report decreased or blurred vision,[1] and headaches.[2] ### Signs[edit] Signs of damage to the retina caused by hypertension include: Laser Doppler imaging of the papilla of a patient with hypertension * Arteriolar changes, such as generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, changes in the arteriolar wall (arteriosclerosis) and abnormalities at points where arterioles and venules cross. Manifestations of these changes include Copper wire arterioles where the central light reflex occupies most of the width of the arteriole and Silver wire arterioles where the central light reflex occupies all of the width of the arteriole, and "arterio-venular (AV) nicking" or "AV nipping", due to venous constriction and banking. * advanced retinopathy lesions, such as microaneurysms, blot hemorrhages and/or flame hemorrhages, ischemic changes (e.g. "cotton wool spots"), hard exudates and in severe cases swelling of the optic disc (optic disc edema), a ring of exudates around the retina called a "macular star" and visual acuity loss, typically due to macular involvement. * Strongly modulated blood flow pulse in central and branch arteries can result from hypertension. Microangiography by laser Doppler imaging[3] may reveal altered hemodynamics non-invasively. Mild signs of hypertensive retinopathy can be seen quite frequently in normal people (3–14% of adult individuals aged ≥40 years), even without hypertension.[4] Hypertensive retinopathy is commonly considered a diagnostic feature of a hypertensive emergency although it is not invariably present.[5] ## Pathophysiology[edit] The changes in hypertensive retinopathy result from damage and adaptive changes in the arterial and arteriolar circulation in response to the high blood pressure.[1] ## Diagnosis[edit] ### Differential Diagnoses[edit] Several other diseases can result in retinopathy that can be confused with hypertensive retinopathy. These include diabetic retinopathy, retinopathy due to autoimmune disease, anemia, radiation retinopathy, and central retinal vein occlusion.[2] ### Keith Wagener Barker (KWB) Grades[edit] Grade 1 Vascular Attenuation Grade 2 As grade 1 + Irregularly located, tight constrictions – Known as "AV nicking" or "AV nipping" – Salus's sign Grade 3 As grade 2 + Retinal edema, cotton wool spots and flame-hemorrhages "Copper Wiring" + Bonnet's Sign + Gunn's Sign Grade 4 As grade 3 + optic disc edema + macular star "Silver Wiring" There is an association between the grade of retinopathy and mortality. In a classic study in 1939 Keith and colleagues[6] described the prognosis of people with differing severity of retinopathy. They showed 70% of those with grade 1 retinopathy were alive after 3 years whereas only 6% of those with grade 4 survived. The most widely used modern classification system bears their name.[4] The role of retinopathy grading in risk stratification is debated, but it has been proposed that individuals with signs of hypertensive retinopathy signs, especially retinal hemorrhages, microaneurysms and cotton-wool spots, should be assessed carefully.[4] ## Management[edit] A major aim of treatment is to prevent, limit, or reverse target organ damage by lowering the person's high blood pressure to reduce the risk of cardiovascular disease and death. Treatment with antihypertensive medications may be required to control the high blood pressure. ## See also[edit] * Hypertensive crisis * List of systemic diseases with ocular manifestations * Ophthalmology * Optometry ## References[edit] 1. ^ a b Bhargava, M; Ikram, M K; Wong, T Y (2011). "How does hypertension affect your eyes?". Journal of Human Hypertension. 26 (2): 71–83. doi:10.1038/jhh.2011.37. PMID 21509040. 2. ^ a b Yanoff, Myron; Duker, Jay S. (2009-01-01). Ophthalmology. Elsevier Health Sciences. ISBN 978-0323043328. 3. ^ Puyo, Léo, Michel Paques, Mathias Fink, José-Alain Sahel, and Michael Atlan. "Waveform analysis of human retinal and choroidal blood flow with laser Doppler holography." Biomedical Optics Express 10, no. 10 (2019): 4942-4963. 4. ^ a b c Wong TY, Mcintosh R (2005). "Hypertensive retinopathy signs as risk indicators of cardiovascular morbidity and mortality". British Medical Bulletin. 73–74: 57–70. doi:10.1093/bmb/ldh050. PMID 16148191. 5. ^ Cremer, A.; Amraoui, F.; Lip, G. Y. H.; Morales, E.; Rubin, S.; Segura, J.; Van den Born, B. J.; Gosse, P. (2016-08-01). "From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency". Journal of Human Hypertension. 30 (8): 463–466. doi:10.1038/jhh.2015.112. ISSN 0950-9240. PMID 26582411. S2CID 205167912. 6. ^ Keith NM, Wagener HP, Barker NW (1939) Some different types of essential hypertension: their course and prognosis. Am J Med Sci, 197, 332–43. ## Further reading[edit] * The Wills Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease, J.B. Lippincott, 1994. * Hypertensive retinopathy ## External links[edit] Classification D * ICD-10: H35.0 * ICD-9-CM: 362.11 * MeSH: D058437 External resources * MedlinePlus: 000999 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hypertensive retinopathy	c0152132	8,750	wikipedia	https://en.wikipedia.org/wiki/Hypertensive_retinopathy	2021-01-18T18:34:35	{"mesh": ["D058437"], "umls": ["C0152132"], "wikidata": ["Q425811"]}
Dysspondyloenchondromatosis is a rare skeletal dysplasia characterized by anisospondyly and multiple enchondromas in vertebrae and the metaphyseal and diaphyseal parts of long tubular bones, leading to kyphoscoliosis and lower limb asymmetry. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Dysspondyloenchondromatosis	c4302548	8,751	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85198	2021-01-23T17:37:09	{"icd-10": ["Q78.4"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant periodic fever is caused by heterozygous mutation in the tumor necrosis factor receptor-1 gene (TNFRSF1A; 191190) on chromosome 12p13. Drenth and van der Meer (2001) reviewed hereditary periodic fever syndromes, including TNF receptor-associated periodic syndrome. Clinical Features Williamson et al. (1982) described an Irish-Scottish family with an autosomal dominant 'periodic disease' characterized by recurrent attacks of fever, abdominal pain, localized tender skin lesions, and myalgia. Pleurisy, leukocytosis, and high erythrocyte sedimentation rate were other features. The disease pursued a benign course and no patient had developed amyloidosis. At least 13 persons in 5 sibships of 3 generations were affected, with 4 instances of male-to-male transmission. Bouroncle and Doan (1957) described 12 cases of periodic fever in 6 sibships in 5 generations of a family. No abnormality was detected by clinical examinations during and between attacks or by many laboratory studies. In 2 brothers with periodic fever, Driessen et al. (1968) found that the nonesterified etiocholanolone level of the blood was raised not only during febrile attacks but also in fever-free periods. A sister had attacks of fever of unexplained origin accompanied by abdominal pain and rash but had no symptoms after menarche. Drenth et al. (1994) included the family of Driessen et al. (1968) in a series of cases of the hyper-IgD syndrome (260920). They stated that measurements on subsequent occasions in both brothers showed normal values of etiocholanolone. Wang et al. (1999) reported a 10-year-old Ashkenazi Jewish boy who developed lymphadenopathy at age 11 months, followed by bouts of prolonged fever, splenomegaly, elevated sedimentation rate, anemia, and reticulocytosis. At age 3 years, he had noninfectious lymphocytic meningitis followed by optic neuritis, indicating a pattern of disparate inflammatory conditions. At the time of report, he exhibited adenopathy and splenomegaly. Autoantibodies were not detected, but lymphocyte phenotyping showed a dramatic T and B lymphocytosis and increased CD4-, CD8- T cells, especially a striking increase in CD4-, CD8- gamma/delta T cells. Both parents were clinically normal. Although the boy was originally diagnosed with autoimmune lymphoproliferative syndrome type IIA (ALPS2A; 603909), he was later found to have a pathogenic mutation in the TNFRSF1A gene, consistent with a diagnosis of TRAPS (Zhu et al., 2006). Toro et al. (2000) described the cutaneous features of 25 patients with clinically and molecularly diagnosed FPF, which they referred to as 'tumor necrosis factor receptor-associated periodic syndrome' (TRAPS). Twenty-one patients (84%) had cutaneous manifestations. Migratory macules and patches were the most common findings. In addition, 10 patients (40%) exhibited erythematous edematous plaques. Lesions usually occurred during febrile episodes, were most commonly seen on the extremities, were often associated with myalgia, and lasted 4 to 21 days. Biopsies of lesional skin were obtained from 10 patients. The histologic findings were nonspecific, consisting of infiltrating T lymphocytes and monocytes, and could not be distinguished from a viral exanthem or serum sickness-like reaction. Wildemann et al. (2007) reported a man with periodic fever syndrome who developed central nervous system involvement. Since childhood, he had experienced recurrent attacks of fever, myalgias, arthralgias, and painful migratory rashes. At age 38, he developed brainstem and cerebellar symptoms from a T-cell predominant inflammatory infiltrate without evidence of demyelination. Treatment with a TNF-alpha antagonist resulted in marked clinical improvement with mild residual symptoms. Genetic analysis identified a heterozygous mutation in the TNFRSF1A gene (C55A; 191190.0012). Clinical Management Weyhreter et al. (2003) reported a Danish family with TRAPS in which the youngest affected member was treated successfully with etanercept (a fusion protein of the extracellular domain of TNFRSF1A and the Fc portion of IgG1) at age 18 months following lack of response to infliximab or of a sustained response to prednisolone. Mapping Mulley et al. (1997, 1998) found frequent recombination of FPF with the marker D16S2622 located within 1 Mb of familial Mediterranean fever at 16p13.3, thus excluding allelism between these clinically similar conditions. By a genomewide search, they detected linkage to a cluster of markers at 12p13, with a multipoint lod score of 6.14 at D12S356. Assuming penetrance of 90%, they assigned the relevant gene (symbolized FPF by them) to a 19-cM interval between D12S314 and D12S364. McDermott et al. (1998) confirmed the assignment of familial Hibernian fever to 12p13 by studies in the originally reported Irish-Scottish family (6:Williamson et al., 1982) and in 2 Irish families with similar clinical features (Quane et al., 1997). Cumulative multipoint linkage analyses indicated that the gene, which they symbolized FHF (in parallel with the FMF of familial Mediterranean fever), is likely to be located in an 8-cM interval between D12S77 and D12S356, with a maximum lod score of 3.79. The 2-point maximum lod score was 3.11 for D12S77. There was no evidence of genetic heterogeneity in these 3 families. Molecular Genetics McDermott et al. (1999) identified germline mutations in the TNFRSF1A gene, which had been identified as a candidate gene by linkage studies. The families studied included those reported by Mulley et al. (1998) and McDermott et al. (1998), a Finnish family reported by Karenko et al. (1992), and 3 small North American families of Irish/English/German, Irish, and French-Canadian ancestry. Aganna et al. (2001) identified a mutation in the TNFRSF1A gene (191190.0007) in a 2-generation Dutch family with TRAPS. The mutation was present in the affected father and in all of his 4 children (the affected proposita, a mildly affected son, and 2 unaffected children) but was not found in 120 control chromosomes from unaffected Dutch individuals. Low soluble plasma levels of TNFRSF1A segregated with the mutation in all the children, including those who were unaffected. The authors suggested that low levels of soluble TNFRSF1A in combination with particular environmental insults may be necessary to produce the full-blown phenotype. They also raised the possibility that TNFRSF1A mutations may be present in mildly symptomatic or indeed asymptomatic persons. Nomenclature According to Kastner (2003), the gene for 'Hibernian fever' came from the Scottish (mother's) side of the family; hence, it should be called Caledonian fever rather than Hibernian fever. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Periorbital edema \- Conjunctival injection CHEST \- Pleuritic pain ABDOMEN \- Recurrent abdominal pains Liver \- Hepatic amyloidosis SKELETAL \- Arthralgias SKIN, NAILS, & HAIR Skin \- Migratory rashes, painful MUSCLE, SOFT TISSUES \- Myalgias \- Muscle stiffness METABOLIC FEATURES \- Fever, periodic, recurrent LABORATORY ABNORMALITIES \- Increased erythrocyte sedimentation rate \- Increased white blood cell count \- Systemic amyloidosis may occur MISCELLANEOUS \- Variable age at onset \- Favorable response to high-dose steroids \- Prevalence of 1 in 150 to 1 in 1,000 \- High incidence in Iraqis and Sephardic Jewish individuals MOLECULAR BASIS \- Caused by mutation in the tumor necrosis factor receptor superfamily member 1A gene (TNFRSF1A, 191190.0001 ). ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT	c1275126	8,752	omim	https://www.omim.org/entry/142680	2019-09-22T16:40:11	{"doid": ["0090018"], "mesh": ["C536657"], "omim": ["142680"], "orphanet": ["32960"], "synonyms": ["Alternative titles", "FPF", "HIBERNIAN FEVER, FAMILIAL", "FAMILIAL HIBERNIAN FEVER", "TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME", "TNF RECEPTOR-ASSOCIATED PERIODIC SYNDROME"]}
A number sign (#) is used with this entry because of evidence that MALT lymphoma is associated with somatic mutation in the BCL10 gene (603517) on chromosome 1p22. Description The concept of mucosa-associated lymphoid tissue (MALT) lymphomas was introduced by Isaacson and Wright (1983). MALT lymphomas are now recognized as a distinct subtype of non-Hodgkin lymphoma (605027). B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) are the most common form of lymphoma arising in extranodal sites, in most cases arising in the gastric mucosa (Isaacson and Spencer, 1995). Clinical Features Hayoz et al. (1993) observed primary gastric lymphoma in a 78-year-old man and 2 of his daughters. Familial lymphoma is uncommon and is usually associated with various forms of hereditary immunodeficiencies. In this family there was, however, no overt immunodeficiency or cancer of nonlymphomatous origin. The sisters presented with a low-grade lymphoma of the mucosa-associated lymphoid tissue type. Their father presented with a high-grade form of later onset. All lymphomas were characterized as being of B-cell origin. BCL2 rearrangement (151430) was observed in none of them. Two other sisters, who were thus far free of gastric lymphoma, had at some time presented with a gastric ulcer. Molecular Genetics In cases of MALT lymphoma, Willis et al. (1999) identified somatic mutations in the BCL10 gene (603517.0001-603517.0003). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	LYMPHOMA, MUCOSA-ASSOCIATED LYMPHOID TYPE	c0242647	8,753	omim	https://www.omim.org/entry/137245	2019-09-22T16:40:46	{"doid": ["0050909"], "mesh": ["D018442"], "omim": ["137245"], "orphanet": ["52417"], "synonyms": ["Alternative titles", "MALT LYMPHOMA", "GASTRIC LYMPHOMA, PRIMARY"]}
Episcleritis Eye with Episcleritis SpecialtyOphthalmology SymptomsEye redness without pain Watery eyes TypesNodular and simple/diffuse Diagnostic methodHistory and physical examination Differential diagnosisScleritis TreatmentArtificial tears, supportive care MedicationTopical corticosteroids Non-steroidal anti-inflammatory drugs. PrognosisGood Episcleritis is a benign, self-limiting inflammatory disease affecting part of the eye called the episclera. The episclera is a thin layer of tissue that lies between the conjunctiva and the connective tissue layer that forms the white of the eye (sclera). Episcleritis is a common condition, and is characterized by the abrupt onset of painless eye redness. There are two types of episcleritis, nodular and simple. Nodular episcleritis lesions have raised surface. Simple episcleritis lesions are flat. There are two subtypes. In diffuse simple episcleritis, inflammation is generalized. In sectoral simple episcleritis, the inflammation is restricted to one region. Most cases of episcleritis have no identifiable cause, although about a third of cases are associated with various systemic diseases. Often people with episcleritis experience it recurrently. Treatment focuses on decreasing discomfort, and includes lubricating eye drops. More severe cases may be treated with topical corticosteroids or oral anti-inflammatory medications (NSAIDs). ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Episcleritis of a 40 years old female Symptoms of episcleritis typically include painless redness of the eye (mild pain is possible but atypical), and watery eyes.[1] The pain of episcleritis is typically mild, less severe than in scleritis,[2] and may be tender to palpation.[3] There are two types of episcleritis: the diffuse type, where the redness involves the entire episclera, and the nodular type, where the redness appears more nodular, involving only a small, well-circumscribed area (sectoral).[4] The diffuse type of episcleritis may be less painful than the nodular type. Sometimes, small nodules are present within the episclera, which move slightly over the sclera with gentle pressure.[4] Discharge is absent with episcleritis, and vision is unaffected.[4] Patients with episcleritis experience far less photophobia than patients with uveitis.[1] Episcleritis does not cause the presence of cells or flare in the anterior chamber of the eye.[1] In 80 percent of cases, episcleritis affects only one eye,[5] whereas scleritis often affects both eyes. ## Pathophysiology[edit] Episcleritis is caused by inflammation due to the activation of immune cells, including lymphocytes and macrophages.[5] Most of the time, the cause of episcleritis is never determined (idiopathic). An identifiable cause is discovered in about one third of cases.[6] Several diseases are associated with episcleritis, including systemic vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis, Behçet's disease), connective tissue diseases (rheumatoid arthritis, relapsing polychondritis, systemic lupus erythematosus),[7] psoriatic arthritis, ankylosing spondylitis, Cogan syndrome, rosacea, gout,[4] atopy,[6] Crohn's disease, and ulcerative colitis.[8][5] 59 percent of patients with relapsing polychondritis have either episcleritis or scleritis.[9] Rarely, episcleritis may be caused by scleritis.[10] Very rarely, episcleritis is associated with infections, including Lyme disease, tuberculosis, syphilis, and herpes zoster.[5] The redness in the eye associated with episcleritis is due to engorgement of the large episcleral blood vessels, which run in a radial direction from the limbus.[4] Typically, there is no uveitis, or thickening of the sclera. ## Diagnosis[edit] The diagnosis of episcleritis is based upon the history and physical examination. The history should be explored for the presence of the diseases associated with episcleritis, and the symptoms they cause, such as rash, arthritis, venereal disease, and recent viral infection.[4] Episcleritis may be differentiated from scleritis by using phenylephrine or neosynephrine eye drops, which causes blanching of the blood vessels in episcleritis, but not in scleritis.[2] A blue color to the sclera suggests scleritis, rather than episcleritis. After anesthetizing the eye with medication, the conjunctiva may be moved with a cotton swab to observe the location of the enlarged blood vessels. In very rare cases, if episcleritis does not respond to treatment, then a biopsy may be considered,[5] which help provide information regarding any underlying condition (granulomatosis with polyangitis, vasculitis, etc.). However, a biopsy is not routinely necessary in the diagnosis of episcleritis. ## Treatment[edit] Often, treatment is not necessary, because episcleritis is a self-limiting condition. Artificial tears may be used to help with irritation and discomfort. More severe cases can be treated with either topical corticosteroids or oral non-steroidal anti-inflammatory drugs.[6] Ketorolac, a topical NSAID, may be used, but it is not more effective than artificial tears and it causes more side effects.[11] ## Prognosis[edit] Episcleritis is a benign, self-limiting condition, meaning patients recover without any treatment. Most cases of episcleritis resolve within 7–10 days.[1] The nodular type is more aggressive and takes longer to resolve.[1] Although rare, some cases may progress to scleritis.[12] However, in general, episcleritis does not cause complications in the eye.[12] Smoking tobacco delays the response to treatment in patients with episcleritis.[13] ## Epidemiology[edit] While episcleritis is a common disease,[14] its exact prevalence and incidence are unknown.[5] It typically affects young[14] or middle aged women.[5] The diffuse form of episcleritis (70%) is more common than the nodular form (30%).[5] One retrospective study found 28 percent of individuals with episcleritis experienced recurrent episodes of the disease.[15] ## References[edit] 1. ^ a b c d e Heath, Greg (10 February 2010). "The episclera, sclera and conjunctiva An overview of relevant ocular anatomy" (PDF). OT: 36–42. Archived from the original (PDF) on 13 May 2013. Retrieved 30 November 2012. 2. ^ a b Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. pp. 2440. ISBN 978-1437727883. 3. ^ Chumley H; Usatine RP; Smith MA; Chumley H; Mayeaux Jr. E; Tysinger J (2009). The Color Atlas of Family Medicine: Chapter 16. Scleritis and Episcleritis (2nd ed.). New York: McGraw-Hill Education Medical. ISBN 978-0071769648. 4. ^ a b c d e f Kunimoto, Derek; Kunal Kanitkar; Mary Makar (2004). The Wills eye manual: office and emergency room diagnosis and treatment of eye disease (4 ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 99–100. ISBN 978-0781742078. 5. ^ a b c d e f g h Schonberg, S; Stokkermans, TJ (January 2020). "Episcleritis". PMID 30521217. Cite journal requires `\|journal=` (help) 6. ^ a b c Yanoff, Myron; Jay S. Duker (2008). Ophthalmology (3rd ed.). Edinburgh: Mosby. pp. 255–261. ISBN 978-0323057516. 7. ^ Watson, PG; Hayreh, SS (March 1976). "Scleritis and episcleritis". The British Journal of Ophthalmology. 60 (3): 163–91. doi:10.1136/bjo.60.3.163. PMC 1042706. PMID 1268179. 8. ^ Langholz, E. (March 2010). "Review: Current trends in inflammatory bowel disease: the natural history". Therapeutic Advances in Gastroenterology. 3 (2): 77–86. doi:10.1177/1756283X10361304. PMC 3002570. PMID 21180592. 9. ^ Sabatine, Marc S. (2011). Pocket Medicine (4th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 8–4. ISBN 978-1608319053. 10. ^ "Episcleritis: MedlinePlus Medical Encyclopedia". Bethesda, MD: United States National Library of Medicine. Retrieved 20 June 2010. 11. ^ Williams, CP; Browning, AC; Sleep, TJ; Webber, SK; McGill, JI (July 2005). "A randomised, double-blind trial of topical ketorolac vs artificial tears for the treatment of episcleritis". Eye (London, England). 19 (7): 739–42. doi:10.1038/sj.eye.6701632. PMID 15359265. 12. ^ a b Jabs, Douglas A.; Mudun, Abdulbaki; Dunn, J.P.; Marsh, Marta J. (Oct 2000). "Episcleritis and scleritis: clinical features and treatment results". American Journal of Ophthalmology. 130 (4): 469–476. doi:10.1016/S0002-9394(00)00710-8. PMID 11024419. 13. ^ Boonman, Z F H M; de Keizer, R J W; Watson, P G (September 2005). "Smoking delays the response to treatment in episcleritis and scleritis". Eye. 19 (9): 949–955. doi:10.1038/sj.eye.6701731. PMID 15543188. 14. ^ a b Levsky M.E.; DeFlorio P. (2010). Atlas of emergency medicine: Chapter 2 Ophthalmologic Conditions (3rd ed.). New York: McGraw-Hill Professional. ISBN 978-0071496186. 15. ^ Akpek, EK; Uy, HS; Christen, W; Gurdal, C; Foster, CS (April 1999). "Severity of episcleritis and systemic disease association". Ophthalmology. 106 (4): 729–31. doi:10.1016/S0161-6420(99)90157-4. PMID 10201593. ## External links[edit] Classification D * ICD-10: H15.1 * ICD-9-CM: 379.0 * MeSH: D015423 * DiseasesDB: 4375 External resources * MedlinePlus: 001019 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Episcleritis	c0014583	8,754	wikipedia	https://en.wikipedia.org/wiki/Episcleritis	2021-01-18T18:33:19	{"mesh": ["D015423"], "icd-9": ["379.0"], "icd-10": ["H15.1"], "wikidata": ["Q3726949"]}
This syndrome is characterized by the association of Möbius syndrome (congenital facial palsy with impaired ocular abduction; see this term) with peripheral axonal neuropathy and hypogonadotropic hypogonadism. ## Epidemiology Only seven cases have been described in the literature so far. ## Genetic counseling All of the reported cases were sporadic. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome	c2931024	8,755	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2560	2021-01-23T17:14:31	{"gard": ["3698"], "mesh": ["C535806"], "umls": ["C2931024"]}
Pituitary pars intermedia dysfunction (PPID), or equine Cushing's disease, is an endocrine disease affecting the pituitary gland of horses. It is most commonly seen in older animals,[1] and is classically associated with the formation of a long, wavy coat (hirsutism) and chronic laminitis. Cushing's disease commonly causes hirsutism, muscle wasting along the top line, and abnormal fat distribution. ## Contents * 1 Pathophysiology * 1.1 Dopaminergic control of the pars intermedia * 1.2 POMC * 2 Age and breed prevalence * 3 Clinical signs * 3.1 Laboratory findings * 3.2 Differentiating from Equine Metabolic Syndrome * 4 Diagnosis * 4.1 Plasma ACTH concentration * 4.2 Thyrotropin-releasing hormone stimulation test * 4.3 Dexamethasone suppression test * 4.4 Urinary corticoid-to-creatinine ratio * 4.5 Plasma cortisol concentration * 4.6 Current recommendations for testing * 5 Insulin dysregulation * 5.1 Testing for insulin resistance * 5.2 Management of insulin resistance * 6 Treatment * 7 See also * 8 References ## Pathophysiology[edit] Unlike the human and canine forms of Cushing's disease, which most commonly affect the pars distalis region of the pituitary gland, equine Cushing's disease is a result of hyperplasia or adenoma formation in the pars intermedia.[2] This adenoma then secretes excessive amounts of normal products, leading to clinical signs. ### Dopaminergic control of the pars intermedia[edit] The pituitary gland consists of three parts: the pars nervosa, the pars intermedia, and the pars distalis. The most critical structure to PPID, the pars intermedia, is regulated by the hypothalamus. The neurons of the hypothalamus innervate cells known as melanotropes within the pars intermedia, releasing dopamine which then binds to dopamine receptors on the melanotropes. Activation of these dopamine receptors leads to the inhibition of proopiomelanocortin (POMC) production from these cells.[1] In PPID-affected horses, dopamine is not produced from these neurons, leading to dopamine levels about 10% of the level normally found in the pars intermedia.[2] This is thought to be due to neurodegeneration of the neurons, secondary to free radical formation and oxidative stress.[3] Without regulation from dopamine, the pars intermedia develops hyperplasia and adenoma formation, leading to gross enlargement and excessive production of POMC. These adenomas also have the potential to compress the hypothalamus and optic chiasm.[1][2] ### POMC[edit] POMC produced from the melanotropes of the pars intermedia is cleaved into adrenocorticotropic hormone (ACTH) and β-lipotropin (β-LPH). The majority of ACTH[1] is then cleaved into α-MSH and corticotropin-like intermediate peptide (CLIP). CLIP is thought to have an influence on subsequent insulin resistance that can be seen in PPID horses.[4] ACTH is also produced by corticotropes in the pars distalis of the equine pituitary. In a normal horse, this accounts for the majority of ACTH production. ACTH produced by the pars distalis is subject to negative feedback in a normal horse, so high cortisol levels reduce ACTH production by the pituitary, subsequently reducing cortisol levels. In a horse with PPID, ACTH levels are high as a result of pars intermedia production, but it is not subject to negative feedback regulation. Despite the high levels of ACTH, cortisol levels vary, and are sometimes lower than normal. Additionally, hyperplasia of the adrenal cortex is infrequent.[1] The role of ACTH is, therefore, still poorly understood. ## Age and breed prevalence[edit] PPID has been diagnosed in horses as young as 7 years old,[1] although most horses are first diagnosed at ages 19 to 20.[1] An estimated 21% of horses older than 15 years have PPID.[5] All breeds may develop PPID, but pony breeds and Morgans seem to be more commonly affected.[1] [6] ## Clinical signs[edit] Many signs are associated with PPID, but only a subset of these are displayed in any single horse. Some horses may present with chronic laminitis without other overt signs of the disease.[1] * Hypertrichosis (hirsutism) produces a long, thick, wavy coat that often has delayed shedding or fails to shed completely, and may lighten in color.[7] Hirsutism has been suggested to be pathognomonic for PPID, with up to 95% of horses having PPID.[5] * Laminitis[5][6] * Increased drinking and increased urination[6] * Pot-bellied appearance[6] * Weight loss[2] * Redistribution of fat, leading to bulging supraorbital fat pad, a "cresty" neck, and fat over the tail head[6] or in the sheath of males[2] * Lethargy[1][2] * Behavioral changes, often an increased docility[1] * Muscle wasting, especially along the top line[1][6] * Increased sweating, or less commonly, decreased sweating[8] * Increased appetite[1] * Decreased sensitivity to pain[1] * Recurrent infections due to immune impairment[6][8] * Rarely neurologic signs such as narcolepsy, blindness, or seizures[1][2] * Suspensary ligament degeneration[9] ### Laboratory findings[edit] Complete blood counts and serum chemistry profiles may be normal in affected horses. Persistent hyperglycemia and glucosuria are very commonly seen.[1] Hyperlipidemia may be present, especially in ponies.[1] Other abnormalities associated with the disease include mild anemia, neurophilia, lymphopenia, eosinopenia, and increased liver enzymes.[2] ### Differentiating from Equine Metabolic Syndrome[edit] PPID shares similarities to Equine Metabolic Syndrome, which also causes regional adiposity, laminitis, and insulin resistance. Treatment and management may differ between the two endocrinopathies, making differentiation important. However, it is important to keep in mind that horses with EMS may develop PPID, therefore both diseases may occur simultaneously.[10] EMS vs PPID EMS PPID Age of Onset 5-15 years 15+ years Clinical signs Resistance to weight loss Hirsutism, increased drinking and urination, muscle atrophy Serum ACTH levels Normal Elevated ## Diagnosis[edit] ### Plasma ACTH concentration[edit] This test may also be referred to as a ‘’resting ACTH’’, ’’endogenous ACTH’’, or ‘’basal ACTH’’. The majority of ACTH produced in normal horses comes from corticotrope cells in the pars distalis, with only 2% thought to come from melanotropes in the pars intermedia. In horses with PPID, melanotropes produce abnormally high levels of ACTH.[7] Basal plasma ACTH concentrations, which measure the blood levels of circulating ACTH, can therefore be useful in diagnosing the disease. ACTH levels naturally fluctuate in healthy horses, with a significant rise occurring the in autumn (August through October) in North American horses. Horses with PPID have a similar, but much more significant, rise in the autumn. Therefore, a seasonally adjusted reference range must be used that correlates with the time of year the sample is taken.[7] Failure to use a seasonally adjusted reference range may lead to false-positive results in normal horses if they are sampled in the fall. Autumnal testing is thought to be more sensitive and specific than testing at other times of the year, so is preferred.[5] Basal plasma ACTH levels may increase if the horse is severely ill or under great stress or pain, such as if it has laminitis. However, such events must be fairly significant to confound the results.[7] Additionally, ACTH levels may not be significantly increased early on in the disease, leading to false negatives.[11] ### Thyrotropin-releasing hormone stimulation test[edit] Thyrotropin-releasing hormone (TRH) receptors are present in both the melanotropes of the pars intermedia and the corticotropes in the pars distalis. The administration of exogenous TRH causes an increase in ACTH and α-MSH in plasma of both normal horses and those with PPID. In both cases, plasma ACTH peaks 2–10 minutes after administration, before slowly dropping to normal levels over the course of an hour. PPID horses, however, show a much greater peak than normal horses, especially in the autumn.[7] The test is relatively simple, involving one blood sample taken before TRH administration, and one 10 minutes following TRH.[11] TRH is currently not licensed for use in horses, and can cause various side effects, including yawning, flehmen, muscle trembling, and coughing.[12] This test is thought to have greater sensitivity than other tests, but has drawbacks including cost, TRH availability, and lack of defined seasonal reference intervals.[7] Due to a lack of seasonal references, it is only recommended for use from December until June.[11] ### Dexamethasone suppression test[edit] The dexamethasone suppression test involves administering dexamethasone, a synthetic glucocorticoid, to the horse, and measuring its serum cortisol levels before and 19–24 hours after injection. In a normal horse, dexamethasone administration results in negative feedback to the pituitary, resulting in decreased ACTH production from the pars distalis and, therefore, decreased synthesis of cortisol at the level of the adrenal gland. A horse with PPID, which has an overactive pars intermedia not regulated by glucocorticoid levels, does not suppress ACTH production and, therefore, cortisol levels remain high. False negatives can occur in early disease.[1] Additionally, dexamethasone administration may increase the risk of laminitis in horses already prone to the disease.[7] For these reasons, the dexamethasone suppression test is currently not recommended for PPID testing. ### Urinary corticoid-to-creatinine ratio[edit] Although corticoid-to-creatinine ratios are generally higher in horses with PPID, numerous false positives and false negatives occur with this test, so it is not recommended.[1] ### Plasma cortisol concentration[edit] Resting plasma cortisol may be slightly elevated in affected horses, but is commonly within normal limits or below normal. Additionally, elevations may occur secondary to stress, concurrent disease, and due to individual variation. Therefore, resting cortisol levels alone are not adequate to diagnose or rule out the presence of PPID.[2] ### Current recommendations for testing[edit] As of 2013, horses suspected of having PPID should undergo testing both for the disease and for insulin dysfunction (see below). Horses showing obvious signs of PPID will likely have a positive endogenous ACTH test. Horses with early disease may produce a false-negative result. In these horses, the thyrotropin-releasing hormone stimulation test should either be used as an initial screening test, or to confirm a false resting ACTH.[11] ## Insulin dysregulation[edit] Insulin dysregulation is commonly seen in horses with PPID or equine metabolic syndrome, and is associated with obesity. It is of interest primarily because of its link to laminitis. Horses with ID will have an increased insulin response after they are given oral sugars, which will cause a subsequent rise in blood insulin levels, or hyperinsulinemia. Hyperinsulinemia results in decreased tissue sensitivity to insulin, or insulin resistance especially by the skeletal muscle, liver and adipose tissue. Tissue insulin resistance causes increased insulin secretion, which perpetuates the cycle.[4] The trigger to insulin resistance is not fully understood. Genetics is likely to have some impact on the risk of postprandial hyperinsulinemia. Obesity, pregnancy, PPID, and inflammatory states may contribute to tissue insulin resistance. PPID is thought to result in increased insulin secretion due to higher levels of CLIP produced by melanotrophs, and to cause insulin resistance secondary to hyperadrenocorticism.[4] ### Testing for insulin resistance[edit] Due to the strong link between PPID and insulin resistance, testing is recommended for all horses suspected or confirmed to be suffering from PPID. There are two tests commonly used for insulin resistance: the oral sugar test and fasting insulin blood concentration. The fasting insulin concentration involves giving a horse a single flake of hay at 10 pm the night before testing, with blood being drawn the following morning. Both insulin and glucose blood levels are measured. Hyperinsulinemia suggests insulin resistance, but normal or low fasting insulin does not rule out PPID. This test is easy to perform, but is less sensitive than the oral sugar test.[11] It is best used in cases where risks of laminitis make the oral sugar test potentially unsafe.[13] The oral sugar test also requires giving the horse only a single flake of hay at 10pm the night before the test. The following morning, karo corn syrup is given orally, and glucose and insulin levels are measured at 60 and 90 minutes after administration. Normal or excessively high insulin levels are diagnostic. However, equivocal test results require retesting at a later date, or performing a different test.[11] A similar test is available outside the US, in areas where corn-syrup products are less readily available, where horses are given a morning meal of chaff with dextrose powder, and blood insulin levels are measured 2 hours later.[13] ### Management of insulin resistance[edit] The main methods of management involve exercise and diet change, in addition to treatment of PPID. The primary goal is reduction of weight in an obese animal. Diet changes include limiting pasture access and reducing or eliminating grain. Obese animals are often best maintained on a diet consisting ration balancer and hay, fed at 1.5% body weight and decreased if needed.[13] Feed should be selected based on low non-structural carbohydrate levels. Hay NSC levels may be reduced by soaking it in cold water for 30 minutes.[13] Exercise is increased in non-laminitic horses. Animals resistant to weight loss, despite diet and exercise changes, can be placed on levothyroxine to increase metabolism. Metformin can also be used to reduce glucose absorption through the intestinal tract.[13] ## Treatment[edit] The primary treatment of PPID is pergolide, a dopamine agonist that provides suppression to the pars intermedia in place of the dysfunctional hypothalamus. Horses should be reassessed in 30 days following the start of treatment, through evaluation of clinical signs and by baseline diagnostic testing, to ensure the appropriate dose is being prescribed. Results from that test dictate changes in dose. Horses that are responding to treatment should be retested every 6 months, including a test in the autumn when there is a seasonal increase in ACTH, to ensure their ACTH levels are appropriately suppressed during this time. Drug side effects include a transient decrease in appetite, which can be reduced by slowly increasing the dose to therapeutic levels, and by breaking up the daily dose into twice-daily administrations.[11] Attitude, activity levels, hyperglycemia, and increased drinking and urination are usually improved within 30 days of initiating treatment. Other clinical signs, such as hirsutism, potbellied appearance, muscle wasting, laminitic episodes, and increased predisposition to infection usually take between 30 days and 1 year to improve.[11] Cyproheptadine may be added to the treatment regime in horses that are inadequately responding to pergolide,[11] but is usually only used in horses with advanced PPID on high doses of pergolide.[13] ## See also[edit] * Equine metabolic syndrome * Henneke horse body condition scoring system ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s Stephen M. Reed; Warwick M. Bayly; Debra C. Sellon (2010). Equine Internal Medicine (3rd ed.). St. Louis, MO: Saunders/Elsevier. ISBN 978-1416056706. 2. ^ a b c d e f g h i Robinson, Edward (2003). Current Therapy in Equine Medicine (5th ed.). Elsevier. pp. 807–811. ISBN 978-0-7216-9540-2. 3. ^ McFarlane, D., Dybdal, N., Donaldson, M. T., Miller, L. and Cribb, A. E. (2005), Nitration and Increased α-Synuclein Expression Associated With Dopaminergic Neurodegeneration In Equine Pituitary Pars Intermedia Dysfunction. Journal of Neuroendocrinology, 17: 73–80. doi: 10.1111/j.1365-2826.2005.01277.x 4. ^ a b c Frank, N. and Tadros, E. M. (2014), Insulin dysregulation. Equine Veterinary Journal, 46: 103–112. doi: 10.1111/evj.12169 5. ^ a b c d McGowan, T.W., Pinchbeck, G.P. and McGowan, C.M. (2013b) Evaluation of basal plasma a-melanocyte-stimulating hormone and adrenocorticotrophic hormone concentrations for the diagnosis of pituitary pars intermedia dysfunction from a population of aged horses. Equine Vet. J. 45, 66-73. 6. ^ a b c d e f g MCGOWAN, T. W., PINCHBECK, G. P. and MCGOWAN, C. M. (2013), Prevalence, risk factors and clinical signs predictive for equine pituitary pars intermedia dysfunction in aged horses. Equine Veterinary Journal, 45: 74–79. doi: 10.1111/j.2042-3306.2012.00578 7. ^ a b c d e f g Durham, A. E., McGowan, C. M., Fey, K., Tamzali, Y. and van der Kolk, J. H. (2014), Pituitary pars intermedia dysfunction: Diagnosis and treatment. Equine Veterinary Education, 26: 216–223. doi: 10.1111/eve.12160 8. ^ a b McFarlane, D. (2011) Equine pituitary pars intermedia dysfunction. Vet. Clin. N. Am.: Equine Pract. 27, 93-113. 9. ^ Hofberger, Sina; Gauff, Felicia; Licka, Theresia (2015-03-01). "Suspensory ligament degeneration associated with pituitary pars intermedia dysfunction in horses". The Veterinary Journal. 203 (3): 348–350. doi:10.1016/j.tvjl.2014.12.037. PMID 25641552. 10. ^ Frank, N., Geor, R.J., Bailey, S.R., Durham, A.E. and Johnson, P.J. (2010), Equine Metabolic Syndrome. Journal of Veterinary Internal Medicine, 24: 467–475. doi: 10.1111/j.1939-1676.2010.0503.x 11. ^ a b c d e f g h i Drs. Nicholas Frank; Frank Andrews; Andy Durham; Dianne McFarlane; Hal Schott (October 2013). Recommendations for the Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction (PPID). Equine Endocrinology Group. 12. ^ Beech, J., Boston, R., Lindborg, S. and Russell, G.E. (2007) Adrenocorticotropin concentration following administration of thyrotropin-releasing hormone in healthy horses and those with pituitary pars intermedia dysfunction and pituitary gland hyperplasia. J. Am. Vet. Med. Ass. 231, 417-426. 13. ^ a b c d e f Frank, N. and Geor, R. (2014), Current best practice in clinical management of equine endocrine patients. Equine Veterinary Education, 26: 6–9. doi: 10.1111/eve.12130 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Pituitary pars intermedia dysfunction	c3670036	8,756	wikipedia	https://en.wikipedia.org/wiki/Pituitary_pars_intermedia_dysfunction	2021-01-18T18:39:56	{"wikidata": ["Q1347819"]}
Juvenile Huntington disease (JHD) is a form of Huntington disease (HD; see this term), characterized by onset of signs and symptoms before 20 years of age. ## Epidemiology Exact prevalence of the juvenile form is not known, but is estimated to be about 1/166,000. JHD is reported in 6% of the total cases of HD, which has a prevalence of 1/10,000. ## Clinical description Behavioral disturbances and learning difficulties at school are often the first signs. Motor behavior is often hypokinetic and bradykinetic with dystonic components. Dementia is present in the early stage of the disease. Chorea, the classical sign of HD, is rarely seen in the 1st decade and only appears in the 2nd decade. Seizures, ataxia and weight loss are common. ## Etiology HD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. In juvenile Huntington disease, the CAG repeat length is over 55 in most cases. The length of the repeat determines about 70% of the variance in age at onset but gives no indication of initial symptoms, course, or duration of illness. In 75% of patients with JHD, the father is the affected parent. ## Diagnostic methods Diagnosis is based on clinical manifestations in an individual with a parent with proven HD, and is confirmed by DNA testing. Premanifest testing has been codified in the Guidelines of the International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group, and is not performed in at-risk patients below the age of 18. ## Differential diagnosis Differential diagnoses of JHD are young-onset type 2 spinocerebellar ataxia (SCA2: 12q) with chorea, dystonia, and dementia, and dentatorubral pallidoluysian atrophy (DRPLA: 12p) with chorea and myoclonic epilepsy, but also SCA3 (14q) with rigidity, ataxia, and dystonia and SCA17 (6q) with psychiatric features and dementia (see these terms). Other causes of chorea including general internal disorders or iatrogenic drug-induced disorders must also be considered. Sydenham chorea and post-streptococcal chorea are is still present in many parts of the world. ## Management and treatment No cure is currently available. Management should be multidisciplinary and is based on treating manifestations with a view to improving quality of life. Chorea should be treated with dopamine receptor blocking (risperidone, tiapride, pimozide) or depleting agents (tetrabenazine). None of these drugs are officially approved for use in children but are prescribed off-label as treatment of the main symptoms of the disease. Attempts have been made to treat hypokinesia with a number of antiparkinsonian drugs, but without success. Paramedical care with speech, occupational, and physical therapy with psychological support for the patient and family are recommended. ## Prognosis The progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The mean disease duration is comparable or slightly shorter than adult HD. The most common cause of death is pneumonia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Juvenile Huntington disease	c0751208	8,757	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=248111	2021-01-23T18:29:13	{"gard": ["10510"], "mesh": ["D006816"], "omim": ["143100"], "umls": ["C0751208"], "icd-10": ["G10"], "synonyms": ["JHD", "Juvenile Huntington chorea"]}
Glycogen storage disease IX Glycogen structure SymptomsEnlarged liver[1] CausesMutations in PHKA1, PHKA2, PHKB, or PHKG2 genes[2] Diagnostic methodCBC, Urinalysis[1][3] TreatmentPhysical therapy, follow metabolic nutritionist[1] Glycogen storage disease type IX is a hereditary deficiency of glycogen phosphorylase kinase B that affects the liver and skeletal muscle tissue. It is inherited in an X-linked or autosomal recessive manner.[1] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Types * 4 Management * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] The signs and symptoms in glycogen storage disease type IX include:[1] * Enlarged liver * Slowed growth * Motor development delay (mild) * Low blood sugar accompanied by ketosis * Lack of muscle tone Most of these signs and symptoms diminish as adulthood sets in.[1] ## Genetics[edit] Glycogen storage disease type IX can be inherited via:[2][4] * X-linked recessive inheritance due to mutations at either PHKA1 or the PHKA2 (most common[5]) gene * Autosomal recessive could be the inheritance pattern for an affected individual when the genes PHKB or PHKG2 have a mutation. ## Diagnosis[edit] Histological study (Microscope with stained slide) The diagnosis of glycogen storage disease IX consists of the following:[1][3] * Complete blood count * Urinalysis * Histological study of the liver (via biopsy) * Genetic testing * Physical exam ### Types[edit] There are two types of this inherited condition, glycogen storage disease IXa1 and glycogen storage disease IXa2 that affect the liver of an individual.[6] Mutations in PHKA2 have been seen in individuals with glycogen storage disease IXa2.[medical citation needed] ## Management[edit] Glucose The management of Glycogen storage disease IX requires treatment of symptoms by frequent intake of complex carbohydrates and protein to combat the low blood sugar. A nutritionist will advise on suitable diets. Liver function is regularly monitored and problems managed as they arise. However, liver problems have only been successfully treated by a transplant. Routine checks of metabolism are needed to ensure blood sugar (glucose) and ketones are managed. Regular moderate exercise is beneficial, although over-vigorous exercise is to be avoided, especially in those with enlarged livers.[1][7] ## See also[edit] * Glycogen storage disease ## References[edit] 1. ^ a b c d e f g h Goldstein, Jennifer; Austin, Stephanie; Kishnani, Priya; Bali, Deeksha (1993). Pagon, Roberta A; Adam, Margaret P; Ardinger, Holly H; Wallace, Stephanie E; Amemiya, Ann; Bean, Lora JH; Bird, Thomas D; Fong, Chin-To; Mefford, Heather C (eds.). Phosphorylase Kinase Deficiency. Seattle (WA): University of Washington. PMID 21634085. update 2011 2. ^ a b "Glycogen storage disease type IX". Genetics Home Reference. Retrieved 2016-08-06. 3. ^ a b Tidy, Colin (21 August 2014). "Glycogen Storage Disorders. GSD information and treatment". Patient Platform. Retrieved 6 August 2016. 4. ^ "Glycogen storage disease due to phosphorylase kinase deficiency". Orphanet. Retrieved 2016-08-06. 5. ^ Bernstein, Laurie E; Rohr, Fran; Helm, Joanna R (2015-06-03). Nutrition Management of Inherited Metabolic Diseases: Lessons from Metabolic University. Springer. p. 303. ISBN 9783319146218. Retrieved 6 August 2016. 6. ^ "Glycogen storage disease IX". OMIM. Johns Hopkins University. Retrieved 2016-08-06. 7. ^ Fernandes, John; Saudubray, Jean-Marie; van den Berghe, Georges (2013-03-14). Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Science & Business Media. p. 80. ISBN 9783662031476. Retrieved 6 August 2016. ## Further reading[edit] * Johnson, Abiodun O.; Goldstein, Jennifer L.; Bali, Deeksha (July 2012). "Glycogen Storage Disease Type IX". Journal of Pediatric Gastroenterology and Nutrition. 55 (1): 90–92. doi:10.1097/MPG.0b013e31823276ea. PMID 21857251. * Özen, Hasan (14 May 2007). "Glycogen storage diseases: New perspectives". World Journal of Gastroenterology. 13 (18): 2541–2553. doi:10.3748/wjg.v13.i18.2541. ISSN 1007-9327. PMC 4146814. PMID 17552001. * Albash, Buthainah; Imtiaz, Faiqa; Al-Zaidan, Hamad; Al-Manea, Hadeel; Banemai, Mohammed; Allam, R.; Al-Suheel, Ali; Al-Owain, Mohammed (2014). "Novel PHKG2 mutation causing GSD IX with prominent liver disease: report of three cases and review of literature". European Journal of Pediatrics. 173 (5): 647–653. doi:10.1007/s00431-013-2223-0. ISSN 1432-1076. PMID 24326380. S2CID 37564174. * Stoler, edited by Raymond R. Tubbs, Mark H.; Stoler, Mark H. (2009). Cell and tissue based molecular pathology (1st ed.). Philadelphia: Churchill Livingstone/Elsevier. ISBN 978-1437719482. Retrieved 6 December 2017.CS1 maint: extra text: authors list (link) ## External links[edit] Scholia has a topic profile for Glycogen storage disease type IX. * Media related to Glycogen storage disease type IX at Wikimedia Commons Classification D * ICD-10: E74.09 * OMIM: 306000 External resources * GeneReviews: Phosphorylase Kinase 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 * 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Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline * v * t * e Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders Including glycogen storage diseases (GSD) Sucrose, transport (extracellular) Disaccharide catabolism * Congenital alactasia * Sucrose intolerance Monosaccharide transport * Glucose-galactose malabsorption * Inborn errors of renal tubular transport (Renal glycosuria) * Fructose malabsorption Hexose → glucose Monosaccharide catabolism Fructose: * Essential fructosuria * Fructose intolerance Galactose / galactosemia: * GALK deficiency * GALT deficiency/GALE deficiency Glucose ⇄ glycogen Glycogenesis * GSD type 0 (glycogen synthase deficiency) * GSD type IV (Andersen's disease, branching enzyme deficiency) * Adult polyglucosan body disease (APBD) Glycogenolysis Extralysosomal: * GSD type III (Cori's disease, debranching enzyme deficiency) * GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency) * GSD type V (McArdle's disease, myophosphorylase deficiency) * GSD type IX (phosphorylase kinase deficiency) Lysosomal (LSD): * GSD type II (Pompe's disease, glucosidase deficiency) Glucose ⇄ CAC Glycolysis * MODY 2/HHF3 * GSD type VII (Tarui's disease, phosphofructokinase deficiency) * Triosephosphate isomerase deficiency * Pyruvate kinase deficiency Gluconeogenesis * PCD * Fructose bisphosphatase deficiency * GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency) Pentose phosphate pathway * Glucose-6-phosphate dehydrogenase deficiency * Transaldolase deficiency * 6-phosphogluconate dehydrogenase deficiency Other * Hyperoxaluria * Primary hyperoxaluria * Pentosuria * Aldolase A deficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Glycogen storage disease type IX	c0268147	8,758	wikipedia	https://en.wikipedia.org/wiki/Glycogen_storage_disease_type_IX	2021-01-18T18:56:41	{"mesh": ["C580130"], "umls": ["C0268147"], "wikidata": ["Q16815740"]}
A number sign (#) is used with this entry because Waardenburg syndrome type 4A (WS4A) is caused by heterozygous or homozygous mutation in the endothelin-B receptor gene (EDNRB; 131244) on chromosome 13q22. The ABCD syndrome (600501), which can also be caused by mutation in the EDNRB gene, has a similar phenotype and may be considered an expression of Waardenburg syndrome 4A (Verheij et al., 2002). Description Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). ### Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). ### Genetic Heterogeneity of Waardenburg Syndrome Type 4 Waardenburg syndrome type 4 is genetically heterogeneous. WS4B (613265) is caused by mutation in the EDN3 gene (131242) on chromosome 20q13, and WS4C (613266) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13. Clinical Features McKusick (1973); Lowry (1975), and Omenn and McKusick (1979) noted the frequent occurrence of Hirschsprung disease (aganglionic megacolon; 142623) in patients with Waardenburg syndrome. Fraser (1976) described a deaf male with no family history of deafness, complete blue-green heterochromia with hypoplastic stroma in the blue iris, and Hirschsprung disease. Kelley and Zackai (1981) reported father and son with aganglionic megacolon and Waardenburg syndrome without dystopia canthorum. Shah et al. (1981) reported studies of 5 families in which a total of 12 babies (7 male; 5 female) with white forelock and white eyebrows and eyelashes presented in the neonatal period with intestinal obstruction. Eight patients had isochromia irides (light brown irides with mosaic pattern); in the other 4, information was not recorded. In 6 patients in whom the observations were recorded, no dystopia canthorum, broad nasal root, or white skin patches were found. Deafness could not be detected in any of the patients. Microcolon was noted in patients in whom contrast enemas were done. At operation, the proximal ileum was dilated with collapse of the distal ileum and colon in 8; operative notes were not available on the other 4. The 12 infants died 3 to 38 days after birth because of failure of the ileostomy to function. This disorder appeared to be clinically and genetically distinct from Waardenburg syndrome, which has a different pigmentary anomaly of the eye and usually does not have associated Hirschsprung disease, although the short segment type may rarely occur in WS. In 3 of 6 Mexican sibs, Liang et al. (1983) observed Hirschsprung disease in association with 'bicolored' irides. They used the term bicolored rather than heterochromia to emphasize that 2 distinct colors were present in the same iris. The unaffected parents were related, suggesting autosomal recessive inheritance. Liang et al. (1983) suggested a defect in the neural crest. Meire et al. (1987) reported Hirschsprung megacolon associated with Waardenburg syndrome without dystopia canthorum. The affected girl, 1 of 3 affected persons in her family, also showed unilateral ptosis with the Marcus Gunn phenomenon; the ptosis decreased on opening the mouth. In a patient with piebaldism and deafness, Kaplan and de Chaderevian (1988) found megacolon, left pulmonic artery stenosis, ocular ptosis, and unilateral duplication of the renal collecting system. Histologically, hypoganglionosis, hyperganglionosis, and ectopic ganglia were found in the lamina propria of the rectum (neuronal colonic dysplasia). The hypopigmented skin was found to be devoid of melanocytes, with no melanin in adjacent basal cells. Because of the absence of dystopia canthorum, the patient can be said to have had type II Waardenburg syndrome. (The name is spelled de Chadarevian in at least 4 other publications cited in Mendelian Inheritance in Man.) Kulkarni et al. (1989) described 3 sibs derived from an uncle-niece marriage who had white forelock, light-colored irides, white eyelashes, multiple hypopigmented skin patches, and obstructive ileal lesions. Syrris et al. (1999) reported a family with Waardenburg-Shah syndrome due to a heterozygous mutation in the EDNRB gene (R253X; 131244.0007). The family was of Afro-Caribbean origin and had variable manifestations of sensorineural deafness, heterochromia iridis, and Hirschsprung disease. Synophrys, hair or skin hypopigmentation, and dystopia canthorum were absent in this family. The data confirmed the role of EDNRB as the cause of Waardenburg-Shah disease and demonstrated that these is a variable expression of disease even within the same family. From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS4 due to EDNRB mutations was 53.3%. Inheritance Shah et al. (1981) reported parental consanguinity in 2 of 5 affected families as well as multiple affected sibs of both sexes in families, suggesting autosomal recessive inheritance. One family was ascertained through a first cousin of a patient with WS4; this proband had white forelock and heterochromia iridis, but no dystopia canthorum or deafness. Badner and Chakravarti (1990) analyzed the 5 families reported by Shah et al. (1981) and Ambani (1983). Because 2 of the families demonstrated parental consanguinity, autosomal recessive inheritance had been suggested. Badner and Chakravarti (1990) concluded, however, that a single dominant gene with pleiotropic effects, with a more severe phenotype in homozygotes, was more plausible. WS type 4A showed autosomal dominant inheritance in the family reported by Syrris et al. (1999). Cytogenetics Tuysuz et al. (2009) reported 3 unrelated patients with variable features of WS4A associated with de novo heterozygous deletions involving chromosome 13q and including the EDNRB gene. Two patients carried deletions of chromosome 13q22.1-q31.3 and had hypopigmentation of irides and HSCR and mild unilateral hearing loss, respectively. One patient carried a slightly larger deletion of chromosome 13q21.1-q31.3. and had prominent bicolored irides, ganglionic megacolon, and mild bilateral hearing loss, as well as severe short stature, scoliosis, and motor retardation. In addition, all 3 patients had mild developmental delay and dysmorphic facial features, including hypertelorism, broad nasal bridge, epicanthal folds, short philtrum, and low-set ears, consistent with the so-called 'proximal 13q deletion syndrome' (Brown et al., 1993). The data confirmed the variable phenotype observed in patients with heterozygous loss of function of EDNRB. Mapping By linkage analysis in a family in which 2 sibs had Waardenburg syndrome and Hirschsprung disease, Van Camp et al. (1995) found evidence for the disease locus on chromosome 13q. Molecular Genetics In individuals with Hirschsprung disease as well as bicolored irides (6.3%), hypopigmentation (2.5%), sensorineural hearing loss (5.1%), and white forelock (7.6%) suggestive of WS4, Puffenberger et al. (1994) identified a mutation in the EDNRB gene (131244.0001). The mutation was found to be dose sensitive, in that the homozygotes and heterozygotes had a 74% and a 21% risk, respectively, of developing Hirschsprung disease. Attie et al. (1995) identified a homozygous mutation in the EDNRB gene (A183G; 131244.0002) in 2 sisters with WS type IVA who were born of consanguineous Tunisian parents. Although neither affected sister had dystopia canthorum, both had deafness, white forelock, heterochromia iridis, and Hirschsprung disease. Inheritance in this family was autosomal recessive. Animal Model In the mouse, at least 3 megacolon genes are associated with pigmentary abnormalities (Lane (1966, 1984)). Matsushima et al. (2002) described a novel mutant mouse with a mutation in the Ednrb gene and proposed the mouse as an animal model of Waardenburg syndrome type IV. These mutants had a mixed genetic background and extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon; their colon distal to the megacolon lacked Auerbach plexus cells. These mutants did not respond to sound, and the stria vascularis of their cochleae lacked intermediate cells, i.e., neural crest-derived melanocytes. The inheritance was autosomal recessive as in human WS4. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis showed that the Ednrb gene lacked 318 nucleotides encoding transmembrane domains owing to deletion of exons 2 and 3. INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Ears \- Deafness, sensorineural Eyes \- Heterochromia iridis \- Bicolored irides \- Bright blue irides ABDOMEN Gastrointestinal \- Hirschsprung disease \- Decreased myenteric and submucosal ganglia in the bowel SKIN, NAILS, & HAIR Skin \- Hypopigmented skin patches Hair \- White forelock \- White eyelashes \- White eyebrows \- Premature graying MISCELLANEOUS \- Variable severity, intrafamilial \- Incomplete penetance of some features \- Both homozygous and heterozygous EDNRB mutations have been found \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the endothelin receptor, type B gene (EDNRB, 131244.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	WAARDENBURG SYNDROME, TYPE 4A	c3266898	8,759	omim	https://www.omim.org/entry/277580	2019-09-22T16:21:12	{"doid": ["0110953"], "mesh": ["D014849"], "omim": ["277580"], "orphanet": ["897"], "synonyms": ["Alternative titles", "WAARDENBURG SYNDROME, TYPE IVA", "WAARDENBURG SYNDROME WITH HIRSCHSPRUNG DISEASE, TYPE 4A", "WAARDENBURG-SHAH SYNDROME", "SHAH-WAARDENBURG SYNDROME", "WS4"]}
Not to be confused with Europhobia or Erotophobia. Eurotophobia SpecialtyPsychology Eurotophobia is the aversion to or dislike of female genitalia.[1][2] ## Contents * 1 Semantics * 2 Origin * 3 Peculiarities * 4 See also * 5 References ## Semantics[edit] A term whose meaning is synonymous with eurotophobia is kolpophobia;[3] however; the scope of kolpophobia can sometimes be broader, allowing for the inclusion of all sex organs.[4] Although eurotophobia does not have an interlingual classical compound, kolpophobia has a Greek etymological derivation with the prefix kolpo meaning a fold that usually alludes to the vulva.[5] Eurotophobia is a hyponym of genitophobia.[6] On the other hand, the term vaginaphobia is used to denote fear of female genitals in the context of sexual orientation.[7] The male counterpart that analogously corresponds with this condition is called phallophobia.[3] ## Origin[edit] Such an exhibit of detestation for the female genitalia can originate from some innate inherency, or learned from frequent denunciations of one's aesthetic appearance and aberrating comments during childhood.[8] Sometimes eurotophobia is a spin-off of aversion to perceived by-products of the female genitalia, such as discharge or mucus.[9] The condition can manifest itself in both men and women and is at times triggered by some strenuous event. This phenomenon has also been observed in medical students, particularly those in the field of obstetrics, at times leading to dropping out.[10] According to the online Romanian women's magazine Ele, the appropriation of this condition by women may lead to various symptoms including depression and self-harm and that it originates from a highly prudish and puritanical upbringing.[11] Other explanations posit the transmission of urban legends such as vagina dentata or Freudian concepts such as castration anxiety.[12][13] Eurotophobes may also have developed their condition after being molested by an adult female.[14] ## Peculiarities[edit] Although an average individual may have an aversion to particular bodyparts, the hallmark of eurotophobia is that it exceeds the disinclinations shown by most people, and is a trait that can inauspiciously affect both men and women.[15] The condition is sometimes linked to erotophobia and can affect an individual's confidence in social and professional interactions.[8] The condition can emanate from both a direct antipathy, to a woman's vicarious perception of what others, such as a spouse, might think of her vulva. Symptoms include anxiety, inhibition, distractions, anaphrodisia and an inability to construct a romantic relationship.[8] People with such inclinations may express a compounded desire to substitute audible mentions of the vulva with euphemisms.[16] The extent of the condition varies from person to person, with some feeling a sense of repulsion, others reacting only once evoked, avoidance of thinking about female sex organs[17] or a sense of deep fear.[18] Eurotophobia has also been given an account by Planned Parenthood in the lexicon section of their publications.[19] Rather than being an anomaly, some historical works point to cultures wherein eurotophobic behavior was mainstream, such as those where couples would avoid copulating in illuminated areas to ensure the vulva remained out of sight.[20] Fear or embarrassment while discussing the vagina manifests itself in some women with health problems, which may impede diagnosing or tackling certain medical conditions.[21] ## See also[edit] * Phobia ## References[edit] 1. ^ Basavanna, M (2000). Dictionary of Psychology. p. 136. 2. ^ Bullough, Bonnie (2014). Human Sexuality: An Encyclopedia. p. 626. ISBN 9781135825096. 3. ^ a b Doctor, Ronald Manual (2010). The Encyclopedia of Phobias, Fears, and Anxieties, Third Edition. p. 251. 4. ^ Davidson, Michele (2012). A Nurse's Guide to Women's Mental Health. p. 209. ISBN 9780826171139. 5. ^ Waters, Richard (2004). Phobias: Revealed and Explained. p. 106. 6. ^ Kent, Fraser (1977). Nothing to Fear: Coping With Phobias. p. 184. 7. ^ American Journal of Psychotherapy - Volume 25. 1971. p. 657. 8. ^ a b c Ruben, Douglas (2001). Treating Adult Children of Alcoholics: A Behavioral Approach. p. 87. 9. ^ Gibellini, Pietro (2015). Sex in Belli's Rome: Eros, Social Groups and Religion. p. 59. 10. ^ "Kenapa Sih Ada Pria yang Justru Ketakutan saat Melihat Kelamin Wanita?". Tribun Lampung. 2014-12-25. "mengapa ini masih menjadi masalah bagi laki-laki dan perempuan ... seorang dokter baru merasa takut melihat kelamin perempuan ketika mereka bekerja melalui rotasi kebidanan ... Tapi fakta menunjukkan beberapa calon dokter akan berhenti sekolah medis jika mengalami masalah ini." 11. ^ "Cele mai ciudate fobii sexuale". Ele.ro. "femeile care nu-si pot controla aceasta frica au tendinta de a-si mutila organele genitale, ceea ce poate duce la nasterea unui copil cu probleme, durere la urinare sau probleme legate de menstruatie ... "Eurotophobia" poate fi legata de educatia primita in copilarie, in familii severe, pentru care organul sexual este considerat a fi ceva "murdar"." 12. ^ Dudy, Mary (2013). The Moral Panics of Sexuality. p. 29. ISBN 9781137353177. 13. ^ Journal of the Institute of Romance Studies, Volume 5. 1998. p. 252. 14. ^ Faller, Kathleen Coulborn. "The Causes of Sexual Abuse." Child Sexual Abuse. Macmillan Education UK, 1988. 89-115. 15. ^ Robertson, John G (2003). An Excess of Phobias and Manias. p. 82. 16. ^ Iva Cheung (6 November 2015). "Where did the word cooties come from?". Slate Magazine. "Snapping turtle began to be used in the South as a eurotophobic euphemism for vagina, and cooter eventually took on the same meaning" 17. ^ Denise Ngo (23 March 2015). "12 Crazy Phobias That Make Sex Sound Terrifying". 18. ^ "9 Fobia Seksual yang Bikin Orang Takut dengan Hubungan Intim". liputan6.com. 19. ^ "Lifeissues.net \| Planned Parenthood's Website "Glossary" - Fake Science, Phobias, and Sexually Obsessive Definitions". 20. ^ Fahs, Breanne. "Genital panics: Constructing the vagina in women's qualitative narratives about pubic hair, menstrual sex, and vaginal self-image." Body image 11.3 (2014): 210-218 21. ^ Lodge, Nicholas; Mallett, Jane; Blake, Peter; Msc, Ian Fryatt (1997). "A study to ascertain gynaecological patients' perceived levels of embarrassment with physical and psychological care given by female and male nurses". Journal of Advanced Nursing. 25 (5): 893–907. doi:10.1046/j.1365-2648.1997.1997025893.x. PMID 9147195. This abnormal psychology–related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Eurotophobia	None	8,760	wikipedia	https://en.wikipedia.org/wiki/Eurotophobia	2021-01-18T18:30:41	{"wikidata": ["Q24946301"]}
A number sign (#) is used with this entry because phosphoglycerate dehydrogenase deficiency (PHGDHD) is caused by homozygous or compound heterozygous mutation in the PHGDH gene (606879) on chromosome 1p12. See also Neu-Laxova syndrome (NLS; 256520), an allelic disorder with a much more severe phenotype that usually results in neonatal death. Description Phosphoglycerate dehydrogenase deficiency is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by Jaeken et al., 1996). Clinical Features Jaeken et al. (1996) described the clinical and biochemical features of 2 Turkish brothers who had a defect in the first enzyme of serine biosynthesis (phosphoglycerate dehydrogenase). The sibs were born from a first-cousin union. The authors noted that serine cerebrospinal fluid concentrations were markedly decreased, as were, to a lesser extent, glycine levels. Both sibs exhibited postnatal growth retardation, congenital microcephaly, hypogonadism, and hypertonia, and later showed profound psychomotor retardation and epilepsy. Magnetic resonance imaging of the brain showed evidence of 'dysmyelination.' Symmetric growth retardation at birth and bilateral congenital cataracts were present in 1 brother. Notably, plasma serine and glycine values were occasionally in the normal value range, as were urine organic acids and amino acids. Ophthalmologic examination of the second brother was normal. Decreased activity of phosphoglycerate dehydrogenase in fibroblasts was noted in both sibs (22% and 13% when compared to controls). Neither the parents nor the normal sibs were tested. Jaeken et al. (1996) noted that although serine is a nonessential amino acid, as it can be synthesized de novo from phosphoglycerate as well as glycine, it appears essential for normal brain function as it plays a role in the biosynthetic reactions of brain constituents such as protein, glycine, cysteine, serine phospholipids, sphingomyelins, and cerebrosides. The authors compared this enzyme deficiency to other 'anabolic' aminoacidopathies such as arginase deficiency (207800) in the urea cycle, homocysteinemia, and phenylketonuria (261600) and contrasted it with the more common 'catabolic' defects of amino acid metabolism. Clinical Management Jaeken et al. (1996) found that treatment with oral serine significantly increased cerebrospinal fluid serine concentrations in a dose-dependent manner and was coincident with the cessation of seizures (at a dose of 200 mg/kg/day divided into 3 doses) in 1 affected sib. De Koning et al. (2002) reported the follow-up data of amino acid therapy in 5 patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency followed for 3 to 7.5 years. Different treatment regimes were used, but a favorable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; 2 patients became seizure free. Amino acids were well tolerated, with no adverse effects documented. The progress of psychomotor development was only observed in 1 patient, diagnosed early, and treated with a high dose of L-serine. De Koning et al. (2004) reported the prenatal diagnosis of an affected fetus with the V90M mutation (606879.0001) in the PHGDH gene. Ultrasound assessment showed a reduction of fetal head circumference in the 75th percentile at 20 weeks' gestation to the 29th percentile at 26 weeks' gestation. L-serine at 190 mg/kg per day in 3 divided doses was given to the mother which resulted in an fetal head circumference increase to the 76th percentile at 31 weeks' gestation. At birth, the girl's head circumference was normal. Within 12 hours after birth, the serine concentration in plasma dropped to a severely deficient value of 33 micromol/l, and serine was also depleted in cerebrospinal fluid. MRI was normal, but EEG showed discrete seizure activity. After initiation of L-serine treatment of 400 mg/kg per day, seizure activity diminished to normal within 1 week. At 4 years of age the girl had normal growth and psychomotor development, with follow-up MRI scans at 12 and 14 months showing no brain abnormalities. Since the consanguineous couple had 2 severely affected children born with congenital microcephaly prior to this child, de Koning et al. (2004) concluded that PHGDH deficiency is an inborn metabolic error that can be successfully treated antenatally. Molecular Genetics To investigate the molecular basis of PHGDH deficiency, Klomp et al. (2000) characterized the PHGDH mRNA sequence and analyzed it for variations in 6 patients from 4 families with this disorder. Five patients in 3 different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine (606879.0001). The sixth patient was homozygous for a valine-to-methionine substitution at position 425 (606879.0002). Both mutations were located in the C terminus of the PHGDH gene. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurologic impairment in these patients, the data suggested an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system. In 3 Dutch patients, including a brother and sister, and 2 unrelated Turkish patients, who presented with congenital microcephaly, psychomotor retardation, and seizures, Tabatabaie et al. (2009) identified compound heterozygosity or homozygosity for 5 mutations in the PHGDH gene, respectively (see, e.g., 606879.0003-606879.0006). Studies in patient fibroblasts, transient overexpression in HEK293 cells, and molecular modeling onto the partial crystal structure of 3-PGDH suggested that missense mutations associated with 3-PGDH deficiency, including the previously identified V490M and V425M substitutions, either primarily affect substrate binding or result in very low residual enzymatic activity. INHERITANCE \- Autosomal recessive GROWTH Other \- Growth retardation HEAD & NECK Head \- Microcephaly, congenital Eyes \- Cataracts, congenital \- Nystagmus GENITOURINARY Internal Genitalia (Male) \- Small testes SKELETAL Hands \- Adducted thumbs NEUROLOGIC Central Nervous System \- Mental retardation \- Seizures \- Dysmyelination \- Hypertonia \- Spastic quadriplegia \- Hypsarrhythmia or severe multifocal epileptic abnormalities with poor background activity on EEG HEMATOLOGY \- Megaloblastic anemia \- Thrombocytopenia LABORATORY ABNORMALITIES \- Decrease plasma serine (fasting) \- Decreased CSF serine \- Decreased PHGDH activity (fibroblasts) \- Normal-to-decreased plasma glycine (fasting) \- Decreased CSF glycine MOLECULAR BASIS \- Caused by mutation in the phosphoglycerate dehydrogenase gene (PHGDH, 606879.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY	c0580190	8,761	omim	https://www.omim.org/entry/601815	2019-09-22T16:14:13	{"doid": ["0050722"], "omim": ["601815"], "orphanet": ["79351"], "synonyms": ["Alternative titles", "PHGDH DEFICIENCY"]}
Asthma is a breathing disorder characterized by inflammation of the airways and recurrent episodes of breathing difficulty. These episodes, sometimes referred to as asthma attacks, are triggered by irritation of the inflamed airways. In allergic asthma, the attacks occur when substances known as allergens are inhaled, causing an allergic reaction. Allergens are harmless substances that the body's immune system mistakenly reacts to as though they are harmful. Common allergens include pollen, dust, animal dander, and mold. The immune response leads to the symptoms of asthma. Allergic asthma is the most common form of the disorder. A hallmark of asthma is bronchial hyperresponsiveness, which means the airways are especially sensitive to irritants and respond excessively. Because of this hyperresponsiveness, attacks can be triggered by irritants other than allergens, such as physical activity, respiratory infections, or exposure to tobacco smoke, in people with allergic asthma. An asthma attack is characterized by tightening of the muscles around the airways (bronchoconstriction), which narrows the airway and makes breathing difficult. Additionally, the immune reaction can lead to swelling of the airways and overproduction of mucus. During an attack, an affected individual can experience chest tightness, wheezing, shortness of breath, and coughing. Over time, the muscles around the airways can become enlarged (hypertrophied), further narrowing the airways. Some people with allergic asthma have another allergic disorder, such as hay fever (allergic rhinitis) or food allergies. Asthma is sometimes part of a series of allergic disorders, referred to as the atopic march. Development of these conditions typically follows a pattern, beginning with eczema (atopic dermatitis), followed by food allergies, then hay fever, and finally asthma. However, not all individuals with asthma have progressed through the atopic march, and not all individuals with one allergic disease will develop others. ## Frequency Approximately 235 million people worldwide have asthma. In the United States, the condition affects an estimated 8 percent of the population. In nearly 90 percent of children and 50 percent of adults with asthma, the condition is classified as allergic asthma. ## Causes The cause of allergic asthma is complex. It is likely that a combination of multiple genetic and environmental factors contribute to development of the condition. Doctors believe genes are involved because having a family member with allergic asthma or another allergic disorder increases a person's risk of developing asthma. Studies suggest that more than 100 genes may be associated with allergic asthma, but each seems to be a factor in only one or a few populations. Many of the associated genes are involved in the body's immune response. Others play a role in lung and airway function. There is evidence that an unbalanced immune response underlies allergic asthma. While there is normally a balance between type 1 (or Th1) and type 2 (or Th2) immune reactions in the body, many individuals with allergic asthma predominantly have type 2 reactions. Type 2 reactions lead to the production of immune proteins called IgE antibodies and the generation of other factors that predispose to bronchial hyperresponsiveness. Normally, the body produces IgE antibodies in response to foreign invaders, particularly parasitic worms. For unknown reasons, in susceptible individuals, the body reacts to an allergen as if it is harmful, producing IgE antibodies specific to it. Upon later encounters with the allergen, IgE antibodies recognize it, which stimulates an immune response, causing bronchoconstriction, airway swelling, and mucus production. Not everyone with a variation in one of the allergic asthma-associated genes develops the condition; exposure to certain environmental factors also contributes to its development. Studies suggest that these exposures trigger epigenetic changes to the DNA. Epigenetic changes modify DNA without changing the DNA sequence. They can affect gene activity and regulate the production of proteins, which may influence the development of allergies in susceptible individuals. ## Inheritance Pattern Allergic asthma can be passed through generations in families, but the inheritance pattern is unknown. People with mutations in one or more of the associated genes inherit an increased risk of allergic asthma, not the condition itself. Because allergic asthma is a complex condition influenced by genetic and environmental factors, not all people with a mutation in an asthma-associated gene will develop the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Allergic asthma	c1833269	8,762	medlineplus	https://medlineplus.gov/genetics/condition/allergic-asthma/	2021-01-27T08:25:36	{"omim": ["600807"], "synonyms": []}
A rare bone disease and a form of microcephalic primordial dwarfism characterized by severe pre- and postnatal growth retardation, with marked microcephaly in proportion to body size, skeletal dysplasia, abnormal dentition, insulin resistance, and increased risk for cerebrovascular disease. ## Epidemiology Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is one of the most common forms of microcephalic primordial dwarfism (MPD) and accounts for more than 150 cases worldwide. ## Clinical description MOPDII is congenital, with a perinatal and infancy onset. It is characterized by severe pre- and postnatal growth retardation, with proportionate severe microcephaly, skeletal dysplasia, abnormal dentition, an increased risk for cerebrovascular disease (aneurysms and Moya Moya disease in 19%-52% of cases) and insulin resistance. Intrauterine growth restriction (IUGR) is common. The average length, weight, and head occipitofrontal circumference (OFC) at birth are respectively 7.0, 3.9, and 4.6 SDs below the population mean (after correcting for gestational age <37 weeks). Head growth appears to stop by 18 months of age giving rise to the appearance of progressive microcephaly. At maturity, the average height, weight, and OFC are respectively 10.3, 14.3, and 8.5 SDs below the population mean. Skeletal dysplasia with progressive scoliosis, radial head dislocation and coxa vara may be seen. Distinct craniofacial features include prominent, small pinnae with attached lobes; small, dysplastic and poorly rooted, opalescent dentition and sparse hair. Further hallmarks of MOPD II include high-pitched nasal voice, areas of hypo- and hyperpigmentation (with café-au-lait spots), poikiloderma, acanthosis nigricans, and truncal obesity in adolescence and adulthood. A disorder initially named primordial short stature-microdontia-opalescent and rootless teeth was originally and mistakenly reported to have distinct MOPD, but it is now recognized to be the same entity as MOPD II. ## Etiology MOPD II is caused by mutations in PCNT (21q22.3), encoding pericentrin, which anchors a wide range of centrosomal proteins and protein complexes during cell division. Disruption of pericentrin is thought to cause mitotic spindle defects, and impaired cell proliferation. A role in ATR DNA damage dependent signaling has also been proposed. ## Diagnostic methods Diagnosis relies on clinical features, radiographic examinations of bone age that usually show disharmonic maturation of centers and a retarded bone age. Diagnosis is confirmed by genetic screening of PCNT. Some individuals have elevated platelet counts. ## Differential diagnosis Differential diagnosis includes Meier-Gorlin syndrome, LIG4 syndrome, XRCC4 deficiency, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke immuno-osseous dysplasia, and Dubowitz syndrome. ## Antenatal diagnosis Pregnancies with affected children are often complicated by the observation of IUGR. Early age of delivery is noted. C-sections may be performed at earlier ages due to the IUGR. Prenatal diagnosis is possible if the causative mutation(s) in PCNT have been identified in the carrier parents. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment Management is mainly symptomatic. Screening for CNS vascular abnormalities with brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) is recommended at diagnosis and every 12 to 18 months. Yearly screening for signs of insulin resistance including a lipid profile should be performed (beginning at grade school age), as well as monitoring for anemia, platelet counts, and hip and spine anomalies. ## Prognosis Life expectancy is generally decreased, but individuals live into their 30s. Many complications arise, but most can be handled by adapting modern medical techniques to the diminutive size. Vascular anomalies are a common complication. They may involve neurovasculature in childhood, and renal and coronary arteries in adulthood, the latter of which may be life-threatening. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Microcephalic osteodysplastic primordial dwarfism type II	c0432246	8,763	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2637	2021-01-23T18:22:40	{"gard": ["9844"], "mesh": ["C565898"], "omim": ["210720"], "umls": ["C0432246"], "icd-10": ["Q87.1"], "synonyms": ["MOPD type II", "Majewski osteodysplastic primordial dwarfism type II"]}
Hypercoagulability in pregnancy SpecialtyObstetrics Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis (blood clots). Pregnancy itself is a factor of hypercoagulability (pregnancy-induced hypercoagulability), as a physiologically adaptive mechanism to prevent post partum bleeding.[1] However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.[1] ## Contents * 1 Causes * 2 Complications * 3 Prevention * 3.1 Indications * 3.2 Strategies * 3.3 Risk score * 3.4 Cautions * 3.5 Monitoring * 4 Reversal * 5 See also * 6 References * 7 External links ## Causes[edit] Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to prevent post partum hemorrhage.[1] Pregnancy changes the plasma levels of many clotting factors, such as fibrinogen, which can rise up to three times its normal value.[2] Thrombin levels increase.[3] Protein S, an anticoagulant, decreases. However, the other major anticoagulants, protein C and antithrombin III, remain constant.[2] Fibrinolysis is impaired by an increase in plasminogen activator inhibitor-1 (PAI-1 or PAI) and plasminogen activator inhibitor-2 (PAI-2), the latter synthesized from the placenta.[2] Venous stasis may occur at the end of the first trimester, due to enhanced compliance of the vessel walls by a hormonal effect.[2] Also, pregnancy can cause hypercoagulability by other factors, e.g. the prolonged bed rest that often occurs post partum that occurs in case of delivery by forceps, vacuum extractor or Caesarean section.[2][4] A study of more than 200,000 women came to the result that admission to inpatient care during pregnancy was associated with an 18-fold increase in the risk of venous thromboembolism (VTE) during the stay, and a 6-fold increase in risk in the four weeks after discharge, compared with pregnant women who did not require hospitalization.[5] The study included women admitted to hospital for one or more days for reasons other than delivery or venous thromboembolism.[5] Pregnancy after the age of 35 augments the risk of VTE, as does multigravidity of more than four pregnancies.[2] Pregnancy in itself causes approximately a five-fold increased risk of deep venous thrombosis.[6] Several pregnancy complications, such as pre-eclampsia, cause substantial hypercoagulability.[2] Hypercoagulability states as a pre-existing condition in pregnancy include both acquired ones, such as antiphospholipid antibodies, and congenital ones, including factor V Leiden, prothrombin mutation, proteins C and S deficiencies, and antithrombin III deficiency. ## Complications[edit] Hypercoagulability in pregnancy, particularly due to inheritable thrombophilia, can lead to placental vascular thrombosis.[7] This can in turn lead to complications like early-onset hypertensive disorders of pregnancy, pre-eclampsia and small for gestational age infants (SGA).[7] Among other causes of hypercoagulability, Antiphospholipid syndrome has been associated with adverse pregnancy outcomes including recurrent miscarriage.[8] Deep vein thrombosis has an incidence of one in 1,000 to 2,000 pregnancies in the United States,[2] and is the second most common cause of maternal death in developed countries after bleeding.[9] ## Prevention[edit] Main article: Thrombosis prophylaxis Unfractionated heparin, low molecular weight heparin, warfarin (not to be used during pregnancy) and aspirin remain the basis of antithrombotic treatment and prophylaxis both before and during pregnancy.[10] While the consensus among physicians is the safety of the mother supersedes the safety of the developing fetus, changes in the anticoagulation regimen during pregnancy can be performed to minimize the risks to the developing fetus while maintaining therapeutic levels of anticoagulants in the mother. The main issue with anticoagulation in pregnancy is that warfarin, the most commonly used anticoagulant in chronic administration, is known to have teratogenic effects on the fetus if administered in early pregnancy.[11][12] Still, there seems to be no teratogenic effect of warfarin before six weeks of gestation.[13] However, unfractionated heparin and low molecular weight heparin do not cross the placenta.[13] ### Indications[edit] In general, the indications for anticoagulation during pregnancy are the same as the general population. This includes (but is not limited to) a recent history of deep venous thrombosis (DVT) or pulmonary embolism, a metallic prosthetic heart valve, and atrial fibrillation in the setting of structural heart disease. In addition to these indications, anticoagulation may be of benefit in individuals with lupus erythematosus, individuals who have a history of DVT or PE associated with a previous pregnancy, and even with individuals with a history of coagulation factor deficiencies and DVT not associated with a previous pregnancy.[14] In pregnant women with a history of recurrent miscarriage, anticoagulation seems to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage.[15] ### Strategies[edit] A consensus on the correct anticoagulation regimen during pregnancy is lacking. Treatment is tailored to the particular individual based on her risk of complications. Warfarin and other vitamin K-inhibiting agents are contraindicated during the first trimester of pregnancy because of the teratogenic effects,[16] and should not be administered when the pregnancy is confirmed.[13] Rather, women who are on chronic anticoagulation may be given the option of conversion to either unfractionated heparin or low molecular weight heparin (LMWH), such as tinzaparin,[13] prior to a planned conception.[17] LMWH is as safe and efficacious as unfractionated heparin.[13] A blood test including platelets and a clotting screen should be performed prior to administration of anticoagulant regimens in pregnancy.[13] Subcutaneous tinzaparin may be given at doses of 175 units of antifactor Xa activity per kg,[13] based on prepregnancy or booking weight at approximately 16 weeks, and not the current weight.[13] While unfractionated heparin is otherwise typically given in an intravenous formulation, this is inconvenient for the prolonged period of administration required in pregnancy. Whether warfarin can be reinitiated after the 12th week of pregnancy is unclear. In a recent retrospective analysis, resumption of warfarin after the first trimester is completed is associated with increased risk of loss of the fetus.[18] However, this analysis included only individuals who were treated with anticoagulants for mechanical heart valves, who generally require high levels of anticoagulation. In pregnant women with mechanical heart valves, the optimal anticoagulation regimen is particularly unclear. Anticoagulation with subcutaneous heparin in this setting is associated with a high incidence of thrombosis of the valve and death.[19][20] Similar issues are likely associated with the use of enoxaparin (a LMWH) in these high-risk individuals.[21] ### Risk score[edit] Prevention of DVT and other types of venous thrombosis may be required if certain predisposing risk factors are present. One example from Sweden is based on the point system below, where points are summed to give the appropriate prophylaxis regimen.[9] Points Risk factors 1 point Minor factors * Heterozygous for factor V Leiden mutation * Heterozygous for factor II mutation * Overweight, in this case defined as a BMI > 28 at early pregnancy[9] * Caesarean section * DVT heredity in a first-degree relative * Age > 40 years * Pre-eclampsia * Hyperhomocysteinemia 2 points Intermediate risk factors * Protein S or protein C deficiency * Immobilization (after e.g. bone fracture or prolonged bed rest 3 points Intermediate risk factors * Homozygous for factor V Leiden mutation * Homozygous for factor II mutation 4 points Severe risk factors * Previous DVT * Antiphospholipid syndrome without previous DVT * Lupus anticoagulant Very high risk * Artificial heart valves * Antithrombin III deficiency * Multiple previous thromboses * Antiphospholipid syndrome with previous DVT * Previous pulmonary embolism[13] After adding any risk factors together, a total of one point or less indicates no preventive action is needed.[9] A total of two points indicates short-term prophylaxis, e.g. with LMWH, may be used in temporary risk factors, as well as administering prophylactic treatment seven days postpartum, starting a couple of hours after birth.[9] A total of 3 points increases the necessary duration of post partum prophylaxis to six weeks.[9] A risk score of four points or higher means prophylaxis in the ante partum period is needed, as well as at least six weeks post partum.[9] A previous distal DVT indicates a minimum of 12 weeks (three months) of therapeutic anticoagulation therapy.[13] A previous proximal DVT or pulmonary embolism requires a minimum of 26 weeks (6.5 months) of therapy[13] If the therapy duration reaches delivery time, the remaining duration may be given after delivery, possibly extending the minimum of six weeks of post partum therapy.[13] In a very high risk, high-dose ante partum prophylaxis should be continued at least 12 weeks after delivery.[9] Women with antiphospholipid syndrome should have an additional low-dose prophylactic treatment of aspirin.[9] ### Cautions[edit] All anticoagulants (including LMWH) should be used with caution in women with suspected coagulopathy, thrombocytopaenia, liver disease and nephropathy.[13] Major side effects of tinzaparin are osteoporosis (occurring in up to 1% of cases), thrombocytopenia (heparin-induced thrombocytopenia), haemorrhage, hair loss and drug allergy.[13] Still, LMWHs are much less likely to cause heparin-induced thrombocytopenia than unfractionated heparin.[13] Regional anaesthesia is contraindicated in women on therapeutic anticoagulation, and should not be used within 24 hours of the last dose of tinzaparin.[13] ### Monitoring[edit] Anticoagulant therapy with LMWH is not usually monitored.[13] LMWH therapy does not affect the prothrombin time (PT) or the INR, and anti-Xa levels are not reliable.[13] It can prolong the partial thromboplastin time (APTT) in some women, but still, the APTT is not useful for monitoring.[13] To check for any thrombocytopenia, platelet count should be checked prior to commencing anticoagulant therapy, then seven to ten days after commencement, and monthly thereafter.[13] Platelet count should also be checked if unexpected bruising or bleeding occurs.[13] ## Reversal[edit] Protamine reverses the effect of unfractionated heparin, but only partially binds to and reverses LMWH. A dose of 1 mg protamine / 100 IU LMWH reverses 90% of its anti-IIa and 60% of anti-Xa activity, but the clinical effect of the residual anti-Xa activity is not known.[13] Both anti-IIa and anti-Xa activity may return up to three hours after protamine reversal, possibly due to release of additional LMWH from depot tissues.[13] ## See also[edit] * Valvular heart disease and pregnancy ## References[edit] 1. ^ a b c Page 264 in: Gresele, Paolo (2008). Platelets in hematologic and cardiovascular disorders: a clinical handbook. Cambridge, UK: Cambridge University Press. ISBN 0-521-88115-3. 2. ^ a b c d e f g h Hypercoagulability during Pregnancy Lab Lines. A publication of the Department of Pathology and Laboratory Medicine at the University of Cincinnati. September/October 2002 Volume 8, Issue 5 3. ^ de Boer K, ten Cate JW, Sturk A, Borm JJ, Treffers PE (1989). "Enhanced thrombin generation in normal and hypertensive pregnancy". Am J Obstet Gynecol. 160 (1): 95–100. doi:10.1016/0002-9378(89)90096-3. PMID 2521425. 4. ^ "Venous Thromboembolism (Blood Clots) and Pregnancy". Centers for Disease Control and Prevention. Retrieved 24 October 2020. 5. ^ a b Abdul Sultan, A.; West, J.; Tata, L. J.; Fleming, K. M.; Nelson-Piercy, C.; Grainge, M. J. (2013). "Risk of first venous thromboembolism in pregnant women in hospital: Population based cohort study from England". BMJ. 347: f6099. doi:10.1136/bmj.f6099. PMC 3898207. PMID 24201164. 6. ^ Eichinger, S.; Evers, J. L. H.; Glasier, A.; La Vecchia, C.; Martinelli, I.; Skouby, S.; Somigliana, E.; Baird, D. T.; Benagiano, G.; Crosignani, P. G.; Gianaroli, L.; Negri, E.; Volpe, A.; Glasier, A.; Crosignani, P. G. (2013). "Venous thromboembolism in women: A specific reproductive health risk". Human Reproduction Update. 19 (5): 471–482. doi:10.1093/humupd/dmt028. PMID 23825156. 7. ^ a b de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, FRUIT Investigators (2012). "Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT". J. Thromb. Haemost. 10 (1): 64–72. doi:10.1111/j.1538-7836.2011.04553.x. PMID 22118560. 8. ^ McNamee, Kelly; Dawood, Feroza; Farquharson, Roy (1 August 2012). "Recurrent miscarriage and thrombophilia". Current Opinion in Obstetrics and Gynecology. 24 (4): 229–234. doi:10.1097/GCO.0b013e32835585dc. PMID 22729089. 9. ^ a b c d e f g h i "Hemostasrubbningar inom obstetrik och gynekologi" (Disorders of hemostasis in obstetrics and gynecology), from ARG (work and reference group) from SFOG (Swedish association of obstetrics and gynecology). Intro available at [1]. Updated 2012. 10. ^ Giannubilo, SR; Tranquilli, AL (2012). "Anticoagulant therapy during pregnancy for maternal and fetal acquired and inherited thrombophilia". Current Medicinal Chemistry. 19 (27): 4562–71. doi:10.2174/092986712803306466. PMID 22876895. 11. ^ Sathienkijkanchai A, Wasant P (2005). "Fetal warfarin syndrome". J Med Assoc Thai. 88 (Suppl 8): S246–50. PMID 16856447. 12. ^ Schaefer C, Hannemann D, Meister R, Eléfant E, Paulus W, Vial T, Reuvers M, Robert-Gnansia E, Arnon J, De Santis M, Clementi M, Rodriguez-Pinilla E, Dolivo A, Merlob P (2006). "Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study". Thromb Haemost. 95 (6): 949–57. doi:10.1160/TH06-02-0108. PMID 16732373. 13. ^ a b c d e f g h i j k l m n o p q r s t u v w [2] Archived 12 June 2010 at the Wayback Machine Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9 June 2006 [review June 2009] 14. ^ Couto E, Nomura ML, Barini R, Pinto e Silva JL (2005). "Pregnancy-associated venous thromboembolism in combined heterozygous factor V Leiden and prothrombin G20210A mutations". Sao Paulo Med J. 123 (6): 286–8. doi:10.1590/S1516-31802005000600007. PMID 16444389. 15. ^ De Jong, P. G.; Goddijn, M.; Middeldorp, S. (2013). "Antithrombotic therapy for pregnancy loss". Human Reproduction Update. 19 (6): 656–673. doi:10.1093/humupd/dmt019. PMID 23766357. 16. ^ Shaul WL, Emery H, Hall JG (1975). "Chondrodysplasia punctata and maternal warfarin use during pregnancy". Am J Dis Child. 129 (3): 360–2. doi:10.1001/archpedi.1975.02120400060014. PMID 1121966. 17. ^ James AH, Grotegut CA, Brancazio LR, Brown H (2007). "Thromboembolism in pregnancy: recurrence and its prevention". Semin Perinatol. 31 (3): 167–75. doi:10.1053/j.semperi.2007.03.002. PMID 17531898. 18. ^ Kim BJ, An SJ, Shim SS, Jun JK, Yoon BH, Syn HC, Park JS (2006). "Pregnancy outcomes in women with mechanical heart valves". J Reprod Med. 51 (8): 649–54. PMID 16967636. 19. ^ Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarías A, Salazar E (1986). "Risks of anticoagulant therapy in pregnant women with artificial heart valves". N Engl J Med. 315 (22): 1390–3. doi:10.1056/NEJM198611273152205. PMID 3773964. 20. ^ Salazar E, Izaguirre R, Verdejo J, Mutchinick O (1996). "Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses". J Am Coll Cardiol. 27 (7): 1698–703. doi:10.1016/0735-1097(96)00072-1. PMID 8636556. 21. ^ Ginsberg JS, Chan WS, Bates SM, Kaatz S (2003). "Anticoagulation of pregnant women with mechanical heart valves" (PDF). Arch Intern Med. 163 (6): 694–8. doi:10.1001/archinte.163.6.694. PMID 12639202. ## External links[edit] Classification D * ICD-10: O22.9, O99.1 * ICD-9-CM: 649.3 * [3] Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9 June 2006 [review June 2009] * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hypercoagulability in pregnancy	None	8,764	wikipedia	https://en.wikipedia.org/wiki/Hypercoagulability_in_pregnancy	2021-01-18T18:54:56	{"icd-9": ["649.3"], "icd-10": ["O99.1", "O22.9"], "wikidata": ["Q5957859"]}
Salivary gland type cancer of the breast describes a group of uncommon neoplasms, usually seen in the salivary glands but occurring in the breast, with a variable clinicopathologic spectrum and divided into those with myoepithelial differentiation and those without. This group includes mammary adenoid cystic carcinoma, adenoid cystic carcinoma (see this term), mucoepidermoid carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma and oncocytic carcinoma. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Salivary gland type cancer of the breast	None	8,765	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=213557	2021-01-23T17:34:13	{"gard": ["12774"], "icd-10": ["C50.0", "C50.1", "C50.2", "C50.3", "C50.4", "C50.5", "C50.6", "C50.8"], "synonyms": ["Salivary gland type carcinoma of the breast"]}
Slang term for a masturbation technique For other uses, see Death grip (disambiguation). This article or section possibly contains synthesis of material which does not verifiably mention or relate to the main topic. Relevant discussion may be found on the talk page. (March 2020) (Learn how and when to remove this template message) Death-grip and death-grip syndrome are slang terms for suffering from one’s aggressive and recurrent male masturbation technique, resulting in not be able to get satisfaction in regular intercourse with a partner. A similar condition, dead-vagina syndrome has been asserted to exist in women.[1][2][3] ## Contents * 1 Concept * 2 Perception * 3 See also * 4 References ## Concept[edit] Death-grip syndrome, sometimes abbreviated as DGS, was arguably coined in 2003 by sex columnist Dan Savage and is an issue that affects both men and women.[3] However, others[who?] have attributed it to normal masturbation that is excessive.[4] For women the slang term used is "dead vagina syndrome."[1][2] Although men with the indisposition may still experience an erection, it may embroil a relationship negatively due to a sense of being sexually incompatible with a partner due to the habit of lasting too long during sexual activity, and subsequent side-effects such as blue balls or inhibited ejaculation.[5] Some people who have claimed to "experience the death-grip" state that although they can still experience pleasure, the typical vagina feels too loose, and fellatio provides insufficient friction to produce an orgasm.[6] Richard Santucci, chief of urology at Detroit Receiving Hospital's Center for Urologic Reconstruction, believes that "too strong masturbation" is not a common cause of delayed ejaculation, and states that "diabetes, medications, low testosterone, anxiety" are the common causes.[7] ## Perception[edit] The concept of death-grip syndrome is not recognized by any mainstream medical bodies.[8] Some analysts[who?] have argued that sexual techniques that have a vacuum effect, such as oral pompoir or vaginal pompoir could alleviate DGS.[9] Some analysts[who?] have argued that there are other forms of social conditioning ingrained during adolescence that occur concurrently with DGS, such as a reluctance among men to make audible sounds of pleasure such as moaning. Such silence during sex is learned from growing up in one's household and attempting to remain discreet when around first and second-degree relatives.[10] ## See also[edit] * Dysorgasmia ## References[edit] 1. ^ a b Jones, Alexandra (2018-10-25). "Is my vibrator stopping me enjoying sex?". BBC Three. Retrieved 2020-03-08. 2. ^ a b Scott, Ellen (2017-12-13). "Is dead vagina syndrome a real thing?". Metro. Retrieved 2020-03-08. 3. ^ a b Barrett-Ibarria, Sofia (22 March 2018). "Women Get 'Death Grip Syndrome' Too, and It Sucks". Vice. 4. ^ Cummins, Eleanor (2017-06-15). "Can You Masturbate Too Much?". Inverse. Retrieved 2020-03-08. 5. ^ POLONSKY, DEREK C. "The Sexual Challenges and Dilemmas of Young Single Men." Handbook of Clinical Sexuality for Mental Health Professionals (2011): 231. ISBN 9781135967499 6. ^ Flemons, Douglas, and Shelley Green. "Just between us: A relational approach to sex therapy." Quickies: The handbook of brief sex therapy (2004): 126-170. ISBN 9780393705270 7. ^ Pearl, Mike (2015-08-28). "Is It Really Possible to Ruin Your Penis From Jerking Off Too Hard?". Vice. Retrieved 2019-11-16. "The idea of too strong masturbation rewiring you to expect really strong feelings during sex? I just don't believe it's that common." 8. ^ Spitzer, Robert L.; Endicott, Jean; Micoulaud Franchi, Jean-Arthur (2018). "Medical and mental disorder: Proposed definition and criteria". Annales Médico-Psychologiques, Revue Psychiatrique. 176 (7): 656–665. doi:10.1016/j.amp.2018.07.004. 9. ^ Ruuhilahti, Susanna. "Good Sex–Enhancing Wellbeing in Sexuality Education by Utilizing Stories." in Proceedings of 2012 NACS conference in Helsinki; page 135. 10. ^ Melnick, Alexandra S. "But What Does “It” Mean: An Analysis of Feminist & Mainstream Pornographies." (2016). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Death-grip syndrome	None	8,766	wikipedia	https://en.wikipedia.org/wiki/Death-grip_syndrome	2021-01-18T18:51:21	{"wikidata": ["Q55609245"]}
Complication of dialysis This article is about the complication of dialysis. For other uses, see Disequilibrium (disambiguation). Dialysis disequilibrium syndrome SpecialtyNeurology, nephrology Dialysis disequilibrium syndrome (DDS) is the collection of neurological signs and symptoms, attributed to cerebral edema, during or following shortly after intermittent hemodialysis[1] or CRRT.[2] Classically, DDS arises in individuals starting hemodialysis due to end-stage chronic kidney disease and is associated, in particular, with "aggressive" (high solute removal) dialysis.[3] However, it may also arise in fast onset, i.e. acute kidney failure in certain conditions. ## Contents * 1 Causes * 2 Symptoms * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Causes[edit] The cause of DDS is currently not well understood. There are two theories to explain it; the first theory postulates that urea transport from the brain cells is slowed in chronic kidney disease, leading to a large urea concentration gradient, which results in reverse osmosis. The second theory postulates that organic compounds are increased in uremia to protect the brain and result in injury by, like in the first theory, reverse osmosis.[1] More recent studies on rats noted that brain concentrations of organic osmolytes were not increased relative to baseline after rapid dialysis. Cerebral edema was thus attributed to osmotic effects related to a high urea gradient between plasma and brain.[4] ## Symptoms[edit] Symptoms of the mild degree of Disequilibrium syndrome is often missed with other dialysis complications. Like malignant hypertension, uremia, encephalopathy, subdural haemorrage, hyper and hypoglycaemia, electrolyte imbalances etc. However moderate and severe degree of DDS should not be missed and need immediate care. Unless it would result in severe neurological issues and finally death. 1\. Headache 2\. Nausea 3\. Dizziness 4\. Confusion 5\. Visual disturbance 6\. Tremor 7\. Seizures 8\. Coma ## Diagnosis[edit] Clinical signs of cerebral edema, such as focal neurological deficits, papilledema[5] and decreased level of consciousness, if temporally associated with recent hemodialysis, suggest the diagnosis. A computed tomography of the head is typically done to rule-out other intracranial causes. MRI of the head has been used in research to better understand DDS.[6] ## Treatment[edit] Avoidance is the primary treatment. Better alternatives are Nocturnal or Daily Dialysis, which are far more gentle processes for the new dialysis patient. Dialysis disequilibrium syndrome is a reason why hemodialysis initiation should be done gradually, i.e. it is a reason why the first few dialysis sessions are shorter and less aggressive than the typical dialysis treatment for end-stage renal disease patients. ## See also[edit] * Kidney failure ## References[edit] 1. ^ a b Bagshaw SM, Peets AD, Hameed M, Boiteau PJ, Laupland KB, Doig CJ (2004). "Dialysis Disequilibrium Syndrome: Brain death following hemodialysis for metabolic acidosis and acute renal failure – A case report". BMC Nephrol. 5: 9. doi:10.1186/1471-2369-5-9. PMC 515303. PMID 15318947. Free Full Text 2. ^ Mistry K. (2019). Dialysis disequilibrium syndrome prevention and management. International journal of nephrology and renovascular disease, 12, 69–77. https://doi.org/10.2147/IJNRD.S165925 3. ^ Port FK, Johnson WJ, Klass DW (1973). "Prevention of dialysis disequilibrium syndrome by use of high sodium concentration in the dialysate". Kidney Int. 3 (5): 327–33. doi:10.1038/ki.1973.51. PMID 4792047. Free Full Text. 4. ^ Silver, S. M. (December 1995). "Cerebral edema after rapid dialysis is not caused by an increase in brain organic osmolytes". Journal of the American Society of Nephrology. 6 (6): 1600–1606. PMID 8749686. 5. ^ Im L, Atabay C, Eller AW (2007). "Papilledema associated with dialysis disequilibrium syndrome". Semin Ophthalmol. 22 (3): 133–5. doi:10.1080/08820530701421585. PMID 17763231. 6. ^ Chen CL, Lai PH, Chou KJ, Lee PT, Chung HM, Fang HC (2007). "A preliminary report of brain edema in patients with uremia at first hemodialysis: evaluation by diffusion-weighted MR imaging". AJNR Am J Neuroradiol. 28 (1): 68–71. PMID 17213426. ## External links[edit] * Dialysis disequilibrium syndrome at the United States National Library of Medicine * Dialysis Disequilibrium Syndrome (DDS) – Rare but serious complication of dialysis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Dialysis disequilibrium syndrome	c0403559	8,767	wikipedia	https://en.wikipedia.org/wiki/Dialysis_disequilibrium_syndrome	2021-01-18T19:03:11	{"umls": ["C0403559"], "wikidata": ["Q1642129"]}
Spondyloepimetaphyseal dysplasia, Pakistani type Other namesSpondyloepimetaphyseal dysplasia, PAPSS2 type[1] Spondyloepimetaphyseal dysplasia, Pakistani type is inherited in an autosomal recessive manner SpecialtyMedical genetics Spondyloepimetaphyseal dysplasia, Pakistani type is a form of spondyloepimetaphyseal dysplasia involving PAPSS2 (also known as "ATPSK2").[2] The condition is rare. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Radiology * 4 Treatment * 5 History * 6 References * 7 External links ## Signs and symptoms[edit] This condition is a skeletal dysplasia characterized by short stature, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints, precocious osteoarthropathy, platyspondyly, delayed epiphyseal ossification, mild metaphyseal abnormalities, short stature and short and bowed legs. Intelligence is normal. Some patients may manifest premature pubarche and hyperandrogenism. Other features that may form part of the syndrome include precocious costal calcification, small iliac bones, short femoral necks, coxa vara, short halluces and fused vertebral bodies. ## Genetics[edit] This condition is inherited in an autosomal recessive fashion. It is due to mutations in the Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) gene which is located on the long arm of chromosome 10 (10q23.2-q23.31).[3] ## Diagnosis[edit] ### Radiology[edit] Radiographic features include delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse early osteoarthritic changes (in the spine and hands), mild brachydactyly and mild metaphyseal abnormalities which predominantly involve the hips and knees. ## Treatment[edit] This section is empty. You can help by adding to it. (November 2017) ## History[edit] This condition was first described in a large eight generation consanguineous Pakistani family. The causative mutation was identified in 1998.[4] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Spondyloepimetaphyseal dysplasia, PAPSS2 type". www.orpha.net. Retrieved 8 April 2019. 2. ^ Faiyaz ul Haque M, King LM, Krakow D, et al. (October 1998). "Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse". Nat. Genet. 20 (2): 157–62. doi:10.1038/2458. PMID 9771708. 3. ^ "Symbol report for PAPSS2". HUGO Gene Nomenclature Committee. 4. ^ Ahmad M, Haque MF, Ahmad W, et al. (August 1998). "Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred". Am. J. Med. Genet. 78 (5): 468–73. doi:10.1002/(SICI)1096-8628(19980806)78:5<468::AID-AJMG13>3.0.CO;2-D. PMID 9714015. ## External links[edit] Classification D * OMIM: 612847 * v * t * e Lysosomal storage diseases: Inborn errors of carbohydrate metabolism (Mucopolysaccharidoses) Catabolism * MPS I * Hurler Syndrome, Hurler-Scheie Syndrome, Scheie Syndrome * MPS II: Hunter Syndrome * MPS III: Sanfilippo Syndrome * MPS IV: Morquio Syndrome * MPS VI: Maroteaux-Lamy Syndrome * MPS VII: Sly Syndrome * MPS IX: Hyaluronidase deficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Spondyloepimetaphyseal dysplasia, Pakistani type	c2748516	8,768	wikipedia	https://en.wikipedia.org/wiki/Spondyloepimetaphyseal_dysplasia,_Pakistani_type	2021-01-18T18:43:29	{"mesh": ["C567552"], "umls": ["C2748516", "C2748515"], "orphanet": ["93282"], "wikidata": ["Q7578957"]}
A number sign (#) is used with this entry because spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME) is caused by homozygous or compound heterozygous mutation in the ASAH1 gene (613468) on chromosome 8p22. Description Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (summary by Zhou et al., 2012). Clinical Features Haliloglu et al. (2002) reported a consanguineous Turkish family in which 3 sibs had childhood-onset spinal muscular atrophy and progressive myoclonic epilepsy. The children presented between ages 2 and 5 years with difficulty walking, frequent falls, and tremor. Physical examination showed proximal muscle weakness, hypotonia, muscular atrophy, and Gowers sign. EMG showed chronic denervation. Two sisters developed myoclonic and generalized seizures at age 7 years, with 2-3 or 3-4 Hz sharp and slow waves on EEG. An affected brother had onset of muscle weakness and seizures at age 2 years. He also developed tremor, scoliosis, and pes cavus. The disorder was progressive, and all patients died in their teens. Another unrelated boy had normal early development, but always had an unsteady gait and was never able to run. He had proximal muscle weakness, lordosis, hypotonia, hyperreflexia, extensor plantar responses, and fasciculations, EMG showed diffuse chronic denervation, and muscle biopsy showed a neurogenic process. At age 4.5 years, he developed daily myoclonic seizures that were refractory to treatment. He also had fine tremor and recurrent lung infections. Zhou et al. (2012) reported 5 patients from 3 unrelated families with SMAPME. The first family included 3 affected sibs born of consanguineous Turkish parents. After early normal development and walking by age 14 months, the affected children developed progressive walking difficulties and frequent falls around age 5 years. Physical examination showed proximal weakness and muscular atrophy with normal serum creatine kinase. One child had tremor of the hands. EMG and muscle biopsies showed a chronic denervation process. Around age 7, the children developed progressive myoclonic epilepsy with slow and sharp bilateral waves of 3 to 4 cycles/sec on EEG. The disease was progressive and caused recurrent lung infections, resulting in death in all 3 children in the teenage years. In a second family, 2 Italian sisters, born of unrelated parents, developed progressive muscular weakness of the lower and then upper limbs at ages 4 to 5 years. Early development was normal. Both had generalized epileptic seizures, numerous brief episodes of loss of consciousness, and myoclonic jerks starting around age 12. Both lost the ability to walk at age 17 years. Other features included mild facial weakness, difficulty swallowing, fasciculations of the tongue, areflexia, severe scoliosis, and respiratory insufficiency. EMG and muscle biopsies showed a denervation process; brain MRI was normal. The third family had 1 affected girl who showed a similar disease course, with onset of progressive muscle weakness at age 5, followed by myoclonic seizures at age 10. Neurologic examination at age 11 years showed diffuse muscle atrophy, mild facial weakness, difficulty swallowing, and fasciculations of the tongue. She died of pneumonia at age 15. Dyment et al. (2014) reported a girl, born of unrelated parents of northern European descent, with SMAPME. She presented at age 10 years with absence and atonic seizures and myoclonic jerks. EEG showed generalized polyspike and wave discharges. Her neurologic development prior to seizure onset and neurologic examination were otherwise normal. The seizures were controlled with medication for 9 months, after which she developed frequent (over 100 per day) refractory myoclonic-absence seizures. She also developed constant tremor of the head, trunk, and extremities, as well as bilateral sensorineural hearing loss. Initial brain MRI was normal, but one at age 13 years showed mild volume loss. EMG at age 16 years showed a diffuse neurogenic disorder affecting motor neurons, with evidence of both active and chronic denervation. Dyment et al. (2014) commented on the absence of both muscle weakness and recurrent respiratory infections in this patient. Inheritance The transmission pattern of SMAPME in the families reported by Zhou et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy, Zhou et al. (2012) identified a homozygous mutation in the ASAH1 gene (T42M; 613468.0006). The mutation was identified by genomewide linkage analysis followed by exome sequencing. Another patient from a third family was found to be compound heterozygous for the T42M mutation and a deletion of the ASAH1 gene (613468.0007). The T42M mutant protein was expressed in various patient tissues and showed decreased enzymatic activity (32% of controls) in in vitro functional studies, although the mutant enzyme still showed activity toward ceramide. Despite the severe phenotype, the disease course was less severe than that observed in the allelic disorder Farber disease (228000), and symptoms in SMAPME appeared to be restricted to the central nervous system. Zhou et al. (2012) postulated that the different phenotype in these patients was related to residual levels of ASAH1 activity. In a girl with onset of SMAPME manifest as seizures at age 10 years, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene (613468.0010 and 613468.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed about 5.5% residual acid ceramidase activity and barely detectable levels of the beta subunit. History Jankovic and Rivera (1979) first reported the association of distal muscular atrophy and myoclonic seizures in a large 4-generation family. Affected individuals showed adult-onset, generalized, stimulus-sensitive myoclonus and slowly progressive distal muscle weakness and wasting. Some patients showed survival into the sixties; some developed dementia. The seizures were well-controlled with clonazepam. Postmortem examination of 1 patient showed neuronal degeneration of the anterior horn cells, Clarke nucleus, and lower cranial nerve nuclei. The transmission pattern in the family reported by Jankovic and Rivera (1979) was consistent with autosomal dominant inheritance. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial weakness Mouth \- Tongue fasciculations RESPIRATORY \- Respiratory insufficiency due to muscle weakness \- Recurrent respiratory infections ABDOMEN Gastrointestinal \- Difficulty swallowing SKELETAL Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Muscle weakness, proximal \- Muscle atrophy \- Gowers sign \- Fasciculations \- Muscle biopsy showed neurogenic atrophy \- EMG shows chronic denervation NEUROLOGIC Central Nervous System \- Normal early psychomotor development \- Difficulty walking \- Frequent falls \- Loss of independent ambulation \- Tremor \- Seizures \- Generalized seizures \- Myoclonic seizures \- 3-4 Hz slow sharp waves seen on EEG Peripheral Nervous System \- Areflexia LABORATORY ABNORMALITIES \- Normal serum creatine kinase MISCELLANEOUS \- Onset of muscle weakness around age 5 years \- Onset of seizures around 7 to 12 years \- Seizures are sensitive to hyperventilation \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the N-acylsphingosine amidohydrolase 1 gene (ASAH1, 613468.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	SPINAL MUSCULAR ATROPHY WITH PROGRESSIVE MYOCLONIC EPILEPSY	c1834569	8,769	omim	https://www.omim.org/entry/159950	2019-09-22T16:37:51	{"mesh": ["C537563"], "omim": ["159950"], "orphanet": ["2590"], "synonyms": ["Alternative titles", "MYOCLONUS, HEREDITARY, WITH PROGRESSIVE DISTAL MUSCULAR ATROPHY"], "genereviews": ["NBK488189"]}
Excessive constriction of the pupil Not to be confused with meiosis, mitosis, or myositis. Miosis Other namesMyosis Miosis caused by high doses of opiates. Patient also shows ptosis of both eyelids and an inattentive look at the camera, a sign of altered level of consciousness caused by the sedative effect of the drug. Pronunciation * /maɪˈoʊ sɪs/ SpecialtyOphthalmology Miosis, or myosis, is excessive constriction of the pupil.[1][2][3][4] The term is from Ancient Greek μύειν mūein, "to close the eyes". The opposite condition, mydriasis, is the dilation of the pupil. Anisocoria is the condition of one pupil being more dilated than the other. ## Contents * 1 Causes * 1.1 Age * 1.2 Diseases * 1.3 Drugs * 2 Physiology of the photomotor reflex * 3 See also * 4 References * 5 External links ## Causes[edit] ### Age[edit] * Senile miosis (a reduction in the size of a person's pupil in old age) ### Diseases[edit] * Horner's syndrome * Hemorrhage into pons (intracranial hemorrhage) * Hereditary disorders * Cluster Headaches with ptosis * Iridocyclitis * Fatal familial insomnia * Aphakia ### Drugs[edit] * Opioids such as fentanyl, morphine, heroin and methadone (the notable exception being pethidine) * Products containing nicotine such as cigarettes, chewing tobacco or gum. * Imidazolines such as clonidine, naphazoline, oxymetazoline and tetrahydrozoline * Antipsychotics, including risperidone, haloperidol, chlorpromazine, olanzapine, quetiapine and others * Antihistamines, such as diphenhydramine[5] * Cholinergic agents such as acetylcholine * Acetylcholinesterase inhibitors * Serotonin antagonists, such as Ondansetron (an anti-emetic) known by its brand name Zofran * Some cancer chemotherapy drugs, including camptothecin derivatives * Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA) * Some MAO Inhibitors. * Pilocarpine eye drops and all other parasympathomimetics * In some rare cases, when exposed to mustard gas * Organophosphates ## Physiology of the photomotor reflex[edit] Light entering the eye strikes three different photoreceptors in the retina: the familiar rods and cones used in image forming and the more newly discovered photosensitive ganglion cells. The ganglion cells give information about ambient light levels, and react sluggishly compared to the rods and cones. Signals from photosensitive ganglion cells have multiple functions including acute suppression of the hormone melatonin, entrainment of the body's circadian rhythms and regulation of the size of the pupil. The retinal photoceptors convert light stimuli into electric impulses. Nerves involved in the resizing of the pupil connect to the pretectal nucleus of the high midbrain, bypassing the lateral geniculate nucleus and the primary visual cortex. From the pretectal nucleus neurons send axons to neurons of the Edinger-Westphal nucleus whose visceromotor axons run along both the left and right oculomotor nerves. Visceromotor nerve axons (which constitute a portion of cranial nerve III, along with the somatomotor portion derived from the Edinger-Westphal nucleus) synapse on ciliary ganglion neurons, whose parasympathetic axons innervate the iris sphincter muscle, producing miosis. ## See also[edit] * Pupillary light reflex * Adie syndrome * Argyll Robertson pupil * Cycloplegia * Marcus Gunn pupil * Parinaud's syndrome * Syphilis * Glaucoma ## References[edit] 1. ^ Farlex medical dictionary citing: * Miller-Keane Encyclopedia & Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. * Saunders Comprehensive Veterinary Dictionary, 3 ed. 2. ^ Seidel, Henry M.; Jane W. Ball; Joyce E. Dains; G. William Benedict (2006-03-29). Mosby's Guide to Physical Examination. Mosby. ISBN 978-0-323-03573-6. 3. ^ Farlex medical dictionary citing: Millodot: Dictionary of Optometry and Visual Science, 7th edition. 4. ^ Farlex medical dictionary citing: Mosby's Medical Dictionary, 8th edition. 5. ^ British Journal of Clinical Pharmacology (27 Feb 2006). "Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine". British Journal of Clinical Pharmacology. 61 (6): 752–60. doi:10.1111/j.1365-2125.2006.02632.x. PMC 1885114. PMID 16722841. ## External links[edit] Classification D * ICD-10: H57.0 * ICD-10-CM: H57.03 * ICD-9-CM: 379.42 * MeSH: D015877 * DiseasesDB: 8243 * FP Notebook * v * t * e Drugs used for glaucoma preparations and miosis (S01E) Sympathomimetics * Apraclonidine * Brimonidine (+timolol) * Clonidine * Dipivefrine * Epinephrine Parasympathomimetics muscarinic * Aceclidine * Pilocarpine muscarinic/nicotinic * Acetylcholine * Carbachol acetylcholinesterase inhibitors * Demecarium * Ecothiopate * Stigmine (Fluostigmine * Neostigmine * Physostigmine) * Paraoxon Carbonic anhydrase inhibitors/ (sulfonamides) * Acetazolamide * Brinzolamide (+timolol, +brimonidine) * Diclofenamide * Dorzolamide (+timolol) * Methazolamide Beta blocking agents * Befunolol * Betaxolol * Carteolol * Levobunolol * Metipranolol * Timolol * Mepindolol Prostaglandin analogues (F2α) * Bimatoprost (+timolol) * Latanoprost (+timolol) * Tafluprost * Travoprost (+timolol) * Unoprostone Other agents * Dapiprazole * Guanethidine * Netarsudil/latanoprost * Ripasudil * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Miosis	c0026205	8,770	wikipedia	https://en.wikipedia.org/wiki/Miosis	2021-01-18T18:43:28	{"mesh": ["D015877"], "umls": ["C0026205"], "icd-9": ["379.42"], "icd-10": ["H57.0"], "wikidata": ["Q596899"]}
Levator ani syndrome Other namesLevator spasm, Puborectalis syndrome, Chronic proctalgia, Piriformis syndrome, Pelvic tension myalgia, Levator syndrome, and Proctodynia Left levator ani muscle seen from within SpecialtyGastroenterology SymptomsBrief intermittent burning anorectal pain or tenesmus CausesPainful spasm of the levator ani muscle TreatmentWalking, pelvic relaxation techniques, massage, warm baths, muscle relaxant medications Levator ani syndrome is a condition characterized by brief intermittent burning pain or tenesmus of the rectal or perineal area,[1] caused by spasm of the levator ani muscle.[2][3][4] The genesis of the syndrome is unknown; however, inflammation of the arcus tendon is a possible cause of levator ani syndrome.[5] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Symptoms include a dull ache to the left 2 inches above the anus or higher in the rectum and a feeling of constant rectal pressure or burning. The pain may last for 30 minutes or longer, and is usually described as chronic or intermittent with prolonged periods, in contrast to the brief pain of the related disorder proctalgia fugax. Pain may be worse when sitting than when standing or lying.[6] Precipitating factors include extended sitting, defecation, stress, sexual intercourse, childbirth, and surgery. Palpation of the levator ani muscle may find tenderness.[7] ## Cause[edit] Levator ani syndrome is characterized by painful spasm of the levator ani muscle.[2][3][4] The genesis of the syndrome is unknown, however it has been suggested that inflammation of the arcus tendon is the possible cause of levator ani syndrome.[5] Proctalgia fugax and levator ani syndrome have not been found to be of psychosomatic origin, although stressful events may trigger attacks.[3] Occurrence of levator ani syndrome is associated with "significant elevations on the hypochondriasis, depression, and hysteria scales of the Minnesota Multiphasic Personality Inventory," which is also the case in general among chronic pain sufferers.[4] ## Diagnosis[edit] The diagnosis of levator ani syndrome is clinical, based on the pattern of signs and symptoms. The diagnosis does not require any routine imaging or additional testing, though other causes of rectal pain must be excluded. Suspected levator ani syndrome is confirmed in the presence of chronic or recurrent rectal pain, occurring in episodes that last at least 30 minutes, with tenderness with posterior traction of the puborectalis muscle. ## Treatment[edit] The discomfort may be relieved by walking or pelvic relaxation techniques. Other treatments include massage of the muscle, warm baths, muscle relaxant medications such as cyclobenzaprine, therapeutic ultrasound and biofeedback. Electrical stimulation of the levator ani muscle has been used to try to break the spastic cycle. Injection of botulinum toxin A has also been used. ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ a b Levator Syndrome, by Parswa Ansari, MD 7/2014, Merck Manuals 3. ^ a b c Giulio Aniello Santoro; Andrzej Paweł Wieczorek; Clive I. Bartram (27 October 2010). Pelvic Floor Disorders: Imaging and Multidisciplinary Approach to Management. Springer. p. 601. ISBN 978-88-470-1542-5. 4. ^ a b c Bharucha AE, Trabuco E (September 2008). "Functional and chronic anorectal and pelvic pain disorders". Gastroenterology Clinics of North America. 37 (3): 685–96, ix. doi:10.1016/j.gtc.2008.06.002. PMC 2676775. PMID 18794003. 5. ^ a b Park DH, Yoon SG, Kim KU, et al. (May 2005). "Comparison study between electrogalvanic stimulation and local injection therapy in levator ani syndrome". International Journal of Colorectal Disease. 20 (3): 272–6. doi:10.1007/s00384-004-0662-9. PMID 15526112. 6. ^ Rao, SS; Bharucha, AE; Chiarioni, G; Felt-Bersma, R; Knowles, C; Malcolm, A; Wald, A (25 March 2016). "Functional Anorectal Disorders". Gastroenterology. doi:10.1053/j.gastro.2016.02.009. PMC 5035713. PMID 27144630. 7. ^ Bharucha, Adil E.; Lee, Tae Hee (October 2016). "Anorectal and Pelvic Pain". Mayo Clinic Proceedings (review). 91 (10): 1471–1486. doi:10.1016/j.mayocp.2016.08.011. ISSN 1942-5546. PMC 5123821. PMID 27712641. ## External links[edit] Classification D * ICD-10: 59.4 * MeSH: C535890 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Levator ani syndrome	c0423738	8,771	wikipedia	https://en.wikipedia.org/wiki/Levator_ani_syndrome	2021-01-18T18:59:32	{"gard": ["6899"], "mesh": ["C535890"], "umls": ["C0423738"], "wikidata": ["Q6534949"]}
Primary pigmented nodular adrenocortical disease Other namesPPNAD Macroscopic appearance of adrenal gland in PPNAD following adrenalectomy Primary pigmented nodular adrenocortical disease (PPNAD) was first coined in 1984 by Carney et al. it often occurs in association with Carney complex (CNC). CNC is a rare syndrome that involves the formation of abnormal tumours that cause endocrine hyperactivity. PPNAD arises due to the enlargement of the cortex of the adrenal glands, resulting in Cushing's syndrome that is independent of the pituitary hormone ACTH.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Diagram of Cushing's symptoms. Picture of lentigines associated with Carney Complex PPNAD is a rare cause of high cortisol levels in the blood and often manifests as ACTH-independent Cushing's syndrome.[2][3] The effects of PPNAD can often be cyclical so the symptoms of Cushing's syndrome will not always be as severe, which may complicate diagnosis.[4] The classic symptoms of Cushing's syndrome include rapid central weight gain, a puffy red face and a buffalo hump at the back of the neck due to fat deposits. Skin changes in Cushing's syndrome include thinning and bruising easily, developing striae and hyperpigmentation at skin folds. The hormonal changes can lead to hirsutism, males developing breast tissue, females no longer having periods and both sexes may become infertile. High cortisol levels can lead to psychological disturbances such as anxiety or depression and insomnia. Bone health can deteriorate, leading to an increased fracture risk in people with Cushing's syndrome.[5] PPNAD is unique as it often causes Cushing's at a young age, in children and adolescents.[3] In addition to the other symptoms of Cushing's syndrome, the patient may have a short stature due to interrupted growth because of ACTH suppression.[5] In 90% of people with PPNAD it is associated with Carney Complex.[citation needed] Carney Complex is usually inherited, however it can also occur sporadically.[6] A visible sign of Carney complex is abnormal skin hyperpigmentation. There may also be myxomas which can appear as lumps in the skin and breast as well as often being present in the heart, which can lead to multiple cardiovascular problems.[7] The majority of people with PPNAD will have some of these signs/symptoms due to the strong association between PPNAD and Carney Complex.[citation needed] ## Causes[edit] PPNAD, the endocrine manifestation that comes from Carney Complex (CNC), can be syndromic or isolated. The main cause of isolated PPNAD is a mutation of PRKAR1α, located at 17q22-24, which is the gene encoding the regulatory R1α subunit of protein kinase A. Germline heterozygous PRKAR1α inactivation mutations are present in 80% of CNC patients affected by Cushing's syndrome.[8] There are over 117 mutations of the PRKAR1α gene that can cause CNC, with many of these mutations producing premature stop codons, thus resulting in the complete loss of PRKAR1α protein. CNC patients have also been discovered with an unusually shortened PRKAR1α protein, detected in tumours and leukocytes, following a splice-site mutation, which causes exon-6 skipping.[9] Therefore, both haploinsufficiency and the complete loss of PRKAR1α can lead to the increased PKA activity observed in PPNAD patients, due to the disruption of the cAMP signalling pathway.[citation needed] Sahut-Barnola et al. used a mouse model to cre-lox knockout the Prkar1a gene specifically from cells of the adrenal cortex and observed that the mice subsequently developed Cushing syndrome that is independent of the pituitary. They also observed that the mutation caused increased PKA activity. The R1α loss caused the adult adrenal gland became hyperactive and hyperplastic on both sides, as seemingly the foetal adrenal cells within it were not maintained and thus expanded. This established tumoral growths. This mouse KO model phenocopies what happens in human cases of PPNAD.[10] Inactivation of PDE11A4, located at 2q31-5, has also been identified in PPNAD patients without PRKAR1α mutations. PDE11A4 is the gene encoding phosphodiesterase 11A4, another participant of the cAMP signalling pathway.[11] ## Diagnosis[edit] Diagnosis usually occurs upon investigation of a cause for already suspected Cushing's syndrome. High levels of cortisol observed in patients with PPNAD are not suppressed upon administration of dexamethasone (dexamethasone suppression test), and upon MRI or CT imaging, the pituitary will show no abnormalities. Measuring ACTH will confirm that the cause of the patients Cushing's syndrome is ACTH independent. The nature of Cushing's syndrome itself is periodic, which can make diagnosing PPNAD increasingly difficult.[12] Diagnosis of PPNAD can be difficult to determine preoperatively as CT scan findings can be variable i.e. appear normal or suggest unilateral adrenal lesions therefore impeding the correct diagnosis. NP-59 scintigraphy may be particularly useful in identifying the bilateral nature of the disease.[13] Gene studies are not necessary for diagnosis as there are clear gross and histological diagnostic markers, as the nodules can usually be seen clearly in both cases A positive family history of PPNAD has been shown to be associated with abnormal histological findings, e.g. mitotic figures, which may further hinder diagnosis. At the point where abdominal CT scanning and pituitary fossa MRI show no clear abnormalities, adrenalectomy may be performed.[12] ## Treatment[edit] After diagnosis, it is important for patients to be continually monitored. The most common treatment for PPNAD is bilateral laparoscopic adrenalectomy; the process by which both adrenal glands are removed by a small incision.[2] Patients who have received this treatment will be prescribed mineralocorticoid and glucocorticoid steroids as they are no longer being naturally produced.[14] This is a treatment which has been used and refined since 1984.[15] ## References[edit] 1. ^ Larsen, Jennifer L; Cathey, W.J; Odell, William D (1986). "Primary adrenocortical nodular dysplasia, a distinct subtype of cushing's syndrome. Case report and review of the literature". The American Journal of Medicine. 80 (5): 976–84. doi:10.1016/0002-9343(86)90648-0. PMID 3010718. 2. ^ a b Choi, Kyung Mook; Seu, Jae Hong; Kim, Yong Hyun; Lee, Eun Jong; Kim, Sang Jin; Baik, Sei Hyun; Choi, Dong Seop (1995). "Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease - A Case Report Reviews of the Literature-". The Korean Journal of Internal Medicine. 10 (1): 68–72. doi:10.3904/kjim.1995.10.1.68. PMC 4532033. PMID 7626560. 3. ^ a b Courcoutsakis, Nikos; Prassopoulos, Panos; Stratakis, Constantine A (2010). "CT Findings of Primary Pigmented Nodular Adrenocortical Disease: Rare Cause of ACTH-Independent Cushing Syndrome". American Journal of Roentgenology. 194 (6): W541. doi:10.2214/AJR.09.4056. PMID 20489078. 4. ^ Stratakis, Constantine A; Kirschner, Lawrence S; Carney, J. Aidan (2001). "Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation". The Journal of Clinical Endocrinology & Metabolism. 86 (9): 4041–6. doi:10.1210/jcem.86.9.7903. PMID 11549623. 5. ^ a b Wagner-Bartak, Nicolaus A; Baiomy, Ali; Habra, Mouhammed Amir; Mukhi, Shalini V; Morani, Ajaykumar C; Korivi, Brinda R; Waguespack, Steven G; Elsayes, Khaled M (2017). "Cushing Syndrome: Diagnostic Workup and Imaging Features, with Clinical and Pathologic Correlation". American Journal of Roentgenology. 209 (1): 19–32. doi:10.2214/AJR.16.17290. PMID 28639924. 6. ^ Stratakis, Constantine A; Kirschner, Lawrence S; Carney, J. Aidan; Pack, Svetlana D; Taymans, Susan E; Giatzakis, Christoforos; Cho, Yee Sook; Cho-Chung, Yoon S (2000). "Mutations of the gene encoding the protein kinase a type I-alpha regulatory subunit in patients with the Carney complex". Nature Genetics. 26 (1): 89–92. doi:10.1038/79238. PMID 10973256. S2CID 36818715. 7. ^ Jain, Sonia; Maleszewski, Joseph J; Stephenson, Christopher R; Klarich, Kyle W (2015). "Current diagnosis and management of cardiac myxomas". Expert Review of Cardiovascular Therapy. 13 (4): 369–75. doi:10.1586/14779072.2015.1024108. PMID 25797902. S2CID 6935363. 8. ^ Bertherat, Jérôme (2006). "Carney complex (CNC)". Orphanet Journal of Rare Diseases. 1: 21. doi:10.1186/1750-1172-1-21. PMC 1513551. PMID 16756677. 9. ^ Gangoda, L; Doerflinger, M; Srivastava, R; Narayan, N; Edgington, L E; Orian, J; Hawkins, C; O'Reilly, L A; Gu, H; Bogyo, M; Ekert, P; Strasser, A; Puthalakath, H (2014). "Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice". Cell Death and Differentiation. 21 (11): 1815–24. doi:10.1038/cdd.2014.98. PMC 4211378. PMID 25012505. 10. ^ Sahut-Barnola, Isabelle; De Joussineau, Cyrille; Val, Pierre; Lambert-Langlais, Sarah; Damon, Christelle; Lefrançois-Martinez, Anne-Marie; Pointud, Jean-Christophe; Marceau, Geoffroy; Sapin, Vincent; Tissier, Frédérique; Ragazzon, Bruno; Bertherat, Jérôme; Kirschner, Lawrence S; Stratakis, Constantine A; Martinez, Antoine (2010). "Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice". PLOS Genetics. 6 (6): e1000980. doi:10.1371/journal.pgen.1000980. PMC 2883593. PMID 20548949. 11. ^ Cazabat, Laure; Ragazzon, Bruno; Groussin, Lionel; Bertherat, Jérôme (2006). "PRKAR1A mutations in primary pigmented nodular adrenocortical disease". Pituitary. 9 (3): 211–9. doi:10.1007/s11102-006-0266-1. PMID 17036196. S2CID 95749. 12. ^ a b Manipadam, Mariet; Sen, Sudipta; Abraham, Rachel; Simon, Anna (2011). "Primary pigmented nodular adrenocortical disease". Journal of Indian Association of Pediatric Surgeons. 16 (4): 160–2. doi:10.4103/0971-9261.86881. PMC 3221162. PMID 22121318. 13. ^ Vezzosi, Delphine; Tenenbaum, Florence; Cazabat, Laure; Tissier, Frédérique; Bienvenu, Marie; Carrasco, Carmen A; Laloi-Michelin, Marie; Barrande, Gaëlle; Lefebvre, Hervé; Hiéronimus, Sylvie; Tabarin, Antoine; Bertagna, Xavier; Legmann, Paul; Vantyghem, Marie-Christine; Bertherat, Jérôme (2015). "Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients with Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD)". The Journal of Clinical Endocrinology & Metabolism. 100 (11): 4332–8. doi:10.1210/jc.2015-2174. PMID 26390100. 14. ^ Liu, James K; Fleseriu, Maria; Delashaw, Johnny B; Ciric, Ivan S; Couldwell, William T (2007). "Treatment options for Cushing disease after unsuccessful transsphenoidal surgery". Neurosurgical Focus. 23 (3): E8. doi:10.3171/foc.2007.23.3.10. PMID 17961031. 15. ^ Shenoy, B. V; Carpenter, P. C; Carney, J. A (1984). "Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome". The American Journal of Surgical Pathology. 8 (5): 335–44. doi:10.1097/00000478-198405000-00002. PMID 6329005. ## External links[edit] Classification D * ICD-10: E24.8 * OMIM: 61047 * MeSH: C566472 C566469, C566472 External resources * Orphanet: 189439 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Primary pigmented nodular adrenocortical disease	c1864846	8,772	wikipedia	https://en.wikipedia.org/wiki/Primary_pigmented_nodular_adrenocortical_disease	2021-01-18T18:46:56	{"gard": ["10906"], "mesh": ["C566472", "C566469"], "umls": ["C1864846", "C1864851"], "orphanet": ["189439"], "wikidata": ["Q18987129"]}
A number sign (#) is used with this entry because of evidence that sideroblastic anemia-3 (SIDBA3), which is refractory to pyridoxine treatment, is caused by homozygous or compound heterozygous mutation in the GLRX5 gene (609588) on chromosome 14q32. Description Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit (summary by Liu et al., 2014). For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (300751). Clinical Features Camaschella et al. (2007) reported a 60-year-old southern Italian man, born of consanguineous parents, who presented with severe microcytic anemia, jaundice, hepatosplenomegaly, iron overload, cirrhosis, and type II diabetes. Bone marrow showed moderate erythroid expansion and increased iron staining both in erythroblasts and macrophages, with 28% ringed sideroblasts. Folic acid and vitamin B6 supplementation was ineffective. Iron chelation therapy resulted in clinical improvement. Further analysis showed dysregulation of iron-regulatory proteins aconitase (ACO1; 100800) and IREB2 (147582). Liu et al. (2014) reported a 46-year-old Chinese man who had severe anemia since age 29 years. Features included dark skin, hepatosplenomegaly, anisocytosis on peripheral blood smear, and 19% ringed sideroblasts on bone marrow biopsy. Liver biopsy showed increased iron in parenchymal cells. The anemia was responsive to iron chelation therapy, but not vitamin B6 supplementation. The patient also developed type II diabetes. Peripheral blood cells showed decreased Fe-S-ACO1 protein levels and decreased activity of aconitase compared to controls. Inheritance The transmission pattern of SIDBA3 in the family reported by Camaschella et al. (2007) was consistent with autosomal recessive inheritance. Molecular Genetics In a southern Italian man with SIDBA3, Camaschella et al. (2007) identified a homozygous mutation in the GLRX5 gene (609588.0001). The was considered to be the human counterpart of the zebrafish shiraz mutant, which shows a similar but more severe phenotype due to a deletion in the Glrx5 gene (see ANIMAL MODEL and Wingert et al., 2005). In a Chinese man with SIDBA3, Liu et al. (2014) identified compound heterozygous missense mutations in the GLRX5 gene (K101Q, 609588.0002 and L148S, 609588.0003). Direct functional studies of the variants were not performed, but mitochondrial Fe-S biogenesis was impaired in patient peripheral blood cells, as demonstrated by decreased ferrochelatase (FECH; 612386) levels. Pathogenesis Ye et al. (2010) found undetectable GLRX5 protein levels in cells derived from the patient reported by Camaschella et al. (2007). Mitochondrial aconitase (ACO2; 100850) activity was undetectable, and cytosolic aconitase (ACO1; 100880) activity was decreased to less than 10% of controls. Mitochondrial complex I activity was also decreased to 20% of normal, consistent with a defect in Fe-S cluster biogenesis. Defects in Fe-S cluster biogenesis negatively impacted ALAS2 (301300) activity and heme biosynthesis. FECH levels were decreased in patient lymphoblast cells, but not in patient fibroblasts, further suggesting that GLRX5 has a specific role in hematopoietic cells. However, patient fibroblasts showed punctate iron deposition in a pattern consistent with mitochondrial iron overload. Transfection of patient cells with wildtype GLRX5 rescued morphologic and growth defects and biochemical abnormalities. Animal Model Wingert et al. (2005) showed that the hypochromic anemia in 'shiraz' (sir) zebrafish mutants is caused by deficiency of grx5, a gene required in yeast for Fe/S cluster assembly. Wingert et al. (2005) found that grx5 is expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of delta-grx5 yeast Fe/S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein-1 (IRP1; 100880) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. Wingert et al. (2005) found that loss of Fe/S cluster assembly in sir animals activated IRP1 and blocked heme biosynthesis catalyzed by aminolevulinate synthase-2 (ALAS2; 301300). Overexpression of ALAS2 RNA without the 5-prime iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2, including the iron response element, did not. Further, antisense knockdown of IRP1 restored sir embryo hemoglobin synthesis. Wingert et al. (2005) concluded that their findings uncover a connection between heme biosynthesis and Fe/S clusters, indicating that hemoglobin production in the differentiating red cell is regulated through Fe/S cluster assembly. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Hepatomegaly \- Hepatic iron accumulation \- Cirrhosis (1 patient) Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Jaundice ENDOCRINE FEATURES \- Type II diabetes mellitus HEMATOLOGY \- Anemia \- Microcytosis \- Anisocytosis \- Hypochromia \- Ringed sideroblasts seen on bone marrow aspirate LABORATORY ABNORMALITIES \- Increased serum ferritin MISCELLANEOUS \- Onset in mid-adulthood \- Anemia is not responsive to pyridoxine supplementation \- Anemia may be responsive to iron chelation treatment \- Two unrelated men have been reported (last curated March 2016) MOLECULAR BASIS \- Caused by mutation in the glutaredoxin 5 gene (GLRX5, 609588.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	ANEMIA, SIDEROBLASTIC, 3, PYRIDOXINE-REFRACTORY	c2673914	8,773	omim	https://www.omim.org/entry/616860	2019-09-22T15:47:43	{"doid": ["0080343"], "mesh": ["C567145"], "omim": ["616860"], "orphanet": ["255132"]}
A rare inherited disorder of branched-chain amino acid metabolism classically characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The four overlapping phenotypic subtypes are: classic, intermediate, intermittent and thiamine-responsive MSUD. ## Epidemiology The estimated prevalence is around 1/150,000 live births, from published and unpublished newborn screening data. ## Clinical description Classic MSUD presents in the first days of life with poor feeding and drowsiness followed by a worsening encephalopathy with lethargy, intermittent apnea, stereotypic movements ("fencing" and ''bicycling") and opisthotonus. Coma and central respiratory failure supervene 7 to 10 days after birth. The only abnormality in biochemistry is ketosis. Intermediate MSUD clinically resembles classic MSUD but it can have a later onset and less severe symptoms. Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood. Thiamin-responsive MSUD is clinically similar to intermediate MSUD with thiamin therapy improving dietary leucine tolerance. ## Etiology MSUD is due to mutations in the genes encoding subunits E1a, E1b, and E2 of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex, involved in the second enzymatic step in the degradation of the branched chain amino acids (BCAAs): leucine, isoleucine and valine. BCKAD has four subunits: E1a, E1b, E2, and E3, which are encoded by the genes BCKDHA (19q13.1-q13.2), BCKDHB (6q14.1), DBT (1p31) and DLD (7q31-q32) respectively. Mutations in these genes lead to the accumulation of BCAAs (especially leucine) and their branched-chain alpha-ketoacids. Mutations in the E3 subunit gene (DLD) are not associated with MSUD but lead to pyruvate dehydrogenase E3 deficiency (see this term). A mutation in the PPM1K gene (4q22.1) has been reported in a single case of mild intermediate MSUD. ## Genetic counseling MSUD follows an autosomal recessive inheritance pattern and genetic counseling is possible. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Maple syrup urine disease	c0024776	8,774	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=511	2021-01-23T19:05:54	{"gard": ["3228"], "mesh": ["D008375"], "omim": ["248600", "615135"], "umls": ["C0024776", "C0268576"], "icd-10": ["E71.0"], "synonyms": ["BCKD deficiency", "BCKDH deficiency", "Branched-chain 2-ketoacid dehydrogenase deficiency", "Branched-chain ketoaciduria", "MSUD"]}
Hyalohyphomycosis is a group of opportunistic mycotic infections[1] caused by nondematiaceous molds, and may be contrasted with phaeohyphomycosis.[2]:329 A hyalohyphomycetes example is Fusarium.[3] ## See also[edit] * Acremonium * List of cutaneous conditions ## References[edit] 1. ^ Naggie S, Perfect JR (June 2009). "Molds: hyalohyphomycosis, phaeohyphomycosis, and zygomycosis". Clin. Chest Med. 30 (2): 337–53, vii–viii. doi:10.1016/j.ccm.2009.02.009. PMID 19375639. 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. ^ Nucci M, Anaissie E (September 2006). "Emerging fungi". Infect. Dis. Clin. North Am. 20 (3): 563–79. doi:10.1016/j.idc.2006.06.002. PMID 16984869. 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hyalohyphomycosis	c0343952	8,775	wikipedia	https://en.wikipedia.org/wiki/Hyalohyphomycosis	2021-01-18T18:30:34	{"mesh": ["D060605"], "umls": ["C0343952"], "wikidata": ["Q5402292"]}
Dermatochalasis Dermatochalasis in an elderly woman SpecialtyMedical genetics Dermatochalasis is a medical condition, defined as an excess of skin in the upper or lower eyelid, also known as "baggy eyes."[1] It may be either an acquired or a congenital condition. It is generally treated with blepharoplasty. ## Contents * 1 Presentation * 1.1 Associated conditions * 2 Pathophysiology * 3 Treatment * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Presentation[edit] ### Associated conditions[edit] People with dermatochalasis often also have blepharitis, a condition caused by the plugging of glands in the eye that produce lubricating fluid (meibomian glands).[2] Dermatochalasis can be severe enough that it pushes the eyelashes into the eye, causing entropion.[2] Weakness in the orbital septum may cause the herniation of the orbital fat pads.[3] This is observed as the presence of bulges (fat pads) in the soft tissue of the baggy eyes.[3] It can also be observed in various hereditary connective tissue disorders, including classical Ehlers-Danlos syndrome and cutis laxa. Dermatochalasis can be a major contributing factor for headaches [4] due to tonic reflex contraction of muscles in an attempt to compensate, which then causes tension-type headaches. ## Pathophysiology[edit] Dermatochalasis is caused by a loss of elasticity in the connective tissue supporting the structure of the front portion of the eyelid.[3] Normally, in Caucasians, the orbicularis muscle and overlying skin form a crease near the tarsal border.[3] In dermatochalasis, the excess tissues hangs down, over the front edge of the eyelid. The excess tissue can sometimes obstruct the visual field, especially the superior visual field.[1] In severe cases, it may obstruct as much as 50 percent of the superior visual field.[2] ## Treatment[edit] If dermatochalasis is severe enough to obstruct the peripheral or superior visual fields, then it may be treated with a surgical procedure called blepharoplasty.[3] In blepharoplasty surgery, excess skin, muscle and fat are removed. While the improvement of vision is an indication for blepharoplasty on the superior eyelid, if the visual fields are not obstructed, it may be performed for cosmetic reasons. In general, blepharoplasty of the inferior eyelid is considered cosmetic, as dermatochalasis in the lower eyelid does not interfere with vision.[3] ## Epidemiology[edit] Dermatochalasis commonly affects the elderly, although sometimes it is congenitally acquired. The elderly version may begin to develop as early as 40 years of age, and it continues to progress with age.[2] The congenital version may begin around 20 years of age.[2] There is no racial predisposition towards developing dermatochalasis, and men and women are equally affected.[2] ## See also[edit] * Cutis laxa * Ptosis ## References[edit] 1. ^ a b Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. pp. 2426. ISBN 978-1437727883. 2. ^ a b c d e f Gilliland, Grant. "Dermatochalasis". WebMD, LLC. Medscape. Retrieved 1 December 2012. 3. ^ a b c d e f Cunningham, Emmett T.; Paul Riordan-Eva (2011). "Chapter 4: Lids & Lacrimal Apparatus". Vaughan & Asbury's general ophthalmology (18th ed.). New York: McGraw-Hill Medical. ISBN 978-0071634205. 4. ^ Bahceci Simsek, Ilke (2017). "Association of Upper Eyelid Ptosis Repair and Blepharoplasty With Headache-Related Quality of Life". JAMA Facial Plastic Surgery. ww.ncbi.nlm.nih.gov. 19 (4): 293–297. doi:10.1001/jamafacial.2016.2120. PMC 5815105. PMID 28253391. ## External links[edit] Classification D * ICD-10: H02.3 or Q10.0 * ICD-9-CM: 374.87 * OMIM: 219200 * DiseasesDB: 29439 * SNOMED CT: 58588007 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Dermatochalasis	c0010495	8,776	wikipedia	https://en.wikipedia.org/wiki/Dermatochalasis	2021-01-18T18:40:02	{"mesh": ["D003483"], "icd-9": ["374.87"], "icd-10": ["Q10.0", "H02.3"], "wikidata": ["Q1200233"]}
Cynanthropy (sometimes spelled kynanthropy; from Ancient Greek κύων/kúōn, "dog" + ἄνθρωπος/ánthrōpos, "man; human") is, in psychiatry, the pathological delusion of real persons that they are dogs[1] and in anthropology and folklore, the supposed magical practice of shape-shifting alternately between dog and human form, or the possession of combined canine and human anatomical features, a form of therianthropy. The Greeks spoke of cynanthropy (kyon, dog). The term existed by at least 1901, when it was applied to myths from China about humans turning into dogs, dogs becoming people, and sexual relations between humans and canines (De Groot, 184). After lycanthropy, cynanthropy is the best known term for a specific variety of therianthropy. Anthropologist David Gordon White called Central Asia the "vortex of cynanthropy" because races of dog-men were habitually placed there by ancient writers. Hindu mythology puts races of "Dog Cookers" to the far north of India, the Chinese placed the "Dog Jung" and other human/canine barbarians to the extreme west, and European legends frequently put the dog men called Cynocephali in unmapped regions to the east. Some of these races were described as humans with dog heads, others as canine shapeshifters (White, 114-15). The weredog or cynanthrope is also known in Timor. It is described as a human/canine shapeshifter who is also capable of transforming other people into animals against their wills. These transformations are usually into prey animals such as goats, so that the cynanthrope can devour them without discovery of the crime (Rose, 390). ## In fiction[edit] * In the series Codename: Kids Next Door two episodes "Operation: H.O.U.N.D." and "Operation: D.O.G.H.O.U.S.E." featured weredogs where Valerie, Mrs. Thompson and the students turn into. * The Snoop Dogg music video "Who Am I (What's My Name)" also featured cynanthropy, where Snoop Dogg and others turn into dogs to evade angry fathers and dog catchers. ## See also[edit] * Cynocephaly * Clinical lycanthropy * Shapeshifting * Skin-walker * Therianthropy * Were * Werewolf * Wererat * Werehyena * Werecat * Otherkin ## References[edit] 1. ^ https://www.medilexicon.com/dictionary/22309 2\. White, David Gordon. Myths of the Dog-Man. The University of Chicago Press, 1992. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Cynanthropy	None	8,777	wikipedia	https://en.wikipedia.org/wiki/Cynanthropy	2021-01-18T19:01:01	{"wikidata": ["Q5199884"]}
A number sign (#) is used with this entry because cataract-23 (CTRCT23) is caused by heterozygous mutation in the crystallin beta-A4 gene (CRYBA4; 123631) on chromosome 22q12. Description Mutation in the CRYBA4 gene has been found in families with cataract described as congenital, lamellar, and nuclear. Clinical Features Santhiya et al. (2004) reported a 4-generation Indian family with autosomal dominant congenital lamellar cataract. Billingsley et al. (2006) examined 13 affected and several unaffected individuals from this family. Most affected individuals had been diagnosed during childhood; however, 2 affected individuals had not yet had cataracts removed, suggesting early insult with variable expressivity. Billingsley et al. (2006) reported a patient with bilateral microphthalmia and cataracts with secondary enophthalmia (sinking of the eyes) identified in a series of 32 patients with bilateral microphthalmia. Zhou et al. (2010) reported a 3-generation Chinese family in which a father and son had congenital nuclear cataract with microcornea. Both showed symptoms of vision decrease before 2 years of age. Molecular Genetics In the Indian family with autosomal dominant congenital lamellar cataract originally reported by Santhiya et al. (2004), Billingsley et al. (2006) detected a heterozygous missense mutation in the CRYBA4 gene (F94S; 123631.0001). In a patient with bilateral microphthalmia and cataracts, Billingsley et al. (2006) detected a heterozygous mutation in exon 4 of the CRYBA4 gene (L69P; 123631.0002). Protein structure modeling predicted that the L69P change, in the middle of the CRYBA4 beta-sheet, would likely break the beta-sheet. The mutant structure would be very unstable and would not fold properly. Billingsley et al. (2006) sought mutations in the CRYBA4 gene in microphthalmia based on the demonstration of CRYBB2 involvement in microphthalmia and cataract (see 601547) and the interaction of CRYBB2-CRYBA4 monomers. In a Chinese father and son with congenital nuclear cataract and microcornea, Zhou et al. (2010) identified a heterozygous mutation in the CRYBA4 gene (G64W; 123631.0003) that segregated with the disease in the family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	CATARACT 23, MULTIPLE TYPES	c3808012	8,778	omim	https://www.omim.org/entry/610425	2019-09-22T16:04:41	{"doid": ["0110271"], "omim": ["610425"], "icd-10": ["Q12.0"], "orphanet": ["91492"], "synonyms": ["CATARACT 23, MULTIPLE TYPES, WITH OR WITHOUT MICROCORNEA", "Alternative titles"], "genereviews": ["NBK1378"]}
Psychological phenomenon In psychology, a false memory is a phenomenon where a person recalls something that did not happen or recalls it differently from the way it actually happened. Suggestibility, activation of associated information, the incorporation of misinformation, and source misattribution have been suggested to be several mechanisms underlying a variety of types of false memory phenomena. False memories are a component of false memory syndrome (FMS).[1] ## Contents * 1 Early work * 2 Manifestations and types * 2.1 Mandela effect * 2.2 Presuppositions and the misinformation effect * 2.3 Word lists * 2.4 Staged naturalistic events * 2.5 Relational processing * 3 Theories * 3.1 Strength hypothesis (situational strength) * 3.2 Construction hypothesis * 3.3 Skeleton theory * 4 Natural factors for the formation of false memories * 4.1 Individual differences * 4.2 Trauma * 4.3 Sleep deprivation * 4.4 False memory syndrome * 5 Psychiatry * 5.1 Hypnosis * 6 Effects on society * 6.1 Legal cases * 6.2 Children * 6.3 Ethics and public opinion * 6.4 Potential benefits * 7 See also * 8 References * 9 Further reading ## Early work[edit] The false memory phenomenon was initially investigated by psychological pioneers Pierre Janet and Sigmund Freud.[2] Sigmund Freud is known as the founder of psychoanalysis, a field of psychology that has been deemed by many as dead or dying. One thing that has kept it alive is the emphasis Freud put on his study of memory. Freud was fascinated with memory and all the ways it could be understood, used, and manipulated. Some claim that his studies have been quite influential in contemporary memory research, including the research into the field of false memory.[3] Pierre Janet was a French Neurologist also credited with great contributions into memory research. Pierre contributed to false memory through his ideas on dissociation and memory retrieval through hypnosis.[4] In 1974, Elizabeth Loftus and John Palmer conducted a study[5] to investigate the effects of language on the development of false memory. The experiment involved two separate studies. In the first test, 45 participants were randomly assigned to watch different videos of a car accident, in which separate videos had shown collisions at 20 mph (32 km/h), 30 mph (48 km/h) and 40 mph (64 km/h). Afterwards, participants filled out a survey. The survey asked the question, "About how fast were the cars going when they smashed into each other?" The question always asked the same thing, except the verb used to describe the collision varied. Rather than "smashed", other verbs used included "bumped", "collided", "hit", or "contacted". Participants estimated collisions of all speeds to average between 35 mph (56 km/h) to just below 40 mph (64 km/h). If actual speed was the main factor in estimate, it could be assumed that participants would have lower estimates for lower speed collisions. Instead, the word being used to describe the collision seemed to better predict the estimate in speed rather than the speed itself.[5] The second experiment also showed participants videos of a car accident, but the phrasing of the follow-up questionnaire was critical in participant responses. 150 participants were randomly assigned to three conditions. Those in the first condition were asked the same question as the first study using the verb "smashed". The second group was asked the same question as the first study, replacing "smashed" with "hit". The final group was not asked about the speed of the crashed cars. The researchers then asked the participants if they had seen any broken glass, knowing that there was no broken glass in the video. The responses to this question had shown that the difference between whether broken glass was recalled or not heavily depended on the verb used. A larger sum of participants in the "smashed" group declared that there was broken glass. In this study, the first point brought up in discussion is that the words used to phrase a question can heavily influence the response given.[5] Second, the study indicates that the phrasing of a question can give expectations to previously ignored details, and therefore, a misconstruction of our memory recall. This indication supports false memory as an existing phenomenon. Replications in different contexts (such as hockey games instead of car crashes) have shown that different scenarios require different framing effects to produce differing memories.[6] ## Manifestations and types[edit] ### Mandela effect[edit] "Mandela Effect" redirects here. For other uses, see Mandela Effect (disambiguation). False memories can sometimes be shared by multiple people. One prominent example comes from a 2010 study that examined people familiar with the clock at Bologna Centrale railway station, which was damaged in the Bologna massacre bombing in August 1980. In the study, 92% of respondents falsely remembered the clock had remained stopped since the bombing when, in fact, the clock was repaired shortly after the attack. Years later the clock was again stopped and set to the time of the bombing in observance and commemoration of the bombing.[7] Other such examples include memories of the Berenstain Bears' name being spelled Berenstein,[8][9] the logo of clothing brand Fruit of the Loom featuring a cornucopia,[10] and the existence of a 1990s movie entitled Shazaam starring comedian Sinbad as a genie.[11] The Bologna station clock, subject of a collective false memory In 2010, this shared false memory phenomenon was dubbed "the Mandela effect" by self-described 'paranormal consultant' Fiona Broome, in reference to her false memory of the death of South African anti-Apartheid leader Nelson Mandela in prison in the 1980s (he actually died in 2013, after having served as President of South Africa from 1994 to 1999), which she claimed was shared by "perhaps thousands" of other people.[12][13][14] Scientists suggest that these are examples of false memories shaped by similar cognitive factors affecting multiple people and families,[15][16][17][9][18][19] such as social and cognitive reinforcement of incorrect memories[20][21] or false news reports and misleading photographs that influence the formation of memories based on them.[22][21][23][24] For example, the false memories of Shazaam have been explained as a confabulation of memories of the comedian wearing a genie-like costume during a TV presentation of Sinbad the Sailor movies in 1994,[25][26] and a similarly named 1996 film Kazaam featuring a genie played by Shaquille O'Neal.[24][11] In addition, in the 1960s, Hanna-Barbera had an animated series about a genie called Shazzan.[27] ### Presuppositions and the misinformation effect[edit] A presupposition is an implication through chosen language. If a person is asked, "What shade of blue was the wallet?", the questioner is, in translation, saying, "The wallet was blue. What shade was it?" The question's phrasing provides the respondent with a supposed "fact". This presupposition creates one of two separate effects: true effect and false effect. * In true effect, the implication was accurate: the wallet really was blue. That makes the respondent's recall stronger, more readily available, and easier to extrapolate from. A respondent is more likely to remember a wallet as blue if the prompt said that it was blue, than if the prompt did not say so. * In false effect, the implication was actually false: the wallet was not blue even though the question asked what shade of blue it was. This convinces the respondent of its truth (i.e., that the wallet was blue), which affects their memory. It can also alter responses to later questions to keep them consistent with the false implication. Regardless of the effect being true or false, the respondent is attempting to conform to the supplied information, because they assume it to be true.[28] Loftus' meta-analysis on language manipulation studies suggested the misinformation effect taking hold on the recall process and products of the human memory. Even the smallest adjustment in a question, such as the article preceding the supposed memory, could alter the responses. For example, having asked someone if they had seen "the" stop sign, rather than "a" stop sign, provided the respondent with a presupposition that there was a stop sign in the scene. This presupposition increased the number of people responding that they had indeed seen the stop sign.[29] The strength of verbs used in conversation or questioning also has a similar effect on the memory; for example – the words met, bumped, collided, crashed, or smashed would all cause people to remember a car accident at different levels of intensity. The words bumped, hit, grabbed, smacked, or groped would all paint a different picture of a person in the memory of an observer of sexual harassment if questioned about it later. The stronger the word, the more intense the recreation of the experience in the memory is. This in turn could trigger further false memories to better fit the memory created (change how a person looks or how fast a vehicle was moving before an accident).[30] ### Word lists[edit] One can trigger false memories by presenting subjects a continuous list of words. When subjects were presented with a second version of the list and asked if the words had appeared on the previous list, they found that the subjects did not recognize the list correctly. When the words on the two lists were semantically related to each other (e.g. sleep/bed), it was more likely that the subjects did not remember the first list correctly and created false memories (Anisfeld & Knapp, 1963).[31] In 1998 Kathleen McDermott and Henry Roediger III conducted a similar experiment. Their goal was to intentionally trigger false memories through word lists. They presented subjects with lists to study all containing a large number of words that that were semantically related to another word that was not found on the list. For example, if the word that they were trying to trigger was “river” the list would contain words such as flow, current, water, stream, bend, etc. They would then take the lists away and ask the subjects to recall the words on the lists. Almost every time the false memory was triggered and the subjects would end up recalling the target word as part of the list when it was never there. Mc Dermott and Roediger even went as far as informing the subjects of the purpose and details of the experiment, and still the subjects would recall the non listed target word as part of the word list they had studied.[32] ### Staged naturalistic events[edit] Subjects were invited into an office and were told to wait there. After this they had to recall the inventory of the visited office. Subjects recognized objects consistent with the “office schema” although they did not appear in the office. (Brewer & Treyens, 1981)[31] In another study, subjects were presented with a situation where they witnessed a staged robbery. Half of the subjects witnessed the robbery live while the other half watched a video of the robbery as it took place. After the event, they were sat down and asked to recall what had happened during the robbery. The results surprisingly showed that those who watched the video of the robbery actually recalled more information more accurately than those who were live on the scene. Still false memory presented itself in ways such as subjects seeing things that would fit in a crime scene that weren't there, or not recalling things that don't fit the crime scene. This happened with both parties, displaying the idea of staged naturalistic events.[33] ### Relational processing[edit] Memory retrieval has been associated with the brain's relational processing. In associating two events (in reference to false memory, say tying a testimony to a prior event), there are verbatim and gist representations. Verbatim matches to the individual occurrences (e.g., I do not like dogs because when I was five a chihuahua bit me) and gist matches to general inferences (e.g., I do not like dogs because they are mean). Keeping in line with the fuzzy-trace theory, which suggests false memories are stored in gist representations (which retrieves both true and false recall), Storbeck & Clore (2005) wanted to see how change in mood affected the retrieval of false memories. After using the measure of a word association tool called the Deese–Roediger–McDermott paradigm (DRM), the subjects' moods were manipulated. Moods were either oriented towards being more positive, more negative, or were left untouched. Findings suggested that a more negative mood made critical details, stored in gist representation, less accessible.[34] This would imply that false memories are less likely to occur when a subject was in a worse mood. See also: Suggestibility ## Theories[edit] ### Strength hypothesis (situational strength)[edit] The strength hypothesis states that in strong situations (situations where one course of action is encouraged more than any other course of action due to the objective payoff) people are expected to demonstrate rational behavior, basing their behavior on the objective payoff.[35] Current laws present a great example of this. Most people, no matter how daring, will conform to the laws of the land because the objective payoff means they receive safety and security. ### Construction hypothesis[edit] The construction hypothesis says that if a true piece of information being provided can alter a respondent's answer, then so can a false piece of information.[36] Construction hypothesis has major implications for explanations on the malleability of memory. Upon asking a respondent a question that provides a presupposition, the respondent will provide a recall in accordance with the presupposition (if accepted to exist in the first place). The respondent will recall the object or detail.[36] ### Skeleton theory[edit] Loftus developed what some refer to as "the skeleton theory" after having run an experiment involving 150 subjects from the University of Washington.[36] Loftus noticed that when a presupposition was one of false information it could only be explained by the construction hypothesis and not the strength hypothesis. Loftus then stated that a theory needed to be created for complex visual experiences where the construction hypothesis plays a significantly more important role than situational strength. She presented a diagram as a “skeleton” of this theory, which later became referred to by some as the skeleton theory. The skeleton theory explains the procedure of how a memory is recalled, which is split into two categories: the acquisition processes and the retrieval processes. The acquisition processes are in three separate steps. First, upon the original encounter, the observer selects a stimulus to focus on. The information that the observer can focus on compared to all of the information occurring in the situation as a whole, is very limited. In other words, a lot is going on around us and we only pick up on a small portion. This forces the observer to begin by selecting a focal point for focus. Second, our visual perception must be translated into statements and descriptions. The statements represent a collection of concepts and objects; they are the link between the event occurrence and the recall. Third, the perceptions are subject to any "external" information being provided before or after the interpretation. This subsequent set of information can reconstruct the memory.[36] The retrieval processes come in two steps. First, the memory and imagery are regenerated. This perception is subject to what foci the observer has selected, along with the information provided before or after the observation. Second, the linking is initiated by a statement response, "painting a picture" to make sense of what was observed. This retrieval process results in either an accurate memory or a false memory.[36] ## Natural factors for the formation of false memories[edit] ### Individual differences[edit] Greater creative imagination and dissociation are known to relate to false memory formation.[37] Creative imagination may lead to vivid details of imagined events. High dissociation may be associated with habitual use of lax response criteria for source decisions due to frequent interruption of attention or consciousness. Social desirability and false memory have also been examined.[38] Social desirability effects may depend on the level of perceived social pressure.[37] Individuals who feel under greater social pressure may be more likely to acquiesce. Perceived pressure from an authority figure may lower individuals' criteria for accepting a false event as true. The new individual difference factors include preexisting beliefs about memory, self-evaluation of one's own memory abilities, trauma symptoms, and attachment styles. Regarding the first of these, metamemory beliefs about the malleability of memory, the nature of trauma memory, and the recoverability of lost memory may influence willingness to accept vague impressions or fragmentary images as recovered memories and thus, might affect the likelihood of accepting false memory.[39] For example, if someone believes that memory once encoded is permanent, and that visualization is an effective way to recover memories, the individual may endorse more liberal criteria for accepting a mental image as true memory. Also, individuals who report themselves as having better everyday memories may feel more compelled to come up with a memory when asked to do so. This may lead to more liberal criteria, making these individuals more susceptible to false memory. There is some research that shows individual differences in false memory susceptibility are not always large (even on variables that have previously shown differences—such as creative imagination or dissociation[40]), that there appears to be no false memory trait,[41][42] and that even those who have highly superior memory are susceptible to false memories.[43] ### Trauma[edit] A history of trauma is relevant to the issue of false memory. It has been proposed that people with a trauma history or trauma symptoms may be particularly vulnerable to memory deficits, including source-monitoring failures.[44] Possible associations between attachment styles and reports of false childhood memories were also of interest. Adult attachment styles have been related to memories of early childhood events, suggesting that the encoding or retrieval of such memories may activate the attachment system. It is more difficult for avoidant adults to access negative emotional experiences from childhood, whereas ambivalent adults access these kinds of experiences easily.[45] Consistent with attachment theory, adults with avoidant attachment styles, like their child counterparts, may attempt to suppress physiological and emotional reactions to activation of the attachment system. Significant associations between parental attachment and children's suggestibility exist. These data, however, do not directly address the issue of whether adults' or their parents' attachment styles are related to false childhood memories. Such data nevertheless suggest that greater attachment avoidance may be associated with a stronger tendency to form false memories of childhood. ### Sleep deprivation[edit] Sleep deprivation can also affect the possibility of falsely encoding a memory. In two experiments, participants studied DRM lists (lists of words [e.g., bed, rest, awake, tired] that are semantically associated with a non-presented word) before a night of either sleep or sleep deprivation; testing took place the following day. One study showed higher rates of false recognition in sleep-deprived participants, compared with rested participants.[46] Sleep deprivation can increase the risk of developing false memories. Specifically, sleep deprivation increased false memories in a misinformation task when participants in a study were sleep deprived during event encoding, but did not have a significant effect when the deprivation occurred after event encoding.[47] ### False memory syndrome[edit] Main article: False memory syndrome False memory syndrome recognizes false memory as a prevalent part of one's life in which it affects the person's mentality and day-to-day life. False memory syndrome differs from false memory in that the syndrome is heavily influential in the orientation of a person's life, while false memory can occur without this significant effect. The syndrome takes effect because the person believes the influential memory to be true.[48] However, its research is controversial and the syndrome is excluded from identification as a mental disorder and, therefore, is also excluded from the Diagnostic and Statistical Manual of Mental Disorders. False memory is an important part of psychological research because of the ties it has to a large number of mental disorders, such as PTSD.[49] The false memory syndrome is loosely defined, and not a part of the DSM. However, the syndrome suggests that false memory can be declared a syndrome when recall of a false or inaccurate memory takes great effect on a person's life. This false memory can completely alter the orientation of your personality and lifestyle.[2] ## Psychiatry[edit] Therapists who subscribe to recovered memory theory point to a wide variety of common problems, ranging from eating disorders to sleeplessness, as evidence of repressed memories of sexual abuse.[50] Psychotherapists tried to reveal “repressed memories” in mental therapy patients through “hypnosis, guided imagery, dream interpretation and narco-analysis”. The reasoning was that if abuse couldn't be remembered, then it needed to be recovered by the therapist. The legal phenomena developed in the 1980s, with civil suits alleging child sexual abuse on the basis of “memories” recovered during psychotherapy. The term “repressed memory therapy” gained momentum and with it social stigma surrounded those accused of abuse. The “therapy” led to other psychological disorders in persons whose memories were recovered. Memories recovered through therapy have become more difficult to distinguish between simply being repressed or having existed in the first place. Therapists have used strategies such as hypnotherapy, repeated questioning, and bibliotherapy. These strategies may provoke the recovery of nonexistent events or inaccurate memories.[51][52][53] A recent report indicates that similar strategies may have produced false memories in several therapies in the century before the modern controversy on the topic which took place in the 1980s and 1990s.[54] According to Loftus, there are different possibilities to create false therapy-induced memory. One is the unintentional suggestions of therapists. For example, a therapist might tell their client that, on the basis of their symptoms, it is quite likely that they had been abused as a child. Once this "diagnosis" is made, the therapist sometimes urges the patient to pursue the recalcitrant memories. It is a problem resulting from the fact that people create their own social reality with external information.[55] The "lost-in-the-mall" technique is another recovery strategy. This is essentially a repeated suggestion pattern. The person whose memory is to be recovered is persistently said to have gone through an experience even if it may have not happened. This strategy can cause the person to recall the event as having occurred, despite its falsehood.[56] ### Hypnosis[edit] Laurence and Perry conducted a study testing the ability to induce memory recall through hypnosis. Subjects were put into a hypnotic state and later woken up. Observers suggested that the subjects were woken up by a loud noise. Nearly half of the subjects being tested concluded that this was true, despite it being false. However, by therapeutically altering the subject's state, they may have been led to believe that what they were being told was true.[57] Because of this, the respondent has a false recall. A 1989 study focusing on hypnotizability and false memory separated accurate and inaccurate memories recalled. In open-ended question formation, 11.5% of subjects recalled the false event suggested by observers. In a multiple-choice format, no participants claimed the false event had happened. This result led to the conclusion that hypnotic suggestions produce shifts in focus, awareness, and attention. Despite this, subjects do not mix fantasy up with reality.[2] ## Effects on society[edit] ### Legal cases[edit] Therapy-induced memory recovery has made frequent appearances in legal cases, particularly those regarding sexual abuse.[58] Therapists can often aid in creating a false memory in a victim's mind, intentionally or unintentionally. They will associate a patient's behavior with the fact that they have been a victim of sexual abuse, thus helping the memory occur. They use memory enhancement techniques such as hypnosis dream analysis to extract memories of sexual abuse from victims. According to the FMSF (False Memory Syndrome Foundation), these memories are false and are produced in the very act of searching for and employing them in a life narrative. In Ramona v. Isabella,[citation needed] two therapists wrongly prompted a recall that their patient, Holly Ramona, had been sexually abused by her father. It was suggested that the therapist, Isabella, had implanted the memory in Ramona after use of the hypnotic drug sodium amytal. After a nearly unanimous decision, Isabella had been declared negligent towards Holly Ramona. This 1994 legal issue played a massive role in shedding light on the possibility of false memories' occurrences. In another legal case where false memories were used, they helped a man to be acquitted of his charges. Joseph Pacely had been accused of breaking into a woman's home with the intent to sexually assault her. The woman had given her description of the assailant to police shortly after the crime had happened. During the trial, memory researcher Elizabeth Loftus testified that memory is fallible and there were many emotions that played a part in the woman's description given to police. Loftus has published many studies consistent with her testimony.[36][59][60] These studies suggest that memories can easily be changed around and sometimes eyewitness testimonies are not as reliable as many believe. Another notable case is Maxine Berry. Maxine grew up in the custody of her mother, who opposed the father having contact with her (Berry & Berry, 2001). When the father expressed his desire to attend his daughter's high school graduation, the mother enrolled Maxine in therapy, ostensibly to deal with the stress of seeing her father. The therapist pressed Maxine to recover memories of sex abuse by her father. Maxine broke down under the pressure and had to be psychiatrically hospitalized. She underwent tubal ligation, so she would not have children and repeat the cycle of abuse. With the support of her husband and primary care physician, Maxine eventually realized that her memories were false and filed a suit for malpractice. The suit brought to light the mother's manipulation of mental health professionals to convince Maxine that she had been sexually abused by her father. In February 1997 Maxine Berry sued her therapists[61] and clinic that treated her from 1992 to 1995 and, she says, made her falsely believe she had been sexually and physically abused as a child when no such abuse ever occurred. The lawsuit, filed in February 1997 in Minnehaha Co. Circuit Court South Dakota, states that therapist Lynda O'Connor-Davis had an improper relationship with Berry, both during and after her treatment. The suit also names psychologist Vail Williams, psychiatrist Dr. William Fuller and Charter Hospital and Charter Counseling Center as defendants. Berry and her husband settled out of court[62] Although there have been many legal cases in which false memory appears to have been a factor, this does not ease the process of distinguishing between false memory and real recall. Sound therapeutic strategy can help this differentiation, by either avoiding known controversial strategies or to disclosing controversy to a subject.[51][2][63] Harold Merskey published a paper on the ethical issues of recovered-memory therapy.[63] He suggests that if a patient had pre-existing severe issues in their life, it is likely that "deterioration" will occur to a relatively severe extent upon memory recall. This deterioration is a physical parallel to the emotional trauma being surfaced. There may be tears, writhing, or many other forms of physical disturbance. The occurrence of physical deterioration in memory recall coming from a patient with relatively minor issues prior to therapy could be an indication of the recalled memory's potential falsehood.[63] ### Children[edit] False memory is often considered for trauma victims[64] including those of childhood sexual abuse.[65][66][51][67] If a child experienced abuse, it is not typical for them to disclose the details of the event when confronted in an open-ended manner.[68] Trying to indirectly prompt a memory recall can lead to the conflict of source attribution, as if repeatedly questioned the child might try to recall a memory to satisfy a question. The stress being put on the child can make recovering an accurate memory more difficult.[65] Some people hypothesise that as the child continuously attempts to remember a memory, they are building a larger file of sources that the memory could be derived from, potentially including sources other than genuine memories. Children that have never been abused but undergo similar response-eliciting techniques can disclose events that never occurred.[68] One of children's most notable setbacks in memory recall is source misattribution. Source misattribution is the flaw in deciphering between potential origins of a memory. The source could come from an actual occurring perception, or it can come from an induced and imagined event. Younger children, preschoolers in particular, find it more difficult to discriminate between the two.[69] Lindsay & Johnson (1987) concluded that even children approaching adolescence struggle with this, as well as recalling an existent memory as a witness. Children are significantly more likely to confuse a source between being invented or existent.[70] For example, Shyamalan, Lamb and Sheldrick (1995) partially re-created a study that involved attempted memory implanting in children. The study comprised a series of interviews concerning a medical procedure that the children may have undergone. The data was scored so that if a child made one false affirmation during the interview, the child was classified as inaccurate. When the medical procedure was described in detail, "only 13% of the children answered 'yes' to the question 'Did you ever have this procedure?'". As to the success of implantation with false 'memories', the children "assented to the question for a variety of reasons, a false memory being only one of them. In sum, it is possible that no false memories have been created in children in implanted-memory studies".[71] ### Ethics and public opinion[edit] A 2016 study surveyed the public's attitude regarding the ethics of planting false memories as an attempt to influence healthy behavior. People were most concerned with the consequences, with 37% saying it was overly manipulative, potentially harmful or traumatic. Their reasons against are that the ends do not justify the means (32%), potential for abuse (14%), lack of consent (10%), practical doubts (8%), better alternative (7%), and free will (3%). Of those who thought implanting false memories would be acceptable, 36% believed the end justified the means, with other reasons being increasing treatment options (6%), people need support (6%), no harm would be done (6%), and it's no worse than alternatives (5%).[72] ### Potential benefits[edit] Several possible benefits associated with false memory arrive from fuzzy-trace theory and gist memory. Valerie F. Reyna, who coined the terms as an explanation for the DRM paradigm, explains that her findings indicate that reliance on prior knowledge from gist memory can help individuals make safer, well informed choices in terms of risk taking.[73] Other positive traits associated with false memory indicate that individuals have superior organizational processes, heightened creativity, and prime solutions for insight based problems. All of these things indicate that false memories are adaptive and functional.[74] False memories tied to familiar concepts can also potentially aid in future problem solving in a related topic, especially when related to survival.[75] ## See also[edit] * False memory syndrome, a condition in which a person's identity and relationships are affected by strongly believed but false memories of traumatic experiences. * Source-monitoring error, an effect in which memories are incorrectly attributed to different experiences than the ones that caused them. * Misinformation effect, false memories caused by exposure to misleading information presented between the encoding of an event and its subsequent recall. * Confabulation, the production of fabricated, distorted, or misinterpreted memories without the conscious intention to deceive. * Repressed memory, the idea that traumatic memories can be repressed and also potentially brought back through therapy. * Jamais vu, the feeling of unfamiliarity with recognised memories. * Cryptomnesia, a memory that is not recognised as such. * Memory implantation in people's minds has implications for therapy and legal settings. * Inception, a science fiction film dealing with the concept of implanting ideas in sleeping individuals ## References[edit] 1. ^ "APA Dictionary of Psychology". dictionary.apa.org. 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"Public Attitudes on the Ethics of Deceptively Planting False Memories to Motivate Healthy Behavior". Applied Cognitive Psychology. 30 (6): 885–897. doi:10.1002/acp.3274. PMC 5215583. PMID 28111495. 73. ^ Dodgson, Lindsay. Our brains sometimes create 'false memories' — but science suggests we could be better off this way” Business Insider. 74. ^ “Future Thinking and False Memories.” Psychology Today, Sussex Publishers, www.psychologytoday.com/us/blog/time-travelling-apollo/201607/future-thinking-and-false-memories. 75. ^ Jarrett, Christian (23 September 2013). "False memories have an upside". British Psychological Society. ## Further reading[edit] * Bjorklund, D. F. (2014). False-memory Creation in Children and Adults: Theory, Research, and Implications. Psychology Press. ISBN 9781138003224 * Conway, M. A. (1997). Recovered Memories and False Memories. Oxford University Press. * French, C (2003). "Fantastic Memories: The Relevance of Research into Eyewitness Testimony and False Memories for Reports of Anomalous Experiences" (PDF). Journal of Consciousness Studies. 10: 153–174. ISSN 1355-8250. Archived from the original on 13 March 2013.CS1 maint: bot: original URL status unknown (link) * Roediger, Henry L.; Marsh, Elizabeth J. (2009). "False memory". Scholarpedia. 4 (8): 3858. Bibcode:2009SchpJ...4.3858I. doi:10.4249/scholarpedia.3858. * Schacter, D. L; Curran, T. (1995). "The Cognitive Neuroscience of False Memories". Psychiatric Annals. 25 (12): 727–731. doi:10.3928/0048-5713-19951201-08. Listen to this article (20.9 megabytes) This audio file was created from a revision of this article dated 30 July 2019 (2019-07-30), and does not reflect subsequent edits. (Audio help · More spoken articles) * v * t * e Human memory Basic concepts * Encoding * Storage * Recall * Attention * Consolidation * Neuroanatomy Types Sensory * Echoic * Eidetic * Eyewitness * Haptic * Iconic * Motor learning * Visual Short-term * "The Magical Number Seven, Plus or Minus Two" * Working memory Intermediate * Long-term * Active recall * Autobiographical * Explicit * Declarative * Episodic * Semantic * Flashbulb * Hyperthymesia * Implicit * Meaningful learning * Personal-event * Procedural * Rote learning * Selective retention * Tip of the tongue Forgetting * Amnesia * anterograde * childhood * post-traumatic * psychogenic * retrograde * transient global * Decay theory * Forgetting curve * Interference theory * Memory inhibition * Motivated forgetting * Repressed memory * Retrieval-induced forgetting * Selective amnesia * Weapon focus Memory errors * Confabulation * False memory * Hindsight bias * Imagination inflation * List of memory biases * Memory conformity * Mere-exposure effect * Misattribution of memory * Misinformation effect * Source-monitoring error * Wernicke–Korsakoff syndrome Research * Art of memory * Memory and aging * Deese–Roediger–McDermott paradigm * Exceptional memory * Indirect tests of memory * Lost in the mall technique * Memory disorder * Memory implantation * Methods used to study memory * The Seven Sins of Memory * Effects of exercise on memory In society * Collective memory * Cultural memory * False memory syndrome * Memory and social interactions * Memory sport * Politics of memory * Shas Pollak * World Memory Championships Related topics * Absent-mindedness * Atkinson–Shiffrin memory model * Context-dependent memory * Childhood memory * Cryptomnesia * Effects of alcohol * Emotion and memory * Exosomatic memory * Flashbacks * Free recall * Involuntary memory * Levels-of-processing effect * Memory and trauma * Memory improvement * Metamemory * Mnemonic * Muscle memory * Priming * Intertrial * Prospective memory * Recovered-memory therapy * Retrospective memory * Sleep and memory * State-dependent memory * Transactive memory People * Robert A. Bjork * Stephen J. Ceci * Susan Clancy * Hermann Ebbinghaus * Sigmund Freud * Patricia Goldman-Rakic * Jonathan Hancock * Judith Lewis Herman * HM (patient) * Ivan Izquierdo * Marcia K. Johnson * Eric Kandel * KC (patient) * Elizabeth Loftus * Geoffrey Loftus * Chris Marker * James McGaugh * Paul R. McHugh * Eleanor Maguire * George Armitage Miller * Brenda Milner * Lynn Nadel * Dominic O'Brien * Ben Pridmore * Henry L. Roediger III * Steven Rose * Cosmos Rossellius * Daniel Schacter * Richard Shiffrin * Arthur P. Shimamura * Andriy Slyusarchuk * Larry Squire * Susumu Tonegawa * Anne Treisman * Endel Tulving * Robert Stickgold * Clive Wearing * Psychology portal * Philosophy portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	False memory	None	8,779	wikipedia	https://en.wikipedia.org/wiki/False_memory	2021-01-18T18:33:44	{"wikidata": ["Q2051704"]}
AIDS-related complex Kaposi's sarcoma is a part of AIDS-related complex SpecialtyInfectious disease AIDS-related complex (ARC) was introduced after discovery of the HIV (human immunodeficiency virus) when the medical community became aware of the inherent difficulties associated with treating patients suffering from an advanced case of HIV which gave rise to the term acquired immune deficiency syndrome (AIDS). The necessity for doctors to quickly and accurately understand the special needs of unknown patients suffering from AIDS in an emergency department situation was addressed with the creation of the term ARC.[citation needed] ARC is a "prodromal phase of infection with the human immunodeficiency virus (HIV)" that includes: low grade fever, unexplained weight loss, diarrhea, opportunistic infections and generalized lymphadenopathy. "Laboratory criteria separating AIDS-related complex (ARC) from AIDS include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in AIDS; follicular or mixed hyperplasia in ARC lymph nodes, leading to lymphocyte degeneration and depletion more typical of AIDS; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the full-blown AIDS."[1] Clinical use of this term was widely discontinued by the year 2000 in the United States after having been replaced by modern laboratory criteria. ## References[edit] 1. ^ As listed by the National Library of Medicine under Medical Subject Headings ## External links[edit] Classification D * MeSH: D000386 This infectious disease article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	AIDS-related complex	c0001857	8,780	wikipedia	https://en.wikipedia.org/wiki/AIDS-related_complex	2021-01-18T18:44:12	{"mesh": ["D000386"], "umls": ["C0001857"], "wikidata": ["Q4651855"]}
Paraganglioma is a type of noncancerous (benign) tumor that occurs in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. Paragangliomas are usually found in the head, neck, or torso. However, a type of paraganglioma known as pheochromocytoma develops in the adrenal glands. Adrenal glands are located on top of each kidney and produce hormones in response to stress. Most people with paraganglioma develop only one tumor in their lifetime. Some people develop a paraganglioma or pheochromocytoma as part of a hereditary syndrome that may affect other organs and tissues in the body. However, the tumors often are not associated with any syndromes, in which case the condition is called nonsyndromic paraganglioma or pheochromocytoma. Pheochromocytomas and some other paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Although most sympathetic paragangliomas are pheochromocytomas, some are found outside the adrenal glands, usually in the abdomen, and are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating. Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing. Although most paragangliomas and pheochromocytomas are noncancerous, some can become cancerous (malignant) and spread to other parts of the body (metastasize). Extra-adrenal paragangliomas become malignant more often than other types of paraganglioma or pheochromocytoma. ## Frequency It is estimated that the prevalence of pheochromocytoma is 1 in 500,000 people, and the prevalence of other paragangliomas is 1 in 1 million people. These statistics include syndromic and nonsyndromic paraganglioma and pheochromocytoma. ## Causes The VHL, RET, SDHB, and SDHD genes can be mutated in both syndromic and nonsyndromic forms of paraganglioma and pheochromocytoma. Mutations in at least three additional genes, TMEM127, SDHA, and KIF1B, have been identified in people with the nonsyndromic form of these conditions. Gene mutations increase the risk of developing paraganglioma or pheochromocytoma by affecting control of cell growth and division. Mutations in the VHL, SDHA, SDHB, and SDHD genes increase the risk of developing nonsyndromic paraganglioma or pheochromocytoma. The protein produced from the VHL gene helps break down other, unneeded proteins, including a protein called HIF that stimulates cell division and blood vessel formation under certain cellular conditions. The proteins produced from the SDHA, SDHB, and SDHD genes are each pieces (subunits) of an enzyme that is important for energy production in the cell. This enzyme also plays a role in the breakdown of the HIF protein. Mutations in the VHL, SDHA, SDHB, and SDHD genes stabilize the HIF protein, causing it to build up in cells. Excess HIF protein stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors. Mutations in the RET gene have been found in nonsyndromic pheochromocytoma in addition to a pheochromocytoma-predisposing syndrome. The protein produced from the RET gene is involved in signaling within cells that can stimulate cell division or maturation. Mutations in the RET gene overactivate the protein's signaling function, which can trigger cell growth and division in the absence of signals from outside the cell. This unchecked cell division can lead to the formation of tumors in the adrenal glands. Mutations in the TMEM127 gene have been identified most commonly in people with nonsyndromic pheochromocytoma and are rarely seen in people with other paraganglioma. The TMEM127 protein normally controls a signaling pathway that induces cell growth and survival. Studies suggest that mutations in the TMEM127 gene lead to abnormal activation of cell growth, which may cause tumor formation. Mutations in the KIF1B gene have been reported in nonsyndromic pheochromocytoma. Studies suggest that these mutations impair the function of the KIF1B protein, which normally triggers cells to self-destruct in a process called apoptosis. When apoptosis is impaired, cells grow and divide too quickly or in an uncontrolled way, potentially leading to tumor formation. Many people with nonsyndromic paraganglioma or pheochromocytoma do not have a mutation in any of the genes associated with the conditions. It is likely that other, unidentified genes also predispose to development of paraganglioma or pheochromocytoma. ### Learn more about the genes associated with Nonsyndromic paraganglioma * KIF1B * RET * SDHA * SDHB * SDHD * TMEM127 * VHL ## Inheritance Pattern Nonsyndromic paraganglioma can be inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing a paraganglioma or pheochromocytoma. People with mutations in the gene inherit an increased risk of this condition, not the condition itself. Not all people with this condition have a mutation in the gene, and not all people with a gene mutation will develop the disorder. Most cases of nonsyndromic paraganglioma and pheochromocytoma are considered sporadic, which means the tumors 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Nonsyndromic paraganglioma	c0031511	8,781	medlineplus	https://medlineplus.gov/genetics/condition/nonsyndromic-paraganglioma/	2021-01-27T08:24:52	{"gard": ["10599", "7385"], "mesh": ["D010673"], "omim": ["171300"], "synonyms": []}
## Cloning and Expression Nitric oxide (NO) accounts for the biologic activity of endothelium-derived relaxing factor (EDRF), discovered by Furchgott and Zawadzki (1980) and Rapoport and Murad (1983). NO is synthesized in endothelial cells from L-arginine by nitric oxide synthase (NOS). EDRF is important in regulation of vasomotor tone and blood flow by inhibiting smooth muscle contraction and platelet aggregation. Janssens et al. (1992) isolated a cDNA encoding a human vascular NOS. The translated human protein was 1,203 amino acids long with a predicted molecular mass of 133 kD. They showed that the cDNA encodes a calcium-regulated, constitutively expressed endothelial NOS, capable of producing EDRF in blood vessels. Marsden et al. (1992) likewise cloned and sequenced human endothelial NO synthase. Their cDNA clones predicted a protein of 1,203 amino acids with about 60% identity with the rat brain NO synthase isoform (163731). (Nitric oxide synthases have been assigned to 2 classes: a constitutively expressed, calcium-regulated class identified in brain, neutrophils, and endothelial cells, and a calcium-independent class identified in endotoxin- or cytokine-induced macrophages and endothelial cells (163730).) Gene Structure Marsden et al. (1993) isolated genomic clones encoding human endothelial NO synthase and determined the structural organization of the gene. It contains 26 exons spanning approximately 21 kb of genomic DNA and encodes an mRNA of 4,052 nucleotides. Characterization of the 5-prime-flanking region indicated that the NOS3 gene is TATA-less and exhibits proximal promoter elements consistent with a constitutively expressed gene, namely, SP1 and GATA motifs. Mapping By Southern blot hybridization of human/rodent somatic cell hybrids, Marsden et al. (1993) assigned the NOS3 gene to chromosome 7 and regionalized it to 7q35-q36 by fluorescence in situ hybridization. By PCR amplification applied to a panel of DNAs from human/rodent somatic cell hybrids, by Southern blot analysis, and by fluorescence in situ hybridization, Robinson et al. (1994) localized the NOS3 gene to 7q36. By analysis of interspecific backcross progeny, Gregg et al. (1995) mapped the mouse homolog to chromosome 5. Biochemical Features ### Crystal Structure Raman et al. (1998) reported the crystal structure of the heme domain of endothelial NOS in tetrahydrobiopterin (BH4)-free and -bound forms at 1.95-angstrom and 1.9-angstrom resolution, respectively. In both structures a zinc ion is tetrahedrally coordinated to pairs of symmetry-related cysteine residues at the dimer interface. The conserved Cys-(X)4-Cys motif and its strategic location establish a structural role for the metal center in maintaining the integrity of the BH4-binding site. The unexpected recognition of the substrate L-arginine at the BH4 site indicates that this site is poised to stabilize a positively charged pterin ring and suggests a model involving a cationic pterin radical in the catalytic cycle. Gene Function Fulton et al. (1999) demonstrated that AKT (164730) directly phosphorylated eNOS and activated the enzyme leading to nitric oxide production, whereas eNOS mutated at a putative AKT phosphorylation site was resistant to phosphorylation and activation by AKT. Activated AKT increased basal nitric oxide release from endothelial cells, and activation-deficient AKT attenuated NO production stimulated by VEGF (192240). Thus, Fulton et al. (1999) concluded the eNOS is an AKT substrate linking signal transduction by AKT to the release of the gaseous second messenger nitric oxide. Dimmeler et al. (1999) stated that physiologically, the most important stimulus for the continuous formation of nitric oxide is the viscous drag (or shear stress) generated by the streaming blood on the endothelial layer. PI3K (see 601232) and AKT are activated in endothelial cells in response to shear stress. Dimmeler et al. (1999) demonstrated that AKT mediates the activation of eNOS, leading to increased nitric oxide production. Inhibition of the PI3K AKT pathway or mutation of the AKT site on eNOS protein at serine-1177 attenuated the serine phosphorylation and prevented the activation of eNOS. Mimicking the phosphorylation of ser1177 directly enhanced enzyme activity and altered the sensitivity of the enzyme to calcium, rendering its activity maximal at subphysiologic concentrations of calcium. Thus, phosphorylation of eNOS by AKT represented a novel calcium-independent regulatory mechanism for activation of eNOS. Napolitano et al. (2000) investigated the interactions between ET1 (131240) and the NO system in the feto-placental unit. They examined the mRNA expression of ET1, inducible NOS (163730), and eNOS in human cultured placental trophoblastic cells obtained from preeclamptic (PE) and normotensive pregnancies. ET1 expression was increased in PE cells, whereas iNOS, which represents the main source of NO synthesis, was decreased; conversely, eNOS expression was increased. ET1 was able to influence its own expression as well as NOS isoform expression in normal and PE trophoblastic cultured cells. The findings suggested the existence of a functional relationship between ET(s) and NOS isoforms that could constitute the biologic mechanism leading to the reduced placental blood flow and increased resistance to flow in the feto-maternal circulation that are characteristic of the pathophysiology of preeclampsia. Using a yeast 2-hybrid screen, Dedio et al. (2001) found that the oxygenase domain of human ENOS interacted with human NOSIP (616759). Reciprocal coimmunoprecipitation and Western blot analysis confirmed interaction between ENOS and NOSIP in cotransfected COS-7 cells. Deletion analysis showed that NOSIP bound the C-terminal portion of the ENOS oxygenase domain in a region that overlapped the binding site for plasma membrane caveolin (see 601047). Overexpression of NOSIP reduced calcium-stimulated nitric oxide production in ENOS-expressing Chinese hamster ovary (CHO) cells. Overexpression of NOSIP also reduced membrane localization of ENOS in CHO cells, causing a shift from caveolin-rich membrane fractions to intracellular compartments. Dedio et al. (2001) concluded that NOSIP promotes translocation of ENOS from the plasma membrane to intracellular sites, thus inhibiting nitric oxide synthesis. Autosomal dominant adult polycystic kidney disease (ADPKD; 173900) is associated with altered endothelial-dependent vasodilation and decreased vascular production of NO. Thus, eNOS could have a modifier effect in ADPKD. To test this hypothesis, Persu et al. (2002) genotyped 173 unrelated European ADPKD patients for the glu298-to-asp (163729.0001), intron 4 VNTR, and -786T-C (163729.0002) polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In 93 males, the glu298-to-asp polymorphism was associated with a lower age at ESRD. This effect was confirmed in a subset of males linked to PKD1 (601313) and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NOS activity was decreased in renal artery samples from PKD males harboring the asp298 allele, in association with posttranslational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. Persu et al. (2002) concluded that glu298-to-asp is associated with a 5 year lower mean age at ESRD in a subset of ADPKD males. They hypothesized that the effect could be due to decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO. Nisoli et al. (2003) found that NO triggers mitochondrial biogenesis in cells as diverse as brown adipocytes and 3T3-L1, U937, and HeLa cells. This effect of NO was dependent on cGMP and was mediated by the induction of PPARGC1 (604517), a master regulator of mitochondrial biogenesis. Moreover, Nisoli et al. (2003) found that mitochondrial biogenesis induced by exposure to cold was markedly reduced in brown adipose tissue of eNOS -/- mice, which had a reduced metabolic rate and accelerated weight gain compared to wildtype mice. Thus, Nisoli et al. (2003) concluded that a NO-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance. Simoncini et al. (2004) demonstrated that tibolone and its estrogenic metabolites activate NO synthesis by recruiting functional estrogen receptors, whereas the progestogenic/androgenic metabolite had no effect. During prolonged exposures, tibolone and the estrogenic compounds enhanced the expression of eNOS. In addition, tibolone was able to induce rapid activation of eNOS, leading to rapid increases in the release of NO. Different from estrogen, rapid activation of eNOS did not rely on recruitment of PI3K but rather on MAPK-dependent cascades. Robb et al. (2004) found that the 5-prime UTR of the NOS3AS (612205) transcript was complementary to the portion of NOS3 mRNA derived from exons 23 to 26. RT-PCR analysis showed that expression of NOS3 in human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (HAOVSMCs) was inversely proportional to that of NOS3AS. Both the NOS3 and NOS3AS genes were transcriptionally active; however, NOS3AS appeared to downregulate the steady-state levels of NOS3 mRNA and protein. RT-PCR showed that overexpression of the overlapping region of NOS3AS had little impact on NOS3 mRNA levels in HUVECs; however, Western blot analysis showed that NOS3 protein levels were markedly reduced. NOS3AS also reduced the expression of a chimeric transcript containing the NOS3-overlapping sequence fused to a reporter gene. Inhibition of NOS3AS expression by RNA interference (RNAi) in HAOVSMCs increased NOS3 expression, and inhibition of histone deacetylase (see HDAC1; 601241) in HAOVSMCs increased expression of NOS3AS mRNA prior to decrease in NOS3 mRNA expression. Robb et al. (2004) concluded that NOS3AS participates in the posttranscriptional regulation of NOS3. Fish et al. (2007) found that NOS3AS was induced by hypoxia in cultured human endothelial and smooth muscle cells and in aortas of hypoxic rats. NOS3AS induction preceded the decrease in NOS3 steady-state mRNA in endothelial cells, and knockdown of NOS3AS by RNAi indicated that NOS3AS downregulated NOS3 expression during hypoxia. Hypoxia did not induce transcription of NOS3AS, but instead stabilized NOS3AS transcripts, predominantly the short NOS3AS variant, leading to elevated NOS3AS levels. RT-PCR of fractionated cells showed that both NOS3AS pre-mRNA and mature NOS3AS mRNA were enriched in the nucleus under basal conditions. Under hypoxic conditions, the cytoplasmic levels of mature NOS3AS mRNA increased more than 30-fold, whereas levels in the nucleus increased only moderately. In contrast, the nuclear/cytoplasmic distribution of NOS3 mRNA was not altered under hypoxic conditions, with NOS3 mRNA levels decreasing in both the cytoplasm and nucleus. NOS3 associated with polyribosomes in normoxic cells, but its association with polyribosomes was attenuated in hypoxic cells, concurrent with association of the short NOS3AS variant with polyribosomes. Fish et al. (2007) concluded that NOS3 expression is regulated by its overlapping NOS3AS transcript in a hypoxia-dependent fashion. Nisoli et al. (2005) reported that calorie restriction for either 3 or 12 months induced eNOS expression and 3-prime/5-prime-cyclic GMP in various tissues of male mice. This was accompanied by mitochondrial biogenesis, with increased oxygen consumption and ATP production, and an enhanced expression of Sirt1 (604479). Nisoli et al. (2005) reported these effects were strongly attenuated in eNOS null-mutant mice. Thus, Nisoli et al. (2005) concluded that nitric oxide plays a fundamental role in the processes induced by calorie restriction and may be involved in the extension of life span in mammals. Using human platelets, Ji et al. (2007) demonstrated that polymerization of beta-actin (ACTB; 102630) regulated the activation state of NOS3, and hence NO formation, by altering its binding to heat-shock protein-90 (HSP90, or HSPCA; 140571). NOS3 bound the globular, but not the filamentous, form of beta-actin, and the affinity of NOS3 for globular beta-actin was, in turn, increased by HSP90. Formation of this ternary complex of NOS3, globular beta-actin, and HSP90 increased NOS activity and cyclic GMP, an index of bioactive NO, and increased the rate of HSP90 degradation, thus limiting NOS3 activation. Ji et al. (2007) concluded that beta-actin regulates NO formation and signaling in platelets. Lim et al. (2008) demonstrated that blocking phosphorylation of the AKT substrate eNOS inhibits tumor initiation and maintenance. Moreover, eNOS enhances the nitrosylation and activation of endogenous wildtype Ras proteins (see 190020), which are required throughout tumorigenesis. Lim et al. (2008) suggested that activation of the PI3K-AKT-eNOS-(wildtype) Ras pathway by oncogenic Ras in cancer cells is required to initiate and maintain tumor growth. Chen et al. (2010) showed that S-glutathionylation of eNOS reversibly decreases NOS activity with an increase in superoxide generation primarily from the reductase, in which 2 highly conserved cysteine residues are identified as sites of S-glutathionylation and found to be critical for redox-regulation of eNOS function. Chen et al. (2010) showed that e-NOS S-glutathionylation in endothelial cells, with loss of nitric oxide and gain of superoxide generation, is associated with impaired endothelium-dependent vasodilation. In hypertensive vessels, eNOS S-glutathionylation is increased with impaired endothelium-dependent vasodilation that is restored by thiol-specific reducing agents, which reverse this S-glutathionylation. Chen et al. (2010) concluded that S-glutathionylation of eNOS is a pivotal switch providing redox regulation of cellular signaling, endothelial function, and vascular tone. Straub et al. (2012) reported a model for the regulation of NO signaling by demonstrating that hemoglobin alpha, encoded by the HBA1 (141800) and HBA2 (141850) genes, is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to hemoglobin alpha and is abrogated by its genetic depletion. Mechanistically, endothelial hemoglobin alpha heme iron in the Fe(3+) state permits NO signaling, and this signaling is shut off when hemoglobin alpha is reduced to the Fe(2+) state by endothelial CYB5R3 (613213). Genetic and pharmacologic inhibition of CYB5R3 increases NO bioactivity in small arteries. Straub et al. (2012) concluded that their data revealed a mechanism by which the regulation of the intracellular hemoglobin alpha oxidation state controls NOS signaling in nonerythroid cells. The authors suggested that this model may be relevant to heme-containing globins in a broad range of NOS-containing somatic cells. Using immunofluorescence analysis, Lechauve et al. (2018) showed that AHSP (ERAF; 605821) was coexpressed with alpha-globin in mouse and human ECs and regulated alpha-globin protein levels. Expression analysis in human coronary artery ECs and experiments with purified human proteins demonstrated that AHSP and eNOS interacted with alpha-globin in a mutually exclusive manner and enhanced its accumulation in cells. However, only AHSP could stabilize oxidized Fe(3+)-alpha-globin. The authors demonstrated that eNOS rapidly reduced AHSP-bound Fe(3+)-alpha-globin via direct electron transfer from its flavin-associated reductase domain. Molecular Genetics In a Japanese study of 100 patients with essential hypertension (145500) and 123 patients with normal blood pressure, Nakayama et al. (1997) found that the distribution of allele frequencies for the CA repeat in the NOS3 gene was not significantly different between the 2 groups. However, comparing the allele frequencies in the hypertensive group without left ventricular hypertrophy (LVH) and the normotensive group, the overall distributions were significantly different (p = 0.019). The 33-repeat allele was found more frequently in the hypertensive group without LVH than in the normotensive group. Bonnardeaux et al. (1995) found that the highly polymorphic (CA)n repeats in intron 13 and 2 biallelic markers in intron 18 of the NOS3 gene are not associated with essential hypertension. Wang et al. (1996) studied a marker closer to the 5-prime end of the NOS3 gene, the 27-bp repeat in intron 4, in relation to coronary artery disease. They identified 2 alleles: a common larger allele (allele frequency, 0.830) and a smaller rare allele (0.170). The larger allele had 5 tandem 27-bp repeats. The smaller allele had only 4 repeats that were apparently missing the third repeat judging by minor a difference in sequence. The distribution of the genotypes appeared to be in Hardy-Weinberg equilibrium and the polymorphism was inherited in a simple mendelian fashion. Wang et al. (1996) found from study of 549 subjects with and 153 without coronary artery disease that in current and ex-cigarette smokers, but not nonsmokers, there was a significant excess of homozygotes for the rare allele in patients with severely stenosed arteries, compared with those with no mild stenosis. This genotype was also associated with a history of myocardial infarction. The authors noted that, since endothelial-dependent vasodilatation is mediated by release of nitric oxide formed by constitutively expressed endothelial nitric oxide synthase, the smoking-dependent excess coronary risk in homozygotes is consistent with a predisposition to endothelial dysfunction. Coronary spasm plays an important role in the pathogenesis not only of variant angina but also of ischemic heart disease in general. However, the prevalence of coronary spasm appears to be higher in Japanese than in Caucasians (Bertrand et al., 1982; Yasue and Kugiyama, 1990), suggesting that genetic factors may be involved in its pathogenesis. Endothelial-derived nitric oxide has been implicated in the control of vascular tone. Kugiyama et al. (1997) and Motoyama et al. (1997) showed that basal acetylcholine-stimulated and flow-dependent nitric oxide activities are decreased in both coronary and brachial arteries of patients with coronary spasm. Yoshimura et al. (1998) identified a glu298-to-asp variant (E298D; 163729.0001) in exon 7 of the NOS3 gene that was more frequent in patients with coronary spasm. In studies of an elderly population in Australia, Liyou et al. (1998) could find no association of the E298D variant with coronary artery disease. Nakayama et al. (1999) reported that a -786T-C mutation (163729.0002) in the promoter region of the eNOS gene reduced transcription of the gene and was strongly associated with coronary spastic angina and myocardial infarction. To elucidate the molecular mechanism for the reduced eNOS gene transcription, Miyamoto et al. (2000) purified a protein that specifically binds to the mutant allele in nuclear extracts from HeLa cells. The purified protein was identical to replication protein A1 (RPA1; 179835), known as a single-stranded DNA-binding protein essential for DNA repair, replication, and recombination. In human umbilical vein endothelial cells, inhibition of RPA1 expression using antisense oligonucleotides restored transcription driven by the mutated promoter sequence, whereas overexpression of RPA1 further reduced it. Serum nitrite/nitrate levels among individuals carrying the -786T-C mutation were significantly lower than among those without the mutation. The authors concluded that RPA1 apparently functions as a repressor protein in the -786T-C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease. Pregnancy-induced hypertension (see 189800) may be regarded as a manifestation of endothelial cell dysfunction. Constitutive nitric oxide production in endothelial cells increases during pregnancy and contributes to vasodilatation and blunting of vasopressor response. In women developing pregnancy-induced hypertension, NO generation is inappropriately low, and administration of an NO donor improves flow in the uterine artery in normal early pregnancy and in women at high risk of developing disease. Yallampalli and Garfield (1993) and others had observed that inhibition of NO synthesis in rats during pregnancy produces hypertension, proteinuria, thrombocytopenia, and fetal growth retardation. These considerations prompted Arngrimsson et al. (1997) to study linkage to the NOS3 gene in affected sisters and in multiplex families. A lod score of 3.36 was obtained for D7S505 when a best-fitting model derived from genetic epidemiologic data was used, and lod scores of 2.54 to 4.03 were obtained when various other genetic models were used. The transmission/disequilibrium test (TDT), a model-free estimate of linkage, showed strongest association and linkage with a microsatellite within intron 13 of the NOS3 gene (P = 0.005). Lewis et al. (1999) were unable to detect linkage of preeclampsia to the NOS3 region on 7q. They studied 2, separately ascertained, affected sister-pairs collections, from Amsterdam and Cambridge (U.K.), that contained 104 sibships. In the Cambridge Centre, a total of 21 extended pedigrees suitable for conventional parametric linkage studies were also identified. The reason for the discrepancy with the results of Arngrimsson et al. (1997) was not clear. Lewis et al. (1999) concluded that although abnormalities in NO production have been observed in preeclampsia, the case for the NOS3 gene or its product, eNOS, having a primary role in the pathophysiology of preeclampsia remained unproved. Tempfer et al. (2001) performed a prospective case-control study of 105 women with idiopathic recurrent miscarriage and 91 healthy controls. Using PCR, they identified the different alleles of a 27-basepair tandem repeat polymorphism in intron 4 of the NOS3 gene. The wildtype allele was identified in 329 of 392 chromosomes (frequency 0.84). The polymorphic A allele was present on 63 chromosomes (frequency 0.16). The genotype frequencies were as follows: 68% (B/B), 31% (A/B), and 0.5% (A/A). The distribution of genotype frequencies was significantly different between the study and in control groups for allele A/B heterozygotes (36.7 vs 23.8%, P = 0.03, odds ratio 1.6, 95% CI 1.1-3.8). Only 1 person in the study group was A/A. Tanus-Santos et al. (2001) studied the distribution of genetic variants of 3 clinically relevant NOS3 polymorphisms in 305 ethnically well-characterized DNA samples (100 Caucasians, 100 African Americans, and 105 Asians). They found marked interethnic differences in the distribution of NOS3 variants, in the estimated haplotype frequency, and in the association between variants. The asp298 variant (163729.0001) was more common in Caucasians (34.5%) than in African Americans (15.5%) or Asians (8.6%) (p less than 0.0001). The -786C variant (163729.0002) was also more common in Caucasians (42.0%) than in African Americans (17.5%) or Asians (13.8%) (p less than 0.0001). The 4a VNTR in intron 4 was more common in African Americans (26.5%) than in Caucasians (16.0%) or Asians (12.9%) (p less than 0.0001). The most common predicted haplotype in the 3 groups combined only wildtype variants. Asians had the highest frequency of this haplotype (77% in Asians vs 46% in the other groups). In Caucasians, the asp298 and -786C variants were associated, and this haplotype was predicted to have a frequency of 24%. Endothelial nitric oxide synthase plays a key role in the regulation of normal function of the vessel wall. Heltianu et al. (2002) found a relatively high frequency of 2 polymorphic variants of NOS3 in males with Fabry disease (301500) and suggested that in addition to mutations in the alpha-galactosidase A gene, variation in NOS3 may be significant in determining the phenotype. Casas et al. (2004) performed a metaanalysis of 26 case-control studies evaluating the association between the NOS3 polymorphisms E298D, -786T-C, and the intron 4 VNTR and ischemic heart disease (myocardial infarction or angiographic coronary artery occlusion), involving 9,867 cases and 13,161 controls. They found that homozygosity for asp298 or the intron 4 A allele was associated with an increased risk of ischemic heart disease (OR, 1.31 and 1.34, respectively), but no significant association was found with the -786C allele. Casas et al. (2004) suggested that common genetic variations in the NOS3 gene contribute to atherosclerosis susceptibility. In 110 dizygotic white twin pairs, Persu et al. (2005) identified NOS3 haplotypes based on 3 polymorphisms, E298D, the intron 4 VNTR, and -786T-C, and the intron 13 CA repeat. Haplotype analysis revealed a significant association between NOS3 haplotypes and daytime ambulatory diastolic and systolic blood pressure, with the latter remaining significant after adjustment for multiple testing (p = 0.032) and mainly attributable to 4 haplotypes accounting for 11.9% of all represented haplotypes. The therapeutic application of NO in high-altitude (HA) disorders, for the improvement of oxygenation and vasodilation, prompted Ahsan et al. (2005) to investigate the NOS3 gene with respect to high-altitude adaptation. They screened 131 HA monks, 136 HA controls, and 170 lowlanders for the NOS3 894G-T (E298D; 163729.0001) polymorphism and for the 4B/4A polymorphisms. NO levels were estimated and correlated with the polymorphisms. The 3 groups were in Hardy-Weinberg equilibrium for the polymorphisms. Wildtype alleles G and 4B were significantly overrepresented in the HA groups as compared with the lowlanders (p = 0.006 and p = 0.02, respectively). NO levels were highest in HA monks, followed by HA controls, and then lowlanders (p less than 0.0001). Combinations of the GG and BB genotypes were distributed significantly more frequently in the HA monks (p less than 0.0001) and HA controls (p = 0.0005) than in lowlanders. Ahsan et al. (2005) concluded that the genotype combination of NOS3 wildtype homozygotes (GG, BB) occurs more frequently in high-altitude groups that in lowlanders and contributes to higher NO levels associated with high-altitude adaptation. Animal Model Pharmacologic blockade of NO production with arginine analogs such as L-nitroarginine or L-N-arginine methylester affects multiple isoforms of nitric oxide synthase and so cannot distinguish their physiologic roles. To study the role of endothelial NOS in vascular function, Huang et al. (1995) disrupted the gene encoding endothelial NOS in mice by homologous recombination. Homozygous mutant mice were found to be viable, fertile, and indistinguishable from wildtype and heterozygous littermates in appearance or routine behavior. Immunoreactive NOS3 protein was not present, as shown by Western blot analysis of the brain, heart, lung, and aorta. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, was absent, and the NOS3 mutant mice were hypertensive. Thus, the author concluded that NOS3 mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggested that nonendothelial isoforms of NOS may be involved in maintaining blood pressure. Huang et al. (1995) suggested that perhaps the renin-angiotensin system and autonomic nervous system evolved to serve primarily as a defense against hypotension, and diminution in their activity is a poor buffer against hypertension. Alternatively, NOS3 may be involved in establishing the baroreceptor set-point. The question of whether subpopulations of humans suffering from hypertension have defects in NOS3 expression awaits an answer from genetic analysis and the development of more selective inhibitors of the NOS isoforms. Snyder (1995) reviewed the significance of the findings of Huang et al. (1995) in the NOS3 'knockout' mouse because so-called nNOS (NOS1; 163731) occurs in nerves that mediate penile erection and NOS inhibitors block erection. It was thought that the null mutant nNOS mice would not procreate. As it turned out, however, these animals do breed and appear to be generally normal. However, they have dilated stomachs with a constricted pyloric sphincter, and so provide a model for infantile hypertrophic pyloric stenosis. The same mice are resistant to brain damage caused by vascular strokes, confirming that nitric oxide is crucial in mediating stroke damage. Further studies indicated that the nNOS-negative mice are highly aggressive toward other males to the extent that they will kill their wildtype littermates if left unattended, and they display strikingly inappropriate and excessive sexual behavior. Mice homozygous for a knockout in NOS2 (macrophage or inducible NOS, iNOS) have markedly reduced defenses against microorganisms such as Listeria and Leishmania and against the proliferation of lymphoma tumor cells. Champion et al. (1999) cited work indicating that NOS activity decreases with age. To determine whether adenoviral-mediated overexpression of NOS3 could enhance erectile responses, they administered a recombinant adenovirus containing the NOS3 gene into the corpora cavernosum of the aged rat. Adenoviral expression of the beta-galactosidase reporter gene was observed in cavernosal tissue one day after the intracavernosal administration of the beta-gal-marked adenovirus; one day after administration of the construct containing NOS3, transgene expression was confirmed by immunoblot staining of NOS3 protein, and cGMP levels were increased. The increase in cavernosal pressure in response to cavernosal nerve stimulation was enhanced in animals transfected with NOS3, and erectile responses to acetylcholine and zaprinast were enhanced. Champion et al. (1999) suggested that in vivo gene transfer of NOS3, alone or in combination with a type V phosphodiesterase inhibitor, may constitute a new therapeutic intervention for the treatment of erectile dysfunction. Steudel et al. (1998) investigated the effects of congenital deficiency of NOS3 on the pulmonary vascular responses to hypoxia. The findings suggested that congenital NOS3 deficiency in mice enhances hypoxic pulmonary vascular remodeling and hypertension, and right ventricular hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress. To study the role of nitric oxide constitutively produced by NOS3 in the regulation of blood pressure and vascular tone, Ohashi et al. (1998) generated transgenic mice overexpressing bovine NOS3 in the vascular wall using murine preproendothelin-1 (ET1) promoter. Blood pressure was significantly lower in NOS3-overexpressing mice than in control littermates. In the transgenic aorta, basal NO release and basal cGMP levels were significantly increased. In contrast, relaxations of transgenic aorta in response to acetylcholine and sodium nitroprusside were significantly attenuated, and the reduced vascular reactivity was associated with reduced response of cGMP elevation to these agents as compared with control aortas. Thus, in addition to the essential role of NOS3 in blood pressure regulation, tonic NO release by NOS3 in the endothelium induces the reduced vascular reactivity to NO-mediated vasodilatators, providing several insights into the pathogenesis of nitrate tolerance. In the heart, nitric oxide inhibits L-type calcium channels but stimulates sarcoplasmic reticulum calcium release, leading to variable effects on myocardial contractility. Barouch et al. (2002) demonstrated that spatial confinement of specific nitric oxide synthase isoforms regulates this process. Endothelial nitric oxide synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type calcium channels allows nitric oxide to inhibit beta-adrenergic-induced inotropy. Neuronal nitric oxide synthase (NOS1; 163731), however, is targeted to cardiac sarcoplasmic reticulum. NO stimulation of sarcoplasmic reticulum calcium release via the ryanodine receptor (RYR2; 180902) in vitro, suggests that NOS1 has an opposite facilitative effect on contractility. Barouch et al. (2002) demonstrated that Nos1-deficient mice have suppressed inotropic response, whereas Nos3-deficient mice have enhanced contractility, owing to corresponding changes in sarcoplasmic reticulum calcium release. Both Nos1 -/- and Nos3 -/- mice developed age-related hypertrophy, although only Nos3 -/- mice were hypertensive. Nos1/3 -/- double knockout mice had suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodeling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function. Aicher et al. (2003) demonstrated that the impaired neovascularization in mice lacking eNOS is related to a defect in progenitor cell mobilization. Mice deficient in eNOS showed reduced vascular endothelial growth factor (VEGF; 192240)-induced mobilization of endothelial progenitor cells and increased mortality after myelosuppression. Intravenous infusion of wildtype progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization of Nos3-deficient mice in a model of hind-limb ischemia, suggesting that progenitor mobilization from the bone marrow is impaired in Nos3-null mice. Mechanistically, MMP9 (120361), required for stem cell mobilization, was reduced in the bone marrow of Nos3-null mice. Aicher et al. (2003) concluded that eNOS expressed by bone marrow stromal cells influences recruitment of stem and progenitor cells. The authors suggested that this may contribute to impaired regeneration processes in ischemic heart disease patients, who are characterized by a reduced systemic nitric oxide bioactivity. Caveolin-3 (CAV3; 601253), a strong inhibitor of all NOS isoforms, is expressed in sarcolemmal caveolae microdomains and binds to NOS3 in cardiac myocytes and NOS1 in skeletal myocytes. Ohsawa et al. (2004) characterized the biochemical and cardiac parameters of P104L (601253.0001)-mutant Cav3 transgenic mice, a model of an autosomal dominant limb-girdle muscular dystrophy (see RMD2, 606072). Transgenic mouse hearts demonstrated hypertrophic cardiomyopathy, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of Cav3 protein. Cardiac muscle showed activation of NOS3 catalytic activity without increased expression of all NOS isoforms. Ohsawa et al. (2004) suggested that a moderate increase in NOS3 activity associated with loss of Cav3 may result in hypertrophic cardiomyopathy. Bivalacqua et al. (2004) studied the contribution of RhoA (AHRA; 165390)/Rho kinase (ROCK1; 601702) signaling to erectile dysfunction in streptozotocin (STZ) diabetic rats. Rho kinase and eNOS colocalized in the endothelium of corpus cavernosum, and RhoA and Rho kinase abundance and Mypt1 (602021) phosphorylation were elevated in STZ diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in STZ diabetic rat penis. Bivalacqua et al. (2004) introduced a dominant-negative RhoA mutant and found that erectile responses in the STZ diabetic rats improved to values similar to controls. Longo et al. (2005) crossbred Nos3-null and wildtype mice to generate 2 types of heterozygous litters, one with a maternally derived mutation that developed in a Nos3-deficient environment and the other with a paternally derived mutation that developed in a uterine environment similar to wildtype mice. In studies of the in vitro reactivity of carotid and mesenteric artery segments of adult mice to vasoactive agents, the maternally derived heterozygous mice had abnormal vascular reactivity that was similar to that of homozygous knockout mice completely lacking functional NOS3, whereas the paternally derived heterozygous mice had normal vascular reactivity that was not different from that of wildtype mice. Longo et al. (2005) stated that this was the first direct evidence in support of a role for uterine environment in determining vascular function in later life. In a mouse model of sepsis, Connelly et al. (2005) observed a temporal reduction in iNOS expression and activity in lipopolysaccharide-treated Nos3-knockout mice as compared with wildtype mice, which was reflected in a more stable hemodynamic profile in Nos3-null mice during endotoxemia. In human umbilical vein cells, lipopolysaccharide led to the activation of Nos3 through phosphoinositide 3-kinase (see 171833)- and Akt/protein kinase B (164730)-dependent enzyme phosphorylation. Connelly et al. (2005) concluded that NOS3 has a proinflammatory role in the pathogenesis of sepsis, in which following initial NOS3 activation the resultant NO acts as a costimulus for the expression of iNOS. Liu et al. (2005) presented evidence suggesting a role for G protein-coupled receptor kinase-2 (GRK2; 109635) in the regulation of NO production and hepatic vascular dynamics in a rat model of liver sinusoidal endothelial injury and portal hypertension induced by bile duct ligation. Sinusoidal endothelial cells isolated from the affected animals had increased levels of GRK2, reduced levels of phosphorylated AKT and eNOS, and decreased levels of NO. Gene silencing of GRK2 using siRNA in injured sinusoidal endothelial cells restored AKT activity and resulted in increased NO production. Liu et al. (2005) also found that heterozygous Grk2 mice had increased levels of phosphorylated Akt and decreased portal hypertension in response to injury compared to wildtype mice. Liu et al. (2005) proposed a mechanism in which upregulation of GRK2 after endothelial cell injury directly inhibits phosphorylation of AKT, leading to reduced activation of eNOS and decreased production of NO, and resulting in portal hypertension. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	NITRIC OXIDE SYNTHASE 3	c1834153	8,782	omim	https://www.omim.org/entry/163729	2019-09-22T16:37:22	{"omim": ["163729"], "synonyms": ["Alternative titles", "NITRIC OXIDE SYNTHASE, ENDOTHELIAL"]}
Ventricular septal defect Illustration showing various forms of ventricular septal defects. 1. Conoventricular, malaligned 2. Perimembranous 3. Inlet 4. Muscular SpecialtyCardiac surgery A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one common ventricle. The ventricular septum consists of an inferior muscular and superior membranous portion and is extensively innervated with conducting cardiomyocytes. The membranous portion, which is close to the atrioventricular node, is most commonly affected in adults and older children in the United States.[1] It is also the type that will most commonly require surgical intervention, comprising over 80% of cases.[2] Membranous ventricular septal defects are more common than muscular ventricular septal defects, and are the most common congenital cardiac anomaly.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 4.1.1 Multiple * 4.1.2 Type 1 * 4.1.3 Type 2 * 4.1.4 Type 3 * 4.1.5 Type 4 * 4.1.6 Type: Gerbode * 5 Treatment * 5.1 Transcatheter closure * 5.2 Surgery * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Ventricular septal defect is usually symptomless at birth. It usually manifests a few weeks after birth. VSD is an acyanotic congenital heart defect, aka a left-to-right shunt, so there are no signs of cyanosis in the early stage. However, uncorrected VSD can increase pulmonary resistance leading to the reversal of the shunt and corresponding cyanosis. * Pansystolic (Holosystolic) murmur along lower left sternal border (depending upon the size of the defect) +/- palpable thrill (palpable turbulence of blood flow). Heart sounds are normal. Larger VSDs may cause a parasternal heave, a displaced apex beat (the palpable heartbeat moves laterally over time, as the heart enlarges). An infant with a large VSD will fail to thrive and become sweaty and tachypnoeic (breathe faster) with feeds.[4] The restrictive ventricular septal defects (smaller defects) are associated with a louder murmur and more palpable thrill (grade IV murmur). Larger defects may eventually be associated with pulmonary hypertension due to the increased blood flow. Over time this may lead to an Eisenmenger's syndrome the original VSD operating with a left-to-right shunt, now becomes a right-to-left shunt because of the increased pressures in the pulmonary vascular bed. ## Cause[edit] Congenital VSDs are frequently associated with other congenital conditions, such as Down syndrome.[5] A VSD can also form a few days after a myocardial infarction[6] (heart attack) due to mechanical tearing of the septal wall, before scar tissue forms, when macrophages start remodeling the dead heart tissue. The causes of congenital VSD (ventricular septal defect) include the incomplete looping of the heart during days 24-28 of development. ## Pathophysiology[edit] During ventricular contraction, or systole, some of the blood from the left ventricle leaks into the right ventricle, passes through the lungs and reenters the left ventricle via the pulmonary veins and left atrium. This has two net effects. First, the circuitous refluxing of blood causes volume overload on the left ventricle. Second, because the left ventricle normally has a much higher systolic pressure (~120 mmHg) than the right ventricle (~20 mmHg), the leakage of blood into the right ventricle therefore elevates right ventricular pressure and volume, causing pulmonary hypertension with its associated symptoms. In serious cases, the pulmonary arterial pressure can reach levels that equal the systemic pressure. This reverses the left to right shunt, so that blood then flows from the right ventricle into the left ventricle, resulting in cyanosis, as blood is by-passing the lungs for oxygenation.[7] This effect is more noticeable in patients with larger defects, who may present with breathlessness, poor feeding and failure to thrive in infancy. Patients with smaller defects may be asymptomatic. Four different septal defects exist, with perimembranous most common, outlet, atrioventricular, and muscular less commonly.[8] ## Diagnosis[edit] Echocardiographic image of a moderate ventricular septal defect in the mid-muscular part of the septum. The trace in the lower left shows the flow during one complete cardiac cycle and the red mark the time in the cardiac cycle that the image was captured. Colours are used to represent the velocity of the blood. Flow is from the left ventricle (right on image) to the right ventricle (left on image). The size and position is typical for a VSD in the newborn period. A VSD can be detected by cardiac auscultation. Classically, a VSD causes a pathognomonic holo- or pansystolic murmur. Auscultation is generally considered sufficient for detecting a significant VSD. The murmur depends on the abnormal flow of blood from the left ventricle, through the VSD, to the right ventricle. If there is not much difference in pressure between the left and right ventricles, then the flow of blood through the VSD will not be very great and the VSD may be silent. This situation occurs a) in the fetus (when the right and left ventricular pressures are essentially equal), b) for a short time after birth (before the right ventricular pressure has decreased), and c) as a late complication of unrepaired VSD. Confirmation of cardiac auscultation can be obtained by non-invasive cardiac ultrasound (echocardiography). To more accurately measure ventricular pressures, cardiac catheterization, can be performed. ### Classification[edit] Although there are several classifications for VSD, the most accepted and unified classification is that of Congenital Heart Surgery Nomenclature and Database Project.[9] The classification is based on the location of the VSD on the right ventricular surface of the inter ventricular septum and is as follows: #### Multiple[edit] #### Type 1[edit] Type 1 is sub aortic #### Type 2[edit] * Type 2 also known as perimembranous, paramembranous, conoventricular, membranous septal defect, and subaortic. * Most common variety found in 70% #### Type 3[edit] Type 3 also known as inlet (or AV canal type). * Commonly associated with atrioventricular septal defect, found in about 5% #### Type 4[edit] Type 4 also known as muscular (trabecular) * Located in the muscular septum, found in 20%. Can be sub classified again based on the location into anterior, apical, posterior and mid #### Type: Gerbode[edit] Type: Gerbode also known as left ventricular to right atrial communication * Due to absence of Atrioventricular septum. * Heart anatomic view of right ventricle and right atrium with example ventricular septal defects * Ventricular septal defect * Figure A shows the structure and blood flow in the interior of a normal heart. Figure B shows two common locations for a ventricular septal defect. The defect allows oxygen-rich blood from the left ventricle to mix with oxygen-poor blood in the right ventricle. ## Treatment[edit] A nitinol device for closing muscular VSDs, 4 mm diameter in the centre. It is shown mounted on the catheter into which it will be withdrawn during insertion. Most cases do not need treatment and heal during the first years of life. Treatment is either conservative or surgical. Smaller congenital VSDs often close on their own, as the heart grows, and in such cases may be treated conservatively. Some cases may necessitate surgical intervention, i.e. with the following indications: 1\. Failure of congestive cardiac failure to respond to medications 2\. VSD with pulmonic stenosis 3\. Large VSD with pulmonary hypertension 4\. VSD with aortic regurgitation For the surgical procedure, a heart-lung machine is required and a median sternotomy is performed. Percutaneous endovascular procedures are less invasive and can be done on a beating heart, but are only suitable for certain patients. Repair of most VSDs is complicated by the fact that the conducting system of the heart is in the immediate vicinity. Ventricular septum defect in infants is initially treated medically with cardiac glycosides (e.g., digoxin 10-20 μg/kg per day), loop diuretics (e.g., furosemide 1–3 mg/kg per day) and ACE inhibitors (e.g., captopril 0.5–2 mg/kg per day). ### Transcatheter closure[edit] A device, known as the Amplatzer muscular VSD occluder, may be used to close certain VSDs.[10] It was initially approved in 2009.[10] It appears to work well and be safe.[10] The cost is also lower than having open heart surgery.[10] The device is placed through a small incision in the groin.[11] The Amplatzer septal occluder was shown to have full closure of the ventricular defect within the 24 hours of placement.[12] It has a low risk of embolism after implantation.[13] Some tricuspid valve regurgitation was shown after the procedure that could possibly be due from the right ventricular disc.[12] There have been some reports that the Amplatzer septal occluder may cause life-threatening erosion of the tissue inside the heart.[14] This occurs in one percent of people implanted with the device and requires immediate open-heart surgery.[14] This erosion occurs due to improper sizing of the device resulting with it being too large for the defect, causing rubbing of the septal tissue and erosion.[14] ### Surgery[edit] a) Surgical closure of a Perimembranous VSD is performed on cardiopulmonary bypass with ischemic arrest. Patients are usually cooled to 28 degrees. Percutaneous Device closure of these defects is rarely performed in the United States because of the reported incidence of both early and late onset complete heart block after device closure, presumably secondary to device trauma to the AV node. b) Surgical exposure is achieved through the right atrium. The tricuspid valve septal leaflet is retracted or incised to expose the defect margins. c) Several patch materials are available, including native pericardium, bovine pericardium, PTFE (Gore-Tex or Impra), or Dacron. d) Suture techniques include horizontal pledgeted mattress sutures, and running polypropylene suture. e) Critical attention is necessary to avoid injury to the conduction system located on the left ventricular side of the interventricular septum near the papillary muscle of the conus. f) Care is taken to avoid injury to the aortic valve with sutures. g) Once the repair is complete, the heart is extensively deaired by venting blood through the aortic cardioplegia site, and by infusing Carbon Dioxide into the operative field to displace air. h) Intraoperative transesophageal echocardiography is used to confirm secure closure of the VSD, normal function of the aortic and tricuspid valves, good ventricular function, and the elimination of all air from the left side of the heart. i) The sternum, fascia and skin are closed, with potential placement of a local anesthetic infusion catheter under the fascia, to enhance postoperative pain control. j) Multiple muscular VSDs are a challenge to close, achieving a complete closure can be aided by the use of fluorescein dye.[15] ## Epidemiology[edit] VSDs are the most common congenital cardiac abnormalities. They are found in 30-60% of all newborns with a congenital heart defect, or about 2-6 per 1000 births. During heart formation, when the heart begins life as a hollow tube, it begins to partition, forming septa. If this does not occur properly it can lead to an opening being left within the ventricular septum. It is debatable whether all those defects are true heart defects, or if some of them are normal phenomena, since most of the trabecular VSDs close spontaneously.[16] Prospective studies give a prevalence of 2-5 per 100 births of trabecular VSDs that close shortly after birth in 80-90% of the cases.[17][18] ## See also[edit] * Atrial septal defect * Atrioventricular septal defect * Cardiac output * Congenital heart disease * Heart sounds * Pulmonary hypertension ## References[edit] 1. ^ Taylor, Michael D (2019-02-02). "Muscular Ventricular Septal Defect". eMedicine. Medscape. 2. ^ Waight, David J.; Bacha, Emile A.; Kahana, Madelyn; Cao, Qi-Ling; Heitschmidt, Mary; Hijazi, Ziyad M. (March 2002). "Catheter therapy of Swiss cheese ventricular septal defects using the Amplatzer muscular VSD occluder". Catheterization and Cardiovascular Interventions. 55 (3): 355–361. doi:10.1002/ccd.10124. PMID 11870941. 3. ^ Hoffman, JI; Kaplan, S (2002). "The incidence of congenital heart disease". Journal of the American College of Cardiology. 39 (12): 1890–900. doi:10.1016/S0735-1097(02)01886-7. PMID 12084585. 4. ^ Cameron P. et al: Textbook of Pediatric Emergency Medicine. p116-117 [Elsevier, 2006] 5. ^ Wells, GL; Barker, SE; Finley, SC; Colvin, EV; Finley, WH (1994). "Congenital heart disease in infants with Down's syndrome". Southern Medical Journal. 87 (7): 724–7. doi:10.1097/00007611-199407000-00010. PMID 8023205. 6. ^ Schumacher, Kurt R. "Ventricular septal defect". NIH and US National Library of Medicine. MedlinePlus. 7. ^ Kumar & Clark 2009 8. ^ Mancini, Mary C (2018-06-20). "Ventricular Septal Defect Surgery in the Pediatric Patient". eMedicine. Medscape. 9. ^ Jacobs, Jeffrey; Mavroudis, Constantine (March 2000). "Congenital Heart Surgery Nomenclature and Database Project: ventricular septal defect". Ann Thorac Surg. 69 (3): 25–35. doi:10.1016/S0003-4975(99)01270-9. PMID 10798413. 10. ^ a b c d Fu, YC (February 2011). "Transcatheter device closure of muscular ventricular septal defect". Pediatrics and Neonatology. 52 (1): 3–4. doi:10.1016/j.pedneo.2010.12.012. PMID 21385649. 11. ^ Amplatzer septal occluder. (2013) U.S. Food and Drug Administration. Retrieved February 26, 2014, from https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm083978.htm 12. ^ a b Szkutnik; et al. (2007). "Use of the Amplatzer muscular ventricular septal defect occluder for closure of perimembranous ventricular septal defects". Heart. 93 (3): 355–358. doi:10.1136/hrt.2006.096321. PMC 1861424. PMID 16980519. 13. ^ Fernando Rajeev; et al. (2013). "Patent ductus arteriosus closure using an Amplatzer ventricular septal defect closure device". Experimental & Clinical Cardiology. 18 (1): e50–e54. 14. ^ a b c Rare Serious Erosion Events Associated with St. Jude Amplatzer Atrial Septal Occluder (ASO). (2013, October 17). U.S. Food and Drug Administration. Retrieved February 26, 2014, from https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm371145.htm?source=govdelivery 15. ^ Mathew, Thomas (2014). "Use of Fluorescein Dye to Identify Residual Defects". Ann Thorac Surg. 97 (1): e27-8. doi:10.1016/j.athoracsur.2013.10.059. ISSN 0003-4975. PMID 24384220. 16. ^ Meberg, A; Otterstad, JE; Frøland, G; Søarland, S; Nitter-Hauge, S (1994). "Increasing incidence of ventricular septal defects caused by improved detection rate". Acta Paediatrica. 83 (6): 653–657. doi:10.1111/j.1651-2227.1994.tb13102.x. 17. ^ Hiraishi, S; Agata, Y; Nowatari, M; Oguchi, K; Misawa, H; Hirota, H; Fujino, N; Horiguchi, Y; Yashiro, K; Nakae, S (March 1992). "Incidence and natural course of trabecular ventricular septal defect: two-dimensional echocardiography and color Doppler flow imaging study". The Journal of Pediatrics. 120 (3): 409–15. doi:10.1016/s0022-3476(05)80906-0. PMID 1538287. 18. ^ Roguin, Nathan; Du, Zhong-Dong; Barak, Mila; Nasser, Nadim; Hershkowitz, Sylvia; Milgram, Elliot (15 November 1995). "High prevalence of muscular ventricular septal defect in neonates". Journal of the American College of Cardiology. 26 (6): 1545–1548. doi:10.1016/0735-1097(95)00358-4. PMID 7594083. ## External links[edit] Classification D * ICD-10: Q21.0 * ICD-9-CM: 745.4 * MeSH: D006345 * DiseasesDB: 13808 External resources * MedlinePlus: 001099 * eMedicine: med/3517 * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Ventricular septal defect	c0018818	8,783	wikipedia	https://en.wikipedia.org/wiki/Ventricular_septal_defect	2021-01-18T18:51:09	{"gard": ["7853"], "mesh": ["D006345"], "umls": ["C0018818"], "orphanet": ["1480"], "wikidata": ["Q838139"]}
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by severe intellectual disability with limited or absent speech and language, short stature, acquired microcephaly, kyphoscoliosis or scoliosis, and behavioral disturbances that include hyperactivity, stereotypy and aggressiveness. Facial dysmorphism, that typically includes sloping forehead, mild synophrys, deep-set eyes, strabismus, anteverted large ears, prominent nose and dental malposition, is also characteristic. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome	c3809853	8,784	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391307	2021-01-23T17:09:58	{"omim": ["615541"], "icd-10": ["Q87.8"]}
Hemifacial microsomia (HFM) is a condition in which part of one side of the face is underdeveloped and does not grow normally. The eye, cheekbone, lower jaw, facial nerves, muscles, and neck may be affected. Other findings may include hearing loss from underdevelopment of the middle ear; a small tongue; and macrostomia (large mouth). HFM is the second most common facial birth defect after clefts. The cause of HFM in most cases is unknown. It usually occurs in people with no family history of HFM, but it is inherited in some cases. HFM is part of a group of conditions known as "craniofacial microsomia". It is not known whether the conditions included in the group really are different conditions or part of the same problem with different degrees of severity. Treatment depends on age and the specific features and symptoms 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Hemifacial microsomia	c3495417	8,785	gard	https://rarediseases.info.nih.gov/diseases/6582/hemifacial-microsomia	2021-01-18T18:00:08	{"mesh": ["D006053"], "omim": ["164210"], "orphanet": ["141136"], "synonyms": ["Laterofacial microsomia", "Hemifacial microsomia", "First and second branchial arch syndrome", "Otomandibular dysostosis", "First branchial arch syndrome"]}
Main article: Agnosia Astereognosis SpecialtyNeurology Astereognosis (or tactile agnosia if only one hand is affected) is the inability to identify an object by active touch of the hands without other sensory input, such as visual or sensory information. An individual with astereognosis is unable to identify objects by handling them, despite intact elementary tactile, proprioceptive, and thermal sensation.[1] With the absence of vision (i.e. eyes closed), an individual with astereognosis is unable to identify what is placed in their hand based on cues such as texture, size, spatial properties, and temperature.[1] As opposed to agnosia, when the object is observed visually, one should be able to successfully identify the object. Individuals with tactile agnosia may be able to identify the name, purpose, or origin of an object with their left hand but not their right, or vice versa, or both hands. Astereognosis refers specifically to those who lack tactile recognition in both hands. In the affected hand(s) they may be able to identify basic shapes such as pyramids and spheres (with abnormally high difficulty) but still not tactilely recognize common objects by easily recognizable and unique features such as a fork by its prongs (though the individual may report feeling a long, metal rod with multiple, pointy rods stemming off in uniform direction).[2] These symptoms suggest that a very specific part of the brain is responsible for making the connections between tactile stimuli and functions/relationships of those stimuli, which, along with the relatively low impact this disorder has on a person's quality of life, helps explain the rarity of reports and research of individuals with tactile agnosia.[2] However in some cases, those persons with tactile agnosia may have many challenges in daily life and occupation. An example is a task that requires typing quickly, as this agnosia type prevents the recognition of keys without looking at a keyboard. Astereognosis is associated with lesions of the parietal lobe or dorsal column or parieto-temporo-occipital lobe (posterior association areas) of either the right or left hemisphere of the cerebral cortex.[1][2] Despite cross-talk between the dorsal and ventral cortices, fMRI results suggest that those with ventral cortex damage are less sensitive to object 3D structure than those with dorsal cortex damage. Unlike the ventral cortex, the dorsal cortex can compute object representations. Thus, those with object recognition impairments are more likely to have acquired damage to the dorsal cortex.[3] Those suffering from Alzheimer’s disease show a reduction in stereognosis, the ability to perceive and recognize the form of an object in the absence of visual and auditory information. This supports the notion that astereognosis appears to be an associative disorder in which the connections between tactile information and memory is disturbed. While astereognosis is characterized by the lack of tactile recognition in both hands, it seems to be closely related to tactile agnosia (impairment connected to one hand). Tactile agnosia observations are rare and case-specific. Josef Gerstmann recounts his experience with patient JH, a 34-year-old infantryman who suffered a lesion to the posterior parietal lobe due to a gunshot. Following the injury, JH was unable to recognize or identify everyday objects by their meaning, origin, purpose and use with his left hand using tactile sensation alone. His motility performance, elementary sensitivity, and speech were intact, and he lacked abnormalities in brain nerves.[2] The majority of all objects JH touched with his left hand went unrecognized, but very simple objects (i.e. globes, pyramids, cube, etc.) were regularly recognized based on form alone. For more complex objects, his behavior and recognition varied daily based on his tactile resources that changed over time and depended on his fatigue. That is, JH’s ability to recognize depended on his concentration and ability to recognize simple forms and single qualities like size, shape, etc. With further interrogation and greater effort, he was able to correctly identify more specific features of an object (i.e. softness, rounded or cornered, broad or narrow) and could even draw a copy of it, but he was often left unable to identify the object by name, use, or origin. This behavioral deficit occurred even if JH had handled the object in his fully intact right hand.[2] Interventions tend to focus on helping these patients and their family and caregivers cope and adapt to the condition, and furthermore, to help patients function independently within their context.[4] ## See also[edit] * Stereognosis ## References[edit] 1. ^ a b c O'Sullivan, S.B.; Schmitz, T.J. (2007). Physical Rehabilitation (5th ed.). Philadelphia: F.A. Davis Company. pp. 1180–1181. 2. ^ a b c d e Gerstmann, J. (2001). Pure Tactile Agnosia Cognitive Neuropsychology. pp. 267–274. 3. ^ Freud, E.; Ganel, T.; Shelef, I.; Hammer, M.; Avidan, G.; Behrmann, M. (2015). "Three-Dimensional Representations of Objects in Dorsal Cortex are Dissociable from Those in Ventral Cortex". Cerebral Cortex. doi:10.1093/cercor/bhv229. PMID 26483400. 4. ^ Kumar, Anil; Wroten, Michael (2019), "Agnosia", StatPearls, StatPearls Publishing, PMID 29630208, retrieved 2020-01-21 ## External links[edit] Classification D * ICD-9-CM: 780.99 * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Astereognosis	c0234505	8,786	wikipedia	https://en.wikipedia.org/wiki/Astereognosis	2021-01-18T19:08:33	{"mesh": ["D000377"], "icd-9": ["780.99"], "wikidata": ["Q739221"]}
A number sign (#) is used with this entry because of evidence that pigmented paravenous chorioretinal atrophy (PPCRA) is caused by heterozygous mutation in the CRB1 gene (604210) on chromosome 1q31. Description Pigmented paravenous chorioretinal atrophy is a stationary disease of the ocular fundus in which bone corpuscle pigmentation is seen in a paravenous distribution. Patients are usually asymptomatic; diagnosis is based on the characteristic fundus appearance. Most cases have been reported in males (summary by Traboulsi and Maumenee, 1986). Clinical Features Skalka (1979) reported affected father and son. Traboulsi and Maumenee (1986) described a family in which the condition occurred in a mother and her 3 sons and was associated with hyperopia, esotropia, and vitreoretinal degeneration. The findings were milder in the mother and severe in the 3 children; strabismus and hyperopia occurred only in the sons. Noble (1989) reported 3 brothers, born of nonconsanguineous parents, who showed characteristic paravenous bone spicule accumulation. The onset in all 3 brothers was early in life (possibly congenital) and there was minimal, if any, progression. The brothers were aged 37, 41, and 56 years. The parents were reportedly normal but were not examined. Noble and Carr (1983) described 6 patients, of whom 3 were female. McKay et al. (2005) reported a family in which 6 members had pigmented paravenous chorioretinal atrophy. The earliest clinical sign in this family was subtle symmetrical chorioretinal atrophy in the inferior quadrant. Paravenous pigmentation occurred initially in the far periphery, progressing centrally, with atrophy later becoming more widespread, involving the nasal, then the temporal, and finally the upper quadrant. PPCRA was dominantly inherited in this family but exhibited variable expressivity. McKay et al. (2005) noted that males were more likely to exhibit a severe phenotype, whereas females might remain virtually asymptomatic, even in later years. Choi et al. (2006) followed 15 patients (8 males and 7 females) with PPRCA for 3 to 35 years (average 13 years) and quantified the mean annual changes in visual acuity, visual field area, and full-field electroretinogram amplitude. The results indicated that loss of peripheral vision in PPRCA is slowly progressive. Inheritance Father-to-son transmission of PPCRA in the family reported by Skalka (1979) indicated autosomal dominant inheritance. The pedigree described by Traboulsi and Maumenee (1986) was considered consistent with X-linked inheritance because the sons were more severely affected than the mother. PPCRA was dominantly inherited in the family reported by McKay et al. (2005). Molecular Genetics In all 6 affected members of a family segregating PPCRA, McKay et al. (2005) identified heterozygosity for a val162-to-met (V162M; 604210.0010) mutation within the fourth EGF-like domain of the CRB1 gene. Eyes \- Pigmented paravenous chorioretinal atrophy \- Bone corpuscle fundus pigmentation \- Hyperopia \- Esotropia \- Vitreoretinal degeneration Misc \- Usually asymptomatic Inheritance \- Autosomal dominant vs. X-linked ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	PIGMENTED PARAVENOUS CHORIORETINAL ATROPHY	c1868310	8,787	omim	https://www.omim.org/entry/172870	2019-09-22T16:36:15	{"mesh": ["C566801"], "omim": ["172870"], "orphanet": ["251295"]}
Thoracolaryngopelvic dysplasia is a short-rib dysplasia characterized by thoracic dystrophy, laryngeal stenosis and a small pelvis. ## Epidemiology Prevalence is unknown but less than 10 cases have been reported in the literature so far. ## Clinical description Patients present with severe respiratory distress (requiring intubation) during the neonatal period. The rib shortening is less severe than in Jeune syndrome (see this term) and the thorax is characteristically small, narrow and bell-shaped. The pelvis is reduced in all dimensions and the combination of the thorax anomalies and the small pelvis give the appearance of a protruding abdomen. Subglottic stenosis has also been described but it remains unclear whether this is a congenital anomaly or is secondary to long-term intubation. In addition, several cases of thoracopelvic dysostosis (without laryngeal involvement) have been described, which could represent heterogeneous expression of the same syndrome or a distinct entity. ## Genetic counseling Transmission is autosomal dominant. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Thoracolaryngopelvic dysplasia	c1861197	8,788	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3317	2021-01-23T19:08:14	{"gard": ["5184"], "mesh": ["C536517"], "omim": ["187760", "187770"], "umls": ["C1861197"], "icd-10": ["Q77.2"], "synonyms": ["Barnes syndrome"]}
A number sign (#) is used with this entry because Glass syndrome (GLASS) is caused by heterozygous interstitial deletion on chromosome 2q32-q33. The disorder can also be caused by heterozygous mutation in the SATB2 gene (608148), which is within the Glass syndrome chromosome region. Description Glass syndrome is characterized by intellectual disability of variable severity and dysmorphic facial features, including micrognathia, downslanting palpebral fissures, cleft palate, and crowded teeth. Additional features may include seizures, joint laxity, arachnodactyly, and happy demeanor (summary by Glass et al., 1989; Urquhart et al., 2009; Rainger et al., 2014). Clinical Features Glass et al. (1989) reported a 16-year-old boy with severe mental retardation, microcephaly, and craniofacial dysmorphism associated with an interstitial deletion of chromosome 2q32.2-q33.1. He had no comprehensible speech and was totally dependent for all activities. Facial features included large beaked nose, ptosis, and cleft palate. He also had seizures and a striking scalloped skin pigmentation that did not follow Blaschko lines. Activity of isocitrate dehydrogenase (IDH1; 147700) was normal. Van Buggenhout et al. (2005) reported 4 unrelated patients with interstitial deletions of chromosome 2q32-q33. Common clinical features included pre- and postnatal growth retardation, severe mental retardation, thin and sparse hair, persistent feeding difficulties, inguinal hernia, and broad-based gait. Facial features included high long face, high forehead, ptosis, dacrocystitis, high nasal bridge, small mouth, teeth abnormalities, micrognathia, and cleft or high-arched palate. Two patients had seizures, and 3 had spasticity and contractures. Three patients had a specific behavioral phenotype with hyperactivity and motor restlessness, chaotic behavior, and happy personality intermixed with periods of aggression and anxiety, sleeping problems and self-mutilation. Array CGH and FISH analysis showed that all patients shared an 8.1-Mb minimal deleted region. The cleft or high-arched palate most likely resulted from hemizygosity for the SATB2 gene (608148). Rosenfeld et al. (2009) reported 3 unrelated patients with small heterozygous deletions of chromosome 2q33.1, ranging from 173.1 to 185.2 kb, that affected only the SATB2 gene. Parental samples from the mother were available for only 2 patients, and neither mother carried the deletion; parental samples were not available for the third patient. All patients had severe developmental delay, mental retardation, and tooth anomalies, but other features varied. Dentofacial anomalies included delayed primary dentition and micrognathia in 1 patient; cleft palate, crowded teeth, and small mandible in the second; and fused mandibular central incisors without cleft palate in the third. Two patients had behavioral abnormalities and mild dysmorphic features. Rosenfeld et al. (2009) concluded that haploinsufficiency for SATB2 is responsible for some of the clinical features associated with the 2q32-q33 deletion syndrome. Urquhart et al. (2009) reported a girl with a de novo heterozygous 4.5-Mb microdeletion of chromosome 2q33.1. She had cleft soft palate, feeding problems, febrile seizures, and delayed psychomotor development with poor speech. She was mildly dysmorphic, with broad forehead, flat philtrum, small mouth, thin upper lip, missing lateral incisors, and relative macrocephaly, but ears were normal. She also had joint laxity, valgus foot deformity, broad toes and thumbs, brachydactyly, and contractures of the fourth and fifth fingers. She had a social disposition. Brain MRI showed nonspecific periventricular white matter abnormalities. The deleted region included the SATB2 gene. Rifai et al. (2010) reported a 16-year-old girl, born of unrelated French Caribbean parents, with an interstitial 26.3-Mb deletion of chromosome 2q31.2-q33.2. She had prenatal and postnatal growth retardation, microcephaly, facial dysmorphism, cleft palate, camptodactyly, bilateral talipes equinovarus, severe intellectual disability, and ectodermal anomalies. Ectodermal anomalies included thin, atrophic skin, sparse, brittle, slowly growing hair, oligodontia with abnormally shaped teeth, normal sweating, and normal fingernails. These findings were consistent with a diagnosis of ectodermal dysplasia. The deletion resulted in hemizygosity for the HOXD gene (see, e.g., HOXD1; 142987) cluster and its regulatory elements, which may affect limb development. Haploinsufficiency of other genes such as COL3A1 (120180)/COL5A2 (120190), GTF3C3 (604888), CASP8 (601763), CASP10 (601762), and SATB2 may also influence the phenotype. Balasubramanian et al. (2011) reported 7 unrelated patients with different interstitial deletions of chromosome 2q33.1. The phenotype was variable, but common features included delayed psychomotor development, feeding difficulties early in life, and dysmorphic facies. Dysmorphic features could be delineated into 2 groups: one with upturned nose and myopathic facies, and another with a prominent nose and downslanting palpebral fissures. However, variable features were reported, including slightly low-set ears, sparse hair, high forehead, tented upper lip, downturned mouth corners, hypertelorism, long or short philtrum, and micrognathia. Three had cleft palate, 4 had high-arched palate, and most had dental crowding. Four had digital anomalies, such as overlapping toes, 2 had joint laxity, and 5 had behavioral anomalies, ranging from inappropriate hugging to hyperactivity and aggression. Leoyklang et al. (2007) reported a Thai man with isolated cleft palate, gum hyperplasia, slight micrognathia, generalized osteoporosis, and mental retardation. CT scan of the facial bones revealed multiple anomalies, including asymmetric mandibular hypoplasia, wide mandibular angles, anterior overbite of the upper teeth with marked anterior-pointing incisors, midline cleft palate, abnormal sinuses, short zygomatic arches, and flattened mandibular condylar heads. The patient also had profound mental retardation, seizures, and a jovial personality. Docker et al. (2014) reported a 3-year-old girl with cleft palate, severely delayed speech, hypotonia, and mental retardation. Dysmorphic facial features included hypotonic face with hypersalivation, hypertelorism, downslanting palpebral fissures, long eyelashes, upturned nose with broad tip, microretrognathia, long philtrum, low-set and posteriorly rotated ears, and crowded teeth. She also had severe sleeping disturbances, restlessness/hyperactivity, and recurrent temper tantrums. Rainger et al. (2014) reported a 33-year-old man with severe intellectual disability, aggressive behavior, and dysmorphic features, including small mouth, cleft palate, micrognathia, prominent nasal bridge, long nose, long columella, abnormal dentition, and arachnodactyly. Molecular studies identified a de novo heterozygous t(2;3)(q33.1;q26.33) translocation with the breakpoint on 2q33.1 within the PLCL1 (600597)-SATB2 gene desert. Lieden et al. (2014) reported a 20-year-old man with delayed psychomotor development since infancy and moderate to severe intellectual disability with only a few spoken words. Neurologic features included impairment of fine and gross motor skills, mild hemiparesis, and spasticity with hyperreflexia. He had no seizures, and brain imaging was normal at age 3 years. Additional features included tall forehead, bushy eyebrows, prominent nose, cleft palate, narrow maxilla with malocclusion, oligodontia, and abnormally shaped teeth. He had a slender body habitus with bowing of the tibiae and osteoporosis. He had a happy demeanor without behavioral problems. The phenotype was similar to that observed in other patients with this disorder. Kaiser et al. (2015) reported a 10-year-old German girl who presented at age 33 months with delayed psychomotor development, no speech development, sleeping problems, and feeding difficulties. Brain MRI showed pathologic myelination with increased signal intensity in the right parietooccipital region. At age 10 years, she had mild growth retardation, moderate to severe intellectual disability with nearly absent speech, and attended a school for disabled children. Mild dysmorphic features were also present, including narrow jaw with high palate and crowded teeth, short palpebral fissures, broad nose with broad nasal bridge, bulbous nasal tip and thick columella, short hands, mildly broad thumbs, and big toes. Her sleeping and feeding difficulties had improved. Bengani et al. (2017) reported 20 previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants). Of the 19, all had neurodevelopmental impairment, 16 had absent/near absent speech, 17 had normal somatic growth, 9 had cleft palate, 12 had drooling, and 8 had dental anomalies. Sib recurrence due to gonadal mosaicism was seen in 1 family. Inheritance All patients with Glass syndrome have been shown to carry de novo heterozygous mutations in the SATB2 gene or de novo heterozygous deletions of chromosome 2q32-q33 (Leoyklang et al., 2013). Cytogenetics Brewer et al. (1999) reported 2 unrelated girls with cleft palate, facial dysmorphism, and mildly delayed development and learning difficulties associated with balanced, de novo cytogenetic rearrangements involving the same region of 2q. Molecular cytogenetic analyses localized both translocation breakpoints between markers D2S311 and D2S116 on chromosome 2q32. Facial features included prominent nasal bridge with underhanging columella, small mouth with distinctive upper lip, and long, slender fingers. FitzPatrick et al. (2003) determined that 1 of the breakpoints in the 2 girls reported by Brewer et al. (1999) localized to intron 2 of SATB2, and the other breakpoint was located 130 kb 3-prime to the SATB2 polyadenylation signal, within a conserved region of noncoding DNA. Whole-mount in situ hybridization to mouse embryos showed site- and stage-specific expression of SATB2 in the developing palate. Despite the strong evidence supporting an important role for SATB2 in palatal development, mutation analysis of an additional 70 unrelated patients with isolated cleft palate did not reveal any coding region variants. Rainger et al. (2014) reevaluated 1 of the patients reported by Brewer et al. (1999) and FitzPatrick et al. (2003) at age 24 years. She had long thin face, micrognathia, and arachnodactyly. She had significant intellectual disability and required constant supervision. Rainger et al. (2014) also reevaluated a father and son with cleft palate, micrognathia, microstomia, and oligodontia (OFC13; 613857) previously reported by Ghassibe-Sabbagh et al. (2011). Ghassibe-Sabbagh et al. (2011) had identified a translocation in these patients, t(1;2)(p34;q33), that interrupted the FAF1 gene (604460) on chromosome 1p34; they did not think that the 2q breakpoint contributed to the phenotype. However, Rainger et al. (2014) found that the 2q33 breakpoint in this family was about 896-kb centromeric to the SATB2 gene and likely interrupted SATB2 cis-regulatory elements. Rainger et al. (2014) suggested that the phenotypes in the patients reported by Brewer et al. (1999) and Ghassibe-Sabbagh et al. (2011) resulted from SATB2 haploinsufficiency. By oligonucleotide-based array CGH analysis in 7 patients with chromosome 2q33.1 deletion syndrome, Balasubramanian et al. (2011) determined that the interstitial deletions ranged in size from 35 kb to 10.4 Mb. The smallest deletion was entirely within the SATB2 gene (chr2:199,877,238-199,911,975). Four other deletions also included the SATB2 gene, suggesting that haploinsufficiency for this gene is responsible for many of the features. However, 2 deletions did not include the SATB2 gene and did not overlap, indicating that other genes proximal and distal to SATB2 contribute to the phenotype. Using comparative genomics, Rainger et al. (2014) identified 3 different functional enhancing cis-regulatory elements (CREs) in the gene desert between the PLCL1 and SATB2 genes, 3-prime to SATB2. Sites within these 3 CREs were shown to bind SOX9 (608160) in cells derived from a mouse embryonic pharyngeal arch. Studies in zebrafish showed that CRE2 could drive SATB2-like expression in the embryonic craniofacial region. The findings suggested that the translocation breakpoints identified in patients with craniofacial defects disrupt the long-range cis regulation of SATB2 by SOX9, resulting in functional haploinsufficiency of SATB2. Molecular Genetics In a Thai man with isolated cleft palate, gum hyperplasia, slight micrognathia, generalized osteoporosis, and mental retardation, Leoyklang et al. (2007) identified a de novo heterozygous nonsense mutation in the SATB2 gene (R239X; 608148.0001). Docker et al. (2014) identified a de novo heterozygous R239X mutation (rs137853127) in a 3-year-old girl with cleft palate, severely delayed speech, hypotonia, and mental retardation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Mutant mRNA was present in the patient's cells, suggesting that it does not undergo nonsense-mediated mRNA decay. Docker et al. (2014) concluded that the SATB2 gene is essential for normal craniofacial patterning and cognitive development. In a 20-year-old man with Glass syndrome, Lieden et al. (2014) identified a de novo heterozygous intragenic duplication of the SATB2 gene (608148.0002). The duplication was found by array CGH analysis; functional studies and studies of patient cells were not performed. In a 10-year-old girl with Glass syndrome, Kaiser et al. (2015) identified a de novo heterozygous intragenic duplication of the SATB2 gene (608148.0003), predicted to result in haploinsufficiency. The patient was born of unrelated parents and conceived via intracytoplasmic sperm injection. Bengani et al. (2017) reported 19 different SATB2 mutations, of which 11 were loss-of-function and 8 missense (e.g., 608148.0004-608148.0006). SATB2 nuclear mobility was mutation-dependent. The clinical features in individuals with missense variants were indistinguishable from those with loss-of-function variants. Bengani et al. (2017) found that when mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Growth retardation, pre- and postnatal HEAD & NECK Head \- Microcephaly Face \- Micrognathia \- High forehead \- Frontal bossing \- Midface hypoplasia \- Small mandible \- Long face \- Hypotonic face \- Smooth philtrum Ears \- Low-set ears Eyes \- Downslanting palpebral fissures Nose \- Prominent nasal bridge \- Thin nose \- Long nose \- Bulbous nasal tip Mouth \- High-arched palate \- Cleft palate \- Small mouth Teeth \- Delayed primary dentition \- Crowded teeth \- Oligodontia \- Peg-shaped teeth ABDOMEN External Features \- Inguinal hernia SKELETAL Hands \- Camptodactyly \- Arachnodactyly Feet \- Pes equinovarus SKIN, NAILS, & HAIR Skin \- Thin skin Nails \- Dysplastic nails Hair \- Thin, sparse hair NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Seizures (in some patients) \- Poor speech development \- Broad-based gait Behavioral Psychiatric Manifestations \- Hyperactivity \- Aggression \- Happy demeanor LABORATORY ABNORMALITIES \- Some patients carry a deletion of minimum of 8.1 Mb on 2q32-q33 MISCELLANEOUS \- De novo mutation \- Variable manifestations MOLECULAR BASIS \- Caused by mutation in the special AT-rich sequence-binding protein 2 gene (SATB2, 608148.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	GLASS SYNDROME	c2676739	8,789	omim	https://www.omim.org/entry/612313	2019-09-22T16:01:49	{"doid": ["0060428"], "mesh": ["C567350"], "omim": ["612313"], "orphanet": ["251019"], "synonyms": ["Alternative titles", "CHROMOSOME 2q32-q33 DELETION SYNDROME"], "genereviews": ["NBK458647"]}
Not to be confused with primitive neuroectodermal tumor, which is also abbreviated as PNET. Pancreatic neuroendocrine tumor SpecialtyOncology Treatmentradiation, chemotherapy PrognosisFive year survival rate ~ 61% Pancreatic neuroendocrine tumors (PanNETs, PETs, or PNETs), often referred to as "islet cell tumors",[1][2] or "pancreatic endocrine tumors"[3][4] are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas. PanNETs are a type of neuroendocrine tumor, representing about one third of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Many PanNETs are benign, while some are malignant. Aggressive PanNET tumors have traditionally been termed "islet cell carcinoma". PanNETs are quite distinct from the usual form of pancreatic cancer, the majority of which are adenocarcinomas, which arises in the exocrine pancreas. Only 1 or 2% of clinically significant pancreas neoplasms are PanNETs. ## Contents * 1 Types * 2 Signs and symptoms * 3 Diagnosis * 4 Staging * 5 Treatment * 6 Genetics * 7 References * 8 External links ## Types[edit] The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin.[3] In practice, those tumors termed well or intermediately differentiated PanNETs in the WHO scheme are sometimes called "islet cell tumors". The high grade subtype, termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with "islet cell carcinoma". Types of PNET based on hormones produced Type Relative incidence Typical location of tumor[5] Biomarkers[5] Symptoms[6] Insulinoma 35-40%[6] Head, body, tail of pancreas insulin, proinsulin, C-peptide Hypoglycemia Gastrinoma 16-30%[6] Gastrinoma triangle gastrin, PP * Abdominal pain * Refractory peptic ulcer disease * Secretory diarrhea VIPoma <10%[6] Distal pancreas (body and tail) VIP * Profuse watery diarrhea * Dehydration * Hypokalemia * Achlorhydria Somatostatinoma <5%[6] Pancreatoduodenal groove, ampullary, periampullary somatostatin * Diabetes mellitus * Cholelithiasis * Steatorrhea * Anemia * Weight loss PPoma Head or pancreas pancreatic polypeptide Glucagonoma 1%[7] Body and tail of pancreas glucagon, glycentin * Necrolytic migratory erythema * Diabetes mellitus * Diarrhea * Deep vein thrombosis Relative incidence is given as percentage of all functional pancreatic neuroendocrine tumors. ## Signs and symptoms[edit] Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose.[8]:43–44 Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis.[9][medical citation needed] About 40%[medical citation needed] of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60%[medical citation needed] of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated.[10] In total, 85% of PanNETs have an elevated blood marker.[2] Functional tumors are often classified by the hormone most strongly secreted, for example: * gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and diarrhea * insulinoma:[11] hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide[12] * glucagonoma: the symptoms are not all due to glucagon elevations,[12] and include a rash, sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels[12] * VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera syndrome) * somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea[12] * less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor In these various types of functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available.[13] ## Diagnosis[edit] Because symptoms are non-specific, diagnosis is often delayed.[14] Measurement of hormones including pancreatic polypeptide, gastrin, proinsulin, insulin, glucagon, and vasoactive intestinal peptide can determine if a tumor is causing hypersecretion.[14][15] Multiphase CT and MRI are the primary modalities for morphologic imaging of PNETs. While MRI is superior to CT for imaging, both of the primary tumor and evaluation of metastases, CT is more readily available. Notably, while many malignant lesions are hypodense in contrast-enhanced studies, the liver metastases of PNETs are hypervascular and readily visualized in the late arterial phase of the post-contrast CT study. However, morphological imaging alone is not sufficient for a definite diagnosis [14][16] On biopsy, immunohistochemistry is generally positive for chromogranin and synaptophysin.[17] Genetic testing thereof typically shows altered MEN1 and DAXX/ATRX.[17] ## Staging[edit] The 2010 WHO classification of tumors of the digestive system grades all the neuroendocrine tumors into three categories, based on their degree of cellular differentiation (from well-differentiated "NET G1" through to poorly-differentiated "NET G3"). The NCCN recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma.[8]:52 Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers.[18] A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society.[19] * Pancreatic neuroendocrine tumor staging (AJCC) * Stage T1 * Stage T2 * Stage T3 * Stage T4 * Involvement of nearby lymph nodes – Stage N1 * Metastasis – stage M1 ## Treatment[edit] Main article: Neuroendocrine tumor In general, treatment for PanNET encompasses the same array of options as other neuroendocrine tumors, as discussed in that main article. However, there are some specific differences, which are discussed here.[8] In functioning PanNETs, octreotide is usually recommended prior to biopsy[8]:21 or surgery[8]:45 but is generally avoided in insulinomas to avoid profound hypoglycemia.[8]:69 PanNETs in Multiple endocrine neoplasia type 1 are often multiple, and thus require different treatment and surveillance strategies.[8] Some PanNETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents have shown activity.[12] In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU)[12] and capecitabine with temozolomide.[citation needed] Although marginally effective in well-differentiated PETs, cisplatin with etoposide has some activity in poorly differentiated neuroendocrine cancers (PDNECs),[12] particularly if the PDNEC has an extremely high Ki-67 score of over 50%.[8]:30 Several targeted therapy agents have been approved in PanNETs by the FDA based on improved progression-free survival (PFS): * everolimus (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease.[20][21] The safety and effectiveness of everolimus in carcinoid tumors have not been established.[20][21] * sunitinib (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.[22][23] Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'.[24] A phase III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12 months (either advanced or metastatic disease) showed that sunitinib treatment improved progression-free survival (11.4 months vs. 5.5 months), overall survival, and the objective response rate (9.3% vs. 0.0%) when compared with placebo.[25] ## Genetics[edit] Pancreatic neuroendocrine tumors may arise in the context of multiple endocrine neoplasia type 1, Von Hippel–Lindau disease, neurofibromatosis type 1 (NF-1) or tuberose sclerosis (TSC)[26][27] Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four important findings:[28][6] * as expected, the genes mutated in NETs, MEN1, ATRX, DAXX, TSC2, PTEN and PIK3CA,[28] are different from the mutated genes previously found in pancreatic adenocarcinoma.[29][30] * one in six well-differentiated pancreatic NETs have mutations in mTOR pathway genes, such as TSC2, PTEN and PIK3CA.[28] The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with everolimus, but this awaits validation in a clinical trial. * mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about 40% of pancreatic NETs.[28] The proteins encoded by ATRX and DAXX participate in chromatin remodeling of telomeres;[31] these mutations are associated with a telomerase-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of chromosomes.[31] * ATRX/DAXX and MEN1 mutations were associated with a better prognosis.[28] ## References[edit] 1. ^ Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update". Current Treatment Options in Oncology. 13 (1): 24–34. doi:10.1007/s11864-011-0172-2. PMID 22198808. 2. ^ a b Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) Health Professional Version. National Cancer Institute. March 7, 2014. [1] 3. ^ a b The PanNET denomination is in line with current WHO guidelines. Historically, PanNETs have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors". See: Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (August 2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems" (PDF). Pancreas. 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID 20664470. 4. ^ Oberg K (December 2010). "Pancreatic endocrine tumors". Seminars in Oncology. 37 (6): 594–618. doi:10.1053/j.seminoncol.2010.10.014. PMID 21167379. 5. ^ a b Unless otherwise specified in boxes, reference is: Vinik A, Casellini C, Perry RR, Feliberti E, Vingan H (2015). "Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments". In De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID 25905300. 6. ^ a b c d e f McKenna LR, Edil BH (November 2014). "Update on pancreatic neuroendocrine tumors". Gland Surgery. 3 (4): 258–75. doi:10.3978/j.issn.2227-684X.2014.06.03. PMC 4244504. PMID 25493258. 7. ^ "Glucagonoma: Practice Essentials, Pathophysiology, Epidemiology". Medscape. 2019-02-01. 8. ^ a b c d e f g h "Neuroendocrine tumors, NCCN Guidelines Version 1.2015" (PDF). NCCN Guidelines. National Comprehensive Cancer Network, Inc. November 11, 2014. Retrieved December 25, 2014. 9. ^ Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) National Cancer Institute [2] 10. ^ Jensen RT, Berna MJ, Bingham DB, Norton JA (October 2008). "Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies". Cancer. 113 (7 Suppl): 1807–43. doi:10.1002/cncr.23648. PMC 2574000. PMID 18798544. 11. ^ Grant CS (October 2005). "Insulinoma". Best Practice & Research. Clinical Gastroenterology. 19 (5): 783–98. doi:10.1016/j.bpg.2005.05.008. PMID 16253900. 12. ^ a b c d e f g Benson AB, Myerson RJ, and Sasson AR. Pancreatic, neuroendocrine GI, and adrenal cancers. Cancer Management: A Multidisciplinary Approach 13th edition 2010. ISBN 978-0-615-41824-7 Text is available electronically (but may require free registration) at http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606 13. ^ Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, et al. (June 2005). "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours". Gut. 54. 54 Suppl 4 (suppl_4): iv1-16. doi:10.1136/gut.2004.053314. PMC 1867801. PMID 15888809. 14. ^ a b c Ro C, Chai W, Yu VE, Yu R (June 2013). "Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment". Chinese Journal of Cancer. 32 (6): 312–24. doi:10.5732/cjc.012.10295. PMC 3845620. PMID 23237225. 15. ^ Vinik A, Casellini C, Perry RR, Feliberti E, Vingan H (2015). "Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments". Endotext. MDText.com, Inc. 16. ^ Sundin, Anders; Arnold, Rudolf; Baudin, Eric; Cwikla, Jaroslaw B.; Eriksson, Barbro; Fanti, Stefano; Fazio, Nicola; Giammarile, Francesco; Hicks, Rodney J.; Kjaer, Andreas; Krenning, Eric (2017). "ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine and Hybrid Imaging". Neuroendocrinology. 105 (3): 212–244. doi:10.1159/000471879. ISSN 0028-3835. 17. ^ a b Unless otherwise specified in boxes, reference is: Pishvaian MJ, Brody JR (2017). "Therapeutic Implications of Molecular Subtyping for Pancreatic Cancer". Oncology (Williston Park). 31 (3): 159–66, 168. PMID 28299752. 18. ^ National Cancer Institute. Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) Incidence and Mortality [3] 19. ^ Öberg K, Knigge U, Kwekkeboom D, Perren A (October 2012). "Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology. 23 Suppl 7: vii124-30. doi:10.1093/annonc/mds295. PMID 22997445. (Table 5 outlines the proposed TNM staging system for PanNETs.) 20. ^ a b Everolimus Approved for Pancreatic Neuroendocrine Tumors. The ASCO Post. May 15, 2011, Volume 2, Issue 8 "Archived copy". Archived from the original on 2013-01-17. Retrieved 2014-12-25.CS1 maint: archived copy as title (link) 21. ^ a b http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf 22. ^ National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate. Pancreatic Neuroendocrine Tumors http://www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate 23. ^ http://labeling.pfizer.com/ShowLabeling.aspx?id=607 24. ^ "Pfizer Scores New Approval for Sutent in Europe". 2 Dec 2010. 25. ^ Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. (February 2011). "Sunitinib malate for the treatment of pancreatic neuroendocrine tumors". The New England Journal of Medicine. 364 (6): 501–13. doi:10.1056/NEJMoa1003825. PMID 21306237. 26. ^ Ro C, Chai W, Yu VE, Yu R (June 2013). "Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment". Chinese Journal of Cancer. 32 (6): 312–24. doi:10.5732/cjc.012.10295. PMC 3845620. PMID 23237225. 27. ^ Backman S, Björklund P (2017). Diagnostic and Therapeutic Nuclear Medicine for Neuroendocrine Tumors. Contemporary Endocrinology. Humana Press, Cham. pp. 127–140. doi:10.1007/978-3-319-46038-3_6. ISBN 9783319460369. 28. ^ a b c d e Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. (March 2011). "DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors". Science. 331 (6021): 1199–203. doi:10.1126/science.1200609. PMC 3144496. PMID 21252315. 29. ^ Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. (September 2008). "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses". Science. 321 (5897): 1801–6. doi:10.1126/science.1164368. PMC 2848990. PMID 18772397. 30. ^ Harada T, Chelala C, Crnogorac-Jurcevic T, Lemoine NR (2009). "Genome-wide analysis of pancreatic cancer using microarray-based techniques". Pancreatology. 9 (1–2): 13–24. doi:10.1159/000178871. PMID 19077451. 31. ^ a b Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. (July 2011). "Altered telomeres in tumors with ATRX and DAXX mutations". Science. 333 (6041): 425. doi:10.1126/science.1207313. PMC 3174141. PMID 21719641. ## External links[edit] Classification D * ICD-10: C25.4 * MeSH: D018273 * Pancreatic neuroendocrine tumor at Curlie * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Pancreatic neuroendocrine tumor	c1328479	8,790	wikipedia	https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor	2021-01-18T18:53:37	{"gard": ["13034"], "mesh": ["D018273"], "umls": ["C1328479"], "orphanet": ["97253"], "wikidata": ["Q6084258"]}
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-15 with or without frontotemporal dementia (ALS15) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11. For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400). Clinical Features Deng et al. (2011) identified a 5-generation family with ALS15 including 19 affected individuals. The disease was transmitted in a dominant fashion with reduced penetrance in females. Deng et al. (2011) also identified 4 other unrelated families with ALS15 and obtained clinical data from a total of 40 individuals, including 35 patients and 5 obligate carriers. Penetrance was approximately 90% by age 70 years. The age of onset of disease ranged from 16 to 71 years. There was a significant difference in the age of onset between male and female patients, with male patients having an earlier age of onset (33.9 +/- 14.0 years vs 47.3 +/- 10.8 years, P = 0.003, 2-tailed Student's t-test). However, there were no statistically significant differences in the duration of the disease (43.1 +/- 42.1 months vs 48.5 +/- 19.9 months, P = 0.61). Eight patients manifested both ALS and dementia. Dementia in these patients was similar to frontotemporal lobar type (see 600274), including abnormalities in both behavior and executive function. The dementia was progressive and eventually global in most ALS/dementia patients. In some cases the dementia preceded motor symptoms, but all patients eventually developed motor disability. Pathologic analysis of spinal cord autopsy samples from 2 patients revealed axonal loss in the corticospinal tract, loss of anterior horn cells, and astrocytosis in the anterior horn of the spinal cord. Fahed et al. (2014) reported a 5-generation family in which 6 individuals presented before 30 years of age with a severe neurodegenerative disorder. The family had previously been reported by DeMyer et al. (1964). Disease onset occurred before age 10 years in 3 males, whereas it began between 20 and 30 years of age in 3 females. Initial symptoms included dysarthria and decreased fine motor dexterity. Speech deficits progressively worsened, and drooling, dysphagia, and abnormal involuntary movements developed, followed by spastic paralysis in all limbs and behavioral dementia. Death occurred in both males and females within 17 years after symptom onset. Brain imaging showed progressive atrophy of the cerebral cortex, substantia nigra, caudate, and corticospinal tracts; imaging in 1 patient was suggestive of iron accumulation in deep brain regions. One additional family member was well until age 63 when she presented with typical signs and symptoms of ALS without dementia. Neuropathologic examination of 4 patients showed frontotemporal atrophy with neuronal loss, gliosis, and myelin pallor in the cortex, cerebrum, cerebellum, and corticospinal tracts. Two patients showed UBQLN2- and TDP43 (605078)-immunopositive neuronal inclusions in the brainstem and hippocampus. Inheritance The transmission pattern of a progressive neurodegenerative disorder in the family reported by Fahed et al. (2014) was consistent with X-linked dominant inheritance with incomplete penetrance. Pathogenesis In ALS, protein aggregates or inclusions are most common in spinal motor neurons and are typically skein-like in morphology. These ubiquitin-positive inclusions, among others, are considered to be a hallmark of ALS pathology. Deng et al. (2011) found that the skein-like inclusions from 2 ALS15 patients were immunoreactive with both ubiquilin-2 C-terminus and N-terminus antibodies, indicating that ubiquilin-2 is involved in inclusion formation in X-linked ALS. Furthermore, Deng et al. (2011) found that skein-like inclusions in the X-linked patients were also immunoreactive with antibodies to ALS-implicated proteins ubiquitin (see 191339), p62 (601530), TDP43 (605078), FUS (137070), and optineurin (602432), but not SOD1 (147450). In the brains of patients with UBQLN2 mutations with ALS and dementia, Deng et al. (2011) showed ubiquilin-2 inclusions in the hippocampus, small inclusions in the neuropil, and large inclusions (up to 20 microns in diameter) in some pyramidal neurons, especially those in the CA3 and CA1 regions. Deng et al. (2011) noted that this type of hippocampal pathology had not previously been observed in any other neurodegenerative disorder. Among hippocampal sections from 15 pathologically characterized ALS cases without UBQLN2 mutations, including 5 with dementia, Deng et al. (2011) observed prominent ubiquilin-2 pathology in sections from the cases with dementia but not in those from the 10 cases without dementia. The correlation of hippocampal ubiquilin-2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicated that ubiquilin-2 is widely involved in ALS-related dementia, even without UBQLN2 mutations. Mapping Deng et al. (2011) performed linkage analysis with microsatellite markers on the X chromosome in a 5-generation family with ALS and obtained the highest 2-point lod score of 5.0 with marker DXS9736 at theta = 0. Detailed mapping defined a 21.3-Mb minimum candidate region containing 206 genes, of which 191 are protein-coding. Molecular Genetics Based on expression profile, function, structure, and potential relevance of their encoded proteins, Deng et al. (2011) selected 41 genes for sequencing within the ALS15 candidate region. They identified 5 different proline substitutions in the PXX repeat domain of UBQLN2 as causative of ALS15 (300264.0001-300264.0005) in 5 unrelated families. In affected members of a 5-generation family with a progressive neurodegenerative disorder, originally reported by DeMyer et al. (1964), Fahed et al. (2014) identified a heterozygous missense mutation in the UBQLN2 gene (P497L; 300264.0006). Functional studies of the variant were not performed. INHERITANCE \- X-linked dominant ABDOMEN Gastrointestinal \- Dysphagia NEUROLOGIC Central Nervous System \- Amyotrophic lateral sclerosis \- Frontotemporal dementia \- Dysarthria \- Spastic paralysis \- Abnormal involuntary movements \- Dystonic movements \- Athetoid movements \- Frontotemporal atrophy \- Neuronal loss and gliosis in the cerebral cortex \- Axonal loss and gliosis in the corticospinal tracts \- Loss of anterior horn cells and gliosis in the spinal cord \- UBQLN2- and TDP43-immunopositive inclusions in spinal motor, brainstem, and hippocampal neurons MISCELLANEOUS \- Onset in males in first to third decade \- Onset in females ranges from third to seventh decade \- Progressive disorder \- Motor symptoms are variable \- Incomplete penetrance in females MOLECULAR BASIS \- Caused by mutation in the ubiquilin 2 gene (UBQLN2, 300264.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA	c0002736	8,791	omim	https://www.omim.org/entry/300857	2019-09-22T16:19:29	{"doid": ["0060206"], "mesh": ["D000690"], "omim": ["300857"], "orphanet": ["803"], "genereviews": ["NBK1450"]}
A rare, genetic pulmonary disorder characterized by sweat, thick mucus secretions causing multisystem disease, chronic infections of the lungs, bulky diarrhea and short stature. ## Epidemiology Cystic fibrosis (CF) is the most common genetic disorder among Caucasians. In Europe, the prevalence at birth is estimated at 1/3,000; however, this may vary across certain populations ranging from 1/1,400 in Ireland to 1/25,000 in Finland. ## Clinical description CF is chronic and usually progressive. Symptoms often start at birth and involve the lungs and gastrointestinal tract. A common presentation might include thick secretions and chronic infections in the lung, bulky diarrhea and short stature. Abnormal airway secretions, inflammation and infections lead to bronchiectasis and early death. CF-related diabetes (CFRD) occurs at high frequency, rising to nearly 50% of patients surviving to age 50. Male sterility is common. Individuals with mild phenotypes may have mild or absent respiratory symptoms in childhood, but some may have infertility or may develop bronchiectasis or pancreatitis later in life. These individuals are typically diagnosed by newborn screening, but may be diagnosed later in life. ## Etiology Abnormal chloride channel function causes high salt content sweat and highly viscous mucus secretions. CF is a monogenic autosomal recessive disease caused by CFTR mutations. Among thousands of mutations, less than 300 cause disease when present in a homozygous or compound heterozygous state. About 70% of patients are homozygous for the delta F508 allele; 30 other mutations account for 20% of cases. Genotype and phenotype correlate poorly, but mutations associated with pancreatic insufficiency lead to more severe phenotypes. Mutations permitting residual CFTR function (e.g. R117H) are associated with the milder phenotype. Many factors influence phenotype. ## Diagnostic methods Diagnosis requires a typical clinical syndrome and either laboratory confirmed CFTR protein dysfunction or presence of two disease-causing mutations of CFTR on heteroalleles. Sweat testing confirms protein dysfunction. Newborn screening may presumptively diagnose CF before symptoms. ## Differential diagnosis Any cause of bronchiectasis may mimic CF including primary ciliary dyskinesia, immunodeficiency, autoimmune disease, untreated pneumonia, esophageal reflux, or anatomic limitation to airway clearance such as in scoliosis. Some unusual or rare conditions falsely elevate sweat chloride suggesting CF. Genetic testing helps in these cases. ## Antenatal diagnosis In at risk pregnancies, mutation analysis of chorionic villus samples after gestation week eight is possible for diagnosis. ## Genetic counseling The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at risk couples carrying CF mutations (identified by birth of a child with CF, neonatal screening detection of carrier status or family history), informing them that the risk of having an affected child at each pregnancy is 25%. ## Management and treatment Treatment is transitioning from addressing symptoms to correcting biochemical defects. The oldest therapies include bronchial drainage and broad spectrum antibiotics for increasingly resistant pathogens. Pancreatic enzyme replacement with vitamin and calorie supplements improve digestion and nutrition. Insulin replacement for CFRD addresses lack of insulin release not seen in other types of diabetes. New CFTR modulators partly restore chloride channel function in about 90% of patients. However, they do not treat absent, truncated or severely malformed proteins. ## Prognosis Lung disease is the main driver of morbidity and mortality. However, non-specific treatments improved the expectation of life at birth to more than 35 years, and with the advent of CFTR modulator therapy life expectancy has increased to nearly 50 years. Prognosis for newborns with CF may soon approach that of general populations. However, aging CF patients may be more vulnerable to disease associated with aging than the general population. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Cystic fibrosis	c0010674	8,792	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=586	2021-01-23T18:12:57	{"gard": ["6233"], "mesh": ["D003550"], "omim": ["219700"], "umls": ["C0010674"], "icd-10": ["E84.0", "E84.1", "E84.8", "E84.9"], "synonyms": ["CF", "Mucoviscidosis"]}
Christie et al. (1954) described the disease in sibs who were never in contact, thus tending to discredit an infectious hypothesis. Rogers and Benson (1962) reported affected sibs and reviewed the literature. Falk and Gellei (1963) also observed a family. Schoeck et al. (1963) described 2 sibs with L-S disease. Ten other families with multiple affected sibs were reviewed, including Farquhar 'familial hemophagocytic reticulosis' (267700) and Nelson 'generalized lymphohistiocytic infiltration' (also see 267700), which Schoeck et al. suggested are all the same entity. In a survey of deaths from Letterer-Siwe disease in a 5-year period in the U.S., Glass and Miller (1968) found 5 sib pairs among 270 deaths, a pair of concordant like-sex twins, and a peak of mortality under 1 year of age. Freundlich et al. (1972) reported 2 families with multiple cases of consanguineous parents. Hirsch and Kong (1973) reported a father and son with histiocytosis X of the lung. The father presented with cough and exertional dyspnea, whereas the son was asymptomatic. Biopsies confirmed histiocytosis X (eosinophilic granuloma) in both. Neither father nor son had any evidence of disseminated histiocytosis. I have information from Cook (1967) concerning 8 cases of histiocytosis X occurring in 2 sibships in an inbred Mennonite group in Waterloo County, Ontario. In each case the parents were related as second cousins and all 4 parents shared in common a grandparental couple. In 2 cases, treatment with adrenocorticosteroids was begun early and both patients survived. The other cases pursued an identical course. They were well until ages 8 to 18 weeks, following which they developed general irritability, especially on being touched or moved. There was pallor, dyspnea, distended abdomen, fever, and, in the terminal stages, usually jaundice. Medical investigations showed hepatosplenomegaly, anemia, neutropenia, and thrombocytopenia. Autopsy showed histiocytic infiltration of the liver, spleen and lymph nodes. There was no persistent skin rash and no bone lesions were identified. The course of the illness in all 6 fatal cases was rapid, ranging from 2 to 5 weeks. None of the children had contact with each other. These cases are also discussed under familial histiocytic reticulosis (267700). The nosology of this category is confused, as is the terminology. For example, Donohue and Thompson (1972) concluded that the Mennonite cases represent the disorder reported as 'familial Letterer-Siwe disease' and not histiocytosis X. The occurrence of 'encephalopathy' in both the Mennonite cases and reported familial Letterer-Siwe disease, but not in either nonfamilial L-S disease or histiocytosis X, was one reason for their conclusion. Kloepfer et al. (1972) observed the same or a similar disorder in an inbred triracial group in Louisiana, known locally as 'Redbones.' The entity described here should not be confused with Langerhans cell histiocytosis (604856) The Langerhans cell, a dendritic cell of the epidermis, was described by a medical student, Paul Langerhans, who thought that it was part of the nervous system (Langerhans, 1868). Birbeck et al. (1961) found that the Langerhans cell displays a unique electron-microscopic morphology. The discoveries that these cells are not confined to skin and that they make up a sizable portion of the cellular infiltrate in histiocytosis X, along with other evidence, suggest that they play an immunologic role in protecting against environmental antigens. Egeler and D'Angio (1995) presented a classification of histiocytosis syndromes in children: class I, Langerhans cell histiocytosis; class II, histiocytosis of mononuclear macrophages other than Langerhans cells, including familial hemophagocytic lymphohistiocytosis; and class III, malignant histiocytic disorders, including histiocytic lymphoma. Radiology \- Pulmonic infiltration \- Lytic osseous lesions Neuro \- Infantile irritability \- Encephalopathy Lab \- Histiocytosis X (eosinophilic granuloma) \- Histiocytic infiltration of the liver, spleen and lymph nodes Skin \- Pallor \- Jaundice \- Diffuse papulo-vesicular rash \- Scaly petechial dermatitis \- Intertriginous denudation \- Seborrhea \- Stomatitis Resp \- Dyspnea Inheritance \- Autosomal recessive Misc \- Fever \- Onset in first year Abdomen \- Distended abdomen GI \- Hepatosplenomegaly Heme \- Anemia \- Neutropenia \- Thrombocytopenia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	LETTERER-SIWE DISEASE	c0023381	8,793	omim	https://www.omim.org/entry/246400	2019-09-22T16:25:49	{"doid": ["2571"], "mesh": ["C538636"], "omim": ["246400"], "icd-9": ["202.5"], "icd-10": ["C96.6", "C96.0"], "orphanet": ["99870"], "synonyms": ["Alternative titles", "L-S DISEASE", "HISTIOCYTOSIS X, ACUTE DISSEMINATED"]}
Familial focal epilepsy with variable foci (FFEVF) is an uncommon form of recurrent seizures (epilepsy) that runs in families. Seizures associated with FFEVF can begin at any time from infancy to adulthood. The seizures are described as focal or partial, which means they begin in one region of the brain and do not cause a loss of consciousness. In more than 70 percent of affected individuals, these seizures begin in one of two areas of the brain, either the temporal lobe or the frontal lobe. The region of the brain where the seizures start tends to stay the same over time. In rare instances, seizure activity that starts in one area spreads to affect the entire brain and causes a loss of consciousness, muscle stiffening, and rhythmic jerking. Episodes that begin as partial seizures and spread throughout the brain are known as secondarily generalized seizures. Among family members with FFEVF, individuals may not have the same brain region affected (variable foci), meaning that one person's seizures may not begin in the same part of the brain as their affected relative. Some individuals with FFEVF also have a brain malformation called focal cortical dysplasia. Seizures in these individuals are typically not well-controlled with medication. Most people with FFEVF are intellectually normal, and there are no problems with their brain function between seizures. However, some people with FFEVF have developed psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear whether these additional features are directly related to epilepsy in these individuals. ## Frequency The prevalence of FFEVF is unknown. ## Causes Most cases of FFEVF are caused by mutations in the DEPDC5 gene with fewer cases caused by mutations in the NPRL2 or NPRL3 gene. These three genes provide instructions for making proteins that attach (bind) to each other to form a protein complex called GATOR1. This complex is found in cells throughout the body, where it regulates a signaling pathway involved in cell growth and division (proliferation), the survival of cells, and the creation (synthesis) of new proteins. The role of the GATOR1 complex is to block (inhibit) this pathway when it is not needed. A mutation in any one of the three genes associated with FFEVF reduces GATOR1 complex formation, leading to an abnormally active signaling pathway. It is unclear how overactivity in this pathway leads to the focal seizures of FFEVF. Research suggests that increased signaling in the brain leads to changes in the development of the junctions between nerve cells (synapses) and increased activation (excitation) of nerve cells, which can cause seizures. Increased excitation of nerve cells can also cause enlargement of these cells, which is characteristic of focal cortical dysplasia. It is unknown why some individuals with the same mutation have seizures that start in different regions of the brain. Researchers believe that other, unknown genes may influence the features of FFEVF. Some individuals with FFEVF do not have an identified mutation in any of these three genes. The cause of the condition in these individuals is unknown. ### Learn more about the genes associated with Familial focal epilepsy with variable foci * DEPDC5 * NPRL2 * NPRL3 ## Inheritance Pattern FFEVF is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one parent. For unknown reasons, some people with FFEVF caused by a DEPDC5 gene mutation never develop the condition, a situation known as reduced penetrance. Approximately 60 percent of individuals with DEPDC5 gene mutations go on to develop FFEVF. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Familial focal epilepsy with variable foci	c1858477	8,794	medlineplus	https://medlineplus.gov/genetics/condition/familial-focal-epilepsy-with-variable-foci/	2021-01-27T08:25:17	{"gard": ["13295"], "mesh": ["C565785"], "omim": ["604364", "617116", "617118"], "synonyms": []}
An early-onset distal osteolysis characterised by severe resorption of the hands and feet and absence of the distal and middle phalanges. It has been described in a son and daughter born to consanguineous parents. Other manifestations include distal muscular hypertrophy, flexion contractures, short stature, mild intellectual deficit and characteristic facies (maxillary hypoplasia, exophthalmos, and a broad nasal tip). It is transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Autosomal recessive distal osteolysis syndrome	c1850143	8,795	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2776	2021-01-23T18:03:23	{"gard": ["4299"], "mesh": ["C536052"], "omim": ["259610"], "synonyms": ["Distal osteolysis-short stature-intellectual disability syndrome", "Petit-Fryns syndrome"]}
Splenic diffuse red pulp small B-cell lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal proliferation of small, monomorphous, basophilic B-lymphocytes, with villous cytoplasm, in the splenic red pulp, bone marrow and peripheral blood. It typically presents in the late clinical stages with splenomegaly and moderate lymphocytosis. Cytopenias are rare and likely associated with hypersplenism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Splenic diffuse red pulp small B-cell lymphoma	c2699508	8,796	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300869	2021-01-23T17:19:36	{"icd-10": ["C83.0"], "synonyms": ["SDRPL", "Splenic diffuse red pulp lymphoma"]}
Dysfibrinogenemia is a coagulation (clotting) disorder characterized by having an abnormal form of fibrinogen. Fibrinogen is a protein produced by the liver which helps control bleeding by helping blood clots to form. Having abnormal fibrinogen results in defective clot formation and can cause an increased or decreased ability to clot. Dysfibrinogenemias may be inherited (congenital) or acquired. Congenital dysfibrinogenemia is rare. About 40% of people with this form have no symptoms. About 50% have a bleeding disorder, and the remaining 10% have either a thrombotic disorder (excessive clotting) or both bleeding and thrombotic disorders. Congenital dysfibrinogenemias may be caused by mutations in the FGA, FGB or FGG genes. Inheritance is most often autosomal dominant or codominant, but can also be autosomal recessive. Whether a person has no symptoms, a bleeding tendency, or an increased risk of thrombosis depends on the effect of their specific mutation(s). Most people with dysfibrinogenemia have no symptoms and don't need treatment. For the remainder, treatment is individualized and depends on the symptoms and severity in each person. Acquired dysfibrinogenemia is more common than the congenital form and is associated with liver disease such as cirrhosis, liver tumors, or hepatitis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Dysfibrinogenemia	c0272350	8,797	gard	https://rarediseases.info.nih.gov/diseases/2004/dysfibrinogenemia	2021-01-18T18:00:47	{"mesh": ["C562727"], "omim": ["616004"], "orphanet": ["98881"], "synonyms": ["Dysfibrinogenemia, familial", "Congenital dysfibrinogenemia", "Familial dysfibrinogenemia"]}
Pigeon fever is a disease of horses, also known as dryland distemper or equine distemper, caused by the Gram-positive bacteria Corynebacterium pseudotuberculosis biovar equi.[1] Infected horses commonly have swelling in the chest area, making it look similar to a 'pigeon chest'. This disease is common in dry areas. Pigeon Fever is sometimes confused for Strangles, another infection that causes abscesses. ## Contents * 1 Symptoms * 1.1 Ulcerative lymphangitis * 1.2 External abscess * 1.3 Internal infection * 2 Treatment * 3 Transmission * 4 Prevention * 5 Epidemiology * 6 References * 7 External links ## Symptoms[edit] There are three common forms of pigeon fever that affect horses; ulcerative lymphangitis, external abscess, and internal infection. The severity of symptoms varies depending on various factors such as age, immune system, health and nutrition. The bacteria has an incubation period of 3–4 weeks.[2] ### Ulcerative lymphangitis[edit] This is the least common form of pigeon fever seen in horses. It is characterized by severe limb swelling and cellulitis in one or both hind limbs and can lead to lameness, fever, lethargy and loss of appetite. Antimicrobial and anti-inflammatory treatments are required to prevent further complications such as limb edema, prolonged or recurrent infection, lameness, weakness and weight loss.[3] ### External abscess[edit] External abscesses are the most common form of pigeon fever seen in horses. Abscesses develop on the body, usually in the pectoral region and along the ventral midline of the abdomen. However, abscesses can also develop on other areas of the body such as the prepuce, mammary gland, triceps, limbs and head. The fatality rate for this form infection is very low. The abscess is often drained once it has matured.[3] ### Internal infection[edit] Only 8% of infected horses have this form of pigeon fever, however, it has a 30-40% fatality rate. Organs that are commonly affected are the liver, spleen, and lungs. For a successful recovery, long-term antimicrobial therapy is essential.[2] ## Treatment[edit] Treatment depends on many factors, such as the age of horse, severity of symptoms and duration of infection. As long a horse is eating and drinking, the infection must run its course, much like a common cold virus. Over time a horse will build up enough antibodies to overtake and fight the disease. Other treatment options can be applying heat packs to abscesses to help draw it to the surface and using drawing salves such as Ichthammol. A blood test or bacterial cultures can be taken to confirm the horse is fighting Pigeon Fever.[3] Anti-inflammatory such as phenylbutazone can be used to ease pain and help control swelling. Treating Pigeon Fever with antibiotics is not normally recommended for external abscesses since it is a strong bacterium that takes extended treatment to kill off and to ensure it does not return stronger. However, if the abscesses are internal then antibiotics may be needed.[4] Consulting a veterinarian for treatment is recommended. Making the horse comfortable, ensuring the horse has good food supply and quality hay will help the horse keep their immune system strong to fight off the infection. Once the abscess breaks or pops, it will drain for a week or two. During this time keeping the area clean, applying hot packs or drawing salves will help remove the pus that has gathered in the abscess. ## Transmission[edit] This bacterium is present in soil and is transmitted to horses through open wounds, abrasions or mucous membranes.[3] ## Prevention[edit] It is important to reduce the amount of environmental contamination to prevent the spread of insects or fomites. Owners should regularly apply insect repellent and routinely check their horses for open wounds to prevent chance of infection.[3] A regular manure management program is recommended, including removal of soiled feed and bedding, as the bacteria can survive in hay and shavings for up to two months.[3] Since the disease lives in the ground and is spread by flies, pest control is a good defense but not a guarantee. Horses being introduced to new environments should be quarantined and any infected horses should be isolated to prevent spread of the bacteria.[2] There is currently no vaccination for Pigeon Fever.[2] ## Epidemiology[edit] The disease can occur in horses of any age, breed or gender.[5] In the US, it occurs throughout the country and at any time of year.[6] The disease was traditionally thought to occur mainly in dry, arid regions,[5] but from at least 2005, its range has been increasing into areas where it was not previously seen, such as the Midwestern US,[7] and Western Canada.[8] Environmental risk factors include over 7 days of a weekly average land surface temperatures above 35 °C, and drier soils; these factors were implicated in an outbreak in Kansas in 2012.[5] ## References[edit] 1. ^ Baraúna, RA; Ramos, RT; Veras, AA; Pinheiro, KC; Benevides, LJ; Viana, MV; Guimarães, LC; Edman, JM; Spier, SJ; Azevedo, V; Silva, A (26 January 2017). "Assessing the genotypic differences between strains of Corynebacterium pseudotuberculosis biovar equi through comparative genomics". PLoS ONE. 12 (1): e0170676. doi:10.1371/journal.pone.0170676. PMC 5268413. PMID 28125655. 2. ^ a b c d University of California - Centre for Equine Health (2014). "Pigeon Fever: Varying forms of infection in horses" (PDF). Retrieved December 4, 2016. 3. ^ a b c d e f American Association of Equine Practitioners (2013). "Pigeon Fever" (PDF). Retrieved December 4, 2016. 4. ^ Sharon J. Spier 5. ^ a b c Boysen, C; Davis, EG; Beard, LA; Lubbers, BV; Raghavan, RK (16 October 2015). "Bayesian geostatistical analysis and ecoclimatic determinants of Corynebacterium pseudotuberculosis infection among horses". PLoS ONE. 10 (10): e0140666. doi:10.1371/journal.pone.0140666. PMC 4608828. PMID 26473728. 6. ^ Kilcoyne, I; Spier, SJ; Carter, CN; Smith, JL; Swinford, AK; Cohen, ND (1 August 2014). "Frequency of Corynebacterium pseudotuberculosis infection in horses across the United States during a 10-year period". Journal of the American Veterinary Medical Association. 245 (3): 309–14. doi:10.2460/javma.245.3.309. PMID 25029310. 7. ^ Barba, M; Stewart, AJ; Passler, T; Wooldridge, AA; van Santen, E; Chamorro, MF; Cattley, RC; Hathcock, T; Hogsette, JA; Hu, XP (2015). "Experimental transmission of Corynebacterium pseudotuberculosis biovar equi in horses by house flies". Journal of Veterinary Internal Medicine. 29 (2): 636–43. doi:10.1111/jvim.12545. PMC 4895518. PMID 25818218. 8. ^ Corbeil, LE; Morrissey, JF; Léguillette, R (October 2016). "Is Corynebacterium pseudotuberculosis infection (pigeon fever) in horses an emerging disease in western Canada?". The Canadian Veterinary Journal. 57 (10): 1062–1066. PMC 5026146. PMID 27708444. ## External links[edit] * http://vetmed.tamu.edu/news/pet-talk/pigeon-fever-in-texas * http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/10802.htm * http://oregonvma.org/care-health/pigeon-fever [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Pigeon fever	c3669590	8,798	wikipedia	https://en.wikipedia.org/wiki/Pigeon_fever	2021-01-18T18:49:13	{"wikidata": ["Q7193337"]}
Distal 17p13.1 microdeletion syndrome is a rare chromosomal anomaly syndrome characterized by mild global developmental delay/intellectual disability with poor to absent speech, dysmorphic features (long midface, retrognathia with overbite, protruding ears), microcephaly, failure to thrive, wide-based gait and a body posture with knee and elbow flexion and hands held in a midline. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration [lit.]: literal translation [CMPF]: 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid	Distal 17p13.1 microdeletion syndrome	None	8,799	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319171	2021-01-23T18:19:54	{"gard": ["10996"], "icd-10": ["Q93.5"], "synonyms": ["Distal del(17)(p13.1)"]}

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