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Ethylene glycol poisoning is a rare poisoning resulting in elevated anion gap metabolic acidosis, due to the production of glycolic acid, glyoxylic acid, and oxalic acid by alcohol dehydrogenase (ADH) in the liver when ethylene glycol is metabolized, characterized initially by euphoria, slurred speech, encephalopathy, coma and seizures, and followed by late manifestations such as tachycardia, arrhythmias, myocardial depression, hemodynamic imbalance and, finally, acute renal failure. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Ethylene glycol poisoning	c0413194	3,100	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=31826	2021-01-23T18:34:20	{"umls": ["C0413194"], "icd-10": ["T52.8"]}
A rare idiopathic interstitial pneumonia characterized by a diffuse, dense, polyclonal lymphoid cell infiltration of the pulmonary interstitium and air spaces, with high prevalence in patients with immune dysregulation. Presenting symptoms are non-specific and include dyspnea and cough. The clinical course is highly variable, ranging from spontaneous resolution to progressive, fatal respiratory failure. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lymphoid interstitial pneumonia	c0264511	3,101	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79128	2021-01-23T17:27:01	{"mesh": ["C562489"], "omim": ["247610"], "umls": ["C0264511"], "icd-10": ["J84.1"], "synonyms": ["Lymphocytic interstitial pneumonia"]}
Weber–Christian disease Other namesRelapsing febrile nodular nonsuppurative panniculitis SpecialtyRheumatology Weber–Christian disease, is a cutaneous condition characterized by recurrent subcutaneous nodules that heal with depression of the overlying skin.[1] It is a type of panniculitis.[2] It is a rare disease seen in females 30–60 years of age. It is a recurring inflammation of fatty layers of tissue present beneath the skin. Clinical course is characterised by exacerbations and remissions. Lesions are bilaterally symmetrical and are usually seen in the lower legs. ## Contents * 1 Eponym * 2 See also * 3 References * 4 External links ## Eponym[edit] It is named after[3] Frederick Parkes Weber[4] and Henry Asbury Christian.[5] ## See also[edit] * Alpha-1 antitrypsin deficiency panniculitis * 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 978-1-4160-2999-1. 2. ^ "Weber-Christian disease" at Dorland's Medical Dictionary 3. ^ Weber–Christian disease at Who Named It? 4. ^ Weber, F. Parkes (July 1925). "A CASE OF RELAPSING NON-SUPPURATIVE NODULAR PANNICULITIS, SHOWING PHAGOCYTOSIS OF SUBCUTANEOUS FAT-CELLS BY MACROPHAGES.". British Journal of Dermatology. 37 (7): 301–311. doi:10.1111/j.1365-2133.1925.tb10003.x. 5. ^ Christian, Henry Asbury (1 September 1928). "Relapsing febrile nodular nonsuppurative panniculitis". Archives of Internal Medicine. Chicago. 42 (3): 338. doi:10.1001/archinte.1928.00020020026004. ## External links[edit] Classification D ICD-10: M35.6 * ICD-9-CM: 729.30 * MeSH: D010201 * DiseasesDB: 14055 External resources * eMedicine: ped/2429 * v * t * e Disorders of subcutaneous fat Panniculitis Lobular * without vasculitis * Cold * Cytophagic histiocytic * Factitial * Gouty * Pancreatic * Traumatic * needle-shaped clefts * Subcutaneous fat necrosis of the newborn * Sclerema neonatorum * Post-steroid panniculitis * Lipodermatosclerosis * Weber–Christian disease * Lupus erythematosus panniculitis * Sclerosing lipogranuloma * with vasculitis: Nodular vasculitis/Erythema induratum Septal * without vasculitis: Alpha-1 antitrypsin deficiency panniculitis * Erythema nodosum * Acute * Chronic * with vasculitis: Superficial thrombophlebitis Lipodystrophy Acquired * generalized: Acquired generalized lipodystrophy * partial: Acquired partial lipodystrophy * Centrifugal abdominal lipodystrophy * HIV-associated lipodystrophy * Lipoatrophia annularis * localized: Localized lipodystrophy Congenital * Congenital generalized lipodystrophy * Familial partial lipodystrophy * Marfanoid–progeroid–lipodystrophy syndrome * Poland syndrome 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Weber–Christian disease	c0030328	3,102	wikipedia	https://en.wikipedia.org/wiki/Weber%E2%80%93Christian_disease	2021-01-18T18:32:03	{"gard": ["7879"], "mesh": ["D010201"], "umls": ["C0030328"], "icd-9": ["729.30"], "orphanet": ["33577"], "wikidata": ["Q9190356"]}
Multiple syringomas or sweat gland tumors occur particularly on the face and around the eyes. They are not to be confused with milia, which are intraepithelial cysts. Familial occurrence is, it seems, a commonplace observation of dermatologists and autosomal dominant inheritance is likely (Reed, 1967). Reed (1970) described a family in which 7 females and 1 male in 4 generations were affected. Yesudian and Thambiah (1975) described identically affected brothers. Familial occurrence was reported also by Headington et al. (1972) and by Woringer and Eichler (1951). Inheritance \- Autosomal dominant Skin \- Multiple facial sweat gland tumors ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SYRINGOMAS, MULTIPLE	c1861302	3,103	omim	https://www.omim.org/entry/186600	2019-09-22T16:32:53	{"mesh": ["C566085"], "omim": ["186600"]}
A number sign (#) is used with this entry because this dysmorphic condition is caused by tetrasomy of chromosome 18p. Clinical Features Sebold et al. (2010) summarized the phenotype of tetrasomy 18p with a list of findings reported in more than 25% of theretofore published cases: neonatal feeding problems, growth retardation, microcephaly, strabismus, muscle tone abnormalities, scoliosis/kyphosis, and variants on brain MRI. Developmental delay and cognitive impairment are universally present. To more fully describe the molecular features and clinical presentation of tetrasomy 18p, Sebold et al. (2010) performed array CGH on samples from 42 individuals with tetrasomy 18p, and reviewed the medical records of these individuals. Forty-one of these individuals had an isochromosome 18p in all cells examined; the remaining individual had mosaicism. In addition, 31 of these 42 individuals underwent a series of clinical and genetic evaluations at the Chromosome 18 Clinical Research Center in the University of Texas Health Science Center at San Antonio. Sebold et al. (2010) also reviewed 65 patients reported in the literature. Developmental delay/mental retardation was found in every individual. A clear majority had neonatal complications including feeding difficulties and respiratory distress, and jaundice in about half of the chart-reviewed cohort. Hypoglycemia and bradycardia were rarely seen. Growth retardation was present in about 30%, and microcephaly in about 50%, of all individuals. Palatal anomalies were rare. Strabismus was present in about 50% of cases with refractive errors present in about one-third. A significant proportion of patients suffered from hearing loss or recurrent otitis media, or had small or narrow ear canals. The majority had abnormal muscle tone and about 20% had seizures. Myelomeningocele was present in 6%, and among the 12 patients who underwent MRI, 3 had enlarged lateral ventricles and 3 thin or small corpus callosum. Cardiac defects were present in one-quarter of all patients. Cryptorchidism was seen in 39% of males. Hypospadias and other congenital malformations were rare. History of constipation was present in one-third of patients. Other GI abnormalities were less common. Congenital abnormalities of the bones were present in 22%, with scoliosis and kyphosis developing in 37% and foot abnormalities present in about 23%. No patient had a thyroid abnormality. Four of the 31 patients who underwent clinical assessment had growth hormone deficiency, and 4% had IgA deficiency. About 4% of all patients suffered stillbirth or early death. Dysmorphic features noted during genetic evaluation included ptosis in one-third; posteriorly rotated ears in one-third; simple helices in less than one-third; small ears in half; abnormal columella in half; smooth philtrum in the vast majority; small mouth in half; thin upper lip in one-third; and abnormal Cupid's bow (smooth, ill-defined, or narrow) in about one-third. A high, arched, or narrow palate was present in 25 of 31 patients examined. More than half had a prominent or pointed chin and sloping shoulders or trapezius muscles; about one-third had partial or mild syndactyly of the toes and narrow feet; two-thirds had clinodactyly; and slightly more than half had camptodactyly or finger contractures. Shawl scrotum and proximally placed anus were rarely seen. O'Donnell et al. (2015) provided follow-up of the cohort reported by Sebold et al. (2010) with a special emphasis on cognitive and behavioral features. Intellectual abilities ranged widely from mild impairment and borderline normal function to severe/profound impairment, although the average IQ was 48. Patients with mild cognitive impairment demonstrated deficits in higher order planning and behavioral regulation, with social interaction difficulties; some individuals had autistic features. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TETRASOMY 18p	c0795868	3,104	omim	https://www.omim.org/entry/614290	2019-09-22T15:55:47	{"mesh": ["C538306"], "omim": ["614290"], "orphanet": ["3307"], "synonyms": ["Alternative titles", "ISOCHROMOSOME 18p SYNDROME"]}
Ring chromosome 14 syndrome is characterized by intellectual deficit, retinal and skin pigmentation disorders, seizures, and dysmorphic features, including flat occiput, epicanthal folds, downward slanting eyes, flat nasal bridge, upturned nostrils, short neck, and large low set ears. ## Epidemiology It has been described in about 50 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Ring chromosome 14 syndrome	c2930916	3,105	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1440	2021-01-23T17:10:30	{"gard": ["6072"], "mesh": ["C535487"], "omim": ["616606"], "umls": ["C2930916"], "icd-10": ["Q93.2"], "synonyms": ["Ring 14", "Ring chromosome 14"]}
This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (December 2014) (Learn how and when to remove this template message) Normal Weight Obesity Other namesSkinny fat A man with a mass of 175 lbs/79.3 Kg and a height of 5ft 11 in/181 cm with a Body mass index of 24.4. SpecialtyEndocrinology Risk factorsRapid weight loss, Sedentary lifestyle, Air pollution, Genetics, Diet high in refined carbohydrates and low protein, Age, Sleep deprivation, Stress, Alcohol consumption PreventionGradual weight loss when overweight, Proper diet, Exercise, TreatmentDiet, Exercise, Intermittent Fasting Normal weight obesity is the condition of having normal body weight, but with a high body fat percentage, leading to some of the same health risks as obesity. ## Contents * 1 Definition * 2 Prevalence * 3 Treatment * 4 References ## Definition[edit] Main article: Classification of obesity The term "metabolically obese normal weight" (MONW) refers to people with normal weight and body mass index (BMI), who display some metabolic characteristics which increase the risk of developing metabolic syndrome in the same way as obesity. People with MONW have excess visceral fat, and are predisposed to hyperinsulinemia, insulin-resistance and thus predisposition to type 2 diabetes, hypertriglyceridemia, hypertension and premature coronary heart disease or cardiovascular disease.[1] The BMI does not capture information about percentage body fat (PBF), which is a better predictor of risk due to obesity.[2][3][4][5] Some studies have suggested that the main factor which explains the metabolic abnormalities in MONW individuals is fat distribution. On the basis of these studies, a scoring method has been proposed to identify MONW individuals, based on the presence of associated diseases or biochemical abnormalities related to insulin resistance.[6] ## Prevalence[edit] In 2008, the first prevalence of US adults above 20 years was published, based on the National Health and Nutrition Examination Surveys from 1999-2004, finding that 24% of normal-weight adults were metabolically abnormal; on the other hand 51% of overweight adults and 32% of obese adults were metabolically healthy.[7] An analysis from an earlier NHANES from 1988 to 1994 found people with NWO had a four-fold higher frequency of metabolic syndrome compared with the low body fat group.[8] ## Treatment[edit] As of 2018, optimal treatment is unknown.[9] A 1998 study suggested that energy restriction and weight loss, for example a 4- to 12-week period of diet and exercise was beneficial.[1] A small study of 11 Asians with MONW published June 2018 found that moderate weight loss through dieting reduced their cardiometabolic risk per improved body composition, lipid profile, and insulin sensitivity.[9] ## References[edit] 1. ^ a b Ruderman, N; Chisholm, D; Pi-Sunyer, X; Schneider, S (May 1998). "The metabolically obese, normal-weight individual revisited". Diabetes. 47 (5): 699–713. doi:10.2337/diabetes.47.5.699. PMID 9588440. 2. ^ Gómez-Ambrosi, J; Silva, C; Galofré, JC; Escalada, J; et al. (2012). "Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity". Int J Obes (Lond). 36 (2): 286–94. doi:10.1038/ijo.2011.100. PMID 21587201. 3. ^ Flegal, KM (2010). "Commentary: the quest for weight standards". Int J Epidemiol. 39 (4): 963–7. doi:10.1093/ije/dyq124. PMID 20660171. 4. ^ Sun, Q; van Dam, RM; Spiegelman, D; et al. (2010). "Comparison of Dual-Energy X-Ray Absorptiometric and Anthropometric Measures of Adiposity in Relation to Adiposity-Related Biologic Factors". Am J Epidemiol. 172 (12): 1442–54. doi:10.1093/aje/kwq306. PMC 2998203. PMID 20952596. 5. ^ World Health Organization. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995; 854: 1–452. Okorodudu DO, Jumean MF, Montori VM, et al. Diagnostic performance of body mass index to identify obesity as defined by body adiposity: a systematic review and metaanalysis. Int J Obes 2010 34(5): 791-9 6. ^ Karelis, AD; St-Pierre, DH; Conus, F; Rabasa-Lhoret, R; Poehlman, ET (2004). "Metabolic and body composition factors in subgroups of obesity:what do we know?". J Clin Endocrinol Metab. 89 (6): 2569–2575. doi:10.1210/jc.2004-0165. PMID 15181025. 7. ^ Wildman RP, Muntner P, Reynolds K, et al. The Obese Without Cardiometabolic Risk Factor Clustering and the Normal Weight With Cardiometabolic Risk Factor Clustering. Prevalence and Correlates of 2 Phenotypes Among the US Population (NHANES 1999-2004). Arch Intern Med. 2008;168(15):1617–1624. doi:10.1001/archinte.168.15.1617 8. ^ Abel Romero-Corral, Virend K. Somers, Justo Sierra-Johnson, Yoel Korenfeld, Simona Boarin, Josef Korinek Michael, D. Jensen Gianfranco Parati, Francisco Lopez-Jimenez Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality European Heart Journal, Volume 31, Issue 6, 1 March 2010, Pages 737–746. 9. ^ a b Rubin R. What’s the Best Way to Treat Normal-Weight People With Metabolic Abnormalities? JAMA. 2018;320(3):223–225. doi:10.1001/jama.2018.8188 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Normal weight obesity	None	3,106	wikipedia	https://en.wikipedia.org/wiki/Normal_weight_obesity	2021-01-18T19:06:45	{"wikidata": ["Q22907351"]}
See also: Neonatal lupus erythematosus Congenital heart block The conduction system of the heart (shown in yellow) SpecialtyMedical genetics Symptomsslow heart rate[1] Usual onsetin utero.[1] Diagnostic methodfetal echocardiogram and Doppler and ELISA for the mother[1] Treatmentfluorinated steroids, beta agonists, IVIG, HCQ, pace maker implantation and maternal plasmapheresis.[1][2] Frequency1 child in every 15000-20000[3] The congenital heart block (CHB) is the heart block that is diagnosed in fetus (in utero) or within the first 28 days after birth[1][4] (neonatal period), some studies also include the diagnosis during early childhood to the definition of CHB.[5] It refers to the disorder in the electrical conduction system within the heart muscle,[4] which leads to the failure in pumping the blood efficiently into the aorta and the pulmonary trunk. The result of CHB can be first, second, or third-degree (complete) atrioventricular block (a block in the atrioventricular node) in which no electric signals move from the atrium to the ventricles[5] The congenital heart block is a rare disease that affects around 1 child in every 15,000–20,000 births.[3] However, its high mortality (which can be as high as 85% in some severe cases) makes the early diagnosis and intervention very important.[1] CHB can be isolated, where the fetus does not suffer from any other problems, or it can be a result of other diseases either in the child or in the mother.[1] In most cases, the congenital heart block is associated with other diseases,[5][4][1] and therefore, the symptoms vary a lot between patients. However, low heart rate is usually the main clinical presentation that leads to the diagnosis.[6][5][1] Also, the treatment varies as well due to the associated diseases and it can be non-invasive (medications given to the pregnant woman or to the child),[2][7][1] or a surgery in some cases when the CHB is resulted from anatomical disorders in the heart. ## Contents * 1 Causes and associated disorders * 1.1 Maternal autoimmune disease * 1.1.1 Anti-Ro\SSA autoantibody * 1.1.2 Anti-La\SSB autoantibody * 1.1.3 Other autoantibodies * 1.2 Congenital cardiac structural abnormalities * 2 Symptoms * 3 Diagnosis * 4 Treatment * 4.1 Fluorinated steroids * 4.2 Beta-adrenergic agonist * 4.3 Plasmapheresis * 4.4 Intravenous immunoglobulin * 4.5 Hydroxychloroquine * 5 Risk factors and outcomes * 6 Statistics * 7 Further information * 8 References ## Causes and associated disorders[edit] In some cases the reason behind CHB remains unknown[1][4] but in the great majority of affected kids, this disease is associated with the transference of autoantibodies from the mother during gestation or with major cardiac structural abnormalities that lead to a disturbance in the conducting signals in the atrioventricular node.[6][5][4][1][7] Also, in some rare cases, the congenital heart block was linked with viral infections or treatment with specific medications.[4] ### Maternal autoimmune disease[edit] See also: Autoimmune disease in women In the autoimmune-mediated congenital heart block, autoantibodies are passively transferred through the placenta during gestation.[7][6][5][4][1] The mother might be asymptomatic during or after pregnancy but she is usually positive to anti-Ro\SSA or anti-La\SSB antibodies.[5][4] In this case, the fetus's heart is normally developed and shows no structural malformations.[1][4][5][6] Just like other autoimmune diseases, the autoimmune CHB shows signs of damage resulted from the autoantibodies attacking the normal tissue of the body, inflammation and fibrosis in the fetal heart tissue are the most common ones, mainly in the atrioventricular node.[5][4] These antibodies lead to irreversible injuries in the atrioventricular node which heavily compromise the efficiency of the electrical conduction system,[6] and this results in around 18% mortality rate and 70% of the live-born kids will need early pacemaker implantation.[8] #### Anti-Ro\SSA autoantibody[edit] This autoantibody is found in the serum of the majority of kids with autoimmune CHB,[6][4] and therefore it is the one mostly linked with this disease.[6] It attacks the proteins Ro52 and Ro60 in the antigen Ro\SSA in the fetal heart tissue.[6][5][4] #### Anti-La\SSB autoantibody[edit] This antibody attacks the ribonucleoprotein La48 on the surface of the fetal cardiomyocytes, the links between this autoantibody and autoimmune CHB are less strong than the anti-Ro autoantibody and it usually accompanies it in the majority of cases.[6][4][5] Although the autoimmune CHB has a relatively high mortality and morbidity rates, the chance of kids from -mothers positive to anti-Ro\SSA and/or anti-La\SSB antibodies- to suffer from CHB is only around 1-5%,[9][7][10] which suggests the existence of other factors to influence the disease such as genetic and environmental factors.[4] #### Other autoantibodies[edit] Several autoantibodies were suggested to have links with the autoimmune CHB, mainly the ones associated with the different autoimmune diseases that are common among women (such as the antibodies associated with Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Progressive systemic sclerosis (PSS), and Mixed connective tissue disease).[5] However, the role of these autoantibodies was not studied comprehensively.[5] Also, some antigens of the fetal heart tissue (apart from the "Ro" and the "La") were studied, but no clear link with the autoimmune CHB was proven.[5] ### Congenital cardiac structural abnormalities[edit] The presence of a cardiac structural abnormality is a major determination of the outcome of CHB.[1] Its existence affects the conduction system of the heart and increases the mortality rate and the need for pace-maker implantation.[1] The cardiac structural diseases that are usually associated with the congenital heart block include the left atrial isomerism with or without atrioventricular septal defect.[1] In addition, levo transpositions of the great arteries can accompany CHB but this is less common than the first one.[1] These developmental abnormalities can impair the conduction system of the heart by disrupting its anatomical structure.[5] ## Symptoms[edit] The symptoms of the congenital heart block can vary due to the underlying problems that associate / lead to the CHB, and the features of CHB reflects the other manifestations of these diseases.[1] Bradycardia is usually the first symptom of CHB to be detected in utero.[1][5][6] Due to the block in the atrioventricular node, less electric signals move from the sinoatrial node to the bundle of his and its right and left branches, leading to a lower heart rate. The atrioventricular block can be first degree or much more severe like a complete atrioventricular block (third degree).[5][6] In addition, several changes in the ECG can be detected.[5] Other manifestations of the congenital heart block can be related to the impact of the maternal autoantibodies in the autoimmune-mediated CHB. Fibrosis of the myocardium (Endocardial fibroelastosis) (EFE) is the obvious one and it occurs due to the damage caused by the maternal autoantibodies to the cardiac tissue of the fetus, and can lead to death in some cases.[5] However, it is not a common feature of CHB.[5] Another rare symptom that might accompany the autoimmune CHB is the disorder in the valvular function, and this happens due to the damage in the papillary muscles as a result of the maternal autoantibodies.[5] ## Diagnosis[edit] There is a difference in diagnosis between low risk pregnancies where mothers do not have (or are not aware of) any autoimmune disease, and the high risk ones where mothers are known to have a specific autoimmune disease and / or are positive to anti Ro/La autoanitbodies and / or had a CHB-affected pregnancy previously.[7][5][1] In low risk pregnancies, testing the mothers' serum is not part of the routine prenatal tests.[1][11][6] Therefore, the congenital heart block is usually diagnosed during a routine obstetrical ultra sound.[1] The first symptom in most cases is a slow heart rate which can be detected using fetal echocardiogram and Doppler ultra sound techniques between the weeks 18 - 30.[11][7][5][1] The Doppler is very important to assess the level of AV block as well as to check for other cardiac structural abnormalities that might be associated with CHB such as left atrial isomerism, valvular damages and big arteries inversion,[5][1] while the echocardiogram is useful to detect other complications such as the hydrops fetalis.[1] In the absence of cardiac structural diseases, the second step to confirm the diagnosis is to test the serum of the mother for anti Ro/La autoantibodies using the enzyme-linked immunosorbent assay (ELISA).[7][1] In high risk pregnancies, the diagnosis is relatively easier as fetal and maternal screenings are part of the routine monitoring of the pregnancy.[5][1] ## Treatment[edit] Due to the rarity of this disease, there is a lack of comprehensive and high quality research about the different treatment options,[12] and therefore, no specific treatment plan is followed globally. However, some studies have attempted to outline the most widely accepted approaches in dealing with CHB. ### Fluorinated steroids[edit] There is no agreement on using fluorinated steroids in treating CHB, and the results of the different studies are contradictory.[12] These steroids (such as dexamethasone) are used when the disease is diagnosed in utero as they can cross the placenta without being deactivated.[7][1][2] The main goal of using corticosteroids is to mitigate the inflammation by decreasing the amount of anti Ro/La autoantibodies in the fetal serum.[7][6][1] Therefore, they are used in the autoimmune-mediated CHB. Both the mother and the fetus might suffer from their side effects which can include growth problems and adrenal insufficiency.[2] ### Beta-adrenergic agonist[edit] Trebutaline and Sulbutamol are among the medications that have been used to treat CHB.[2] They are used mainly to increase the heart rate in fetuses suffering from bradycardia.[2] Although they showed positive results, some patients showed intolerance to their side effects.[2] ### Plasmapheresis[edit] Plasma exchange in women positive to anti Ro/La autoantibodies has not been studied thoroughly, but it is suggested to have and effect on the titer of the antibodies in the mother's serum and therefore might have a preventive role.[2][7][1] ### Intravenous immunoglobulin[edit] Using intravenous immunoglobulin showed some promising results in decreasing the possibility of having CHB's complications such as EFE and cardiomyopathy.[6][2] ### Hydroxychloroquine[edit] Hydroxychloroquine is relatively new approach, but it showed promising results in preventing the inflammation and other injuries result from it such as fibrosis.[6][2] Apart from these medications, a pace maker might be needed in around two thirds of the cases,[1] and a procedure might be required when the heart has structural abnormalities. ## Risk factors and outcomes[edit] The outcome of the congenital heart block varies a lot due to several factors, such as the associated diseases, severity of the atrioventricular block, maternal age...etc. In terms of the severity of the AV block, newborn kids with heart rate lower than 55 bpm have a negative outcome and higher chance to need pace-maker implantation,[1] as well as kids with symptomatic bradycardia such as lower tolerance of exercises.[1] Isolated CHB has a better prognosis than the one associated with other disorders,[5][6][13][11] the presence of congenital cardiac abnormalities increases the mortality rate.[1] Also, kids presented with hydrops fetalis and / or EFE and / or cardiomyopathy have poor outcome.[13][11][6][5] Some studies showed a genetic contribution to the autoimmune CHB.[4][6] Among anti Ro/La positive women, older ones have higher possibility of having kids with heart block.[14] Mortality rate in CHB increases with earlier deliveries.[13][11] Kids with congenital heart block have higher chance to face health-related problems (such as infections) than other kids.[15][6] ## Statistics[edit] The congenital heart block occurs in 1 child in every 15,000 to 20,000 births.[3] More than 90% of the cases are associated with autoimmune disease and transference of maternal autoantibodies.[16][13] Without considering the gender, the age of diagnosis or the associated diseases, mortality rate is around 20%.[11] The majority of CHB-related deaths occur in the first 3 months after birth followed by fetal death, and it is less common to occur after the third month of age.[11] Mortality rate is very high when the disease is diagnosed prenatally, and declines dramatically with older diagnosis ages.[13] Around 60% - 70% of the patients will need pace-maker implantation regardless of the age of diagnosis.[13][11] The disease seems to affect both males and females equally.[13][11] The survival rate is heavily affected by the associated diseases, and it is higher in autoimmune-mediated CHB patients compared to CHB patients with congenital cardiac structural problems.[1][17] Recurrence rate: mothers who had pregnancies associated with CHB, have a 16 - 18% chance of having kids with heart block in the following pregnancy.[11][1] A study in the United States showed that the vast majority of the affected mothers are of a Caucasian ethnicity,[11] despite the fact that Systemic Lupus Erythematosus (SLE) is more common among minorities.[18] Table. I: The recurrence rate for pregnancies following the CHB-affected births[11] Outcome Percentage of Pregnancies Healthy 73% CHB 16% Fetal Demise 2% Neonatal Death 2% ## Further information[edit] Although the chance of having kids with CHB in anti Ro/La positive mothers is relatively low (1-5%),[7][9][10] it is recommended that all mothers with autoimmune disease to be screened and seek consultation when decide to get pregnant.[1][4][5][11] For mothers with at least one CHB-affected pregnancy, with 16 - 18% recurrence chance for the directly following pregnancy[11][1] and an overall 9% chance in following ones,[14] monitoring both the mother and the fetus is crucial.[5] External Links Congenital Heart Block https://rarediseases.org/rare-diseases/heart-block-congenital/ Heart Block Types https://my.clevelandclinic.org/health/diseases/17056-heart-block Congenital Heart Defects https://www.nhlbi.nih.gov/health-topics/congenital-heart-defects and https://www.heart.org/en/health-topics/congenital-heart-defects/about-congenital-heart-defects/common-types-of-heart-defects ## 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 ac ad ae af ag ah ai aj ak al am Friedman, DM; Duncanson, LJ; Glickstein, J; Buyon, JP (2003). "A review of congenital heart block". Images in Paediatric Cardiology. 5 (3): 36–48. ISSN 1729-441X. PMC 3232542. PMID 22368629. 2. ^ a b c d e f g h i j Saxena, Amit; Izmirly, Peter M.; Mendez, Barbara; Buyon, Jill P.; Friedman, Deborah M. (November 2014). "Prevention and treatment in utero of autoimmune-associated congenital heart block". Cardiology in Review. 22 (6): 263–267. doi:10.1097/CRD.0000000000000026. ISSN 1538-4683. PMC 4539276. PMID 25050975. 3. ^ a b c Michaëlsson, M.; Engle, M. A. (1972). "Congenital complete heart block: an international study of the natural history". Cardiovascular Clinics. 4 (3): 85–101. ISSN 0069-0384. PMID 4273004. 4. ^ a b c d e f g h i j k l m n o p Ambrosi, Aurélie; Wahren-Herlenius, Marie (2012-04-26). "Congenital heart block: evidence for a pathogenic role of maternal autoantibodies". Arthritis Research & Therapy. 14 (2): 208. doi:10.1186/ar3787. ISSN 1478-6362. PMC 3446439. PMID 22546326. 5. ^ 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 ac Brito-Zerón, Pilar; Izmirly, Peter M.; Ramos-Casals, Manuel; Buyon, Jill P.; Khamashta, Munther A. (May 2015). "The clinical spectrum of autoimmune congenital heart block". Nature Reviews. Rheumatology. 11 (5): 301–312. doi:10.1038/nrrheum.2015.29. ISSN 1759-4804. PMC 5551504. PMID 25800217. 6. ^ a b c d e f g h i j k l m n o p q r s Wainwright, Benjamin; Bhan, Rohit; Trad, Catherine; Cohen, Rebecca; Saxena, Amit; Buyon, Jill; Izmirly, Peter (2019-10-08). "Autoimmune-mediated congenital heart block". Best Practice & Research Clinical Obstetrics & Gynaecology. doi:10.1016/j.bpobgyn.2019.09.001. ISSN 1521-6934. PMID 31685414. 7. ^ a b c d e f g h i j k Friedman, Deborah M.; Rupel, Ann; Glickstein, Julie; Buyon, Jill P. (June 2002). "Congenital heart block in neonatal lupus: the pediatric cardiologist's perspective". Indian Journal of Pediatrics. 69 (6): 517–522. doi:10.1007/bf02722656. ISSN 0019-5456. PMID 12139139. 8. ^ Izmirly Peter M.; Saxena Amit; Kim Mimi Y.; Wang Dan; Sahl Sara K.; Llanos Carolina; Friedman Deborah; Buyon Jill P. (2011-11-01). "Maternal and Fetal Factors Associated With Mortality and Morbidity in a Multi–Racial/Ethnic Registry of Anti-SSA/Ro–Associated Cardiac Neonatal Lupus". Circulation. 124 (18): 1927–1935. doi:10.1161/CIRCULATIONAHA.111.033894. PMC 3206147. PMID 21969015. 9. ^ a b Buyon, J. P.; Kim, M. Y.; Copel, J. A.; Friedman, D. M. (August 2001). "Anti-Ro/SSA antibodies and congenital heart block: necessary but not sufficient". Arthritis and Rheumatism. 44 (8): 1723–1727. doi:10.1002/1529-0131(200108)44:8<1723::AID-ART305>3.0.CO;2-0. ISSN 0004-3591. PMID 11508420. 10. ^ a b Brucato, A.; Frassi, M.; Franceschini, F.; Cimaz, R.; Faden, D.; Pisoni, M. P.; Muscarà, M.; Vignati, G.; Stramba-Badiale, M.; Catelli, L.; Lojacono, A. (August 2001). "Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women". Arthritis and Rheumatism. 44 (8): 1832–1835. doi:10.1002/1529-0131(200108)44:8<1832::AID-ART320>3.0.CO;2-C. ISSN 0004-3591. PMID 11508435. 11. ^ a b c d e f g h i j k l m n Buyon, Jill P.; Hiebert, Rudi; Copel, Joshua; Craft, Joseph; Friedman, Deborah; Katholi, Margaret; Lee, Lela A.; Provost, Thomas T.; Reichlin, Morris; Rider, Lisa; Rupel, Ann (1998-06-01). "Autoimmune-Associated Congenital Heart Block: Demographics, Mortality, Morbidity and Recurrence Rates Obtained From a National Neonatal Lupus Registry". Journal of the American College of Cardiology. 31 (7): 1658–1666. doi:10.1016/S0735-1097(98)00161-2. ISSN 0735-1097. PMID 9626848. 12. ^ a b Brucato, Antonio; Tincani, Angela; Fredi, Micaela; Breda, Silvia; Ramoni, Veronique; Morel, Nathalie; Costedoat-Chalumeau, Nathalie (2017-11-01). "Should we treat congenital heart block with fluorinated corticosteroids?". Autoimmunity Reviews. 16 (11): 1115–1118. doi:10.1016/j.autrev.2017.09.005. ISSN 1568-9972. PMID 28899797. 13. ^ a b c d e f g Jaeggi, Edgar T; Hamilton, Robert M; Silverman, Earl D; Zamora, Samuel A; Hornberger, Lisa K (2002-01-02). "Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block: A single institution's experience of 30 years". Journal of the American College of Cardiology. 39 (1): 130–137. doi:10.1016/S0735-1097(01)01697-7. ISSN 0735-1097. PMID 11755298. 14. ^ a b Ambrosi, Aurélie; Salomonsson, Stina; Eliasson, Håkan; Zeffer, Elisabeth; Skog, Amanda; Dzikaite, Vijole; Bergman, Gunnar; Fernlund, Eva; Tingström, Joanna; Theander, Elke; Rydberg, Annika (2012-03-01). "Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern". Annals of the Rheumatic Diseases. 71 (3): 334–340. doi:10.1136/annrheumdis-2011-200207. ISSN 0003-4967. PMID 21953338. 15. ^ Mofors, Johannes; Eliasson, Håkan; Ambrosi, Aurelie; Salomonsson, Stina; Skog, Amanda; Fored, Michael; Ekbom, Anders; Bergman, Gunnar; Sonesson, Sven-Erik; Wahren-Herlenius, Marie (2019-05-01). "Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero". Annals of the Rheumatic Diseases. 78 (5): 696–703. doi:10.1136/annrheumdis-2018-214406. ISSN 0003-4967. PMID 30808622. 16. ^ Chameides, L.; Truex, R. C.; Vetter, V.; Rashkind, W. J.; Galioto, F. M.; Noonan, J. A. (1977-12-01). "Association of maternal systemic lupus erythematosus with congenital complete heart block". The New England Journal of Medicine. 297 (22): 1204–1207. doi:10.1056/NEJM197712012972203. ISSN 0028-4793. PMID 917056. 17. ^ Kertesz, N. J.; Fenrich, A. L.; Friedman, R. A. (1997). "Congenital complete atrioventricular block". Texas Heart Institute Journal. 24 (4): 301–307. ISSN 0730-2347. PMC 325472. PMID 9456483. 18. ^ Fessel, W. Jeffrey (1974-12-01). "Systemic Lupus Erythematosus in the Community: Incidence, Prevalence, Outcome, and First Symptoms; the High Prevalence in Black Women". Archives of Internal Medicine. 134 (6): 1027–1035. doi:10.1001/archinte.1974.00320240061006. ISSN 0003-9926. PMID 4433183. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Congenital heart block	c3884338	3,107	wikipedia	https://en.wikipedia.org/wiki/Congenital_heart_block	2021-01-18T18:29:42	{"gard": ["6164"], "mesh": ["C535758"], "umls": ["C3884338"], "orphanet": ["60041"], "wikidata": ["Q18558252"]}
Methylmalonic acidemia refers to a group of inherited conditions in which the body can’t breakdown certain parts of proteins and fats. This leads to a build-up of toxic substances and bouts of serious illness called decompensation events or metabolic crises. Symptoms of a decompensation event include poor feeding, vomiting, trouble breathing, and lack of energy (lethargy). These can occur at different ages and can range from mild to severe. Methylmalonic acidemia is caused by changes in several different genes and is inherited in an autosomal recessive fashion. Treatment includes aggressive management of decompensation events, a low-protein diet, certain medications, antibiotics and, in some cases, liver and kidney transplantation. Some subtypes of methylmalonic acidemia respond to vitamin B12. Long-term complications can include growth delay, intellectual disability, kidney disease, and pancreatitis. Methylmalonic acidemia can be isolated or may occur along with another condition called homocystinuria. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Methylmalonic acidemia	c0268583	3,108	gard	https://rarediseases.info.nih.gov/diseases/7033/methylmalonic-acidemia	2021-01-18T17:59:06	{"mesh": ["C537358"], "synonyms": ["MMA", "Acidemia, methylmalonic"]}
Nuchal fibroma SpecialtyOncology Nuchal-type fibroma is a rare benign proliferation involving the dermis and subcutaneous tissues, that is a collection of dense, hypocellular bundles of collagen with entrapped adipocytes and increased numbers of small nerves. It is no longer called a nuchal fibroma, but instead a "nuchal-type fibroma" since it develops in other anatomic sites. There is no known etiology.[1][2] ## Contents * 1 Signs and symptoms * 2 Pathology * 2.1 Immunohistochemistry * 3 Diagnosis * 3.1 Differential diagnoses * 4 Management * 5 Epidemiology * 6 See also * 7 References * 8 Further reading ## Signs and symptoms[edit] These lesions are generally asymptomatic, although patients give a long history of a solitary, superficial mass. The mass is usually in the neck (hence the name "nuchal-type"), but it can be seen in the extremities, lumbosacral area, buttocks, and face.[2][3] There is a strong association with diabetes mellitus and Gardner syndrome; in fact, it may be the initial manifestation of Gardner syndrome.[4] ## Pathology[edit] A low power of a nuchal-type fibroma showing entrapped fat. The tumors are unencapsulated and poorly circumscribed, showing a firm, white cut surface. Most tumors are about 3.5 cm, but can be up to 8 cm.[1] By microscopic examination, there are haphazardly arranged thick collagen fibers, with a low cellularity and no pleomorphism. There are usually entrapped fat cells, skeletal muscle, and peripheral nerves. The may be perineural fibrosis. The elastic fibers may be altered, which is why an elastofibroma is considered in the differential diagnosis.[1] Nuchal fibroma ### Immunohistochemistry[edit] The tumor cells are strongly positive for vimentin, CD34, and sometimes with CD99. There is often (up to 2/3rds) a nuclear reaction with β-catenin.[1] ## Diagnosis[edit] ### Differential diagnoses[edit] The differential diagnosis includes elastofibroma, fibrolipoma, desmoid-type fibromatoses, and nuchal fibrocartilaginous pseudotumor.[1] ## Management[edit] Simple excision is curative. However, in patients with Gardner syndrome, up to 45% will develop desmoid-type fibromatosis at other sites, and so this should be searched for and excluded. Patients can develop a recurrence, so follow-up is required.[2] ## Epidemiology[edit] This is a rare tumor, presenting over a wide age range, but usually in the 3rd to 5th decades of life. There is a slight male predilection, although this is not seen in syndrome associated patients. The most common site is the posterior neck, but may also be seen in other sites (extremities, lumbosacral area, buttocks, face).[1] ## See also[edit] Fibrous Lesions ## References[edit] 1. ^ a b c d e f Michal, M.; Fetsch, J. F.; Hes, O.; Miettinen, M. (1999). "Nuchal-type fibroma". Cancer. 85 (1): 156–163. doi:10.1002/(SICI)1097-0142(19990101)85:1<156::AID-CNCR22>3.0.CO;2-O. PMID 9921988. 2. ^ a b c Samadi, D. S.; McLaughlin, R. B.; Loevner, L. A.; Livolsi, V. A.; Goldberg, A. N. (2000). "Nuchal fibroma: A clinicopathological review". The Annals of Otology, Rhinology, and Laryngology. 109 (1): 52–55. doi:10.1177/000348940010900110. PMID 10651413. 3. ^ Balachandran, K.; Allen, P. W.; MacCormac, L. B. (1995). "Nuchal fibroma. A clinicopathological study of nine cases". The American Journal of Surgical Pathology. 19 (3): 313–317. doi:10.1097/00000478-199503000-00009. PMID 7872429. 4. ^ Dawes, L. C.; La Hei, E. R.; Tobias, V.; Kern, I.; Stening, W. (2000). "Nuchal fibroma should be recognized as a new extracolonic manifestation of Gardner-variant familial adenomatous polyposis". The Australian and New Zealand Journal of Surgery. 70 (11): 824–826. doi:10.1046/j.1440-1622.2000.01958.x. PMID 11147449. ## Further reading[edit] Lester D. R. Thompson; Bruce M. Wenig (2011). Diagnostic Pathology: Head and Neck: Published by Amirsys. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 8:44–45. ISBN 978-1-931884-61-7. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nuchal fibroma	c1532393	3,109	wikipedia	https://en.wikipedia.org/wiki/Nuchal_fibroma	2021-01-18T19:07:49	{"umls": ["C1532393"], "wikidata": ["Q7067892"]}
A rare, acquired, life-threatening, infectious disease due to the tick-borne bacteria Rickettsia rickettsii characterized by an acute onset of fever, malaise, and severe headache, variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia, associating (2-5 days after fever onset) a typically erythematous, blanching or non-blanching, maculopapluar rash with petechiae, starting on the wrists and ankles and progressing centrifugally to the palms and soles and centripetally to the arms, legs and trunk. Additonal variable features may include conjunctivitis, mucosal ulcers, post-inflammatory hyperpigmentation, jaundice, pneumonia, hepatomegaly, renal failure, meningismus, amnesia, optic disc edema, and ocular arterial occlusion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Rocky Mountain spotted fever	c0035793	3,110	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83311	2021-01-23T17:07:52	{"gard": ["7585"], "mesh": ["D012373"], "umls": ["C0035793"], "icd-10": ["A77.0"]}
A number sign (#) is used with this entry because glycogen storage disease type IXb (GSD9B) is caused by compound heterozygous mutation in the PHKB gene (172490), which encodes the beta subunit of phosphorylase kinase, on chromosome 16q12. For a discussion of genetic heterogeneity of GSD IX (GSD9), see X-linked GSD IXa (GSD9A; 306000). Clinical Features In an Israeli Arab family reported by Bashan et al. (1981), a 4-year-old brother and 2 sisters had marked hepatomegaly and marked accumulation of glycogen in both liver and muscle, without clinical symptoms. Liver phosphorylase kinase (PK) activity was 20% of normal, resulting in undetectable activity of phosphorylase a. Muscle PK was about 25% of normal, resulting in a marked decrease of phosphorylase a activity. This finding of a seemingly autosomal recessive form of phosphorylase kinase deficiency suggests that there are at least 2 different structural genes, only one of which is X-linked, that code for subunits of the enzyme. Mild clinical manifestations of muscle involvement were observed by Fernandes et al. (1974) in a 4-year-old patient, and Abarbanel et al. (1986) found symptoms resembling McArdle disease (232600) in a 35-year-old man. Ohtani et al. (1982) reported histochemical and biochemical study of a female child who lacked phosphorylase kinase in muscle. Gray et al. (1983) described affected sister and 2 brothers with unrelated parents. Normal level of enzyme activity in the mother and comparable levels in an affected brother and sister argued against X-linked inheritance (306000). The sister presented at 15 months with hepatomegaly, short stature, and acute attacks of diarrhea. Burwinkel et al. (1997) reported 3 children, including 2 sibs, with GSD IXb. The first child was German, and presented at age 22 months with distended abdomen due to hepatomegaly. At the age of 4 years, the child had a height at the tenth percentile and weight at the fiftieth percentile, hepatomegaly, and a tendency to develop hypoglycemic symptoms after several hours of fasting or physical activity. There were no clinical indications of muscle involvement. The second child and his affected sister came to medical attention as infants because of hepatomegaly. Residual phosphorylase kinase activities were 18% of normal in red cells, 5% in liver of the sister, and 0 to 13% (depending on pH) in muscle of the male. At the age of approximately 25, both patients were fully capable of everyday physical activities, but tended to develop hypoglycemic symptoms upon activity or fasting that were ameliorated by carbohydrate intake. Hepatomegaly had receded; clinical muscle symptoms had never been noted. Beauchamp et al. (2007) reported 3 patients from 2 families with GSD IXb confirmed by genetic analysis. Clinical features were variable, and included hepatomegaly, short stature, liver dysfunction, hypoglycemia, fasting ketosis, and hypotonia. The authors emphasized that molecular analysis results in accurate diagnosis for GSD IX when enzymology is uninformative, and thus allows for proper genetic counseling. Roscher et al. (2014) reported on 21 patients (17 males and 4 females) from 17 unrelated families with glycogen storage disease (GSD) IXa (306000), GSD IXb, GSD IXc (613027), or GSD VI (232700), which are caused by phosphorylation deficiencies. The average age was 11.66 years, with a range of 3 to 18 years. Eleven patients (53%) had GSD IXa1; 3 (14%) had GSD IXb; 3 (14%) had GSD IXc; and 4 (19%) had GSD VI. The average age of initial presentation was 20 months (range 4-160 months). The GSD IXb patients presented earliest at the age of 5 months (range 4-6 months). Hepatomegaly was present in 95% of patients on physical examination and 100% on liver ultrasound. Four patients presented with failure to thrive, and 2 with short stature. None of the patients had intellectual disability or global developmental delay at most recent evaluation, although some had early developmental delay. Alanine transaminase (ALT) was elevated in 18 patients (86%), and aspartate transaminase (AST) was elevated in 19 (90%). Hypercholesterolemia was present in 14 of the 21 patients, and hypertriglyceridemia was present in 16. While previous reports noted hypoglycemia in 17 to 44% of patients with GSD VI or subtypes of GSD IX, hypoglycemia occurred in less than 5% of the patients in the cohort of Roscher et al. (2014). Two patients had developed likely liver adenomas at long-term follow-up, which had not been theretofore reported. Molecular Genetics In 1 female and 4 male patients with glycogen storage disease IXb, Burwinkel et al. (1997) identified mutations in the PHKB gene. There were 5 different nonsense mutations (see, e.g., 172490.0002), a 1-bp insertion (172490.0001), a splice site mutation, and a large deletion involving the loss of exon 8. Although the mutations severely disrupted translation and occurred in constitutively expressed sequences of the only known beta-subunit gene of phosphorylase kinase, they were associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and with a relatively high residual enzyme activity of approximately 10%. Inheritance was autosomal recessive. Nomenclature Lederer et al. (1975) pointed out that what had been numbered glycogen storage disease VI includes at least 3 different genetic defects: X-linked phosphorylase b kinase deficiency, in which the muscle enzyme is unaffected (called here glycogen storage disease VIII; 306000); the autosomal kinase deficiency discussed here; and deficiency of liver phosphorylase (called here glycogen storage disease VI; 232700). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, postnatal onset ABDOMEN Liver \- Hepatomegaly Gastrointestinal \- Diarrhea MUSCLE, SOFT TISSUES \- Hypotonia \- Mild weakness LABORATORY ABNORMALITIES \- Phosphorylase kinase deficiency in liver and muscle \- Glycogen accumulation in both liver and muscle MOLECULAR BASIS \- Caused by mutation in phosphorylase kinase, beta subunit (PHKB, 172490.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GLYCOGEN STORAGE DISEASE IXb	c0543514	3,111	omim	https://www.omim.org/entry/261750	2019-09-22T16:23:30	{"doid": ["0111041"], "mesh": ["C563008"], "omim": ["261750"], "orphanet": ["79240"], "synonyms": ["Alternative titles", "GSD IXb", "GLYCOGENOSIS OF LIVER AND MUSCLE, AUTOSOMAL RECESSIVE", "PHOSPHORYLASE KINASE DEFICIENCY OF LIVER AND MUSCLE, AUTOSOMAL RECESSIVE"], "genereviews": ["NBK55061"]}
Bing–Neel syndrome SpecialtyNeurology Bing–Neel syndrome (BNS) is an extremely rare neurologic complication of Waldenström macroglobulinemia (WM), which is a chronic lymphoproliferative disorder.[1] There's no clear definition of BNS but what is known so far is that unlike WM, It involves the central nervous system (CNS), infiltrated by differentiated malignant B cells and by having hyperglobulinemia.[2] This infiltration increases blood viscosity, which impairs blood circulation through small blood vessels of the brain and the eye. Some scientists proposed that a person diagnosed with BNS is typically classified into Group A and Group B depending on whether or not plasma cells are present within the brain parenchyma, leptomeninges, dura, and/or the cerebral spinal fluid (CSF).[3] Symptoms are diverse and nonspecific, and they can vary depending on which aspect of the CNS is being affected. Symptoms can include a range of severity of nausea and seizures. Since the symptoms vary, there are multiple treatment options to treat the symptoms for this non-curable disease. Although there is no specific set of diagnosis for BNS, different combinations of diagnostic tools are used to narrow down and conclude the presence of BNS. ## Contents * 1 Symptoms and signs * 2 Diagnosis * 2.1 Histology * 2.2 Cerebrospinal fluid analysis * 2.3 Radiology * 2.4 Sequence analysis * 3 Treatment * 3.1 Steroids * 3.2 Chemotherapy * 3.3 Stem-Cells * 3.4 Radiation * 4 History * 5 References ## Symptoms and signs[edit] Symptoms of BNS gradually progress over the span of a week or even a month, and there is typically a delay in diagnosis after the initial symptoms arise. Although BNS arises due to complications from WM, some individuals may experience symptoms of BNS without having a past history of WM.[4] Given that BNS is so rare, the symptoms are diverse and nonspecific. Symptoms range in severity from nausea to seizures and are characterized by how they interfere with the function of the CNS. Where certain symptoms are present depends on which branch of the CNS is being affected by plasma B-cells. People diagnosed with BNS experience some sensory symptoms as well. Some sensory symptoms include a pin and needles sensation experienced in the lower limbs, the hands, and in the arms, along with pain and extreme numbness.[4] Symptoms Common to BNS Symptom Example Nausea[4] Not Specific Seizures[4] Interference in CNS function Vomiting[4] Not Specific Visual Disturbance[4] Not Specific Hearing Loss[4] Not Specific Cranial neuropathies Predominantly in Oculomotor nerve Meningeal Involvement[4] Usually accompanied by cranial neuropathies Cognitive Decline[4] * Memory loss * Periods of Confusion aphasia[4] Loss of language function * Slurred speech * inability to form words psychosis [4] Inference in CNS function Cerebellar dysfunction[4] * Uncontrollable movement * Loss of Balance Impaired Consciousness[4] Coma Headache[4] Not specific Fatigue[4] Not Specific paresis[4] Muscle weakness ## Diagnosis[edit] There is no clear-cut route to diagnosing BNS, meaning just one diagnostic tool alone is not conclusive in diagnosing BNS. But through the utilization of several different tools cooperatively, a diagnosis can be reached through the elimination of other CNS pathologies.[citation needed] ### Histology[edit] Infiltration of malignant, differentiated B-cells linked to WM into the nervous system precipitates BNS. Histological practices that entail a biopsy of the cerebrum and/or the meninges look for the presence of lymphoplasmacytic lymphomas (Mature B-cells). Though a biopsy alone is not indicative of BNS, it is a necessary step that ensures that at the very least, the CNS has been infiltrated by some sort of lymphoma.[3][4] ### Cerebrospinal fluid analysis[edit] Analysis entails analyzing several different aspects of the cerebrospinal fluid (CSF) to identify characteristics linked to WM and BNS. Quantification of leukocytes and their differentiation, as well as a morphological analysis of any detected malignant lymphomas found in the CSF are some parameters assed by CSF analysis.[citation needed]Flow cytometry, used to identify cell biomarkers, is an auxiliary tool used in CSF analysis. With respect to diagnosing BNS, flow cytometry analyzes CSF contents for B-cells expressing the pan antigens CD19 and CD20, commonly found in WM; not all cases of BNS show conclusive findings in CSF analysis.[3][4][5] ### Radiology[edit] MRI with gadolinium contrast is the primary radiologic tool used to diagnose ailments of the central nervous system, BNS included. MRI’s effect is twofold in that it is able to identify brain and spine abnormalities, as well as identifying tissues appropriate for biopsy. MRI with gadolinium contrast can also discern which form of BNS has formed. Where the tumoral form of BNS is highlighted by tumor growth in the subcortical hemispheric regions, the diffuse form of BNS is characterized by leptomeningeal and perivascular infiltration by lymphoid cells. Other characteristics of BNS identified via MRI are abnormal enhancement of cranial and spinal nerves, as well as thickening and enhancement of the cauda equina.[3][4][5] ### Sequence analysis[edit] The MYD88 L265P is a gene mutation found in the majority of WM cases. During CSF analysis, PCR amplification of genomic DNA found in the fluid, followed by sequencing, can determine if the mutation is present within the CNS; if so, this would be indicative of, though not conclusive, of BNS.[4][6] ## Treatment[edit] Treatment for BNS has a multitude of options. If people with BNS are asymptomatic, physicians will watch for progression of the disease using MRI. If any signs of further disease is shown, they will take action to alleviate the symptoms. Because this disease is non-curative and rather rare, treatment is only used to get rid of symptoms. Even so, due to the lack of regeneration of the nervous system, some symptoms may not be reversible and stay with the person with BNS. There are some costs, along with the benefits, of treating the symptoms depending on the type, which may include lesions or brain damage. Doctors will make a risk assessment and monitor by MRI to validate that complications do not occur.[4] There are a few options when it comes to treatment so the type one will choose is completely individualized, taking into consideration the person's state or condition and liking. ### Steroids[edit] Steroids are mostly used for short term and quick use. The use provides improvement, but should not be considered a long term plan. Physicians would normally prescribe steroids after a biopsy and after further analysis has been completed.[4] ### Chemotherapy[edit] Treatment also involves central nervous system penetrating chemotherapy. Options include intrathecal, intraventricular, and systemic chemotherapy. These must penetrate the blood-brain barrier in order to be effective. Sometimes mixing multiple forms of treatment with chemotherapy seems to be the best route.[4][7] For example, some significant improvement has been shown as a result of cranial radiation treatment preceding a brief course of intrathecal chemotherapy.[6] Although this is an effective treatment to do, penetrating the blood-brain barrier can cause side effects due to the toxicity in the nervous system. These would include dizziness, confusion, and changes in mental status. Another form could be the use of pharmaceuticals, which have all shown positive results for treatment but should always be consulted with a physician to assess risks.[4][7] ### Stem-Cells[edit] Autologous stem-cell transplants are shown to be an effective treatment. However, this should be only considered for certain people due to toxicity concerns. It is possible that the transplant may cause problems like septic shock.[7] ### Radiation[edit] Lastly, radiation is normally used as a rescue type treatment and is not recommended as a first line treatment. The doctor would perform localized radiation therapy at a dose of 30 to 40 Gy on the lesions. This is to limit the amount of radiation and prevent further damage to the nervous system, which could happen due to the toxicity of radiation therapy.[4] ## History[edit] Bing–Neel syndrome was first described by Jens Bing and Axel Valdemar Neel, who observed a case of 2 women, 56 and 39 years old, presenting with rapid neurodegeneration in the setting of hyperglobulinemia.[4] This discovery was reported eight years before the first report on WM, which was discovered and described by Jan Waldenström.[7] From the first publication, there was never a clear consensus and guideline to the diagnosis and treatment of BNS. It was only 80 years later that there was a meeting with a group of people at the 8th International Workshop on WM to come up with broad diagnostic criteria for BNS. This group of people included radiologists, immunologists, hematologists, and neurologists from all over the world using PubMed as their source for the guideline. The first draft was reviewed by a multidisciplinary team of experts in WM.[4][7] ## References[edit] 1. ^ Malkani RG, Tallman M, Gottardi-Littell N, et al. (February 2010). "Bing-Neel syndrome: an illustrative case and a comprehensive review of the published literature". J. Neurooncol. 96 (3): 301–12. doi:10.1007/s11060-009-9968-3. PMID 19618118. S2CID 2605705. 2. ^ Fintelmann F, Forghani R, Schaefer PW, Hochberg EP, Hochberg FH (March 2009). "Bing-Neel Syndrome revisited". Clin Lymphoma Myeloma. 9 (1): 104–6. doi:10.3816/CLM.2009.n.028. PMID 19362988. 3. ^ a b c d Ly, KI; Fintelmann, F; Forghani, R; Schaefer, PW; Hochberg, EP; Hochberg, FH (February 2011). "Novel diagnostic approaches in Bing-Neel syndrome". Clinical Lymphoma, Myeloma & Leukemia. 11 (1): 180–3. doi:10.3816/CLML.2011.n.043. PMID 21856555. 4. ^ 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 Minnema, Monique C.; Kimby, Eva; D’Sa, Shirley; Fornecker, Luc-Matthieu; Poulain, Stéphanie; Snijders, Tom J.; Kastritis, Efstathios; Kremer, Stéphane; Fitsiori, Aikaterini (2017-01-01). "Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome". Haematologica. 102 (1): 43–51. doi:10.3324/haematol.2016.147728. PMC 5210231. PMID 27758817. 5. ^ a b Castillo, Jorge J.; D'Sa, Shirley; Lunn, Michael P.; Minnema, Monique C.; Tedeschi, Alessandra; Lansigan, Frederick; Palomba, M. Lia; Varettoni, Marzia; Garcia-Sanz, Ramon (2016-03-01). "Central nervous system involvement by Waldenström macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study". British Journal of Haematology. 172 (5): 709–715. doi:10.1111/bjh.13883. PMC 5480405. PMID 26686858. 6. ^ Poulain, S; Boyle, EM; Roumier, C; Demarquette, H; Wemeau, M; Geffroy, S; Herbaux, C; Bertrand, E; Hivert, B; Terriou, L; Verrier, A; Pollet, JP; Maurage, CA; Onraed, B; Morschhauser, F; Quesnel, B; Duthilleul, P; Preudhomme, C; Leleu, X (November 2014). "MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome". British Journal of Haematology. 167 (4): 506–13. doi:10.1111/bjh.13078. PMID 25160558. 7. ^ a b c d e Simon L, Fitsiori A, Lemal R, Dupuis J, Carpentier B, Boudin L, Corby A, Aurran-Schleinitz T, Gastaud L, Talbot A, Leprêtre S, Mahe B, Payet C, Soussain C, Bonnet C, Vincent L, Lissandre S, Herbrecht R, Kremer S, Leblond V, Fornecker LM (December 2015). "Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO)". Haematologica. 100 (12): 1587–94. doi:10.3324/haematol.2015.133744. PMC 4666335. PMID 26385211. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bing–Neel syndrome	None	3,112	wikipedia	https://en.wikipedia.org/wiki/Bing%E2%80%93Neel_syndrome	2021-01-18T19:03:16	{"wikidata": ["Q863725"]}
## Clinical Features Holmes et al. (1995) described 3 sibs, 1 female and 2 male, with absence or hypoplasia of the tibia in association with other malformations. The parents were first cousins once removed. The girl had unilateral cleft lip, absence of the diaphragm, and postaxial polydactyly of the feet. The second born was found by prenatal ultrasonography at 20 weeks of gestation to have a small cystic mass in the posterior fossa, a unilateral choroid plexus cyst, bowing of the radius and ulna, forelimb postaxial polydactyly, absence of the tibia, and a clubfoot deformity. The abnormality in the third infant was likewise recognized by prenatal ultrasonography. There was no cleft palate or polydactyly of the hands but there was preaxial polydactyly of both feet. Holmes et al. (1995) identified no abnormalities in the HOX genes studied: HOXD10 (142984), HOXA9 (142956), and HOXC9 (142971). They concluded that this represents a 'new' autosomal recessive syndrome. It should be noted that the 2 males who were investigated by the authors both showed retrocerebellar arachnoid cysts. Neuro \- Posterior fossa cyst. Choroid plexus cyst. Limbs \- Absent/hypoplastic tibia. Bowed radius and ulna. Postaxial polydactyly of hands. Postaxial polydactyly of feet. Preaxial polydactyly of feet. Clubfoot. Mouth \- Cleft lip. Thorax \- Absent diaphragm. Inheritance \- Autosomal recessive. ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TIBIA, ABSENCE OR HYPOPLASIA OF, WITH POLYDACTYLY, RETROCEREBELLAR ARACHNOID CYST, AND OTHER ANOMALIES	c2931368	3,113	omim	https://www.omim.org/entry/601027	2019-09-22T16:15:29	{"mesh": ["C536918"], "omim": ["601027"], "orphanet": ["3328"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant hypocalcemia-1 (HYPOC1) is caused by heterozygous mutation in the CASR gene (601199) on chromosome 3q21. Description Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013). Thakker (2001) noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see 146200). Thakker (2001) suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. ### Genetic Heterogeneity of Autosomal Dominant Hypocalcemia Autosomal dominant hypocalcemia-2 (HYPOC2; 615361) is caused by mutation in the GNA11 gene (139313) on chromosome 19p13. Clinical Features Pollak et al. (1994) reported a family in which 16 members over 4 generations had autosomal dominant hypocalcemia. Parathyroid hormone levels were normal in affected individuals, and serum phosphate levels were normal or mildly elevated. Affected family members did not exhibit the usual signs and symptoms of hypocalcemia, with the exception of 1 who experienced intermittent overt tetany. Bone films of this patient were normal, and target organ responsiveness to PTH was also normal. Baron et al. (1996) studied 2 families and 1 sporadic patient with hypocalcemia. 'Family N' had 5 affected individuals over 3 generations who all had low serum calcium concentrations, elevated serum phosphate concentrations, and low serum levels of PTH. Most of the affected members presented in childhood with seizures or tetany, and all required treatment with calcium and vitamin D. Other features included paresthesias, basal ganglia calcification, and nephrolithiasis. The affected mother and daughter of 'family B' had milder symptoms, primarily muscle cramps; the daughter presented for medical attention in adolescence and the mother in adulthood. Serum PTH levels were low despite low serum calcium concentrations. Both pedigrees suggested autosomal dominant transmission. In addition, Baron et al. (1996) reported a female patient who presented in infancy with hypocalcemic seizures. The patient also had muscle cramps and/or tetany and laryngospasm, and exhibited hypercalciuria even during hypocalcemia. Her twin sister, 3 other sibs, and her parents were unaffected. Pearce et al. (1996) studied 20 affected and 17 unaffected members of 6 kindreds originally diagnosed with isolated hypoparathyroidism, but in whom hypocalcemia was associated with normal serum PTH concentrations. Of the 20 affected individuals, 11 had carpopedal spasm or childhood seizures, 2 of whom had calcification of basal ganglia in addition to seizures; in 1 patient, the seizures continued into adult life. The remaining 9 affected individuals had asymptomatic hypocalcemia; 16 patients also had hypomagnesemia. Urinary calcium excretion was either inappropriately within the normal range or high at the time of diagnosis. Of 19 patients treated with oral vitamin D, serum PTH levels became low or undetectable in 16 of them, and 9 had hypercalciuria. Renal calcification developed in 8 of the 9 hypercalciuric patients, and renal impairment in 7 of them; renal calcification and renal impairment also developed in 7 other patients during vitamin D therapy. Bone mineral density of the lumbar spine was normal in 4 patients from 2 families but increased in 3 patients from another family. Pearce et al. (1996) noted the importance of differentiating patients with familial hypercalciuric hypocalcemia from those with hypoparathyroidism because treatment with vitamin D to correct hypocalcemia in the former may cause hypercalciuria, nephrocalcinosis, and renal impairment. De Luca et al. (1997) described a 25-year-old woman who presented with fatigue and depression at 18 years of age and was found to be hypocalcemic and hyperphosphatemic, with an inappropriately low-normal serum PTH level. She had a history of a generalized seizure of unknown etiology at 2 weeks of age. Examination at 20 years of age was normal except for short stature, and she had minimal basal ganglia calcifications on CT scan. The authors also reported a 23-year-old woman who had a hypocalcemic seizure at 7 months of age, at which time hyperphosphatemia and low PTH levels were detected. Despite oral calcium and vitamin D analogs, she was repeatedly hospitalized for hypocalcemia and was treated with anticonvulsants for recurrent seizures. At 14 years of age, her CT scan showed calcifications of the frontal cortex and basal ganglia. Both patients had nephrocalcinosis on CT scan but normal renal function. Mapping In a 3-generation family segregating autosomal dominant hypocalcemia, Finegold et al. (1994) demonstrated probable linkage to marker D3S1303 on 3q13 by multipoint linkage analysis (maximum lod = 2.71 at theta = 0). Affected family members had low serum calcium, high serum phosphorus, and PTH levels that were low or undetectable; no family member was disabled by symptoms of hypocalcemia. By use of dinucleotide markers and RFLP analysis in a large Norwegian family with isolated autosomal dominant hypoparathyroidism, Lovlie et al. (1996) excluded the loci for the PTH gene (168450), the PTH receptor gene (168468), and the RET protooncogene (164761) as sites of causative mutations. They found complete cosegregation of this trait with chromosome 3q13 and subsequently identified a missense mutation in the CASR gene (601199.0012). Molecular Genetics In a family in which at least 16 members over 4 generations had autosomal dominant hypocalcemia, Pollak et al. (1994) found a missense mutation in the CASR gene (601199.0004). The authors hypothesized that, in contrast to familial hypocalciuric hypercalcemia (145980) in which mild hypercalcemia is caused by mutations in CASR that reduce the activity of the Ca(2+)-sensing receptor, mild hypocalcemia might be caused by a mutation that inappropriately activates the receptor at subnormal Ca(2+) levels. Such activating mutations had been described in other G protein-coupled receptors. Xenopus oocytes expressing the mutant receptor exhibited a larger increase in inositol 1,4,5-triphosphate in response to Ca(2+) than did oocytes expressing the wildtype receptor. In 2 families with autosomal dominant hypoparathyroidism, Baron et al. (1996) identified heterozygous missense mutations in the CASR gene (601199.0009 and 601199.0010, respectively) that were not found in normal controls. In addition, a female infant with hypocalcemic seizures and severe sporadic hypoparathyroidism was found to carry a de novo heterozygous missense mutation in the CASR gene (601199.0011). Baron et al. (1996) suggested that these were activating mutations of the CASR gene. Because the receptor negatively regulates calcium resorption by kidney cells, receptor activation leads to hypercalciuria even in the presence of low serum calcium concentrations, and because the receptor participates in a negative feedback loop regulating parathyroid function, CASR activation is accompanied by hypoparathyroidism. Pearce et al. (1996) sequenced the CASR gene in probands from 6 families with hypercalciuric hypocalcemia and identified heterozygous missense mutations in 5 probands (601199.0012-601199.0014 and 601199.0016-601199.0017) that cosegregated with hypocalcemia in the respective families and were not found in 55 controls. Transfection studies in HEK293 cells confirmed that the mutant receptors were active at lower extracellular calcium concentrations than wildtype receptors, consistent with a gain of function. In 2 patients with sporadic isolated hypoparathyroidism, one who was severely symptomatic from infancy and another who presented with mild symptoms at 18 years of age, De Luca et al. (1997) identified de novo heterozygous gain-of-function mutations in the CASR gene (601199.0013 and 601199.0019, respectively). The authors noted that these patients demonstrated that CASR mutations can cause severe disease presenting in infancy or mild disease occurring in adulthood, and that even patients presenting in adulthood without affected relatives should not be assumed to have an autoimmune etiology. Watanabe et al. (1998) reported a Japanese family with severe autosomal dominant hypocalcemia in which the proband presented with a seizure at 6 days of age and her older brother and mother also experienced seizures and tetany, respectively. However, some patients in the family did not experience seizures despite their severe hypocalcemia. A heterozygous missense mutation (601199.0027) was identified in the fifth transmembrane domain of the CASR protein and was shown to cosegregate with the disease. The mutation was absent in DNA from 50 control subjects. Functional analysis in transiently transfected HEK293 cells demonstrated that the mutant receptor was more sensitive than normal to activation by cytosolic calcium. The authors stated that this condition needs to be differentiated from other causes of hypoparathyroidism. In a 41-year-old man who had asymptomatic hypocalcemia with a history of recurrent nephrolithiasis, Okazaki et al. (1999) identified heterozygosity for a missense mutation in the CASR gene (601199.0028). The mutation was present in his father, who also had asymptomatic hypocalcemia, but was not found in his normocalcemic mother. In 5 affected members of a 3-generation family segregating autosomal dominant hypocalcemia, short stature, and premature osteoarthritis, Stock et al. (1999) identified heterozygosity for a missense mutation in the CASR gene (601199.0029). Lienhardt et al. (2000) reported a 3-generation family with autosomal dominant hypocalcemia caused by a large in-frame deletion of 181 amino acids in the C-terminal tail of CASR (601199.0030). The affected grandfather was homozygous for the deletion but was not more severely affected than the heterozygous affected individuals. Functional studies in transiently transfected HEK293 cells demonstrated a gain of function with the mutant receptor, but there was no difference between cells transfected with mutant cDNA alone or cotransfected with mutant and wildtype cDNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. In 6 affected members of a 3-generation Japanese family with autosomal dominant hypocalcemia, Nagase et al. (2002) identified heterozygosity for an activating missense mutation in the CASR gene (601199.0038). Five of the 6 patients were asymptomatic; 1 patient had a history of seizures. In 2 sibs with hypocalcemia, Hendy et al. (2003) identified a heterozygous missense mutation in exon 7 of the CASR gene (601199.0039). Both parents and a third sib were clinically unaffected and were found to be genotypically normal by direct sequencing. However, the mother was mosaic for the mutation as shown by sequence analysis of multiple subclones as well as by denaturing HPLC of the CASR exon 7 leukocyte PCR product. The authors stated that this was the first report of mosaicism for an activating CASR mutation and suggested that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely. In affected members of a 3-generation family with autosomal dominant hypocalcemia, Tan et al. (2003) identified heterozygosity for an activating missense mutation in the CASR gene (601199.0041). Although all affected individuals had marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. ### Hypocalcemia, Autosomal Dominant 1, With Bartter Syndrome In a 19-year-old man and an unrelated 26-year-old woman, both of whom presented soon after birth with tetany and hypocalcemia and demonstrated features of Bartter syndrome (see 607364), including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia, Watanabe et al. (2002) identified heterozygous missense mutations in the CASR gene (601199.0034 and 601199.0035, respectively). The authors noted that in rats it had been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome (241200). Watanabe et al. (2002) suggested that other molecules that inhibit activity of Bartter syndrome-associated genes might be additional causes of Bartter and related syndromes. Vargas-Poussou et al. (2002) reported a boy who had severe autosomal dominant hypocalcemia associated with Bartter syndrome-like features, characterized by a decrease in the distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. At 3 weeks of age he was found to have severe hypocalcemia and hyperphosphatemia with an inappropriately low serum PTH; he was diagnosed with neonatal hypoparathyroidism and treated with calcium and vitamin D. At 7 years of age, during an episode of severe hypocalcemia with seizures and electrocardiographic disturbances, he also had polyuria; increased doses of vitamin D resulted in marked hypercalciuria, and he was diagnosed with Bartter syndrome. Renin levels normalized and there was improvement of plasma ion abnormalities and polyuria while on treatment with indomethacin and magnesium, calcium, and potassium supplementation. Metabolic analysis in the absence of indomethacin therapy at age 9 years showed low levels of plasma potassium, calcium, magnesium, and chloride, elevated levels of phosphorus, renin, and aldosterone, and undetectable PTH. Renal ultrasound showed a small stone in the right kidney, without nephrocalcinosis. The patient was negative for mutation in the CLCNKB gene (602023), but sequencing of the CASR gene identified a de novo missense mutation (L125P; 601199.0037) that was not present in his unaffected parents or sister or in 50 unrelated controls. Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb of the loop of Henle sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia. Hu et al. (2004) described monozygotic twin sisters of Italian origin who presented in the neonatal period with apnea, tremors, tonic contractions of the limbs, and seizures, and were found to be severely hypocalcemic, with hyperphosphatemia and undetectable serum PTH. Follow-up at 20 months of age showed low serum calcium, high serum phosphorus, and high urinary calcium excretion. Despite treatment to reduce the hypercalciuria, both sibs developed nephrocalcinosis in early childhood and nephrolithiasis in the second decade of life, although renal function remained normal and neither developed cataract. Low-normal magnesium levels were a constant finding as well. Sequence analysis of the CASR gene revealed a heterozygous de novo gain-of-function missense mutation (K29E; 601199.0053) in the affected twins that was not present in their unaffected parents and sister. In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome-like features at 22 years of age, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis; the authors designated the disorder 'type 5 Bartter syndrome.' Vezzoli et al. (2006) noted that all 4 CASR mutations causing hypocalcemia associated with Bartter syndrome-like features were highly activating, with EC50 values less than 1.5 mmol/L, whereas the EC50 values for other CASR mutations causing autosomal dominant hypocalcemia but not Bartter syndrome ranged between 1.5 and 3 mmol/L. Clinical Management Pearce et al. (1996) and Baron et al. (1996) reported that patients with activating CASR mutations generally show a milder degree of hypocalcemia before treatment and more profound hypercalciuria during treatment than those with idiopathic hypoparathyroidism. To test the validity of this generalization, Yamamoto et al. (2000) analyzed the data of serum and urinary calcium collected from 85 patients with idiopathic hypoparathyroidism and 15 with activating CASR mutations. The mean serum calcium concentration before treatment was significantly higher in patients with activating CASR mutations than in those with idiopathic hypoparathyroidism, but there was substantial overlap in the range of hypocalcemia between the 2 groups. The mean urinary calcium/creatinine ratio (Ca/Cr) in patients with activating CASR mutations before treatment was almost equal to that in normocalcemic controls and markedly higher than in patients with idiopathic hypoparathyroidism. In contrast to pretreatment findings, however, the degree of hypercalciuria during treatment was not different between the 2 disorders. The data points of urinary Ca/Cr plotted as a function of serum calcium were not separable between 15 patients with CASR mutations and 40 with idiopathic hypoparathyroidism. Comparison of urinary Ca/Cr between 2 patients with a CASR mutation and 7 with idiopathic hypoparathyroidism over a wide range of serum calcium concentrations measured during 4 to 8 years of treatment also indicated that the 2 disorders were inseparable. The authors suggested that inappropriately normal urinary Ca/Cr in patients with untreated hypocalcemia, mostly of mild degree, might be a better biochemical clue than the development of severe hypercalciuria during treatment to suspect gain-of-function mutations in the CASR. Because thiazide diuretics have been used successfully to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CASR gene. Sato et al. (2002) reported on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in 2 Japanese patients with gain-of-function mutations of the CASR gene (601199.0034 and 601199.0037). Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia. Despite treatment with the standard dose of 1,25-dihydroxyvitamin D3 in one patient and 1-alpha-hydroxyvitamin D3 in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D3 and 1-alpha-hydroxy vitamin D3 doses to be reduced, and alleviated their symptoms. In an infant presenting with hypocalcemia at 3 weeks of age who was found to have an activating mutation in the CASR gene (601199.0045), Mittelman et al. (2006) demonstrated short-term efficacy of treatment with PTH(134). During treatment, the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably. The authors concluded that PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients. Animal Model Hough et al. (2004) described a mouse model of autosomal dominant hypocalcemia, named Nuf, originally identified by having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice displayed ectopic calcification, hypocalcemia, hyperphosphatemia, cataracts, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. An activating missense mutation in the Gprc2a gene, the mouse ortholog of human CASR, was identified as the cause of the phenotype. Ectopic calcification and cataract formation tended to be milder in the heterozygous Nuf mice, indicating that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CASR mutations is required. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (rare) RESPIRATORY Larynx \- Laryngospasm (rare) GENITOURINARY Kidneys \- Hypercalciuria \- Nephrocalcinosis \- Nephrolithiasis \- Decreased renal function SKELETAL \- Osteoarthritis, premature (rare) Spine \- Increased bone mineral density of lumbar spine (rare) MUSCLE, SOFT TISSUES \- Muscle cramps \- Carpopedal spasm \- Tetany NEUROLOGIC Central Nervous System \- Seizures \- Paresthesias \- Calcification of the basal ganglia ENDOCRINE FEATURES \- Hypocalcemia, mild or severe \- Parathyroid hormone concentration low or low-normal \- Normal or mildly elevated serum phosphate \- Hypomagnesemia \- Hypokalemia (rare) \- Hyperreninemia (rare) \- Hyperaldosteronemia (rare) MISCELLANEOUS \- Some patients have asymptomatic hypocalcemia MOLECULAR BASIS \- Caused by mutation in the calcium-sensing receptor gene (CASR, 601199.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOCALCEMIA, AUTOSOMAL DOMINANT 1	c1832648	3,114	omim	https://www.omim.org/entry/601198	2019-09-22T16:15:14	{"doid": ["0090107"], "mesh": ["C537156"], "omim": ["601198"], "orphanet": ["2238", "263417", "112", "428"], "synonyms": ["Alternative titles", "HYPERCALCIURIC HYPOCALCEMIA", "HYPOCALCEMIA, FAMILIAL"]}
## Clinical Features Circulating mature T lymphocytes constitute a heterogeneous cell population with 2 major phenotypes, one expressing the CD4 marker (186940) on its surface (generally associated with helper/inducer function), and the other expressing the CD8 antigen (186910) (usually associated with cytotoxic/suppressor activity). Amadori et al. (1995) noted that evaluation of the CD4/CD8 ratio is routine in AIDS patients for the assessment of immune function and added that not only HIV infection but also other acute viral diseases, such as infections by cytomegalovirus, Epstein-Barr virus, and influenza virus, are usually associated with an inversion of the CD4/CD8 ratio. A low ratio is also a hallmark of intense, chronic immune responses, such as allograft rejection and graft-versus-host disease (GVHD; 614395). CD4/CD8 ratios of 1.5 to 2.5 are usually considered normal. The occasional finding of a CD4/CD8 ratio less than 1 in otherwise normal, healthy individuals is usually disregarded. Because of a personal interest on the part of one member of the group (A.A.) who had shown an invariable ratio less than 1 over many years, and because the ratio in mice was shown by Kraal et al. (1983) to be under genetic control, Amadori et al. (1995) studied the genetic pattern of inheritance of the ratio in a population of 468 healthy blood donors. Distribution of the ratio in males and females was significantly different and was significantly affected by age. In 46 randomly selected families, the parental CD4/CD8 ratios significantly influenced the ratio in offspring. Complex segregation analysis of the data rejected the non-genetic hypothesis; among the genetic models tested, a major recessive gene with a polygenic component and random environmental effects was the most parsimonious model. Overall, Amadori et al. (1995) found that 57% of the variation in the CD4/CD8 ratio could be attributed to genetic factors, as opposed to noninherited (stochastic or environmental) factors. In mice, the CD4/CD8 ratio appears to be under the genetic control of a single dominant gene (Kraal et al., 1983). Chakravarti (1995) pointed to several important implications of the simple observation in this study. First, norms for the ratio must be defined separately for different ages, genders, and perhaps even populations. The possibility of a major gene determining the ratio implies that family history of low ratios may need to be considered for accurate prognosis of HIV or other infection. The identification of genes underlying this phenotype will lead to a better understanding of the mechanisms that commit immature thymocytes to the helper or cytotoxic lineages, and the site in the developmental chain in which they function. Lastly, identification of the genes will also help answer questions regarding genetic factors that control infection and immunity. To define the mode of inheritance of the CD4/CD8 ratio, Clementi et al. (1999) examined the absolute number of CD4 and CD8 cells in a large unselected control population and in members of 70 nuclear families. Pedigrees of nuclear families were analyzed by complex segregation analysis. Data were adjusted before this analysis to remove the effects of relevant covariates. The nongenetic transmission and the multifactorial model could be easily rejected for both CD4 and CD8 cells. The best fitting models were a major autosomal recessive gene with a residual multifactorial effect controlling the high number of CD4 and a major autosomal recessive gene with a residual multifactorial effect controlling the high number of CD8 cells. The authors pointed out that the knowledge of the CD4+ cell number and the proportion between CD4+ and CD8+ T cells could be a useful parameter in predicting human immunodeficiency virus infection outcome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CD4/CD8 T-CELL RATIO	c1832816	3,115	omim	https://www.omim.org/entry/601083	2019-09-22T16:15:26	{"omim": ["601083"]}
Epithelioid Hemangioendothelioma Micrograph of an epithelioid hemangioendothelioma of the liver. SpecialtyOncology Epithelioid hemangioendothelioma (eHAE) is a rare tumor, first characterized by Sharon Weiss and Franz Enzinger[1] that both clinically and histologically is intermediate between angiosarcoma and hemangioma. However, a distinct, disease-defining genetic alteration recently described for EHE indicates that it is an entirely separate entity from both angiosarcoma and hemangioma. EHE is a soft tissue sarcoma and is generally considered a vascular cancer insofar as the ‘lesional’ cells have surface markers typical of endothelial cells (cells lining the interior of blood vessels). EHE was originally described as occurring most commonly in the veins of the extremities (arms and legs) and two organs, the liver[2] and lungs. It has since been described in organs throughout the body. In addition to liver and lungs, bones and skin have been the most frequent organs. Before the initial description of Weiss, the tumor had been reported under a variety of other names, including histiocytoid hemangioendothelioma, intravascular bronchoalveolar tumor (in the lung), and sclerosing cholangiocarcinoma. In the lung and liver, common sites of metastatic tumor, it was most likely to be confused with carcinoma a far more common type of tumor. EHE typically occurs in the 20 – 40 age range although the overall age range involved is much broader and a modest predilection for females over males. It often has an indolent course, and many affected people have survived for decades with multi-organ disease.[1]:601 The extent and number of organs involved apparently has little effect on longevity. ## Contents * 1 Genetics * 2 Treatment * 3 Prognosis * 4 Epidemiology * 5 Society * 6 See also * 7 References * 8 External links ## Genetics[edit] The cytogenetics of EHE gave some of the first clues of an underlying genetic alteration. A balanced, reciprocal translocation t(1;3)(p36.3;q25) in EHE tumor cells was first described by Mendlick et al. in 2001 (Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara G, Rosenthal H, Bridge JA (2001). "Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma". Am. J. Surg. Pathol. 25 (5): 684–7. doi:10.1097/00000478-200105000-00019. PMID 11342784.CS1 maint: multiple names: authors list (link)). This led to the landmark paper by Tanas et al. in 2011(Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP (2011). "Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma". Sci Transl Med. 3 (98): 98ra82. doi:10.1126/scitranslmed.3002409. PMID 21885404.CS1 maint: multiple names: authors list (link)) describing the specific genes involved in the translocation associated with the most common forms of EHE. This alteration results in the fusion of genes coding for two transcription co-activators (transcriptional regulators): TAZ (transcriptional co-activator with PDZ-binding motif) also known as WWTR1 (WW domain-containing transcription regulator protein 1) and CAMTA1 (calmodulin-binding transcription activator 1). The names in parenthesis are not relevant to casual (or even science) readers but are included to help distinguish them from other genes. For instance, another gene with an entirely different function, Tafazzin, is unrelated to EHE but confusingly, also referred to as TAZ. In any case, the EHE translocation results in an abnormal ‘fusion gene’ that expresses an abnormal mRNA resulting in synthesis of a fusion protein variant of TAZ that is always turned on. This form of TAZ always resides in the nucleus and therefore is constitutively active. It binds and turns on a very important member of the TEAD family of transcription factors and this causes cells to proliferate. It is this production of the TAZ-TEAD transcriptome that causes the affected endothelial cells to grow into tumors. In normal cells, TAZ is considered a major negative transducer of the Hippo pathway, a signaling system that regulates organ size by causing cells to stop growing when they touch each other (contact inhibition). Many upstream inputs regulate the Hippo signal which normally functions to turn off or de-activate TAZ by keeping it in the cytoplasm and out of the nucleus. In EHE cells, the abnormal fusion TAZ is ‘immune’ to this input and just stays in the nucleus, and continuing to stimulate cell growth. Note that about 10% of EHE patients harbor a different translocation. This one similarly results in the constitutive activation of YAP, an orthologue of TAZ (i.e., a gene that has sequence and function that are very similar to TAZ). This also results in persistent, unregulated growth of the affected cells and therefore causes EHE-type tumors. ## Treatment[edit] •Sirolimus: Also known as rapamycin, this oral medication suppresses the immune system and slows the growth of abnormal lymphatic vessels that form the tumor. This can help shrink EHE tumors and improve symptoms, including pain •Tyrosine kinase inhibitors: These drugs, designed as targeted therapies for cancers, have shown short-term success with EHE. Examples include sorafenib, sunitinib and pazopanib. •Vincristine: This chemotherapy drug targets all dividing cells within the body and is therefore used to treat many cancers. It is also used for aggressive benign vascular tumors. Interferon: The body produces interferon to combat infections or control inflammation. It has been formulated into a medication that targets blood vessel growth. •Multi-agent chemotherapy: EHE tumors that grow rapidly, spread to other tissues or do not respond to other medications may require more aggressive drug therapy. However, this combination of medications is rarely needed in children and young adults with EHE. •Others like surgery can be done as treatment for the virus during its most severe. ## Prognosis[edit] Although Epithelioid Hemangioendothelioma typically presents as a low-grade tumor, occasionally, eHAE presents as high grade and more aggressive. eHAE presenting in the pleura, for example, is associated with a much more aggressive and hard to treat course.[3] There is no standard chemotherapy treatment for eHAE at current but success with drugs such as Interferon, Paclitaxel, MAID combination chemotherapy, Thalidomide and Doxorubicin have been reported. ## Epidemiology[edit] It is so rare that only 0.01 percent of the cancer population has it and it affects about 1 person in every 1,000,000 worldwide.[4] Around 20 cases are diagnosed in America every year – the cause is unknown.[5] It is unresponsive to any known strain of chemotherapy, making treatment very difficult. ## Society[edit] There is a Facebook site set up for people with EHE.[6] There is also a Registry for patients to enter their medical history.[7] CRAVAT Center for Research and Analysis of VAscular Tumors is a website for the EHE community.[8] The EHE Rare Cancer Foundation Australia was established in 2015 by Australians with Epithelioid Hemangioendothelioma (EHE).[9] The core objective of the EHE Rare Cancer Foundation Australia is to proactively fundraise in order to support research into this rare cancer in the hope that a maintenance program or cure can be found.[10] In 2003 photographer and actress Kris Carr was diagnosed with a stable and low grade version of eHAE. Carr has become a success as a 'Wellness Warrior' advocating a vegan lifestyle as a way to avoid and stabilize disease.[11] ## See also[edit] * List of cutaneous conditions * Skin lesion ## References[edit] 1. ^ Weiss, S. W.; Enzinger, F. M. (1982-09-01). "Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma". Cancer. 50 (5): 970–981. doi:10.1002/1097-0142(19820901)50:5<970::AID-CNCR2820500527>3.0.CO;2-Z. ISSN 0008-543X. PMID 7093931. 2. ^ Mistry A. M.; Gorden D. L.; Busler J. F.; Coogan A. C.; Kelly B. S. (2012). "Diagnostic and therapeutic challenges in hepatic epithelioid hemangioendothelioma". J Gastrointest Cancer. 43 (4): 521–525. doi:10.1007/s12029-012-9389-y. PMID 22544493. 3. ^ Crotty, Eric J.; McAdams, H. Page; Erasmus, Jeremy J.; Sporn, Thomas A.; Roggli, Victor L. (2000). "Epithelioid Hemangioendothelioma of the Pleura". American Journal of Roentgenology. 175 (6): 1545–1549. doi:10.2214/ajr.175.6.1751545. PMID 11090371. 4. ^ http://www.childrenshospital.org/az/Site844/mainpageS844P1.html[permanent dead link] 5. ^ "Archived copy". Archived from the original on 2013-07-24. Retrieved 2013-02-18.CS1 maint: archived copy as title (link) 6. ^ "Epithelioid Hemangioendothelioma (EHE) Cancer". 7. ^ "Home". 8. ^ "Epithelioid Hemangioendothelioma Cancer Foundation". 9. ^ generator, metatags. "EHE Rare Cancer Foundation Australia". www.ehefoundation.com.au. Retrieved 2016-07-06. 10. ^ generator, metatags. "EHE Rare Cancer Foundation Australia". www.ehefoundation.com.au. Retrieved 2016-07-06. 11. ^ Living with Cancer: The Kris Carr's Story 12^ http://www.childrenshospital.org/conditions-and-treatments/conditions/e/epithelioid-hemangioendothelioma/diagnosis-and-treatment ## External links[edit] Classification D * ICD-10: D18.0 * ICD-O: M9133/ * MeSH: D000230 * DiseasesDB: 34264 External resources * Orphanet: 157791 * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Epithelioid hemangioendothelioma	c0206732	3,116	wikipedia	https://en.wikipedia.org/wiki/Epithelioid_hemangioendothelioma	2021-01-18T18:33:58	{"mesh": ["D018323"], "umls": ["C0206732"], "orphanet": ["157791"], "wikidata": ["Q1887340"]}
A number sign (#) is used with this entry because of evidence that spherocytosis type 1 is caused by heterozygous, compound heterozygous, or homozygous mutation in the gene encoding ankyrin (ANK1; 612641) on chromosome 8p11. Description Hereditary spherocytosis refers to a group of heterogeneous disorders that are characterized by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear. The disorders are characterized clinically by anemia, jaundice, and splenomegaly, with variable severity. Common complications include cholelithiasis, hemolytic episodes, and aplastic crises (review by Perrotta et al., 2008). Elgsaeter et al. (1986) gave an extensive review of the molecular basis of erythrocyte shape with a discussion of the role of spectrin and other proteins such as ankyrin, actin (102630), band 4.1 (130500), and band 3 (109270), all of which is relevant to the understanding of spherocytosis and elliptocytosis (see 611904). See Delaunay (2007) for a discussion of the molecular basis of hereditary red cell membrane disorders. ### Genetic Heterogeneity of Hereditary Spherocytosis Also see SPH2 (616649), caused by mutation in the SPTB gene (182870) on chromosome 14q23; SPH3 (270970), caused by mutation in the SPTA1 gene (182860) on chromosome 1q21; SPH4 (612653), caused by mutation in the SLC4A1 gene (109270) on chromosome 17q21; and SPH5 (612690), caused by mutation in the EPB42 gene (177070) on chromosome 15q15. Clinical Features MacKinney et al. (1962) and Morton et al. (1962) studied 26 families. They concluded that after the initial case in a family has been identified, 4 tests suffice for the diagnosis in other family members: smear, reticulocyte count, hemoglobin, and bilirubin. The fragility test (increased osmotic fragility characterizes the disease) is unnecessary after the diagnosis has been made in the proband. It was estimated that the prevalence is 2.2 per 10,000, that the mutation rate is 0.000022 and that about one-fourth of cases are sporadic. No evidence of reproductive compensation or of increased prenatal and infant mortality was found. No enzyme defect was identified (Miwa et al., 1962). Several observations suggest that more than one type of hereditary spherocytosis exists in man (review by Zail et al., 1967). Barry et al. (1968) pointed out that hemochromatosis is a serious complication of untreated spherocytosis. Fargion et al. (1986) described 2 brothers who were thought to be heterozygous for the hemochromatosis gene and who also were affected with hereditary spherocytosis. Both had severe iron overload whereas all relatives without hereditary spherocytosis, including those with HLA haplotypes identical to those of the 2 brothers, had normal iron stores. Montes-Cano et al. (2003) reported a similar situation in a Spanish family: 3 members of different generations were diagnosed with hereditary spherocytosis and 1 of them, 44 years of age, presented iron overload with hepatic deposit and required treatment with periodic phlebotomies. Other members of the family showed normal values in iron metabolism. The patient with iron overload was a compound heterozygote for the H63D (235200.0002) and C282Y (235200.0001) mutations in the HFE gene. In a family with 6 persons affected in 3 generations, Wiley and Firkin (1970) found a form of hereditary spherocytosis with unusual features; other reports of atypical disease were reviewed. Aksoy et al. (1974) described severe hemolytic anemia in a patient seemingly with both elliptocytosis (inherited probably from the father) and spherocytosis (inherited from the mother). This finding raises a question of possible allelism of spherocytosis and one form of elliptocytosis. A genetic compound is more likely to show summation of effects than is a double heterozygote. Epidemic aplastic crisis in congenital chronic hemolytic anemias has been attributed to the human parvovirus (HPV) which also causes erythema infectiosum, or fifth disease (Tsukada et al., 1985; Rao et al., 1983). Lefrere et al. (1986) showed that in both children and adults the human parvovirus can precipitate aplastic crisis in hereditary spherocytosis just as it does in other forms of hereditary hemolytic anemia, particularly sickle cell disease. Healthy persons probably develop an erythroblastopenia when experiencing their first contact with HPV, but this escapes notice when the normal red cell life span allows maintenance of hemoglobin level throughout the interruption of red cell production. Ng et al. (1987) described a father and a son in whom aplastic crisis in hereditary spherocytosis was precipitated by parvovirus infection. Moiseyev et al. (1987) described a kindred in which hereditary spherocytosis occurred in combination with hypertrophic cardiomyopathy in 5 individuals in 4 successive generations. In another branch of the family, 4 individuals in 3 successive generations had either hereditary spherocytosis or hypertrophic cardiomyopathy (192600), but not both. Coetzer et al. (1988) described a 41-year-old man and an unrelated 49-year-old woman who had atypical, severe spherocytosis with partial response to splenectomy. No information on the family aided in evaluating inheritance in the second case; in the first case, the deceased father had had chronic anemia and a sib had died at age 3 months of unknown cause. In these 2 patients, the authors found a partial deficiency of ankyrin and spectrin in red cells. Coetzer et al. (1988) concluded that a defect in synthesis of ankyrin was the primary abnormality. In the offspring of first-cousin parents, both of whom had hereditary spherocytosis, Duru et al. (1992) observed a 6-month-old male infant with severe anemia. The infant required red blood cell transfusions starting at the age of 1 month and continuing until splenectomy was performed at the age of 1 year to produce a complete hematologic remission. Duru et al. (1992) concluded that this represented an example of homozygosity for the spherocytosis gene, presumably an ankyrin mutant, and that splenectomy can cure the anemia, even in the homozygote. Both sickle cell anemia and hereditary spherocytosis are known causes of leg ulcers. Peretz et al. (1997) reported the case of an 18-year-old Bedouin with leg ulcers of 12-months duration; past history revealed HS since childhood. Treatment for 6 months with various conservative modalities had no effect on the ulcers. However, complete clearance was achieved 2 months after splenectomy. The precocious formation of bilirubinate gallstones is the most common complication of hereditary spherocytosis, and the prevention of this problem represents a major impetus for splenectomy in many patients with compensated hemolysis. Because Gilbert syndrome (143500) had been considered a risk factor for gallstone formation, Miraglia del Giudice et al. (1999) postulated that the association of this common inherited disorder of hepatic bilirubin metabolism with hereditary spherocytosis could increase cholelithiasis. To test this hypothesis, 103 children with mild to moderate hereditary spherocytosis who, from age 1 year, had undergone a liver and biliary tree ultrasonography every year, were retrospectively examined. The 2-bp TA insertion within the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome, was screened. The risk of developing gallstones was statistically different among the 3 groups of patients (homozygotes for the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele with the TA insertion). Miraglia del Giudice et al. (1999) concluded that although patients with hereditary spherocytosis were the only ones studied, extrapolating these findings to patients who have different forms of inherited (e.g., thalassemia, intraerythrocytic enzymatic deficiency) or acquired (e.g., autoimmune hemolytic anemia, hemolysis from mechanical heart valve replacement) chronic hemolysis may be warranted. ### Reviews Davies and Lux (1989) gave a useful review of hereditary disorders of the red cell membrane skeleton. They referred to a form of spherocytosis due to a defect in ankyrin as spherocytosis-1 and a form due to a defect in beta-spectrin as spherocytosis-2. Perrotta et al. (2008) reviewed the several forms of hereditary spherocytosis. Diagnosis On behalf of the General Haematology Task Force of the British Committee for Standards in Haematology, Bolton-Maggs et al. (2004) provided comprehensive guidelines for the diagnosis and management of hereditary spherocytosis. Cytogenetics Kimberling et al. (1975) demonstrated linkage between spherocytosis and a translocation involving the short arms of chromosomes 8 and 12. They concluded that the spherocytosis locus is either very close to the centromere of chromosome 8 or on 12p. Kimberling et al. (1978) reported further on their studies of a family with HS and an 8-12 translocation. They concluded that a locus for HS is located near the breakpoint of the translocation. Cohen et al. (1991) described 2 sibs in whom congenital spherocytosis was associated with an inherited interstitial deletion of 8p, del8(p11-p21). This abnormal chromosome was inherited from their mother who showed this deletion as well as a small fragment representing the deleted segment. Centromeric material from chromosome 8 was detected in this chromosome fragment by in situ hybridization using an alpha-satellite probe, but not by C banding. Chromosome analysis of skin fibroblasts from the mother and a third sib, both normal but with a similar karyotype, showed the deleted fragment in over 80% of cells. Since the chromosome abnormality was not observed in 5 of the mother's sibs, it probably arose de novo in her. The 2 sibs with congenital spherocytosis had multiple other phenotypic abnormalities. The male had short stature, severe mental retardation, microcephaly, and micrognathia with bat ears, primary failure of sexual development, and bilateral conductive deafness secondary to congenital stapedial fixation. In addition to these features, the sister had torticollis associated with fusion of several vertebrae; she developed diabetes mellitus at the age of 15 years, which was controlled by diet and chlorpropamide. Stratton et al. (1992) described an infant with a de novo interstitial deletion of the proximal short arm of chromosome 8 (p21p11.2). The infant had bilateral cleft lip and palate and apparent hypogonadism. Four previous reports of similar deletions (p21p11.1) were associated with hypogonadotropic hypogonadism and hereditary spherocytosis. Since their patient demonstrated no red blood cell abnormality, Stratton et al. (1992) suggested that the gene for HS is located in the region 8p11.2-p11.1. Bass et al. (1983) presented evidence for the chromosome 8 localization of a spherocytosis locus: they observed mother and son with hereditary spherocytosis and a balanced translocation between chromosomes 3 and 8. The breakpoint on 8 in the family of Kimberling et al. (1975) and in their family was at 8p11. Chilcote et al. (1987) studied 2 dysmorphic sibs with neurologic findings and hemolytic anemia. Clinical and laboratory findings were consistent with the diagnosis of congenital spherocytosis whereas both parents and 2 unaffected sibs were normal. The 2 affected children had an interstitial deletion of the short arm of chromosome 8, 46,XX,del(8)(p11.1p21.1). Chilcote et al. (1987) suggested that together with the evidence from the families of Kimberling et al. (1975) and Bass et al. (1983), their family provides strong evidence for a gene for congenital spherocytosis in the proximal part of 8p. Glutathione reductase (GSR; 138300) levels were slightly reduced in the 2 affected children relative to their parents and an unaffected sib but did not approach the half-normal values that might be expected and it was unlikely that the moderate reduction in the glutathione reductase activity would cause hemolysis. The presence of abnormalities in 2 sibs with normal parents may have its explanation in mosaicism of 1 parent. Close linkage to GSR, which is at 8p21, was excluded by the family of Nakashima et al. (1978). Kitatani et al. (1988) studied a 1-year-old boy with spherocytosis associated with a de novo minute deletion involving 8p21.1-p11.22. Contradictory information on the mapping of hereditary spherocytosis may reflect genetic heterogeneity in this condition as in elliptocytosis. Costa et al. (1990) identified reports of 5 cases of deletion or translocation involving chromosome 8p and leading to spherocytosis. Lux et al. (1990) reported that 1 copy of the ankyrin gene was missing from DNA of 2 unrelated children with severe spherocytosis and heterozygous deletion of chromosome 8--del(8)(p11-p21.1). Affected red cells were also ankyrin-deficient. Okamoto et al. (1995) described a 30-month-old Japanese boy with spherocytic anemia in association with multiple anomalies and mental retardation. The karyotype had a deletion of interstitial deletion of 8p: del(8)(p11.23p21.1). Glutathione reductase activity was moderately reduced, consistent with deletion of that locus as well as of the ankyrin locus. Okamoto et al. (1995) reviewed the other cases of 8p deletion associated with spherocytic anemia. Pathogenesis Jacob and Jandl (1964) were of the view that the primary defect is in the red cell membrane, which is abnormally permeable to sodium. Jacob et al. (1971) demonstrated altered membrane protein in hereditary spherocytosis. Microfilamentous proteins resembling actin are important to the shape of the red cell. Comparable membrane proteins occur throughout phylogeny under circumstances suggesting a role in cell plasticity and shape. Actin and myosin-like filamentous proteins occur in platelets. Heterogeneity in hereditary spherocytosis was indicated by studies of structural proteins of the red cell membrane, including alpha and beta spectrin,. actin (see 102630), and protein 4.1 (EPB41; 130500). In a systematic assay of the interactions of spectrin in 6 kindreds with autosomal dominant hereditary spherocytosis, Wolfe et al. (1982) found 1 in which all 4 affected members had reduced enhancement of spectrin-actin binding by protein 4.1, owing to a 39% decrease in the binding of normal protein 4.1 by spectrin. The defective spectrin was separated into 2 populations by affinity chromatography on immobilized normal protein 4.1. One population lacked ability to bind 4.1, but the other functioned normally. Hill et al. (1982) concluded that 'the difference between HS and normal membranes, which persists in isolated cytoskeletons, suggests that alterations in either the primary structure or the degree of phosphorylation of protein bands 2.1 or 4.1 may be central to the molecular basis of hereditary spherocytosis.' The 2.1 band is also known as ankyrin. The major proteins of the cytoskeleton, spectrin and actin, are attached to the cell membrane by bands 2.1 and 4.1. Johnsson and Himberg (1982) presented evidence that platelets, as well as red cells, are defective in HS. In a 41-year old man with severe spherocytosis, Coetzer et al. (1988) studied the synthesis, assembly, and turnover of spectrin and ankyrin in the reticulocytes of the first patient. The synthesis of spectrin, when measured in the cell cytosol, was normal (alpha-spectrin; 182860) or increased (beta-spectrin; 182870). The principal defect appeared to be a diminished incorporation of ankyrin into the cell membrane, leading to decreased deposition of spectrin as a secondary phenomenon. Ankyrin is the principal binding site for spectrin on the membrane. Normal red cells contain 1 copy of ankyrin per spectrin tetramer. The red cell membrane skeleton is a submembranous network composed mainly of spectrin, actin, and proteins that migrate on gel electrophoresis as bands 4.1 (EPB41; 130500) and 4.9 (EPB49; 125305). Visualization of the skeleton by electron microscopy shows a primarily hexagonal lattice of fibers of spectrin tetramers linked to junctional complexes containing actin and proteins 4.1 and 4.9. The skeleton is attached to the cell membrane by ankyrin (protein 2.1), which connects beta-spectrin to the cytoplasmic portion of band 3 (SLC4A1; 109270), which is the major integral membrane protein. In addition, protein 4.1 links the distal ends of spectrin tetramers to transmembrane glycoprotein. Hanspal et al. (1991) concluded that the primary defect underlying the combined spectrin and ankyrin deficiency in severe hereditary spherocytosis is a deficiency of ankyrin mRNA leading to a reduced synthesis of ankyrin, which, in turn, underlies a decreased assembly of spectrin on the membrane. Mapping Using RFLPs defined by a cDNA for human erythrocyte ankyrin, Forget et al. (1989) demonstrated close linkage between hereditary spherocytosis and the ankyrin gene, with no crossovers observed. The calculated lod score was 3.63 at a theta of 0.0. The ankyrin gene appears to be located on the short arm of chromosome 8. The large kindred in which the linkage was established had classic features. Costa et al. (1990) analyzed a large kindred with typical dominant hereditary spherocytosis for genetic linkage with the genes for alpha spectrin, beta spectrin, protein 4.1, and ankyrin by means of RFLPs. Close linkage was excluded for all of the candidate genes except that for ankyrin, which was found to show no recombination, with a lod score of 3.63. By fluorescence-based in situ hybridization, Tse et al. (1990) localized the ankyrin gene to 8p11.2. Molecular Genetics Davies and Lux (1989) stated that dosage analysis in 2 hereditary spherocytosis patients with chromosome 8p11 deletions showed them to be hemizygous for the ankyrin gene. A corresponding reduction of approximately 50% in the amount of ankyrin protein was also seen in these patients, who had mental retardation in addition to the red cell defect. In both normoblastosis mice and hereditary spherocytosis humans, spectrin is also reduced as a secondary phenomenon. Iolascon et al. (1991) described 2 Italian families with ankyrin deficiency spherocytosis. In both, the disorder was a new mutation in the proband; 1 proband transmitted it to an offspring. Eber et al. (1996) screened all 42 coding exons plus the 5-prime untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense mutations and a mutation in the putative ankyrin-1 promoter were common in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accumulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. The findings indicated to Eber et al. (1996) that ankyrin-1 mutations are a major cause of dominant and recessive HS (between 35 and 65%), that band 3 mutations are less common (between 15 and 25%), and that the severity of HS is modified by factors other than the primary gene defect. Gallagher and Forget (1998) tabulated a total of 34 mutations in the ANK1 gene that have been associated with hereditary spherocytosis, as contrasted with 2 mutations in the alpha-spectrin gene and 19 in the beta-spectrin gene. In the proband reported by Duru et al. (1992), Edelman et al. (2007) identified a homozygous splice site mutation in the ANK1 gene (612641.0007). Each parent was heterozygous for the mutation. Animal Model Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb locus maps to mouse chromosome 8 in a segment that shows homology of synteny with human 8p (White and Barker, 1987). White et al. (1990) used immunologic and biochemical methods to demonstrate an altered (150 kD) immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+) reticulocytes. Mice deficient in ankyrin have, in addition to hemolytic anemia, significant neurologic dysfunction associated with Purkinje cell degeneration in the cerebellum and the development of a late-onset neurologic syndrome characterized by persistent tremor and gait disturbance (Peters et al., 1991). Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin (HBG1; 142200) reporter gene in an erythroid-specific, position-independent, copy number-dependent fashion in transgenic mice to study spherocytosis-associated promoter mutations. They detected abnormalities in reporter gene mRNA and protein expression. Mice with the wildtype promoter demonstrated normal expression in all erythrocytes, whereas mice with the -108T-C promoter mutation (612641.0002) demonstrated varied expression. Undetectable or significantly lower expression was found in mice with linked -108T-C and -153G-A (612641.0006) promoter mutations. Gallagher et al. (2001) concluded that functional defects can be caused by HS-related ankyrin gene promoter mutations. History Sengar et al. (1977) presented some fragmentary evidence that HLA and hereditary spherocytosis may be linked. De Jongh et al. (1982) could demonstrate no linkage of spherocytosis with Gm or with HLA. Lod scores with PI were also negative. INHERITANCE \- Autosomal dominant \- Autosomal recessive ABDOMEN Liver \- Jaundice Biliary Tract \- Gallstones Spleen \- Splenomegaly HEMATOLOGY \- Spherocytosis \- Hemolytic anemia \- Reticulocytosis LABORATORY ABNORMALITIES \- Increased reticulocyte count \- Hyperbilirubinemia \- Increased osmotic fragility \- Negative direct antiglobulin (Coombs) test \- Elevated MCHC MISCELLANEOUS \- Patients with homozygous mutations have a more severe disorder MOLECULAR BASIS \- Caused by mutation in the ankyrin 1 gene (ANK1, 612641.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPHEROCYTOSIS, TYPE 1	c0221409	3,117	omim	https://www.omim.org/entry/182900	2019-09-22T16:34:37	{"doid": ["0110916"], "mesh": ["C536356"], "omim": ["182900"], "orphanet": ["822"], "synonyms": ["Alternative titles", "SPHEROCYTOSIS, HEREDITARY, 1", "SPH"]}
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: "Idiosyncratic drug reaction" – news · newspapers · books · scholar · JSTOR (April 2016) (Learn how and when to remove this template message) Idiosyncratic drug reaction SpecialtyEmergency medicine Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known. They frequently occur with exposure to new drugs, as they have not been fully tested and the full range of possible side-effects have not been discovered; they may also be listed as an adverse drug reaction with a drug, but are extremely rare. Some patients have multiple-drug intolerance. Patients who have multiple idiopathic effects that are nonspecific are more likely to have anxiety and depression.[1] Idiosyncratic drug reactions appear to not be concentration dependent. A minimal amount of drug will cause an immune response, but it is suspected that at a low enough concentration, a drug will be less likely to initiate an immune response. ## Contents * 1 Mechanism * 2 See also * 3 References * 4 External links ## Mechanism[edit] In adverse drug reactions involving overdoses, the toxic effect is simply an extension of the pharmacological effect (Type A adverse drug reactions). On the other hand, clinical symptoms of idiosyncratic drug reactions (Type B adverse drug reactions) are different from the pharmacological effect of the drug. The proposed mechanism of most idiosyncratic drug reactions is immune-mediated toxicity. To create an immune response, a foreign molecule must be present that antibodies can bind to (i.e. the antigen) and cellular damage must exist. Very often, drugs will not be immunogenic because they are too small to induce immune response. However, a drug can cause an immune response if the drug binds a larger molecule. Some unaltered drugs, such as penicillin, will bind avidly to proteins. Others must be bioactivated into a toxic compound that will in turn bind to proteins. The second criterion of cellular damage can come either from a toxic drug/drug metabolite, or from an injury or infection. These will sensitize the immune system to the drug and cause a response. Idiosyncratic reactions fall conventionally under toxicology. ## See also[edit] * Idiosyncrasy ## References[edit] 1. ^ Davies SJ, Jackson PR, Ramsay LE, Ghahramani P (2003). "Drug intolerance due to nonspecific adverse effects related to psychiatric morbidity in hypertensive patients". Arch. Intern. Med. 163 (5): 592–600. doi:10.1001/archinte.163.5.592. PMID 12622606. ## External links[edit] Classification D * ICD-10: T78.4 * ICD-9-CM: 995.3 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Idiosyncratic drug reaction	c0919578	3,118	wikipedia	https://en.wikipedia.org/wiki/Idiosyncratic_drug_reaction	2021-01-18T18:55:06	{"icd-9": ["995.3"], "icd-10": ["T78.4"], "wikidata": ["Q3739665"]}
Acute panmyelosis with myelofibrosis SpecialtyHematology, oncology Acute panmyelosis with myelofibrosis (APMF) it is a poorly defined disorder that arises as either a clonal disorder, or following toxic exposure to the bone marrow.[1] ## Contents * 1 Signs and symptoms * 2 Prognosis and treatment * 3 Terminology * 4 See also * 5 References * 6 See also * 7 External links ## Signs and symptoms[edit] Tamir Lichaa's bone biopsy shows abnormal schmete megakaryocytes, macrocytic erythropoiesis, and defects in neutrophil production and fibrosis of the marrow (myelofibrosis). Clinically patients present with reduction in the count of all blood cells (pancytopenia), a very few blasts in the peripheral blood and no or little spleen enlargement (splenomegaly). Cells are usually CD34 positive.[2] ## Prognosis and treatment[edit] Median survival is about 9 months.[citation needed] Autologous stem cell transplantation has been used in treatment.[3] ## Terminology[edit] Controversy remains today whether this disorder is a subtype of acute myeloid leukemia or myelodysplastic syndromes; however, it is currently classified as a form of AML.[4][5] ## See also[edit] * List of hematologic conditions ## References[edit] 1. ^ Hoffman R, Benz E, Shattil S, Furie B, Cohen H (2004). Hematology: Basic Principles and Practice (4th ed.). Churchill Livingstone. 2. ^ Orazi A, O'Malley DP, Jiang J, et al. (May 2005). "Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia". Mod. Pathol. 18 (5): 603–14. doi:10.1038/modpathol.3800348. PMID 15578075. 3. ^ Ngirabacu MC, Ravoet C, Dargent JL, et al. (December 2006). "Long-term follow-up of autologous peripheral blood stem cell transplantation in the treatment of a patient with acute panmyelosis with myelofibrosis". Haematologica. 91 (12 Suppl): ECR53. PMID 17194659. 4. ^ Thiele J, Kvasnicka HM, Schmitt-Graeff A (April 2004). "Acute panmyelosis with myelofibrosis". Leuk. Lymphoma. 45 (4): 681–7. doi:10.1080/10428190310001625692. PMID 15160939. 5. ^ Thiele J, Kvasnicka HM, Zerhusen G, et al. (August 2004). "Acute panmyelosis with myelofibrosis: a clinicopathological study on 46 patients including histochemistry of bone marrow biopsies and follow-up". Ann. Hematol. 83 (8): 513–21. doi:10.1007/s00277-004-0881-8. PMID 15173958. ## See also[edit] * Acute myeloid leukemia * Panmyelosis * Myelofibrosis ## External links[edit] Classification D * ICD-10: C94.4 * ICD-9-CM: 238.79 * ICD-O: 9931/3 * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Acute panmyelosis with myelofibrosis	c0334674	3,119	wikipedia	https://en.wikipedia.org/wiki/Acute_panmyelosis_with_myelofibrosis	2021-01-18T18:59:13	{"gard": ["11907"], "umls": ["C0334674"], "icd-9": ["238.79"], "icd-10": ["C94.4"], "orphanet": ["86843"], "wikidata": ["Q4677944"]}
Charcot-Marie-Tooth disease, type 2B1 (CMT2B1, also referred to as CMT4C1) is an axonal CMT peripheral sensorimotor polyneuropathy. ## Epidemiology It has been described exclusively in families originating from North-Western Africa (northwest Algeria and the east of Morocco). ## Clinical description Onset occurs in the second decade of life. The disease course and severity are variable, even between affected members of the same family. In general, the disease manifests as distal muscle weakness and atrophy that progress gradually to the proximal muscles. Involvement of the upper and lower limbs has been reported. Sensory impairment may also be present but foot deformities are either moderate or absent. Proximal muscle atrophy of the pelvic and scapular girdle may occur later in the disease course. ## Etiology CMT2B1 is caused by a p.R644C missense mutation in the lamin A/C protein (encoded by the LMNA gene, 1q22). ## Genetic counseling CMT2B1 is transmitted in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Charcot-Marie-Tooth disease type 2B1	c1854154	3,120	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98856	2021-01-23T18:12:07	{"gard": ["8548"], "mesh": ["C537990"], "omim": ["605588"], "umls": ["C1854154"], "icd-10": ["G60.0"], "synonyms": ["AR-CMT2B1", "Autosomal recessive Charcot-Marie-Tooth disease type 2B1", "Autosomal recessive axonal CMT4C1"]}
Systemic sclerosis (SSc) is a generalized disorder of small arteries, microvessels and connective tissue, characterized by fibrosis and vascular obliteration in the skin and organs, particularly the lungs, heart, and digestive tract. There are two main subsets of SSc: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) (see these terms). A third subset of SSc has also been observed, called limited Systemic Sclerosis (lSSc) or systemic sclerosis sine scleroderma (see these terms). ## Epidemiology The prevalence is estimated at about 1/6,500 adults. Women are predominantly affected (F/M sex ratio around 4:1). ## Clinical description The disease usually manifests between 40 and 50 years of age. Raynaud's phenomenon is often the first sign of the disease. The other signs usually appear a few months later in the diffuse cutaneous subset and some years later in the limited cutaneous subset. In the limited cutaneous subset, skin involvement is limited to the hands, face, feet and forearms while in the diffuse subset it rapidly becomes generalized. Esophageal dysmotility is common and provokes gastroesophageal reflux and sometimes dysphagia. Life-threatening complications can occur such as pulmonary fibrosis and, less frequently, pulmonary arterial hypertension. The limited SSc patients have no skin involvement but only Raynaud's phenomenon, and are at risk of organ involvement. ## Etiology The exact cause of SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, SSc is associated with exposure to chemicals (including silica, solvents and hydrocarbons). ## Diagnostic methods Diagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on capillaroscopy. Blood tests show typical antinuclear autoantibodies. The extent of the disease should be evaluated by computed tomography (CT), electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed. ## Differential diagnosis Differential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, polymyositis, and rheumatoid arthritis (see these terms). ## Management and treatment Management is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Low doses of corticosteroids with immunosuppressive agents are needed in cases with recent and severe cutaneous involvement or in progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography. ## Prognosis The prognosis depends on the subset of SSc. The prognosis for limited cutaneous SSc is relatively good (10-year survival rate of 80-90%). However, pulmonary arterial hypertension, which occurs in about 10% of cases, and severe lung fibrosis, may lead to a more severe prognosis. The prognosis for diffuse cutaneous SSc is more severe (10-year survival rate of 60-80%) because of the higher risk of life-threatening complications: renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Systemic sclerosis	c0036421	3,121	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90291	2021-01-23T16:53:16	{"gard": ["9748"], "mesh": ["D012595"], "omim": ["181750"], "umls": ["C0036421"], "icd-10": ["M34.0", "M34.1", "M34.2", "M34.8", "M34.9"], "synonyms": ["Systemic scleroderma"]}
Wartenberg wheel pain stimulation of the areola and nipple Algolagnia (/ælɡəˈlæɡniə/; from Greek: ἄλγος, álgos, "pain", and Greek: λαγνεία, lagneía, "lust") is a sexual tendency which is defined by deriving sexual pleasure and stimulation from physical pain,[1] often involving an erogenous zone. Studies conducted indicate differences in how the brains of those with algolagnia interpret nerve input.[1] ## Contents * 1 History of research * 2 Research * 3 See also * 4 Footnotes * 5 References ## History of research[edit] In 1892, Albert von Schrenck-Notzing introduced the term algolagnia to describe "sexual" masochism, to differentiate it from Charles Féré's earlier term called "algophilia"; Schrenck-Notzing's interpretation was that algolagnia involved lust, not love as Fere interpreted the phenomenon.[2] (It should be cautioned, though, that the definitions regarding sadism and masochism as medical terms have changed over the years (as also noted in the main article for that topic) and are still evolving,[2] and there are also non-medical definitions of sadomasochism.) However, Krafft-Ebing's theories in Psychopathia Sexualis – where the terms sadism and masochism were used – were adopted by Sigmund Freud and became an integral part of psychoanalysis, thereby ensuring their predominance over the concept of "algolagnia". The neurologist Albert Eulenberg was another one of the first researchers to look into algolagnia,[2] in the 1902 Sadismus und Masochismus (Sadism and Masochism). Soon thereafter, Havelock Ellis also looked into algolagnia, in the early 1900s, and stated "Sadism and Masochism – Algolagnia Includes Both Groups of Manifestations"[3] but maintained that that enjoyment of pain was restricted to an erotic context,[4] in contrast to Krafft-Ebing's interpretations. With such titles as Analysis of the Sexual Impulse, Love and Pain, The Sexual Impulse in Women and The Evolution of Modesty, The Phenomena of Sexual Periodicity, Auto-Erotism, he described the basics of the condition. Eugen Kahn, Smith Ely Jelliffe, William Alanson White, and Hugh Northcote were other early psychological researchers into algolagnia. ## Research[edit] As of 1992, algolagnia was described as a physical phenomenon in which the brain interprets pain signals as pleasurable leading to psychological effects.[5][page needed][original research?] Dolf Zillmann wrote that: > ...most algolagniacs see their actions as an active lust, not a motivational one. Patients with algolagnia could lead normal lives, enjoy normal arousal sequences, and indulge in fairly normal sexual intercourse, but when exposed to sexual pain, were unable to control their reaction. One woman described it as being unable to prevent her arousal or subsequent orgasm due to pain, even if she was not aroused when it began.[6] This and other research [7] have linked algolagnia to aggression, hypersexuality, or other control psychoses. Research using MRI and computer models of neuron firing patterns has shown that most algolagniacs experience pain differently from others. Algolagniacs may have DNA errors such as SCN9A, causing inaccurate nociception to occur.[8] At least one researcher in the 1900s,[9] Albert Freiherr von Schrenck-Notzing, who was a self-professed sadist, thought that algolagnia was a psychological disorder. This view began to change once the Kinsey Reports noted that many seemingly normal people often enjoy pain in a sexual context, and later Norman Breslow found that, before 1977, only four previous studies in all the scientific literature were empirical in nature.[10] One of the researchers whom Breslow cited as having empirically-valid work, Andres Spengler, concluded that earlier research was "heavily burdened with prejudice and ignorance"[11] against those whose sexual practices were in the minority, falsely assuming behaviors to be pathological when in fact they were statistically abnormal, but harmless. In 1993 Thomas Wetzstein published a large-scale study of his local subculture from a sociological viewpoint, confirming Spengler's results and expanding on them.[12] No empirical study has found a connection to violent crimes or evidence for an increased tendency towards any sociopathological behavior in algolagnia or the related features of sexual sadomasochism, as had been generally assumed since Krafft-Ebing's era.[citation needed] The term algolagnia has fallen into rare usage, and there is no entry for it in the American Psychiatric Association's DSM IV-TR.[13] Inflicting pain on others has been termed "active algolagnia" and equated to the pathological form of sadism in Mosby's Medical Dictionary, which also equates the pathological form of masochism to "passive algolagnia",[14] but it cannot be a pathological (dangerous) paraphilia form of sadism or masochism unless it involves pain inflicted on "non-consenting" persons, or "cause[s] marked distress or interpersonal difficulty."[15] And using algolagnia as both a pathological and non-pathological term, some in the modern research community still link it to some but not all BDSM activities.[2] There is little ongoing research, with most neurophysiologists concentrating on neuropathological reasons for such reactions.[16] ## See also[edit] * Sexual masochism disorder * Autosadism * Mortification of the flesh ## Footnotes[edit] 1. ^ a b Kelley, Kathryn; Donn Byrne. Alternative Approaches to the Study of Sexual Behavior. pp. 13–38. ISBN 978-0-89859-677-9. 2. ^ a b c d The pleasure of pain. \| Goliath Business News Archived November 11, 2009, at the Wayback Machine 3. ^ Studies in the Psychology of Sex, Volume 3 by Havelock Ellis - Project Gutenberg 4. ^ Ellis, Havelock. 1967; first published 1939. My Life London: Spearman. 5. ^ Sullivan, Harry Stack (1992). Clinical Studies in Psychiatry. W. W. Norton & Company. ISBN 978-0-393-00688-9. 6. ^ Zillmann, Dolf (1998). Connections Between Sexuality and Aggression. Lawrence Erlbaum Associates. ISBN 978-0-8058-1907-6. 7. ^ Bancroft, John D. (1989). Human Sexuality and Its Problems. Elsevier Health Sciences. ISBN 978-0-443-03455-8. 8. ^ Bloch, Iwan (2006). The Sexual Life of Our Time: In Its Relations to Modern Civilization. Kessinger Publishing. ISBN 978-1-4286-1543-4. 9. ^ Von Schrenck -Notzin, A (2006). Therapeutic Suggestion in Psychopathia Sexualis with Special Reference. Kessinger Publishing. ISBN 978-1-4286-2544-0. 10. ^ Breslow Norman et al. 1985. "On the prevalence and roles of females in the sadomasochistic subculture: Report of an empirical study". In: Archives of Sexual Behavior Vol. 14 11. ^ Duriès, Vanessa. 1993. Le Lien. Spengler ISBN 978-2-909997-03-2 12. ^ Wetzstein, Thomas A. 1993. Sadomasochismus. Szenen und Rituale. Hamburg: Rowohlt 13. ^ http://www.behavenet.com/capsules/disorders/ algolagnia Archived March 15, 2010, at the Wayback Machine 14. ^ [1] and [2] 15. ^ "BehaveNet Clinical Capsule: Sexual Sadism". Archived from the original on 2009-07-16. Retrieved 2009-10-25. 16. ^ Pg 197,Therapeutic Suggestion in Psychopathia Sexualis with Special Reference ## References[edit] Wikimedia Commons has media related to Pain play. * Ellis, on algolagnia * A 1900s book on algolagnia * Lesley Hall. "Pain and the erotic". The Wellcome Trust. Archived from the original on 17 December 2008. Retrieved 2008-11-17. Look up algolagnia in Wiktionary, the free dictionary. * v * t * e Paraphilias List * Abasiophilia * Acrotomophilia * Agalmatophilia * Algolagnia * Apotemnophilia * Autassassinophilia * Biastophilia * Capnolagnia * Chremastistophilia * Chronophilia * Coprophagia * Coprophilia * Crurophilia * Crush fetish * Dacryphilia * Dendrophilia * Emetophilia * Eproctophilia * Erotic asphyxiation * Erotic hypnosis * Erotophonophilia * Exhibitionism * Formicophilia * Frotteurism * Gerontophilia * Homeovestism * Hybristophilia * Infantophilia * Kleptolagnia * Klismaphilia * Lactaphilia * Macrophilia * Masochism * Mechanophilia * Microphilia * Narratophilia * Nasophilia * Necrophilia * Object sexuality * Odaxelagnia * Olfactophilia * Omorashi * Paraphilic infantilism * Partialism * Pedophilia * Podophilia * Plushophilia * Pyrophilia * Sadism * Salirophilia * Scopophilia * Somnophilia * Sthenolagnia * Tamakeri * Telephone scatologia * Transvestic fetishism * Trichophilia * Troilism * Urolagnia * Urophagia * Vorarephilia * Voyeurism * Zoophilia * Zoosadism See also * Other specified paraphilic disorder * Erotic target location error * Courtship disorder * Polymorphous perversity * Sexual fetishism * Human sexual activity * Perversion * Sexology * Book * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Algolagnia	None	3,122	wikipedia	https://en.wikipedia.org/wiki/Algolagnia	2021-01-18T19:04:06	{"wikidata": ["Q1570503"]}
Among the offspring of first-cousin Iraqi Jewish parents, Ben-Ami et al. (1973) observed a mentally retarded boy in whom paper chromatographic examination of the urine showed an abnormal compound having staining reactions with ninhydrin cyanide-nitroprusside and iodoplatinate reagents. The peptide contained cysteine and glycine in 2:1 molar proportions. The urine of the mother and 5 sisters was normal. Neuro \- Mental retardation Lab \- Urinary peptide containing 2:1 cysteine and glycine Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CYSTEINE PEPTIDURIA	c1857438	3,123	omim	https://www.omim.org/entry/219550	2019-09-22T16:29:13	{"mesh": ["C565659"], "omim": ["219550"]}
A blood smear showing hypochromic (and microcytic) anemia. Note the increased central pallor of the red blood cells. Hypochromic anemia is a generic term for any type of anemia in which the red blood cells are paler than normal. (Hypo\- refers to less, and chromic means colour.) A normal red blood cell has a biconcave disk shape and will have an area of pallor in its center when viewed microscopically. In hypochromic cells, this area of central pallor is increased. This decrease in redness is due to a disproportionate reduction of red cell hemoglobin (the pigment that imparts the red color) in proportion to the volume of the cell. Clinically the color can be evaluated by the mean corpuscular hemoglobin (MCH) or mean corpuscular hemoglobin concentration (MCHC). The MCHC is considered the better parameter of the two as it adjusts for effect the size of the cell has on its amount of hemoglobin. [1] Hypochromia is clinically defined as below the normal MCH reference range of 27–33 picograms/cell in adults or below the normal MCHC reference range of 33–36 g/dL in adults.[2] Red blood cells will also be small (microcytic), leading to substantial overlap with the category of microcytic anemia. The most common causes of this kind of anemia are iron deficiency and thalassemia. Hypochromic anemia was historically known as chlorosis or green sickness for the distinct skin tinge sometimes present in patients, in addition to more general symptoms such as a lack of energy, shortness of breath, dyspepsia, headaches, a capricious or scanty appetite and amenorrhea. ## Contents * 1 Historical understanding * 2 Acquired forms * 3 Hereditary forms * 4 See also * 5 Notes * 6 External links ## Historical understanding[edit] > Pandar > Now, the pox upon her green-sickness for me! > > Bawd > 'Faith, there's no way to be rid on't but by the way to the pox. Here comes the Lord Lysimachus disguised. > > Shakespeare (attrib). Pericles Prince of Tyre[3] In 1554, German physician Johannes Lange described a condition, which he called "the disease of virgins" because, he said, it was "peculiar to virgins". The symptoms were wide-ranging, including an appearance which is "pale, as if bloodless", an aversion to food (especially meat), difficulty in breathing, palpitations and swollen ankles.[4] He prescribed that sufferers should "live with men and copulate. If they conceive, they will recover." The symptom picture overlaps to some extent with an earlier condition described in English medical texts, "the green sickness", which was a form of jaundice.[5] However, Lange shifted the cause from digestive errors to the sufferer remaining a virgin, despite being of the age for marriage. The name "chlorosis" was coined in 1615 by Montpellier professor of medicine Jean Varandal from the ancient Greek word "chloros" meaning "greenish-yellow", "pale green", "pale", "pallid" or "fresh". Both Lange and Varandal claimed Hippocrates as a reference, but their lists of symptoms do not match that in the Hippocratic Disease of Virgins, a treatise that was translated into Latin in the 1520s and thus became available to early modern Europe.[4] In addition to "green sickness", the condition was known as morbus virgineus ("virgin's disease") or febris amatoria ("lover's fever"). Francis Grose's 1811 Dictionary of the Vulgar Tongue defined "green sickness" as: "The disease of maids occasioned by celibacy."[6] In 1681, English physician Thomas Sydenham classified chlorosis as a hysterical disease affecting not only adolescent girls but also "slender and weakly women that seem consumptive." He advocated iron as a treatment: "To the worn out or languid blood it gives a spur or fillip whereby the animal spirits which lay prostrate and sunken under their own weight are raised and excited". Daniel Turner in 1714 preferred to term chlorosis "the Pale or White Sickness ... since in its worst State the Complexion is rarely or ever a true Green, tho' bordering on that Hue". He went on to describe it as "an ill Habit of Body, arising either from Obstructions, particularly of the menstrual Purgation, or from a Congestion of crude Humours in the Viscera, vitiating the Ferments of the Bowels, especially those of Concoction, and placing therein a depraved Appetite of Things directly preternatural, as Chalk, Cinders, Earth, Sand, &c". One of his case studies was that of an 11-year-old girl who was found, on investigation, to have been eating large quantities of coal.[7] Chlorosis is briefly mentioned in Casanova's Histoire de ma vie: "I do not know, but we have some physicians who say that chlorosis in girls is the result of that pleasure onanism indulged in to excess". In 1841, the Bohemian doctor and pharmacist Albert Popper published a treatment for Chlorosis containing Vitriolum martis (sulfuric acid and iron) and Sal tartari (potassium carbonate) in Österreichische medicinische Wochenschrift which was republished and refined in the following years.[8][9][10][11][12] In 1845, the French writer Auguste Saint-Arroman gave a recipe for a treatment by medicinal chocolate that included iron filings in his De L'action du café, du thé et du chocolat sur la santé, et de leur influence sur l'intelligence et le moral de l'homme[13] and in 1872, French physician Armand Trousseau also advocated treatment with iron, although he still classified chlorosis as a "nervous disease".[14][15][16] In 1887, physician Sir Andrew Clark of London Hospital proposed a physiological cause for chlorosis, tying its onset to the demands placed on the bodies of adolescent girls by growth and menarche. In 1891, Frank Wedekind's play Spring Awakening referenced the disease. In 1895, University of Edinburgh pathologist Prof Ralph Stockman built upon experiments demonstrating that inorganic iron contributed to hemoglobin synthesis to show that chlorosis could be explained by a deficiency in iron brought on by loss of menstrual blood and an inadequate diet. Despite the work of Stockman and the effectiveness of iron in treating the symptoms of chlorosis, debate about its cause continued into the 1930s. A character in T. C. Boyle's The Road to Wellville suffers from chlorosis, and the narrator describes her green skin and black lips. In 1936, Arthur J. Patek and Clark W. Heath of Harvard Medical School concluded that chlorosis was identical to hypochromic anemia.[17] More recently, some people have suggested that it may have been endometriosis, but the historical descriptions cannot easily be mapped on to this condition.[18] ## Acquired forms[edit] Hypochromic anemia may be caused by vitamin B6 deficiency from a low iron intake, diminished iron absorption, or excessive iron loss. It can also be caused by infections (e.g. hookworms) or other diseases (i.e. anemia of chronic disease), therapeutic drugs, copper toxicity, and lead poisoning. One acquired form of anemia is also known as Faber's syndrome. It may also occur from severe stomach or intestinal bleeding caused by ulcers or medications such as aspirin or bleeding from hemorrhoids.[19][20] ## Hereditary forms[edit] Hypochromic anemia occurs in patients with hypochromic microcytic anemia with iron overload. The condition is autosomal recessive and is caused by mutations in the SLC11A2 gene. The condition prevents red blood cells from accessing iron in the blood, which causes anemia that is apparent at birth. It can lead to pallor, fatigue, and slow growth. The iron overload aspect of the disorder means that the iron accumulates in the liver and can cause liver impairment in adolescence or early adulthood.[21] It also occurs in patients with hereditary iron refractory iron-deficiency anemia (IRIDA). Patients with IRIDA have very low serum iron and transferrin saturation, but their serum ferritin is normal or high. The anemia is usually moderate in severity and presents later in childhood.[22] Hypochromic anemia is also caused by thalassemia and congenital disorders like Benjamin anemia.[23] ## See also[edit] * Microcytic anemia * Iron deficiency anemia * List of circulatory system conditions * List of hematologic conditions * Green children of Woolpit ## Notes[edit] 1. ^ Merritt, Brain Y. (February 12, 2014). "Medscape: Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC): Interpretation". Retrieved February 19, 2017.} 2. ^ Merritt, Brain Y. (February 12, 2014). "Medscape: Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC): Reference Range". Retrieved February 19, 2017.} 3. ^ William Shakespeare (and possibly George Wilkins). Pericles Prince of Tyre, Act 4, Scene 6: A room in the brothel. First published 1609. 4. ^ a b King, Helen (2004). The Disease of Virgins: Greensickness, chlorosis and the problems of puberty. Routledge. p. 24. 5. ^ Paster, Gail Kern (2004). Humoring the Body: Emotions and the Shakespearian Stage. University of Chicago Press. p. 89. 6. ^ 1811 Dictionary of the Vulgar Tongue by Francis Grose 7. ^ Turner, Daniel (1714). De Morbis Cutaneis: a treatise of diseases incident to the skin. London. pp. 90–91, 94. 8. ^ von Raimann, Johannes Nepomuk (17 July 1841). "Vitriolum Martis artefactum und Sal Tartari gegen Chlorosi". Österreichische Medicinische Wochenschrift. Braumüller und Seidel, Vienna. 3 (29): 676–677. 9. ^ Schmidt, Carl Christian (1842). Jahrbücher der in- und ausländischen gesammten Medicin, Volume 35. Leipzig. p. 198. 10. ^ Dierbach, Johann Heinrich (1843). Die neuesten Entdeckungen in der Materia Medica: für praktische Aerzte geordnet, Volume 2. Heidelberg. pp. 1267–1268. 11. ^ "On the Mode of prescribing and preparing Pills composed of the Sulphate of Iron and Carbonate of Potass". The Medical Times: A Journal of English and Foreign Medicine, and Miscellany of Medical Affairs. J. Angerstein Carfrae, Essex Street, Strand, London. 13: 255. 28 March 1846. 12. ^ Anton, Karl Christian (1857). Vollständiges, pathologisch geordnetes Taschenbuch der bewährtesten Heilformeln fuer innere Krankheiten:Mit einer ausfuehrlichen Gaben- und Formenlehre, so wie mit therapeutischen Einleitungen und den noethigen Bemerkungen ueber die specielle Anwendung der Recepte. Leipzig. p. 209. 13. ^ Louis E. Grivetti, "From Aphrodisiac to Health Food: A Cultural History of Chocolate" Karger Gazette 6 no. 68. 14. ^ Guggenheim, KY (1995). "Chlorosis: the rise and disappearance of a nutritional disease" (PDF). The Journal of Nutrition. 125 (7): 1822–5. doi:10.1093/jn/125.7.1822. PMID 7616296. 15. ^ Disease of Virgins; Green Sickness, Chlorosis and the Problems of Puberty by Helen King 16. ^ The appetite as a voice, by Joan Brumberg, pages. 164-165. 17. ^ Patek, Arthur J.; Heath, Clark W. (April 25, 1936). "Chlorosis". Journal of the American Medical Association. 106 (17): 1463–1466. doi:10.1001/jama.1936.02770170029010. 18. ^ Batt, Ronald (2011). A History of Endometriosis. Springer. p. 55. ISBN 9780857295859. 19. ^ Miale JB (1982). Laboratory Medicine: Hematology. (6th ed.) The CV Mosby Company, St. Louis ISBN 1-125-44734-6[page needed] 20. ^ Massey AC (1992). "Microcytic anemia. Differential diagnosis and management of iron deficiency anemia". The Medical Clinics of North America. 76 (3): 549–66. doi:10.1016/s0025-7125(16)30339-x. PMID 1578956. 21. ^ Reference, Genetics Home. "hypochromic microcytic anemia with iron overload". Genetics Home Reference. Retrieved 2016-10-29. 22. ^ Hershko, Chaim; Camaschella, Clara (2014-01-16). "How I treat unexplained refractory iron deficiency anemia". Blood. 123 (3): 326–333. doi:10.1182/blood-2013-10-512624. ISSN 0006-4971. PMID 24215034. 23. ^ "BMJ Blogs: The BMJ » Blog Archive » Jeffrey Aronson: When I use a word . . . More medical patronymics". blogs.bmj.com. Retrieved 2016-10-30. * Green sickness was mentioned in the Space: 1999 episode The Seance Spectre. ## External links[edit] * Rare Anemias Foundation * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypochromic anemia	c0002884	3,124	wikipedia	https://en.wikipedia.org/wiki/Hypochromic_anemia	2021-01-18T19:10:55	{"mesh": ["D000747"], "umls": ["C0002884"], "wikidata": ["Q2306782"]}
A number sign (#) is used with this entry because Rett syndrome (RTT) is caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2; 300005) on chromosome Xq28. See also the congenital variant of Rett syndrome (613454), which is caused by mutation in the FOXG1 gene (164874) on chromosome 14q13. Description Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (Moog et al., 2003). Clinical Features Rett (1966, 1977), a Viennese pediatrician, first described Rett syndrome after observing 2 girls who exhibited the same unusual behavior who happened to be seated next to each other in the waiting room. Hagberg et al. (1983) described 35 patients, all girls from 3 countries (France, Portugal, and Sweden), with a uniform and striking, progressive encephalopathy. After normal development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of high brain functions. Within 1.5 years, this deterioration progressed to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and 'acquired' microcephaly. Thereafter, a period of apparent stability lasted for decades. Additional neurologic abnormalities intervened insidiously, mainly spastic paraparesis, vasomotor disturbances of the lower limbs, and epilepsy. Bruck et al. (1991) described a set of monozygotic female twins with Rett syndrome. The authors noted that normal early development has generally been insisted on as an essential criterion for the diagnosis; however, twin 1 was considered to be abnormal from birth, while delay was not suspected in twin 2 until she was about 1 year old. Some regression occurred during the second year in both twins, who at age 4 years were clinically indistinguishable. A striking deceleration of growth has been found across all measurements in 85 to 94% of girls with Rett syndrome and may provide the earliest clinical indication of this disorder. Motil et al. (1994) studied dietary intake and energy production in 9 Rett syndrome girls, comparing them to 7 healthy controls. Metabolic rate while sleeping was 23% lower in Rett syndrome girls than in controls, while metabolic rates during waking hours did not differ between the 2 groups. Dietary intake and fecal fat loss were also the same. The energy balance in girls with Rett syndrome was 55 +/- 43 kcal/kg lean body mass daily; in controls, the balance was 58 +/- 22 kcal/kg lean body mass per day. Motil et al. (1994) speculated that a small difference in energy balance would be sufficient to account for the growth failure in Rett syndrome girls and may explain the greater time that the Rett syndrome girls spent in involuntary motor activity. Hagberg (1995) reviewed a Swedish series of 170 affected females, aged 2 to 52 years. The well-recognized classic phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly affected mentally retarded girls and adolescent women, were still in a minority, but constituted an expanding cohort. The presence of metatarsal and metacarpal abnormalities in some patients with Rett syndrome prompted Leonard et al. (1995) to conduct radiologic studies of 17 cases. Short fourth and/or fifth metatarsals were identified in 11 (65%), short fourth and/or fifth metacarpals in 8 of 14 (57%), and reduced bone density in the hands was found in 12 of 14 cases (86%). Leonard et al. (1999) examined hand radiographs of 100 girls with Rett syndrome, representing 73% of the known Australian population of girls with Rett syndrome, aged 20 and under. A metacarpophalangeal pattern profile was established, revealing that the shortest bone was the second metacarpal. Short distal phalanx of the thumb was seen in all age groups and in classic and atypical cases. In girls less than 15 years old, bone age was more advanced in Rett syndrome patients compared with controls (left hand p = 0.03, right hand p = 0.004), but was most advanced in the younger group. Bone age normalized with chronological age. Miyamoto et al. (1997) described 2 Japanese sisters with classic RTT. The youngest sister, aged 6 years and 6 months, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly, developed sleep-wake rhythm disturbance from age 4, and seizures from age 5 years. The elder, 7 years and 9 months old at the time of report, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm, and no seizures. The variability in the sisters stood in contrast to that in monozygotic twins with RTT who usually show little clinical difference. Sirianni et al. (1998) reported 3 affected sisters of a Brazilian family who showed rapid deceleration of head growth with subsequent progressive mental deterioration. Two surviving affected daughters, examined at ages 9 and 5.5 years, showed no purposeful hand movements, but had persistent hand stereotypes and rubbing of the torso. They had significant muscle wasting and inability to walk, and showed spontaneous episodes of hyperventilation while awake. They had a severe attention deficit and no language development, with intellectual and adaptive behavior at the 1- to 6-month level. Although the younger daughter was still able to reach for food, she was without other purposeful hand use. Leonard and Bower (1998) retrospectively studied the neonatal characteristics and early development of Australian girls with Rett syndrome. The mean weight and head circumference of newborn girls later identified as Rett patients was lower than that of the reference Australian population. Girls who had learned to walk had larger heads at birth than those who had not; girls who had never been ambulant had the smallest heads at birth. In 46.5% of girls, parents reported unusual development or behavior in the first 6 months. The authors stated that these results provided evidence that girls with Rett syndrome may not be normal at birth. They further suggested that using normal development in the first 6 months and normal neonatal head circumference as diagnostic criteria may cause missed or delayed diagnoses. ### Neuropathologic Findings Papadimitriou et al. (1988) reported light-microscopic evidence of white matter disease in the brain biopsy of a patient with Rett syndrome. Ultrastructurally, many neurons and oligodendroglia contained membrane-bound electron-dense inclusions with a distinct lamellar and granular substructure. Armstrong et al. (1995) systematically studied brains of 16 girls with Rett syndrome who ranged in age from 2 to 35 years. They found no evidence that the pyramidal neurons in Rett syndrome degenerate progressively with increasing age. Instead, they found a striking decrease in the dendritic trees of selected cortical areas, chiefly projection neurons of the motor, association, and limbic cortices. They suggested that this may result in abnormalities of trophic factors. ### Neuroradiographic Findings Horska et al. (2009) performed proton magnetic resonance spectroscopy (MRS) on 40 girls with Rett syndrome with a mean age of 6.1 years. Compared to 12 controls, Rett syndrome patients had a decreased N-acetylaspartate (NAA)/creatinine (Cr) ratio and increased myoinositol/Cr ratio with age (p = 0.03), suggestive of progressive axonal damage and astrocytosis. The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017), and NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in controls (p = 0.043), which may have been secondary to increasing glutamate/glutamine cycling at the synaptic level. The findings indicated that Rett syndrome is associated with mild white matter pathology, and suggested that MRS can provide a noninvasive measure of cerebral involvement in RTT. ### Cardiac Abnormalities Kerr et al. (1997) found an annual mortality rate in Rett syndrome of 1.2%; a high proportion (26%) of these deaths were sudden and unexplained. Sekul et al. (1994) reported prolonged QT interval in patients with Rett syndrome. Guideri et al. (1999) studied the heart rate variability and corrected QT interval in 54 females (mean age, 10 +/- 5.5 years) in various clinical stages of Rett syndrome, using continuous 12-lead ECG monitoring for 10 minutes in the supine position. The total power spectrum of heart rate variability (from 0.03 to 0.4 Hz), mainly its low frequency (LF) and high frequency (HF) components, was significantly lower in children with Rett syndrome compared with that in controls. The sympathovagal balance, expressed by the ratio LF/HF, was significantly higher in patients, reflecting the prevalence of sympathetic activity. The RR interval was significantly shorter and the corrected QT interval longer in the patient group than in the control group. The authors suggested that in children with Rett syndrome, loss of physiologic heart rate variability associated with an increase of adrenergic tone, represents the electrophysiologic basis of cardiac instability and sudden death. Ellaway et al. (1999) determined the prevalence of QT prolongation in a cohort of 34 Australian patients. Nine patients had significantly longer corrected QT values than a group of healthy, age-matched controls. There was no apparent correlation between the presence of QT prolongation and phenotypic severity. The authors concluded that QT prolongation should be considered in all patients with Rett syndrome. ### Zappella Variant De Bona et al. (2000) stated that preserved speech variant (PSV) Rett syndrome shares with classic Rett syndrome the same course and the stereotypic hand-washing activities, but differs in that patients typically recover some degree of speech and hand use, and usually do not show growth failure. Progressive scoliosis, epilepsy, and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. The authors reported mutations in the MECP2 gene in both classic and PSV Rett syndrome (see 300005.0012), establishing that the 2 forms are allelic disorders. Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with preserved speech variant Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. Renieri et al. (2009) presented a detailed evaluation of 29 patients with Zappella variant, also known as preserved speech variant, Rett syndrome. All 29 patients had mutation in the MECP2 gene, of which 28 were missense (see, e.g., R133C; 312750.0001) or late truncating mutations. There was great variability with respect to language, manual abilities, and somatic features, allowing for further statistical subdivision into low, intermediate, and high functioning. In general, patients with Zappella variant Rett syndrome had less microcephaly, later onset of regression, a tendency to be overweight, better hand use, and better speech acquisition compared to patients with classic Rett syndrome. The majority (76%) of patients with Zappella variant had autistic features. Diagnostic criteria was presented. Renieri et al. (2009) proposed the term 'Zappella variant' rather than 'preserved speech variant' to described milder forms of Rett syndrome because other aspects besides speech are involved. Adegbola et al. (2009) reported a 10-year-old girl who had slowing of motor skills and hypotonia at age 12 months. She had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, and had mild autistic features. EEG showed multifocal spike and wave discharges without overt seizures. Full-scale IQ was 70 at age 6 years and 58 at age 8 years. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. His behavioral difficulties improved with age. Both father and daughter were found to have a mutation in the MECP2 gene (300005.0036), that resulted in decreased, but not absent MECP2 function. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. ### Affected Males Coleman (1990) reported a possible case of Rett syndrome in a male, and Philippart (1990) reported 2 such cases. Schwartzman et al. (1999) described a male patient with Rett syndrome and the 47,XXY karyotype of Klinefelter syndrome. The propositus showed normal development until age 8 months. At that time, he sat without support, played normally, and was able to grasp objects and to put food into his mouth. He had started to say some words comprehensibly. At age 11 months, it was noted that he had lost purposeful hand movements and language skills. He also began to show regression in social contact. At age 1 year, he began to show stereotypic hand movements, bruxism, and constipation. At age 28 months, he presented severe global retardation and slight diffuse hypotonia. At the time of the last observation, at age 37 months, loss of purposeful hand movements, manual apraxia, and slight global hypotonia were persistent. The clinical and laboratory findings did not overlap with any described for Klinefelter syndrome. DNA studies indicated that the additional sex chromosome was paternal in origin, i.e., that the nondisjunction occurred in the paternal first meiotic division. Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010) leading to a progressive but nonfatal neurodevelopmental disorder. The patient was a normal-sized product of a full-term gestation. He was a placid baby who never crawled, but walked at 15 months and learned to say some single words in the second year of life. At around 2 years of age, he lost interest in his surroundings and lost his speech. At age 3 years, he began to have generalized seizures, and magnetic resonance imaging (MRI) revealed atrophy of the brainstem and frontal and temporal lobes. Electroencephalography (EEG) showed excessive slow-wave activity during sleep and a relative poverty of rhythmic activity while awake. At 6 years of age, he had a thoracic scoliosis and poor lower-limb musculature, and he walked with an ataxic gait. He had abnormal muscle tone with rigidity of the limbs and truncal hypotonia. His feet were small, blue, and puffy. His hand use was very limited, but there were no obvious hand-wringing movements. Maiwald et al. (2002) reported a 46,XX male with Rett syndrome caused by mutation in the MECP2 gene (300005.0026). Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in a sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. The authors noted that similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY). Topcu et al. (2002) reported a boy with features of classic Rett syndrome who was a somatic mosaic for a mutation in the MECP2 gene (300005.0005). He had normal psychomotor development through the first 6 months. Loss of acquired purposeful hand skills began around 11 months, and stereotypic hand movements became apparent at 15 months. He never crawled or walked and had never spoken. On examination at 12 years of age he was microcephalic with stereotypic hand movements, tremors, and apraxia. He had a thoracic scoliosis and poor lower limb musculature, small and cold hands and feet, hypospadias, and cryptorchidism. Electroencephalography showed an excess of slow wave activity and paroxysmal sharp theta wave activity prominent on wake recordings of frontal regions. ### Atypical Rett Syndrome Molecular analysis has allowed the broadening of the phenotype of MECP2 mutations beyond RTT to include girls who have mild mental retardation, autism, and a phenotype resembling Angelman syndrome (105830), as well as males with severe encephalopathy. Heilstedt et al. (2002) reported a girl with a phenotype of atypical RTT who had a heterozygous mutation in the MECP2 gene (300005.0016). She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports of RTT. The mother did not carry an MECP2 mutation. Watson et al. (2001) identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of Angelman-like phenotype and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like. Imessaoudene et al. (2001) identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (601623). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (300005.0023). Diagnosis Hagberg and Skjeldal (1994) suggested a model of inclusion and exclusion criteria for the diagnosis of Rett syndrome that relaxed the international criteria originally drawn up in Vienna in September 1984. The new model permitted the diagnosis of forme frustes, cases with late regression, and congenital variants. Hagberg et al. (2002) provided an updated diagnostic criteria. Neul et al. (2010) provided revised diagnostic criteria for Rett syndrome and emphasized that it remains a clinical diagnosis, since not all Rett patients have MECP2 mutations and not all patients with MECP2 mutations have Rett syndrome. The most important feature for classic Rett syndrome is a period of clear developmental regression followed by limited recovery or stabilization. Other main criteria include loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements. Although deceleration of head growth is a supportive feature, it is no longer necessary for diagnosis. Exclusion criteria include other primary causes of neurologic dysfunction and abnormal psychomotor development in the first 6 months of life. Criteria for variant or atypical forms of Rett syndrome were also presented. Percy et al. (2010) validated the revised diagnostic criteria provided by Neul et al. (2010) in an analysis of 819 patients enrolled in a natural history study of Rett syndrome. Of the 819 patients, 765 females fulfilled 2002 criteria (Hagberg et al., 2002) for classic (85.4%) or variant (14.6%) Rett syndrome. All those classified as having classic Rett syndrome fulfilled the revised main criteria, and all those with variant Rett syndrome met 3 of 6 main criteria in the 2002 classification, 2 or 4 main criteria in the revised system, and 5 of 11 supportive criteria in both. See early infantile epileptic encephalopathy-2 (EIEE2; 300672) for discussion of a Rett syndrome-like phenotype caused by mutation in the CDKL5 gene (300203). ### Prenatal Diagnosis As pointed out by Amir et al. (1999), the discovery of MECP2 as the gene responsible for Rett syndrome enabled testing for early diagnosis and prenatal detection. In addition, the finding that epigenetic regulation has a role in the pathogenesis of RTT opened possible opportunities for therapy. Amir et al. (1999) suggested that partial loss of function of MECP2 may decrease transcriptional repression of some genes. The relatively normal development during the first 6 to 18 months of life may allow for presymptomatic therapeutic intervention, especially if newborn screening programs can identify affected females. Inheritance Schanen et al. (1997) stated that familial recurrences of Rett syndrome comprise only approximately 1% of the total reported cases; the vast majority of cases are sporadic. However, it is the familial cases that are key for understanding the genetic basis of the disorder. Hagberg et al. (1983) suggested that the exclusive involvement of females is best explained by X-linked dominant inheritance with lethality in the hemizygous males. Tariverdian et al. (1987) and Tariverdian (1990) reported 5-year-old monozygotic Turkish female twins concordant for Rett syndrome, suggesting a genetic cause of RTT. Partington (1988) described affected monozygotic twin sisters. Buhler et al. (1990) pointed to the existence of about 10 familial cases of Rett syndrome and to an elevated parental consanguinity rate of 2.4%. They suggested a model involving autosomal modifying genes that function as a suppressor in relation to an X-chromosomal mutation causing Rett syndrome. Zoghbi et al. (1990) reviewed familial instances including 6 pairs of concordantly affected monozygotic twins; 4 families with 2 affected sisters; and 2 families with 2 affected half sisters. The affected half sisters had the same mother. Anvret et al. (1990) described Rett syndrome in 2 generations of a family. The index case was a 12-year-old girl with classic Rett syndrome; her maternal aunt, aged 44 years, had mild Rett syndrome. Studies with X-linked DNA markers detected no deletions. Martinho et al. (1990), in agreement with others, found no increase in parental age or in spontaneous abortion rates among the mothers of affected children and found a normal sex ratio among sibs. They found no chromosome rearrangements and no correlation between the fragile site at Xp22 and Rett syndrome. In 2 isolated cases of RTT, Benedetti et al. (1992) excluded both maternal uniparental heterodisomy and isodisomy. Webb et al. (1993) likewise excluded unilateral parental disomy through study of the locus DXS255 using the probe M27-beta; all informative probands had inherited an allele from each of their parents. Akesson et al. (1992) presented genealogic data on 77 Swedish females with Rett syndrome suggesting that there is a genetic component in transmission of the disorder. In most cases, ancestry was traced back to 1720-1750. Common ancestry was seen in 2 pairs of females with Rett syndrome. In 39 of the 77 cases, it was possible to trace ancestry to 9 small and separate rural areas, and 17 pairs even originated from the same farm or small group of dwellings. The common origin was found equally often among descendants of the father as of the mother, and there was a raised rate of consanguineous marriages. In what they referred to as 'an a priori test of the first study,' Akesson et al. (1995) examined an additional 20 Rett syndrome females who were consecutively traced. Of these, 10 of 19 (53%) originated from the earlier defined 'Rett areas,' and 11 of 19 (58%) could be traced to the same homestead. In 2 clusters, each consisting of 3 Rett syndrome females, all 6 subjects were descendants of the same 2 couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4 of 37), compared to 1% in the general Swedish population. The authors considered the findings a confirmation of the first study, and postulated that transmission starting with a premutation may result in a full mutation over generations, most likely if the parents have the premutation in homozygous form. A genealogic study of 32 Swedish patients with atypical Rett syndrome led Akesson et al. (1996) to conclude that most atypical cases are variants of classic Rett syndrome. Eleven persons (34%) were traced to a small number of parishes in areas in which classic patients had been found. In 4 cases, typical and atypical Rett syndrome patients were found in the same pedigree. The authors proposed a 2-gene model, including one autosomal and one X-linked gene, to explain the genetics of this disorder. In a follow-up study looking for mutations of the MECP2 gene in 3 clusters and 2 pedigrees chosen at random in Sweden, Xiang et al. (2002) could not demonstrate that patients with Rett syndrome from the same cluster area share a common genetic defect. All of the identified mutations in the MECP2 gene were de novo and not premutations such as trinucleotide expansion. Recurrence of cases with the syndrome present in Rett clusters appeared to be the result of independent mutational events. Thomas (1996) suggested that the exclusive occurrence of RTT in females, without evidence of male lethality, can be explained by de novo X-linked mutations occurring exclusively in male germ cells that result in affected daughters. Thus, he suggested that it is the high male:female de novo germline mutation rate that explains the absence of affected males in Rett syndrome. Villard et al. (2001) identified a mutation in the MECP2 gene in only 1 of 5 families with RTT, suggesting an alternative molecular basis for the phenotype in the other 4 familial cases. X-chromosome inactivation studies showed that all the mothers and 6 of 8 affected girls had a totally skewed pattern of X inactivation, whereas only 9% of 43 sporadic RTT females had a skewed pattern of X inactivation, and all of their mothers had random X inactivation. In the familial cases, it was the paternal X chromosome that was active. Genotype analysis suggested that the skewed X-inactivation phenotype was due to a locus in the region between markers at DXS1068 and DXS1024, although the lod score for this analysis was not significant. The results suggested that the 2 traits, completely skewed X inactivation and RTT, are not linked. Villard et al. (2001) proposed that familial Rett syndrome transmission is due to 2 traits being inherited: an X-linked locus abnormally escaping X inactivation, and the presence of a skewed X inactivation in carrier women. Rosenberg et al. (2001) reported a female patient with Rett syndrome and 46,X,r(X) karyotype. The X-derived marker was about one-tenth the size of a normal X chromosome, with FISH analysis showing that the breakpoint on Xq was proximal to the MECP2 gene. X-inactivation studies demonstrated that the normal X chromosome was active and the ring X chromosome inactive in all cells examined. Methylation studies showed that the ring X was of paternal origin. No mutation was found in the MECP2 gene after sequencing of the whole coding region. The authors proposed a model invoking a second X-linked gene for RTT. Given the model, the second putative RTT gene could account for the minority of sporadic and the majority of familial cases that are negative for MECP2 mutations. To manifest as RTT, the disease allele would have to be expressed in a majority of cells, i.e., be associated with skewing of X inactivation as in cases of X-chromosome rearrangements. Gill et al. (2003) studied 11 families in each of which 2 females were thought to have Rett syndrome. In 1 family, an identical MECP2 mutation was found in 2 affected sisters and their healthy mother. In 5 families, an MECP2 mutation was found in 1 affected female but not in the other, possibly affected female. In 5 families, no MECP2 mutation was found. Gill et al. (2003) concluded that Rett syndrome is only rarely familial and that if girls with Rett syndrome who have MECP2 mutations have sisters with developmental difficulties, the disorder in the sisters is more likely to have a separate cause. Evans et al. (2006) reported a family in which 2 half sisters with the same father were found to have Rett syndrome caused by the same mutation in the MECP2 gene. Genetic analysis detected the mutation in approximately 5% of the father's sperm, but not in his buccal or lymphocyte DNA, indicating paternal germline mosaicism. Venancio et al. (2007) reported a rare familial case of Rett syndrome due to maternal germline mosaicism. A mutation in the MECP2 gene was identified in a girl with classic Rett syndrome and in her brother, who had severe congenital encephalopathy. The mutation was absent in DNA extracted from the blood of both parents. ### X-Inactivation Studies In the unaffected mother of 2 affected half sisters, Zoghbi et al. (1990) found nonrandom X-chromosome inactivation in leukocyte DNA. They also found an increased incidence of nonrandom X inactivation in sporadic RTT patients (36%), as compared to healthy controls (8%). Kormann-Bortolotto et al. (1992) found no abnormality of the X chromosome in 9 girls with Rett syndrome or the 6 mothers who were studied. X-inactivation studies suggested that there 'may be an alteration in the timing of the X-inactivation process in the region Xp11.3 or 4-Xp21' in patients with RTT. Camus et al. (1996) studied X-chromosome inactivation in 30 girls with Rett syndrome, in 30 control girls, 8 sisters, and their mothers. There was a significant increased frequency of partial paternal X inactivation (more than 65%) in lymphocytes from 16 of 30 RTT patients compared with 4 of 30 controls (P = 0.001). These results did not support the hypothesis of a monogenic X-linked mutation, but the authors suggested that there may be a complex secondary role played by X-inactivation in this disorder. In a family with recurrence of Rett syndrome in a maternal aunt and niece, Schanen et al. (1997) and Schanen and Francke (1998) found skewing of the X-chromosome inactivation pattern in the obligatory carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the X-inactivation pattern in the mother of affected half sisters showed random X-inactivation, suggesting germline mosaicism as the cause of repeated transmission in that family. There was an affected male in the family, who was a maternal half brother of the affected niece, also suggesting germline mosaicism in the mother. Brown (1997) noted that males who carry a Rett mutation may survive. The identification of such cases in sibships with diagnosed RTT females requires a carrier mother who either is a germline mosaic or has a favorably skewed X-inactivation pattern. Mapping On the basis of a girl with Rett syndrome and a translocation t(X;22)(p11.22;p11), Journel et al. (1990) suggested that the gene for this disorder may be located on the short arm of the X chromosome. The same translocation was present in her unaffected mother and in her sister, who was affected with a neurologic disorder compatible with a forme fruste of Rett syndrome. In the course of a systematic high-resolution chromosome analysis on 28 patients with Rett syndrome, Zoghbi et al. (1990) found a patient with a de novo balanced translocation t(X;3)(p22.1;q13.31). Zoghbi et al. (1990) noted, however, that the Rett syndrome locus may map to a different location on the X chromosome than the breakpoint, as has occurred in incontinentia pigmenti (308300). Archidiacono et al. (1991) studied the unaffected mother of 2 half sisters with Rett syndrome for evidence of germinal mosaicism. The analysis of 34 X-linked RFLPs in these 2 affected females and in their unaffected mother and half brother, together with the reconstruction of phase for 15 informative RFLPs in somatic cell hybrids retaining a single X chromosome from each female, made it possible to exclude some regions of the X chromosome as sites of the mutation causing the disorder. The 2 regions with X chromosome breakpoints found in RTT patients with X-autosome translocations, Xp22.11 (Zoghbi et al., 1990) and Xp11.22 (Journel et al., 1990), were not excluded as the localization of the RTT gene. In 2 families with maternally related, affected half sisters, Ellison et al. (1992) performed genotypic analysis using 63 DNA markers from the X chromosome. In at least 1 of the 2 families, 36 markers were informative, and 25 markers were informative in both families. On the basis of discordance for maternal alleles in the half sisters, they excluded 20 loci as candidates for the Rett syndrome gene. Using the exclusion criterion of a lod score less than -2, they excluded the region from Xp21.2 to Xq21-q23. Curtis et al. (1993) did linkage studies in 4 families, each with 2 individuals affected by Rett syndrome. In 2 of the families, X-linked dominant inheritance of the RTT defect from a germinally mosaic mother could be assumed. Using maternal X chromosome markers showing discordant inheritance they excluded much of Xp, including 3 candidate genes, OTC (311250), synapsin I (SYN1; 313440), and synaptophysin (313475). Although most of the long arm was inherited in common, it was possible to exclude a centromeric region. Curtis et al. (1993) also presented information on 2 families with affected aunt-niece pairs. To determine which regions of the X chromosome were inherited concordantly and discordantly in an affected maternal aunt and niece, Schanen et al. (1997) genotyped the individuals in the aunt-niece family and 2 previously reported pairs of half sisters. The combined exclusion mapping data allowed exclusion of the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. In a family with 3 affected individuals, including a male, Schanen and Francke (1998) compared haplotypes to narrow the RTT candidate region to a small interval on Xp and the distal long arm. The authors noted that identification of a severely affected male in a family with recurrent classic Rett syndrome strengthened the hypothesis that RTT is caused by an X-linked gene. Xiang et al. (1998) presented haplotype analysis of 9 families with at least 2 closely related females affected by classic Rett syndrome. They concluded that the Rett syndrome locus is likely to lie within Xq28, close to marker DXS15. Xiang et al. (1998) suggested that the GABRE (300093) and GABRA3 (305660) genes are candidate genes for Rett syndrome. Webb et al. (1998) presented a study of 6 families with more than 1 female affected with Rett syndrome. They showed weak linkage to loci in Xq28, with a maximum lod score of 1.935 at theta = 0.0 at DXYS154. Webb et al. (1998) also noted the presence of the candidate genes GABRA3 and L1CAM (308840) in this region, but cautioned that their lod scores did not quite reach significance. Sirianni et al. (1998) presented information that they interpreted as confirming X-linked dominant inheritance of Rett syndrome. They described a family with the largest number (3) of female sibs affected with Rett syndrome identified to that time, and used data from this family, as well as from families previously described, to demonstrate the mode of inheritance and to localize the gene to Xq28. Concordance analysis with DNA markers showed that only Xq28 was shared among the 3 affected girls, whereas the same region was not shared with the unaffected sisters. The data complemented the exclusion-mapping data described by Xiang et al. (1998) who could not exclude the distal region of the long arm of the X chromosome. In a Brazilian family, Sirianni et al. (1998) found that the mother had extreme skewing of X inactivation with the unaffected X active in 95% of cells. Thus, the finding of highly skewed X inactivation in the mother, with preferential use of the unaffected X chromosome, strongly suggested that she was a nonpenetrant carrier of Rett syndrome. An unaffected daughter and an affected daughter did not show the skewed X inactivation. Molecular Genetics ### Exclusion of Linked Genes Ferlini et al. (1990) excluded the synapsin I gene as the cause of RTT. Narayanan et al. (1998) excluded the M6b gene (300051), Wan and Francke (1998) excluded glutamate dehydrogenase-2 (GLUD2; 300144) and Rab GDP-dissociation inhibitor GDI1 (300104), which were chosen because of their location in the nonexcluded region of Xq. Heidary et al. (1998) excluded the gastrin-releasing peptide receptor gene (GRPR; 305670), Cummings et al. (1998) excluded the glycine receptor alpha-2 subunit gene (GLRA2; 305990), and Van den Veyver et al. (1998) excluded the holocytochrome c-type synthetase gene (HCCS; 300056), all of which had been candidate genes for Rett syndrome because they mapped to a region on Xp. ### Mutations in the MECP2 Gene In 5 of 21 sporadic patients with RTT, Amir et al. (1999) identified 3 de novo missense mutations in the MECP2 gene (300005.0001, 300005.0002, 300005.0007). Among 8 cases of familial Rett syndrome, Amir et al. (1999) found an additional missense mutation (300005.0008) in a family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for the mutation. The authors suggested that abnormal epigenetic regulation may be a mechanism underlying the pathogenesis of Rett syndrome. Wan et al. (1999) identified 5 additional mutations in the MECP2 gene (see, e.g., 300005.0003) in patients with RTT. They found that the mutations were de novo, and that female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Villard et al. (2000) reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy. The affected girl and one brother tested showed a mutation in the MECP2 gene (300005.0007). The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months. Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with the preserved speech variant form of Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared. Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010), leading to a progressive but nonfatal neurodevelopmental disorder. In an affected boy, Topcu et al. (2002) identified an R270X mutation (300005.0005) along with the wildtype allele. The authors speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. Bourdon et al. (2001) reported somatic mosaicism for deletions of the MECP2 gene in 2 girls, 1 with a classic Rett phenotype and 1 with an atypical Rett phenotype without a period of regression. The deletions in these girls were detected not by sequence analysis but by CSGE or DGGE. Bourdon et al. (2001) suggested that this had implications for diagnostic methods used in Rett cases and cases of possible Rett syndrome. Mnatzakanian et al. (2004) identified a theretofore unknown isoform of MECP2 that they called MECP2B, which utilizes exon 1 and exons 3 and 4, skipping exon 2. They screened 19 girls with typical Rett syndrome in whom no mutations had been found in exons 2, 3, or 4. In 1 affected individual, they identified a deletion of 11 basepairs in exon 1 (300005.0028). Ravn et al. (2005) identified a mutation in exon 1 of the MECP2 gene (300005.0029) in a patient with typical Rett syndrome. Ravn et al. (2005) emphasized the importance of mutation screening of MECP2 exon 1. Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). Using multiplex ligation-dependent probe amplification (MLPA), Hardwick et al. (2007) identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size. Saunders et al. (2009) identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 are important in the etiology of RTT. ### Disruption of the NTNG1 Gene Borg et al. (2005) reported a girl with characteristic features of Rett syndrome who had no mutations in MECP2 or CDKL5 but carried a de novo balanced translocation, t(1;7)(p13.3;q31.3). No known gene was disrupted by the chromosome 7 breakpoint, but the chromosome 1 breakpoint was located within intron 6 of the NTNG1 gene (608818) and affected alternatively spliced transcripts. Borg et al. (2005) suggested that NTNG1 is a candidate disease gene for RTT. Archer et al. (2006) failed to identify any pathogenic mutations in coding exons of the NTNG1 gene among 115 patients with Rett syndrome. ### Associations Pending Confirmation For a discussion of a possible association between Rett syndrome and variation in the JMJD1C gene, see 604503.0001. Genotype/Phenotype Correlations Zappella et al. (2001) noted that all MECP2 mutations found in PSV patients have been either missense or late truncating mutations. In particular, the 4 early truncating hotspot mutations, R168X (300005.0020), R255X (300005.0021), R270X (300005.0005), and R294X (300005.0011), have not been found in PSV patients. These results suggested that early truncating mutations lead to a poor prognosis (classic Rett), whereas late truncating missense mutations lead either to classic Rett or to PSV. Smeets et al. (2003) reported on 30 adolescent and adult females with classic or atypical Rett syndrome, of whom 24 had an MECP2 mutation. Mutations were found in all of the classic cases and in 64% of the variant cases. No correlation was found between skewing and milder phenotype. Early truncating mutations were associated with a more severe course of the disorder. A deletion hotspot in the C-terminal segment was predominantly characterized by rapid progressive neurogenic scoliosis. The R133C mutation (300005.0001) was associated with a predominantly autistic presentation, whereas the R306C mutation (300005.0016) was associated with a slower disease progression. Smeets et al. (2005) described the long-term history of 10 females with a deletion in the C terminus of the MECP2 gene. Although their disease appeared 'classic' at an older age, in the beginning their symptoms resembled the forme fruste described by Hagberg and Skjeldal (1994). All had a more slowly progressive course with better-preserved cognitive functions in adolescence and adulthood. Their primary clinical problems were a gradual decline in gross motor ability despite preventive measures and a rapidly progressive spine deformation due to marked dystonia present from childhood. Hammer et al. (2003) reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo MECP2 mutation (L100V; 300005.0027). The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. Hammer et al. (2003) suggested that the patient illustrated the importance of allele dosage on phenotypic presentation. Weaving et al. (2003) reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain (MBD) tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. Weaving et al. (2003) concluded that it is likely that X inactivation modulates the phenotype in RTT. In a study of genotype/phenotype correlations, Schanen et al. (2004) analyzed 85 Rett syndrome patients with mutation in the MECP2 gene. Sixty-five (76%) carried 1 of the 8 common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the MBD and the TRD. However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation (300005.0016), including better overall score, later regression, and better language with less motor impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups In 524 females with Rett syndrome and an identified MECP2 mutation, Jian et al. (2005) prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations. Survival among cases with the R270X (300005.0005) mutation was reduced compared to all the other mutations (p = 0.01). Jian et al. (2005) concluded that this might explain the apparent underrepresentation of R270X in older subjects with Rett syndrome in 2 published reports of the MECP2 mutation spectrum (Smeets et al., 2003 and Schanen et al., 2004). Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). The phenotype of both girls was more severe than that of 2 additional unrelated girls with Rett syndrome caused by MECP2 mutations not affecting exon 1. The authors speculated that MECP2 mutations involving exon 1 result in a more severe phenotype because MECP2B is more abundantly expressed in the brain than MECP2A. Among 110 patients with Rett syndrome in whom an MECP2 mutation was not identified, Archer et al. (2006) used dosage analysis to detect large deletions in 37.8% (14 of 37) patients with classic Rett syndrome and 7.5% (4 of 53) patients with atypical Rett syndrome. Most large deletions contained a breakpoint in the deletion prone region of exon 4. Five patients with large MECP2 deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations. Robertson et al. (2006) compared the behavioral profile of cases in the Australian Rett Syndrome Database with those of a British study using the Rett Syndrome Behavioral Questionnaire (Mount et al., 2002). Behavioral patterns were compared to MECP2 gene findings in the probands. Fear/anxiety was more commonly reported in those individuals with R133C and R306C. R294X was more likely to be associated with mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. Hand behaviors were more commonly reported in those with R270X or R255X. Huppke et al. (2006) reported 3 unrelated girls with very mild forms of Rett syndrome due to mutations in the MECP2 gene and skewed X inactivation (X-inactivation ratios of 84:16, 95:5, and 76:24, respectively). All 3 patients had normal hand function, communicated well, and showed hyperventilation only under stress; only 2 patients had a subtle history of developmental regression. None of the patients met the established diagnostic criteria for classic Rett syndrome. The findings indicated that X-inactivation patterns can influence the phenotypic severity of Rett syndrome. Pathogenesis Hendrich and Bickmore (2001) reviewed human disorders that share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome, Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome (303600). In rodent brain tissue, Deng et al. (2007) identified the FXYD1 (602359) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome. Marchetto et al. (2010) generated neurons with RTT-associated MECP2 mutations from induced pluripotent stem cells derived from fibroblasts isolated from patients with Rett syndrome. These cells were able to undergo X inactivation and generate functional neurons. Studies of these neurons in culture showed fewer synapses, reduced spine density, and small soma size compared to controls. In addition, these cells showed altered calcium signaling and electrophysiologic defects, particularly affecting glutamate signaling, compared to controls. The findings demonstrated that human RTT neurons have early developmental defects. Pharmacologic treatment of these cells with IGF1 (147440) and gentamicin, which causes read-through of nonsense mutations, showed some promising results. Muotri et al. (2010) showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Muotri et al. (2010) concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Population Genetics Hagberg (1985) estimated the frequency of Rett syndrome to be about 1 in 15,000 in southwestern Sweden. Among girls aged 0 to 18 years in North Dakota, Burd et al. (1991) found the frequency of Rett syndrome to be 1 in 19,786. Miyamoto et al. (1997) quoted data suggesting that Rett syndrome has a frequency of 1 in 20,000 girls in metropolitan Tokyo. History Zimprich et al. (2006) provided a historical perspective of the work of Andreas Rett (1924-1997), a pediatric neurologist and social reformer in postwar Austria, who first described Rett syndrome. Because of the progressive character of the disease and occasional reports of elevated blood and CSF lactate, it has been suggested that Rett syndrome may be a mitochondrial disorder. Lappalainen and Riikonen (1994) assessed the acid-base balance CSF and blood lactate from 8 girls with Rett syndrome. Only the 3 patients with severe hyperventilation had elevated CSF lactate values. The authors suggested that elevation of CSF lactate is secondary to the intensive hyperventilation in alkalosis rather than a sign of any mitochondriopathy. Animal Model Shahbazian et al. (2002) generated mice expressing a truncated Mecp2 protein similar to those found in RTT patients. The mutant mice exhibited normal motor function for approximately 6 weeks, but then developed a progressive neurologic disease that included many features of RTT: tremors, motor impairments, hypoactivity, increased anxiety-related behavior, seizures, kyphosis, and stereotypic forelimb motions. Shahbazian et al. (2002) showed that although the truncated Mecp2 protein in these mice localized normally to heterochromatic domains in vivo, histone H3 (142780) was hyperacetylated. They presented this as evidence that, in this mouse model of RTT, the chromatin architecture is abnormal and gene expression may be misregulated. Moretti et al. (2005) studied home cage behavior and social interactions in a mouse model of Rett syndrome. Young adult mutant mice showed abnormal home cage diurnal activity in the absence of motor skill deficits. Mutant mice showed deficits in nest building, decreased nest use, and impaired social interaction. They also took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. Abnormalities of diurnal activity and social behavior in Mecp2-mutant mice were reminiscent of the sleep/wake dysfunction and autistic features of RTT. Moretti et al. (2005) suggested that MECP2 may regulate expression and/or function of genes involved in social behavior. Using cDNA microarrays, Nuber et al. (2005) found that Mecp2-null mice differentially expressed several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for SGK1 (602958) and FK506-binding protein-51 (FKBP5; 602623) were observed before and after onset of neurologic symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 binds to Fkbp5 and Sgk1 in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, Nuber et al. (2005) proposed that disruption of MeCP2-dependent regulation of stress-responsive genes may contribute to the symptoms of Rett syndrome. Chao et al. (2010) generated mice lacking Mecp2 from GABA-releasing neurons, designated Viaat-Mecp2(-/y), and showed that they recapitulate numerous Rett syndrome and autistic features, including repetitive behaviors. Viaat-Mecp2(-/y) mice were indistinguishable from controls until approximately 5 weeks of age, when they began to exhibit repetitive behavior such as forelimb stereotypies reminiscent of midline hand-wringing that characterizes Rett syndrome and hindlimb clasping. Viaat-Mecp2(-/y) mice spent 300% more time grooming than wildtype mice, leading to fur loss and epidermal lesions in group- and single-housed mice. Viaat-Mecp2(-/y) mice showed progressive motor dysfunction. The mice also developed motor weakness and by 12 weeks showed a trend toward reduced activity, becoming clearly hypoactive by 19 weeks. MeCP2 deficiency in GABAergic neurons also impaired hippocampal learning and memory. Roughly one-half of Viaat-Mecp2(-/y) mice died by 26 weeks of age after a period of marked weight loss. Coinciding with the weight loss, mice developed severe respiratory dysfunction. Next, Chao et al. (2010) generated male conditional deletion mice, designed Dlx5/6-Mecp2(-/y), missing MeCP2 from a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition. In contrast to Viaat-Mecp2(-/y) mice, Dlx5/6-Mecp2(-/y) mice survived at least 80 weeks without apparent alterations in respiratory function. MeCP2-deficient GABAergic neurons showed reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase-1 (GAD1; 605363) and -2 (GAD2; 138275) levels. Chao et al. (2010) concluded that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. Lioy et al. (2011) showed that in globally Mecp2-deficient mice, reexpression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged life span compared to globally null mice. Furthermore, restoration of Mecp2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Lioy et al. (2011) concluded their study showed that glia, like neurons, are integral components of the neuropathology of Rett syndrome, and supported the targeting of glia as a strategy for improving the associated symptoms. Derecki et al. (2012) examined the role of microglia in a murine model of Rett syndrome and showed that transplantation of wildtype bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype and arrest of disease development. However, when cranial irradiation was blocked by lead shield and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wildtype Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: life span was increased, breathing patterns were normalized, apneas were reduced, body weight was increased to near that of wildtype, and locomotor activity was improved. Mecp2 +/- females also showed significant improvements as a result of wildtype microglial engraftment. These benefits mediated by wildtype microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V (131230) to block phosphatidylserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. Derecki et al. (2012) concluded that their results suggested the importance of microglial activity in Rett syndrome, implicated microglia as major players in the pathophysiology of Rett syndrome, and suggested bone marrow transplantation as a possible therapy. Hao et al. (2015) studied the effects of forniceal deep brain stimulation (DBS) in a well-characterized mouse model of Rett syndrome (RTT), and showed that it rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation and hippocampal neurogenesis. The authors concluded that forniceal DBS might mitigate cognitive dysfunction in RTT. INHERITANCE \- X-linked dominant GROWTH Height \- Short stature Weight \- Cachexia HEAD & NECK Head \- Normal birth head circumference \- Deceleration of head growth \- Microcephaly Teeth \- Bruxism CARDIOVASCULAR Heart \- Prolonged QTc interval \- T-wave abnormalities RESPIRATORY \- Periodic apnea while awake \- Intermittent hyperventilation \- Breath holding ABDOMEN Gastrointestinal \- Constipation \- Gastroesophageal reflux SKELETAL Spine \- Scoliosis \- Kyphosis Feet \- Small feet \- Cold feet \- Vasomotor disturbance MUSCLE, SOFT TISSUES \- Muscle wasting NEUROLOGIC Central Nervous System \- Normal development until 6-18 months \- Mental retardation, profound \- Spasticity \- EEG abnormalities - slow waking background, intermittent rhythmical slowing (3-5Hz), epileptiform discharges \- Seizures \- Reduction or loss of acquired skills (e.g., purposeful hand use, speech) \- Gait ataxia \- Gait apraxia \- Truncal ataxia \- Dystonia \- Cortical atrophy (frontal area) Behavioral Psychiatric Manifestations \- Autistic behaviors \- Hand stereotypies (e.g., hand wringing) \- Sleep disturbance \- Bruxism \- Breath holding MISCELLANEOUS \- Prevalence 1/10,000-1/15,000 female births \- Initially normal for first 6-18 months which is then followed by withdrawal and regression \- Four clinical stages - Stage I, early onset stagnation (onset 6 months-1.5 year) \- Stage II, rapid developmental regression (onset 1-4 years) \- Stage III, pseudostationary period (onset 2-10 years) \- Stage IV, late motor deterioration (when ambulation ceases) \- Most cases are sporadic \- De novo mutations occur almost exclusively on the paternally derived X chromosome MOLECULAR BASIS \- Caused by mutation in the methyl-CpG-binding protein-2 gene (MECP2, 300005.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RETT SYNDROME	c2748910	3,125	omim	https://www.omim.org/entry/312750	2019-09-22T16:17:18	{"doid": ["1206"], "mesh": ["C567576"], "omim": ["312750"], "icd-10": ["F84.2"], "orphanet": ["3095", "778"], "synonyms": ["Alternative titles", "RTS", "AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE"]}
A congenital malformation syndrome characterized by mandibulofacial dystosis (malar hypoplasia, micrognathia, external ear malformations) and variable preaxial limb defects. ## Epidemiology The prevalence is unknown; more than 100 cases of NAFD have been published. ## Clinical description NAFD is characterized by mandibulofacial anomalies that include downward slant of palpebral fissures, ptosis of upper lids, coloboma of lower lids, deficiency of eyelashes of the medial one-third to two-thirds of the lower eyelids, hypoplasia of the malar eminences, hypoplasia of the maxilla, cleft palate, absence or hypopoplasia of the palatal velum, choanal atresia, extension of a ''tongue'' of temporal hair down the sides of the cheeks. Cleft lip is rare. Limb defects are predominantly preaxial with hypoplasia or absence of thumbs being the most characteristic feature, frequently associated with radio-ulnar synostosis and/or aplasia/hypoplasia of the radius. Triphalangeal thumbs and other abnormalities of the digits have also been reported and a small percentage of patients also have lower limb malformations. Otologic and oral anomalies frequently lead to bilateral conductive hearing loss, speech difficulties and upper respiratory airways obstruction. Most Nager syndrome individuals have normal vision and intelligence. ## Etiology In approximately 50% of patients, NAFD has been associated with heterozygous mutations in the SF3B4 gene (1q21.2), coding for a component of the splicing machinery. ## Diagnostic methods Diagnosis is based on physical and radiological examination or the identification of a mutation in SF3B4. ## Differential diagnosis Differential diagnosis may include mandibulofacial dysostosis syndromes such as Treacher-Collins syndrome, and other acrofacial dysostoses (AFD) such as the AFD Catania type, the AFD Palagonia type, the AFD Genee-Wiedemann type, the AFD Rodriquez type as well as mandibulofacial dysostosis with microcephaly (see these terms). Patients with the oculoauriculovertebral (OAV) spectrum (see this term) may also have overlapping features. ## Antenatal diagnosis Antenatal diagnosis can be performed by ultrasonography or molecular testing of SF3B4. ## Genetic counseling Nager syndrome is likely genetically heterogenous with confirmed autosomal dominant inheritance, but autosomal recessive inheritance is suspected based on sibling recurrence in consanguineous families. Genetic counseling requires careful evaluation of parents and sibs of an affected child, in order to determine if the disease has a familial origin or if it occurred sporadically. If one parent is mildly affected, recurrence risk is 50% and a 25% risk cannot be excluded when parents are apparently normal. ## Management and treatment Management must focus on neonatal respiratory distress (tracheostomy) and feeding difficulties (gastrostomy). Surgery can be considered for repair of clefts, management of severe micrognathia as well as temporomandibular joint dysfunction. Hearing aids can be proposed. Language and phonological impairment must be managed by a specific speech therapy. ## Prognosis After infancy, most patients are healthy and are presumed to have a normal lifespan. Ongoing medical issues are usually only related to airway obstruction or temporomandibular joint dysfunction in patients with more severe manbibular malformations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nager syndrome	c0265245	3,126	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=245	2021-01-23T18:30:07	{"gard": ["498"], "mesh": ["C538184"], "omim": ["154400"], "umls": ["C0265245"], "icd-10": ["Q75.4"], "synonyms": ["Mandibulofacial dysostosis with preaxial limb anomalies", "NAFD", "Nager acrofacial dysostosis", "Preaxial acrodysostosis"]}
Distal trisomy 3p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 3, with highly variable phenotype principally characterized by craniofacial dysmorphism (incl. brachy-/microcephaly, square facies, frontal bossing, bitemporal indentation, hypertelorism/telecanthus, low-set and/or dysmorphic ears, short nose with broad, flat nasal bridge, prominent cheeks and philtrum, downturned corners of mouth, micrognathia/retrognathia, short neck) associated with psychomotor delay, moderate to severe intellectual disability, cardiac (e.g. patent ductus arteriosus) and urogenital (e.g. renal hypoplasia, hypogenitalism) abnormalities, as well as seizures and presence of whorls on fingers. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Distal trisomy 3p	c4706938	3,127	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96071	2021-01-23T18:15:13	{"icd-10": ["Q92.3"], "synonyms": ["Distal duplication 3p", "Telomeric duplication 3p", "Trisomy 3pter"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-69 (RP69) is caused by homozygous or compound heterozygous mutation in the KIZ gene (615757) on chromosome 20p11. Description Retinitis pigmentosa (RP), also designated rod-cone dystrophy, is characterized by initial night blindness due to rod dysfunction, with subsequent progressive constriction of visual fields, abnormal color vision, and eventual loss of central vision due to cone photoreceptor involvement (summary by El Shamieh et al., 2014). For a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features El Shamieh et al. (2014) studied 3 unrelated patients with rod-cone dystrophy (retinitis pigmentosa) and mutations in the KIZ gene (see MOLECULAR GENETICS). All were diagnosed in their late teens on the basis of night blindness followed by changes in midperipheral visual fields and undetectable responses on full-field electroretinography by approximately 35 years of age. The first was a 50-year-old man of North African Jewish Sephardic descent with unaffected first-cousin parents. Best corrected visual acuity (BCVA) was 20/800 and 20/640 in the right and left eyes, respectively. A kinetic visual field test revealed decreased central retinal sensitivity in addition to bilateral peripheral field constriction. Fundus examination showed typical pigmentary changes of rod-cone dystrophy in the peripheral retina as well as atrophic changes in the central macula with a ring of hypoautofluorescence; spectral-domain optical coherence tomography (OCT) revealed foveal thinning with loss of outer-segment structures. The second patient was a 34-year-old Spanish man whose BCVA was 20/20 in both eyes. Binocular kinetic visual field testing showed an annular scotoma in the midperiphery and preservation of the peripheral isopter, and fundus examination showed mild pigmentary changes in the peripheral retina in association with slight changes in autofluorescence outside the vascular arcades and a perifoveal ring of increased autofluorescence. Foveal structure was normal on OCT, consistent with the patient's normal central vision. The third patient was a 51-year-old man of mixed Italian and French descent whose medical history included congenital ichthyosis (see 242300). BCVA was 20/40 and 20/32 in the right and left eyes, respectively. Visual fields were reduced to the central 10 degrees, with bitemporal islands of perception peripherally. Fundus changes were typical of retinitis pigmentosa, with relative macular preservation. There was a perifoveal ring of increased autofluorescence and moderate thinning of the fovea on OCT. Molecular Genetics In a 50-year-old man of North African Jewish Sephardic descent with retinitis pigmentosa, who was negative for mutation in genes known to be associated with retinal disease, El Shamieh et al. (2014) performed whole-exome sequencing and identified a homozygous nonsense mutation in the KIZ gene (R76X; 615757.0001) that segregated with disease in the family. Analysis of KIZ in 340 unrelated patients with autosomal recessive and sporadic retinitis pigmentosa identified 1 patient who was homozygous for the R76X mutation and another who was compound heterozygous for a different nonsense mutation (E18X; 615757.0002) and a 4-bp deletion (615757.0003). The authors stated that KIZ accounted for about 1% of disease in their cohort of patients, but noted that this might represent a slight overestimation for autosomal recessive retinitis pigmentosa, since in most of their patients mutations in other retinal disease-associated genes had already been excluded. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Pigmentary changes in the peripheral retina \- Atrophic changes of central macula (in some patients) \- Foveal thinning (in some patients) \- Decreased visual fields \- Undetectable responses on electroretinography (by fourth decade of life) MISCELLANEOUS \- Diagnosis in the second decade of life MOLECULAR BASIS \- Caused by mutation in the kizuna centrosomal protein gene (KIZ, 615757.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RETINITIS PIGMENTOSA 69	c0035334	3,128	omim	https://www.omim.org/entry/615780	2019-09-22T15:50:59	{"doid": ["0110410"], "mesh": ["D012174"], "omim": ["615780"], "orphanet": ["791"]}
Hypocomplementemic urticarial vasculitis (HUV) is an immune complex-mediated small vessel vasculitis characterized by urticaria and hypocomplementemia (low C1q with or without low C3 and C4), and usually associated with circulating anti-C1q autoantibodies. Arthritis, pulmonary disease, ocular inflammation, and glomerulonephritis are common systemic manifestations. ## Epidemiology Prevalence is unknown but less than 200 cases have been reported in the literature. Women are more frequently affected than men (female to male ratio of 8:1). ## Clinical description Patients most commonly present during the fourth decade of life but onset during childhood has been described. Patients present with generalized urticarial eruptions located on the trunk, proximal extremities and face that are often associated with itching or pain and persist for more than 24 hours, with hyperpigmentation after resolution. Angioedema is common and may also be a presenting feature. Cardiorespiratory manifestations include cough, dyspnea, pleural and pericardial effusions, and emphysema, with chronic obstructive pulmonary disease reported in 20-50% of patients. Renal disease is present in around half of patients and is generally mild with proteinuria and hematuria caused by glomerulonephritis. However, renal insufficiency and end-stage renal failure have been reported and renal involvement tends to be more severe in patients with childhood onset. Other systemic findings include gastrointestinal symptoms (abdominal pain, nausea, diarrhea, vomiting), musculoskeletal manifestations (arthritis and transient arthralgia affecting the hands, elbows, knees, ankles, and feet), ocular inflammation (episcleritis, uveitis and conjunctivitis) and, more rarely, neurological findings (pseudotumor cerebri, aseptic meningitis, cranial and peripheral nerve palsies and transverse myelitis). A few patients with the rare combination of HUV, Jaccoud's arthropathy and valvular heart disease have also been reported. HUV may also be associated with an increased susceptibility to pyogenic infections. ## Etiology HUV generally occurs sporadically but occurrence in siblings has been described. Both genetic and environmental factors are likely to play a role in the etiology of HUV and anti-C1q autoantibodies are believed to be involved in the pathogenesis of the disorder. ## Diagnostic methods Diagnosis requires the presence of two major criteria (recurrent urticaria for > 6 months and hypocomplementemia) and at least two minor criteria (leukocytoclastic vasculitis on biopsy, arthralgia and arthritis, ocular inflammation, abdominal pain, glomerulonephritis and positive anti-C1q autoantibodies). ## Differential diagnosis The relationship of HUV to systemic lupus erythematosus (SLE) is complex with many overlapping features (manifestations of HUV are present in 10% of SLE patients and 50% of patients with HUV will later be diagnosed as having SLE). Other syndromes such as mixed cryoglobulinemia, Muckle-Wells syndrome, Cogan syndrome and Schnitzler syndrome should be excluded (see these terms). ## Management and treatment There is no specific treatment and management requires tailored therapy with steroids and immunosuppressives. For example, patients with cutaneous disease and arthralgias but no major organ involvement may be managed with low-dose prednisone, hydroxychloroquine, or dapsone; whereas patients with major organ involvement, such as glomerulonephritis, may require high doses of corticosteroids and cytotoxic agents similar to the treatment for active SLE. Response to treatment is usually accompanied by a decrease in circulating anti-C1q titer and normalization of C3 and C4 levels, although C1q often remains low. ## Prognosis The prognosis for HUV patients is variable and is influenced primarily by the severity of pulmonary, cardiac and renal disease. When present, pulmonary disease is the major cause of death. Acute laryngeal edema can be life-threatening. Although uncommon in childhood, the prognosis is worse for early onset HUV patients because of more frequent severe renal involvement. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypocomplementemic urticarial vasculitis	c0343206	3,129	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36412	2021-01-23T18:28:42	{"gard": ["6725"], "icd-10": ["M31.8"], "synonyms": ["Anti-C1q vasculitis", "Mac Duffie hypocomplementemic urticarial vasculitis", "Mac Duffie syndrome", "McDuffie hypocomplementemic urticarial vasculitis", "McDuffie syndrome"]}
A number sign (#) is used with this entry because of evidence that Pyle disease (PYL) is caused by homozygous mutation in the SFRP4 gene (606570) on chromosome 7p14. Description Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016). Clinical Features Despite bizarre roentgenographic changes, there are few clinical findings in Pyle disease other than genu valgum. The skull is only mildly affected, thus distinguishing this disorder from the craniometaphyseal dysplasias (see 123000, 218400). The femurs show an Erlenmeyer-flask deformity. The humerus is abnormally broad and 'undermodeled' in its proximal two-thirds, the radius and ulna in their distal two-thirds (Gorlin et al. (1969, 1970)). Pyle (1931) described this disorder in a 5-year-old boy. Bakwin and Krida (1937) restudied this boy and described his affected sister. Raad and Beighton (1978) described the disorder in an inbred Afrikaner kindred. Apart from genu valgum of moderate degree, the patients enjoyed good health and their gross radiographic skeletal abnormalities contrasted with the innocuous clinical presentation. Some of the obligatory and potentially heterozygous relatives of the 2 presumed homozygotes showed minor widening of the distal femora on radiographic study. Kiper et al. (2016) studied 4 patients with Pyle disease. The 16-year-old proband in a consanguineous Turkish family was first noted to have progressive genu valgum at age 7 years. He experienced 2 fractures after minimal trauma, of the left radius and right femur. Radiographic survey showed findings consistent with Pyle disease, including disturbed modeling of long bones, with wide metaphyses and thin cortexes, and an absence of paranasal sinuses. His 14-year-old sister had genu valgum, bilateral cubitus valgus, and limitation of extension in the proximal interphalangeal joints of all fingers except the thumb, but had no bone fractures. Radiographic findings were similar to those of her brother, and neither sib had pain or muscle weakness. Other features included delayed tooth eruption in both sibs, and their deciduous teeth did not shed. Bone mineral densitometry of the lumbar spine revealed Z scores of -2.7 and -2.1, with proximal femur Z scores of -1.1 and -1.4, respectively. Serum levels of calcium, phosphate, alkaline phosphatase, vitamin D, and parathyroid hormone were normal in both sibs; however, elevated levels of bone metabolism markers, including osteocalcin (112260), bone-specific alkaline phosphatase (see 171760), and P1NP, indicated a particularly active bone deposition process, whereas normal levels of carboxy-terminal collagen crosslinks suggested a normal bone resorption rate. Their first-cousin parents were unaffected, and they had an unaffected brother. Kiper et al. (2016) also studied a 58-year-old Japanese man who experienced tibial fractures after a workplace accident, at which time it was noted that the tibia also had a highly abnormal shape and structure; radiographic evaluation was consistent with Pyle disease. The fourth patient was a 3.5-year-old boy from India who had progressive genu valgus deformity after he started walking. He had no history of fractures, and his dentition appeared normal. Radiographs showed the metaphyseal tubulation defect, chalk-like appearance of bone, and lack of cortical bone that are typical of Pyle disease. Inheritance Pyle disease is an autosomal recessive disorder. Affected sibs were reported by Bakwin and Krida (1937), Hermel et al. (1953), Feld et al. (1955) and Daniel (1960), among others. Parental consanguinity was present in the cases of Daniel (1960). In the family described by Komins (1954), a brother and sister were affected as well as the mother and a maternal uncle. Beighton (1987) found about 20 reported cases; in 7 instances sibs of normal parents were affected, and in 2 instances parental consanguinity was identified. Molecular Genetics By exome sequencing in 2 Turkish sibs with Pyle disease, Kiper et al. (2016) identified homozygosity for a 1-bp insertion in the SFRP4 gene (606570.0001), for which their parents and unaffected brother were heterozygous. Analysis of SFRP4 in 2 additional patients with Pyle disease revealed homozygosity for a nonsense mutation in an affected Japanese man (R232X; 606570.0002) and homozygosity for a 7-bp deletion in a 3.5-year-old Indian boy (606570.0003). Radiography of the clinically unaffected Turkish father and brother showed undermodeling of the distal radius and distal tibia, as well as mild incurvation of the tibia, consistent with mild expression in the heterozygous state. History Beighton (1987) noted that Edwin Pyle (1891-1961) was an orthopedic surgeon in Waterbury, Connecticut. INHERITANCE \- Autosomal recessive GROWTH Height \- Normal to tall stature HEAD & NECK Teeth \- Delayed tooth eruption (in some patients) \- Failure to shed deciduous teeth (in some patients) CHEST Ribs Sternum Clavicles & Scapulae \- Marked widening of ribs \- Marked widening of clavicles SKELETAL \- Chalk-like appearance of bone \- Decreased bone mineral density \- Fractures upon minimal trauma (in some patients) Skull \- Expansion of the diploe \- Absence of paranasal sinuses \- Underdeveloped frontal sinuses Pelvis \- Marked expansion of the ischial bones \- Marked expansion of the pubic bones Limbs \- Genu valgum deformity, mild to severe \- Valgum deformity of elbows (in some patients) \- Marked metaphyseal widening of long bones ('Erlenmeyer-flask deformity') \- Marked thinning of metaphyseal cortex \- Normal cortical thickness in middle part of diaphysis \- Incurvation of tibia Hands \- Expansion of distal metacarpals \- Expansion of distal phalanges \- Undertubulation of metacarpals \- Undertubulation of phalanges LABORATORY ABNORMALITIES \- Elevated osteocalcin \- Elevated bone-specific alkaline phosphatase \- Elevated procollagen type 1 N-terminal propeptide (P1NP) MISCELLANEOUS \- Homozygous patients reported no joint pain or muscle weakness \- Clinically asymptomatic heterozygous carriers may exhibit mild radiographic changes MOLECULAR BASIS \- Caused by mutation in the secreted frizzled-related protein-4 gene (SFRP4, 606570.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PYLE DISEASE	c0265294	3,130	omim	https://www.omim.org/entry/265900	2019-09-22T16:22:56	{"mesh": ["C536252"], "omim": ["265900"], "icd-10": ["Q78.5"], "orphanet": ["3005"], "synonyms": ["Alternative titles", "METAPHYSEAL DYSPLASIA"]}
A number sign (#) is used with this entry because generalized hypotrichosis-1 (HYPT1) is caused by heterozygous mutation in the APCDD1 gene (607479) on chromosome 18p11. Description Hereditary hypotrichosis simplex (HHS) is a rare form of nonsyndromic hereditary hypotrichosis without characteristic hair shaft anomalies. Affected individuals typically show normal hair at birth, but hair loss and thinning of the hair shaft start during early childhood and progress with age. HHS can be largely divided into 2 forms: the scalp-limited form (e.g., 146520) and the generalized form, in which all body hair is affected. HHS is characterized by progressive hair follicle miniaturization, which is a typical feature of androgenetic alopecia (see 109200). HHS can be inherited either as an autosomal dominant or autosomal recessive trait (e.g., HYPT8, 278150) (summary by Shimomura et al., 2010). ### Genetic Heterogeneity of Nonsyndromic Hypotrichosis See also HYPT2 (146520), caused by mutation in the CDSN gene (602593) on chromosome 6p21; HYPT3 (613981), caused by mutation in the KRT74 gene (608248) on chromosome 12q13; HYPT4 (146550), caused by mutation in upstream regulatory regions of the HR gene (602302) on chromosome 8p21; HYPT5 (612841), mapped to chromosome 1p21-q21; HYPT6 (607903), caused by mutation in the DSG4 gene (607892) on chromosome 18q12; HYPT7 (604379), caused by mutation in the LIPH gene (607365) on chromosome 3q27; HYPT8 (278150), caused by mutation in the LPAR6 gene (609239) on chromosome 13q14; HYPT9 (614237), mapped to chromosome 10q11.23-q22.3; HYPT10 (614238), mapped to chromosome 7p22.3-p21.3; HYPT11 (615059), caused by mutation in the SNRPE gene (128260) on chromosome 1q32; HYPT12 (615885), caused by mutation in the RPL21 gene (603636) on chromosome 13q12; HYPT13 (615896), caused by mutation in the KRT71 gene (608245) on chromosome 12q13; and HYPT14 (618275), caused by mutation in the LSS gene (600909) on chromosome 21q22. Clinical Features In contrast to the total and permanent absence of hair in congenital atrichia (203655), hair is present in hereditary hypotrichosis simplex but is diffusely thinned. Another form of isolated hypotrichosis, the Marie Unna type (146550), is distinguished from hypotrichosis simplex by the presence of a twisting hair dystrophy. Baumer et al. (2000) described a nonconsanguineous Italian family with hypotrichosis simplex in an autosomal dominant pedigree pattern. Nine affected adults presented with sparse, thin, and short hair. Somewhat less sparse and longer hair was observed in 2 affected young children in the third generation. Reduced hair growth affected the scalp and body, although normal eyelashes, eyebrows, and male beards were observed. No associated abnormality was detected, and the overall psychomotor development of the affected individuals was normal. Phenotypic variation was observed. Shimomura et al. (2010) identified 2 Pakistani families with typical clinical features of HHS. All affected individuals had normal scalp hair density at birth; hair loss gradually progressed beginning around age 2 to 5 years. Hair grew slowly and stopped growing after a few inches. Some affected individuals showed light-colored or hypopigmented hair shafts. In most cases body hair, axillary hair, and public hair were also sparse. Eyebrows, eyelashes, and beard hairs were not affected. Under light microscopy, the bulb portion of the plucked hair showed dystrophic features and was miniaturized. The hair shaft was thin and without any characteristic anomalies, and the distal ends appeared tapered. Affected individuals in both families showed normal teeth, nails, and sweating and did not show keratosis pilaris. Mapping After exclusion of linkage to loci previously described in other forms of atrichia or hypotrichosis, Baumer et al. (2000) performed a genomewide linkage analysis in an Italian family with autosomal dominant hypotrichosis simplex, which resulted in a positive 2-point lod score of 3.31 at theta = zero at 18p11.32-p11.23. Shimomura et al. (2010) performed a linkage study in 2 Pakistani families after excluding the CDSN locus on chromosome 6 (602593). Linkage analysis using a dominant model yielded a maximum lod score of 4.6 on chromosome 18p11.22. They further narrowed the interval to a 1.8-Mb region containing 8 genes, 4 pseudogenes, and 3 predicted transcripts. Molecular Genetics In both Pakistani families used to map the disorder and in an Italian family described by Baumer et al. (2000), Shimomura et al. (2010) identified a T-to-G transition at nucleotide 26 of the APCDD1 gene resulting in a leu9-to-arg substitution at codon 9 (L9R; 607479.0001). This mutation segregated with the phenotype and was not identified in 200 unrelated controls. The L9R mutation is located in the signal peptide of APCDD1 and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. Shimomura et al. (2010) hypothesized that L9R-mutated APCDD1 functions in a dominant-negative manner to inhibit the stability and membrane localization of the wildtype protein. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Sparse eyebrows (in some patients) \- Sparse eyelashes (in some patients) Teeth \- Normal teeth SKIN, NAILS, & HAIR Skin \- Normal skin \- Normal sweat glands \- Normal scalp Nails \- Normal nails Hair \- Sparse or absent scalp hair \- Hypotrichosis simplex, generalized \- Normal scalp hair density at birth \- Sparse eyebrows (in some patients) \- Sparse eyelashes (in some patients) Sparse body hair \- Sparse axillary hair (in some patients) \- Sparse pubic hair (in some patients) \- Normal beard hair \- Thin hair shafts with no characteristic abnormality \- Hair shafts normal (family A) \- Sparse, thin, and short scalp hair (family A) MISCELLANEOUS \- Hair loss, progressive, begins about 3-6 months of age \- Complete loss of scalp hair by 15-20 years of age (some patients) \- Regrowth of thin and sparse scalp hair observed after cutting (family A) MOLECULAR BASIS \- Caused by mutation in the APC, downregulated by, 1 gene (APCDD1, 607479.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOTRICHOSIS 1	c1854310	3,131	omim	https://www.omim.org/entry/605389	2019-09-22T16:11:21	{"doid": ["0110698"], "mesh": ["C537160"], "omim": ["605389"], "orphanet": ["55654"], "synonyms": ["Alternative titles", "HYPOTRICHOSIS SIMPLEX, GENERALIZED, HEREDITARY", "HTS"]}
Joske and Laurence (1970) described a family in which the father and 4 of 10 children had chronic liver disease and raised immunoglobulin levels. A possible nongenetic basis is suggested by the example of hepatitis-associated antigen (HAA), or Australian antigen, in a mother and 3 children ascertained through one of the children who had neonatal giant cell hepatitis (Bancroft et al., 1971). Nasrallah et al. (1978) described a family in which the mother and all 6 of her sons but none of her 5 daughters had HBs antigenemia. The mother and her husband were second cousins; see 209800 for a discussion of recessive inheritance of persistent antigenemia. Percutaneous liver biopsies showed no evidence of liver disease in the mother but all 6 sons had evidence of chronic active hepatitis progressing to cirrhosis. Immunology \- Raised immunoglobulin levels GI \- Chronic liver disease \- Chronic active hepatitis \- Cirrhosis 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CIRRHOSIS, FAMILIAL	c1861556	3,132	omim	https://www.omim.org/entry/118900	2019-09-22T16:43:18	{"mesh": ["C566123"], "omim": ["118900"]}
A number sign (#) is used with this entry because the syndrome is caused by a recombinant chromosome 8 characterized by duplication of 8q22.1-qter and deletion of 8pter-p23.1. This chromosome, known as Rec(8), is derived from recombination of a parental pericentric inversion of chromosome 8, known as inv(8). Clinical Features Fujimoto et al. (1975) described a Hispanic girl with multiple anomalies, including tetralogy of Fallot and minor anomalies, who had an unbalanced recombinant chromosome 8 with partial duplication of 8q. The abnormal chromosome was inherited from the mother, who had a pericentric inversion: inv(8)(p23.1q22.1). In patients with Rec(8), Gelb et al. (1991) found that tetralogy of Fallot constituted about 40% of the cardiovascular malformations and conotruncal defects about 55%. Gelb et al. (1991) suggested that the lack of an association between other chromosome 8 abnormalities and tetralogy of Fallot may mean that genes at the Rec(8) breakpoints or an interaction between genes on both arms of chromosome 8 are important. Sujansky et al. (1993) identified 65 patients, published and unpublished, with the same chromosomal inversion described by Fujimoto et al. (1975). Most of the patients were of Hispanic descent, and all had duplication of 8q22-qter with deficiency of 8pter-p23. Sujansky et al. (1993) tabulated the frequency and evolution of phenotypic abnormalities on the basis of information on 42 patients spanning a period of 23 years. Congenital heart disease was present in 39 of the 42, and included tetralogy of Fallot, other conotruncal defects, and septal defects. Dysmorphic craniofacial features included hypertelorism and thin upper lip in all cases; anteverted nares, wide face, abnormal dentition, and abnormal hair whorl in more than 90% of cases; infraorbital creases, abnormally low-set ears, downturned mouth, low posterior hairline, and micrognathia in 80% or more of cases; and gingival hyperplasia, brachycephaly, midface hypoplasia, and thick lower lip in about 75% of cases. All had delayed development with moderate to severe mental retardation. Mild genitourinary tract malformations were found in 14 of 29, but none had evidence of compromised renal function. A conspicuous finding in most cases was a single ossification center in the sternum on radiographic analysis. Other less common skeletal features included scoliosis, pectus excavatum, and joint contractures. Inheritance In an analysis of 31 kindreds from Colorado and New Mexico with a rec(8) proband, Smith et al. (1987) estimated that an inv(8) carrier parent has a 6.2% risk of having a child with the recombinant 8 dup(q) chromosome. The transmission rate was significantly higher for carrier mothers (59%) than for carrier fathers (42%). Cytogenetics Smith et al. (1987) stated that the Hispanic inv(8) encompasses 74% of chromosome 8. The resultant recombinant chromosome 8, dup(q), has a duplication of the distal segment of 8q22.1-qter and a deficiency of the distal end of 8pter-p23.1. The distal segments of the breakpoints comprise 1.59% and 0.44%, respectively, of the haploid autosomal length of inv(8), yielding small enough trisomy and monosomy of these segments to allow viability. The alternative recombinant chromosome, dup(p), has never been observed, suggesting is it lethal. Stevens et al. (2010) reported a 2-year-old boy with multiple congenital cardiac malformations, dysmorphic facies, and severe mental retardation associated with a heterozygous complex chromosome 8 consisting of a 16.9-Mb deletion of 8pter-p22 and a 21.7-Mb duplication of 8q24.13-qter. Each segment included about 150 genes. Molecular analysis of the patient's mother showed a heterozygous balanced 3-way translocation t(8;11;8)(p22;q22;q24.13). FISH analysis showed that region 8pter-8p22 was translocated to 11q; 11qter-11q22 was translocated to 8q; and 8qter-8q24.13 was translocated to 8p. These findings indicated that crossing-over in maternal meiosis led to a recombinant chromosome 8 with material from the q-arm on both ends and a deletion of part of the p-arm. This molecular mechanism was distinct from the usual mechanism of the pericentric inv(8) chromosome in San Luis Valley syndrome. Although the cytogenetics were slightly different, this patient had clinical features overlapping those reported in San Luis Valley syndrome, including a perimembranous ventricular septal defect with inlet extension, pulmonary valve stenosis, and a secundum-type atrial septal defect. Dysmorphic features included wide face with brachycephaly, plagiocephaly, hypertelorism, long eyelashes, thin vermilion border, downturned corners of the mouth, low-set ears, broad alveolar ridges, broad tip of the nose, and long philtrum. He also had hypospadias and cryptorchidism. Stevens et al. (2010) suggested that haploinsufficiency of the GATA4 gene (600576) on chromosome 8p23 may be involved in the cardiac defects. Molecular Genetics In a study of the breakpoint at 8p23.1 associated with the inversion 8 chromosome found in at least 1 parent of all Rec8 syndrome individuals, Patterson et al. (1995) found that the clones contained at least the 5-prime coding region of the squalene synthase gene (FDFT1; 184420). Graw et al. (2000) cloned, sequenced, and characterized the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions showed that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consisted of repetitive gene family members (including Alu, LINE, and LTR elements) and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint showed that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements. Graw et al. (2000) noted that 8p23.1 is an unstable segment of the genome. Population Genetics Smith et al. (1987) noted that all affected families have been of Hispanic origin. They found that 3 kindreds, from Colorado, New Mexico, and Los Angeles, respectively, had a common ancestor who could be traced to a village in northeastern New Mexico in the late 1800s. Ethnohistorical data regarding the Spanish settlement of the southwest was consistent with a Spanish founder effect. The syndrome was estimated to be about 1.5 centuries old. Sujansky et al. (1993) studied 36 kindreds with rec(8) syndrome in the southwestern United States. All Hispanic kindreds for which the ancestral lines were known had relatives originating from a common geographic region, i.e., southern Colorado and northern New Mexico. In Colorado, the condition was known as the 'San Luis Valley syndrome.' INHERITANCE \- Autosomal dominant GROWTH Other \- Postnatal growth retardation HEAD & NECK Head \- Brachycephaly \- Microcephaly, postnatal Face \- Wide face \- Micrognathia \- Midface hypoplasia Ears \- Low-set ears \- Misshapen ears \- Posteriorly angulated ears \- Hearing loss Eyes \- Hypertelorism \- Strabismus \- Infraorbital creases Nose \- Anteverted nares \- Depressed nasal bridge Mouth \- Thin upper lip \- Downturned mouth \- Thick lower lip \- Gingival hyperplasia Teeth \- Abnormal spacing of the teeth CARDIOVASCULAR Heart \- Congenital heart defects \- Conotruncal defects \- Tetralogy of Fallot \- Double-outlet right ventricle \- Ventricular septal defect \- Atrial septal defect \- Pulmonary valve stenosis Vascular \- Patent ductus arteriosus CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum, progressive \- Radiographic studies show a single ossification center in the sternum GENITOURINARY \- Genitourinary anomalies (48%) Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Hydronephrosis \- Dilated collecting tubules SKELETAL \- Joint contractures Spine \- Scoliosis, progressive Hands \- Camptodactyly \- Fifth finger clinodactyly Feet \- Deep plantar furrows SKIN, NAILS, & HAIR Hair \- Low posterior hairline NEUROLOGIC Central Nervous System \- Developmental delay \- Mental retardation, moderate to severe \- Seizures \- Delayed myelination \- Hypertonia \- Hypotonia \- Cerebral atrophy \- Ventriculomegaly LABORATORY ABNORMALITIES \- Cytogenetics - recombinant chromosome 8 characterized by duplication of 8q22.1-qter and deletion of 8pter-p23.1 MISCELLANEOUS \- Asymptomatic carriers of a pericentric chromosome 8 inversion, inv(8), have a 6.2% risk of having an affected child with an unbalanced recombinant chromosome 8, Rec(8). MOLECULAR BASIS \- Caused by duplication of 8q22.1-qter and deletion of 8pter-p23.1 ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RECOMBINANT CHROMOSOME 8 SYNDROME	c0795822	3,133	omim	https://www.omim.org/entry/179613	2019-09-22T16:35:20	{"mesh": ["C535296"], "omim": ["179613"], "orphanet": ["96167"], "synonyms": ["Alternative titles", "REC8 SYNDROME", "CHROMOSOME 8q22.1-qter DUPLICATION AND 8pter-p23.1 DELETION", "SAN LUIS VALLEY SYNDROME"]}
## Summary ### Clinical characteristics. Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia but intellectual disability and epilepsy may be more prevalent. Children usually present as toddlers or at early school age with decreased growth velocity leading to short stature and limb disproportion. Other features also become more prominent over time. ### Diagnosis/testing. The diagnosis of hypochondroplasia is established in a proband with characteristic clinical and radiographic features. Identification of a heterozygous FGFR3 pathogenic variant known to be associated with hypochondroplasia can confirm the diagnosis and help distinguish hypochondroplasia from achondroplasia and other related skeletal dysplasias in individuals with overlapping phenotypes. ### Management. Treatment of manifestations: Management of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Suboccipital decompression if neurologic status is affected by spinal cord compression. Treatment for thoracolumbar kyphosis and/or genu varum as per orthopedic surgeon if necessary. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Epilepsy is treated in the standard fashion. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Connect family with local resources and support. Surveillance: Height, weight, and head circumference should be monitored using achondroplasia-standardized growth curves. The following should be performed at routine well-child visits: neurologic examination for signs of spinal cord compression, assessment of signs and symptoms of sleep apnea, physical examination for emerging leg bowing, and monitoring of development and social adjustment. MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia, spinal cord compression, or central sleep apnea. Pregnancy management: Vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size; epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy; spinal stenosis may be aggravated during pregnancy. ### Genetic counseling. Hypochondroplasia is inherited in an autosomal dominant manner. The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a de novo pathogenic variant. If the proband has a known FGFR3 pathogenic variant that cannot be detected in the leukocyte DNA of either parent and neither parent has an autosomal dominant skeletal dysplasia, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism. An individual with hypochondroplasia who has a partner of average stature is at a 50% risk of having a child with hypochondroplasia. If an affected individual's partner also has hypochondroplasia (or another dominant form of skeletal dysplasia), genetic counseling becomes more complicated because of (1) the risk for inheriting two dominantly inherited skeletal dysplasias, (2) the high incidence of genetic heterogeneity, and (3) the lack of medical literature addressing these circumstances. Prenatal testing and preimplantation genetic testing are possible if the causative pathogenic variant(s) have been identified in the affected parent(s). ## Diagnosis The clinical and radiologic diagnostic criteria for hypochondroplasia remain controversial for several reasons, including the following: * No single radiologic or clinical feature is unique to hypochondroplasia. * The expression of many of the established diagnostic features in affected individuals is variable. * Locus heterogeneity has been established. Genetic heterogeneity and lack of agreement on a definitive set of diagnostic criteria have made it difficult to compare data from the many studies reported in the literature [Walker et al 1971, Hall & Spranger 1979, Heselson et al 1979, Oberklaid et al 1979, Wynne-Davies et al 1981, Maroteaux & Falzon 1988, Song et al 2012]. Nevertheless, it is clear that a complete radiographic survey including skull, pelvis, anteroposterior and lateral spine, legs, arms, and hands is absolutely necessary to make a clinical diagnosis of hypochondroplasia. ### Suggestive Findings Hypochondroplasia should be suspected in individuals with the following clinical and radiographic features. Clinical features * Short stature (adult height 128-165 cm; 2-3 SD below the mean in children) * Stocky build * Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia) * Limitation of elbow extension * Broad, short hands and feet with brachydactyly * Generalized, mild joint laxity * Macrocephaly with relatively normal facies Less common but significant clinical features: * Scoliosis * Bowed legs (genu varum) (usually mild) * Lumbar lordosis with protruding abdomen * Mild-to-moderate intellectual disability * Learning disabilities * Adult-onset osteoarthritis * Acanthosis nigricans * Temporal lobe epilepsy Radiologic features. The most common radiologic features of hypochondroplasia: * Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) * Narrowing of the inferior lumbar interpedicular distances (or failure to widen) * Mild-to-moderate brachydactyly * Short, broad femoral neck * Squared, shortened ilia Less common but significant radiologic features: * Elongation of the distal fibula * Shortening (anterior-posterior) of the lumbar pedicles * Dorsal concavity of the lumbar vertebral bodies * Shortening of the distal ulna * Long ulnar styloid (seen only in adults) * Prominence of muscle insertions on long bones * Shallow "chevron" deformity of distal femur metaphysis * Low articulation of sacrum on pelvis with a horizontal orientation * Flattened acetabular roof ### Establishing the Diagnosis The diagnosis of hypochondroplasia is established in a proband with the characteristic clinical and radiographic features. Identification of a heterozygous FGFR3 pathogenic variant known to be associated with hypochondroplasia can confirm the diagnosis and help distinguish hypochondroplasia from achondroplasia and other related skeletal dysplasias in individuals with overlapping phenotypes (see Table 1). Note: A consensus opinion of which or how many of these features must be present to confirm a clinical diagnosis does not currently exist. Radiographic features vary significantly among affected individuals. Many of these features are not present in affected infants but develop later in life. The mild end of the hypochondroplasia phenotypic spectrum may overlap with idiopathic or familial short stature, making it difficult to establish a definitive clinical diagnosis in these individuals. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of hypochondroplasia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with skeletal dysplasia and/or short stature are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of hypochondroplasia, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing * Targeted analysis for pathogenic variants c.1620C>A and c.1620C>G can be performed first. * Sequence analysis of FGFR3 can be performed next if a pathogenic variant is not identified on targeted analysis. A multigene panel that includes FGFR3 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia, 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. 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 Hypochondroplasia View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method FGFR3Targeted analysis for c.1620C>A and c.1620C>G~70%-80% 3, 4 Sequence analysis 570%-90% 4 Gene-targeted deletion/duplication analysis 6None reported 7 Unknown 8NA10%-30% 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\. The two most common pathogenic variants [Prinos et al 1995, Bellus et al 1996, Rousseau et al 1996, Fofanova et al 1998, Prinster et al 1998, Ramaswami et al 1998, Heuertz et al 2006] 4\. Xue et al [2014] 5\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. No deletions or duplications involving FGFR3 have been reported to cause hypochondroplasia. 8\. Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, Mullis et al [1991] studied 20 children with hypochondroplasia. Two RFLPs identified within introns of IGF1 (12q23) showed a positive LOD score of 3.31 in some families with hypochondroplasia. To date, no further refinement of the genetic locus on 12q23 has been reported and no pathogenic variants have been reported in IGF1. ## Clinical Characteristics ## Differential Diagnosis Numerous forms of skeletal dysplasia with disproportionate limbs are recognized and are characterized by clinical and radiologic features that distinguish them from hypochondroplasia and achondroplasia. Many of these disorders are quite rare. The diagnosis of hypochondroplasia is seldom made at birth unless a prior family history exists. Most affected individuals present with short stature as toddlers or young school-age children. Inappropriate diagnoses of hypochondroplasia are often made because the disorder is considered to be relatively common and the radiologic features are variable and may be subtle. Conditions with a known genetic etiology that may be confused with hypochondroplasia are summarized in Table 3. ### Table 3. Genes of Interest in the Differential Diagnosis of Hypochondroplasia View in own window Gene(s)DisorderMOI B3GALT6Mild forms of spondyloepimetaphyseal dysplasia (e.g., SEMDJL1; OMIM 271640)AR FGFR3Mild achondroplasia 1AD GNASPseudohypoparathyroidism & pseudopseudohypoparathyroidism (see Disorders of GNAS Inactivation)AD 2 COL10A1 PTH1RMild forms of metaphyseal chondrodysplasia (e.g., Schmid metaphyseal chondrodysplasia & Murk Jansen metaphyseal chondrodysplasia; OMIM 156400)AD SHOXMild forms of mesomelic dysplasia (e.g., Langer mesomelic dysplasia; OMIM 249700)Pseudoautosomal recessive Leri-Weill dyschondrosteosis (see SHOX deficiency disorders)Pseudoautosomal dominant AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SEMDJL1 = spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures 1\. See Genetically Related Disorders. 2\. Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele. Other conditions to consider in the differential diagnosis of hypochondroplasia: * Short stature caused by disturbances in the growth hormone axis * Constitutive short stature ## Management ### Evaluations Following Initial Diagnosis Management of children with hypochondroplasia usually does not differ significantly from that of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature. However, because the phenotype of FGFR3 hypochondroplasia may overlap with that of achondroplasia, recommendations for the management of achondroplasia as outlined by the American Academy of Pediatrics Committee on Genetics [Trotter et al 2005] should be considered in children with hypochondroplasia who exhibit more severe phenotypic features. To establish the extent of disease and needs in an individual diagnosed with hypochondroplasia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Hypochondroplasia View in own window System/ConcernEvaluationComment GrowthMeasurement of height, weight, & head circumferencePlot growth parameters on achondroplasia-standardized growth curves. MusculoskeletalClinical assessment for truncal weakness or evidence of thoracolumbar kyphosisLateral spine films to evaluate for thoracolumbar kyphosis if indicated Clinical assessment for genu varumReferral to orthopedist if bowing interferes w/walking Narrow craniocervical junction * Assess for signs/symptoms of sleep apnea; refer for polysomnography if needed. * Neurologic exam for signs of spinal cord compression (e.g., severe hypotonia, hyperreflexia, clonus, & asymmetries) * MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study * Referral to a pediatric neurologist or neurosurgeon if needed NeurologyClinical assessment for symptoms suggestive of epilepsyReferral to pediatric neurologist when indicated DevelopmentDevelopmental assessment * To incl motor, adaptive, cognitive, & speech/language eval * Eval for early intervention / special education Spinal cord stenosisIn newly diagnosed adults: neurologic exam for signs of spinal cord stenosis (intermittent, reversible, exercise-induced claudication to severe, irreversible abnormalities of leg function & continence)If severe signs &/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate. OtherConsultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with Hypochondroplasia View in own window Manifestation/ ConcernTreatmentConsiderations/Other Short stature * Management is influenced by parental expectations & concerns. * Address parents' expectations & prejudices re child's height rather than attempting to treat child. Adult height in hypochondroplasia is considerably greater than achondroplasia & functional limitations (e.g., operating an elevator, driving a car, using an automatic teller machine) usually less severe or not an issue. Narrow craniocervical junction w/spinal cord compressionReferral to pediatric neurosurgeon to consider suboccipital decompression if neurologic status is affected by spinal cord compressionSee Achondroplasia for best predictors of need for suboccipital decompression. Thoracolumbar kyphosisTreatment if necessary per orthopedic surgeon Genu varumTreatment if necessary per orthopedic surgeon Spinal stenosisLaminectomy 1If severe signs &/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate. EpilepsyStandardized treatment w/AEDs by experienced neurologist * No one AED has been demonstrated effective specifically for this disorder. * Education of parents/caregivers 2 DD/IDSee Developmental Delay / Intellectual Disability Management Issues Family/ CommunityConnect family with w/local resources & support (LPA)LPA can: * Assist w/adaptation to short stature through peer support, personal example, & social awareness programs; * Provide info on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, & parenting through local meetings, workshops, seminars, & a national newsletter. AED = antiepileptic drug; DD/ID = developmental delay / intellectual disability; LPA = Little People of America, Inc. 1\. Thomeer & van Dijk [2002] determined that about 70% of symptomatic individuals with achondroplasia experienced total relief of symptoms following decompression without laminectomy. The L2-L3 level most commonly required decompression. 2\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. #### Developmental Disability / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * Individualized education plan (IEP) services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments. Gross motor dysfunction. Physical therapy is recommended to maximize mobility. Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with Hypochondroplasia View in own window System/ConcernEvaluationFrequency GrowthHeight, weight, & head circumferenceMonitor using achondroplasia-standardized growth curves Spinal cord compressionNeurologic exam for signs/symptomsAt routine well-child visits through adulthood MRI or CT exam of the foramen magnum if evidence of severe hypotonia, spinal cord compression, or central sleep apnea Sleep apneaAssessment for signs/symptomsAt routine well-child visits through adulthood Thoracolumbar kyphosisPhysical examAt routine well-child visits through age 3 yrs Genu varumPhysical exam w/orthopedic referral if bowing interferes w/walking DevelopmentAssessment of developmental milestonesMonitor closely during early childhood. Assessment of social adjustmentAt routine well-child visits & then annually ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias. However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries. * In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. * Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy. * If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. ### Therapies Under Investigation #### Growth Hormone Therapy Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Those differences in individual responses published prior to gene discovery in 1995 [Mullis et al 1991, Bridges & Brook 1994] may have resulted from genetic heterogeneity and indicate a need for stratification of affected individuals with regard to genetic etiology (e.g., those with FGFR3 pathogenic variants and those without). Meyer et al [2003] emphasized the importance of considering pubertal development in assessing the response to growth hormone stimulation testing. Tanaka et al [2003] reported data suggesting that children with hypochondroplasia may have a greater response to growth hormone therapy than children with achondroplasia. Pinto et al [2012] treated 19 children with hypochondroplasia (11/19 with confirmed FGFR3 pathogenic variants, mean age 9.0±3.0 years) with human recombinant growth hormone over a three-year period. Their mean height increased 1.32±1.05 standard deviation score (SDS) compared to a historical cohort of 40 untreated individuals with hypochondroplasia. Rothenbuhler et al [2012] treated six children with hypochondroplasia (confirmed FGFR3 p.Asn540Lys substitution, mean age 2.6±0.7 years) with human recombinant growth hormone over a six-year period. Their mean height SDS increased by 1.9 during the study period, and trunk/leg disproportion was improved. Çetin et al [2018] treated six children (mean age 7.8±3.2 years) with hypochondroplasia (confirmed FGFR3 pathogenic variant in a single individual) with human recombinant growth hormone over a mean of 4.45 years. Their mean height SDS increased by 0.26±1.19 during the study period, and trunk/leg disproportion was unchanged. Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition. #### Surgical Limb Lengthening Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [Yasui et al 1997, Lie & Chow 2009]. Nevertheless, the procedure is very invasive and entails considerable disability and discomfort over a long period of time. While some advocate performing the procedure during childhood, many pediatricians, geneticists, and ethicists advocate postponement until adolescence, when the affected individual is able to make an informed decision. Surgical limb lengthening is controversial, but is achieving greater acceptance with fewer complications as larger numbers of operations have been performed. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypochondroplasia	c0410529	3,134	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1477/	2021-01-18T21:18:24	{"mesh": ["C562937"], "synonyms": []}
Chromosome 2q deletion is a chromosome abnormality that occurs when there is a missing copy of the genetic material located on the long arm (q) of chromosome 2. The severity of the condition and the signs and symptoms depend on the size and location of the deletion and which genes are involved. Features that often occur in people with chromosome 2q deletion include developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most cases are not inherited, but people can pass the deletion on to their children. Treatment is based on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Chromosome 2q deletion	c0795804	3,135	gard	https://rarediseases.info.nih.gov/diseases/3744/chromosome-2q-deletion	2021-01-18T18:01:22	{"mesh": ["C538315"], "umls": ["C0795804"], "synonyms": ["Deletion 2q", "Monosomy 2q", "2q deletion", "2q monosomy", "Partial monosomy 2q"]}
Congenital atransferrinemia is a very rare hematologic disease caused by a transferrin (TF) deficiency and characterized by microcytic, hypochromic anemia (manifesting with pallor, fatigue and growth retardation) and iron overload, and that can be fatal if left untreated. ## Epidemiology The prevalence is unknown. To date, there have been 16 reported cases from 14 families. ## Clinical description Disease onset usually occurs in infancy or early childhood. Only one reported patient was diagnosed at the age of 20. The presenting manifestations are those of anemia such as fatigue, anorexia, irritability, tachycardia, systolic murmur and pallor. Growth retardation, hepatomegaly and recurrent infections are other frequent manifestations of the disease. In undiagnosed individuals, iron overload can lead to liver cirrhosis, heart failure and arthropathy. Hypothyroidism and splenomegaly have also been reported separately in two isolated cases. Death can occur due to congestive heart failure or pneumonia. ## Etiology Congenital atransferrinemia is due to mutations in the TF gene (3q21) encoding TF, a blood protein necessary for the proper transport of iron to the liver, spleen, and bone marrow. Without the synthesis of TF, there is a reduction of iron delivery to developing erythroid precursors in bone marrow, which results in reduced hemoglobin synthesis and consequently to anemia and iron storage in peripheral tissues (secondary hemochromatosis). ## Diagnostic methods Diagnosis is based on laboratory testing indicating anemia as well as a serum TF level of less than 35mg/dl. An enlarged liver, due to hemosiderosis may be noted on clinical examination in some cases. Molecular genetic testing can identify a mutation in the TF gene, confirming the diagnosis. ## Differential diagnosis Differential diagnoses include other conditions that manifest with hypotransferrinemia such as GRACILE syndrome and nephrotic syndromes (see these terms) and, in adults, those suffering from chronic alcoholism. ## Antenatal diagnosis Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. ## Genetic counseling Congenital atransferrinemia is inherited in an autosomal recessive manner and genetic counseling is available. ## Management and treatment There is no cure for congenital atransferrinemia. Treatment usually involves monthly phlebotomies followed by infusions of whole plasma or purified apotransferrin which remove excess iron and replenish TF levels, allowing for the proper formation of hemoglobin. Treatment is life-long and regular follow-up is recommended. ## Prognosis With proper treatment the prognosis is good but due to the small number of patients, long-term complications remain unknown. . [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Congenital atransferrinemia	c0521802	3,136	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1195	2021-01-23T17:11:07	{"gard": ["9595"], "mesh": ["C538259"], "omim": ["209300"], "umls": ["C0521802", "C1859593"], "icd-10": ["E88.0"], "synonyms": ["Congenital hypotransferrinemia"]}
X-linked intellectual disability, Wilson type is characterised by severe intellectual deficit with mutism, epilepsy, growth retardation and recurrent infections. It has been described in three males from three generations of one family. The causative gene has been localised to the 11p region of the X chromosome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-linked intellectual disability, Wilson type	c1839792	3,137	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85290	2021-01-23T19:11:31	{"mesh": ["C564106"], "omim": ["309545"], "icd-10": ["Q87.8"]}
Natural, unexpected death from cardiac arrest of athletes "Sudden death (athletes)" redirects here. For tie-breaking procedure, see Sudden death (sports). For similar terms, see Sudden death (disambiguation). Defibrillator training kit It remains a difficult medical challenge to prevent the sudden cardiac death of athletes, typically defined as natural, unexpected death from cardiac arrest within one hour of the onset of collapse symptoms, excluding additional time on mechanical life support.[1] (Wider definitions of sudden death are also in use, but not usually applied to the athletic situation.) Most causes relate to congenital or acquired cardiovascular disease with no symptoms noted before the fatal event. The prevalence of any single, associated condition is low, probably less than 0.3% of the population in the athletes' age group,[citation needed] and the sensitivity and specificity of common screening tests leave much to be desired. The single most important predictor is fainting or near-fainting during exercise, which should require detailed explanation and investigation.[2] The victims include many well-known names, especially in professional soccer, and close relatives are often at risk for similar cardiac problems. ## Contents * 1 Causes * 2 Genetics * 2.1 Cardiomyopathies * 2.2 Channelopathies * 2.3 Heritable connective tissue diseases * 2.4 DNA testing * 3 Screening * 4 Incidence * 5 Notable cases * 6 See also * 7 References ## Causes[edit] The sudden cardiac deaths of 387 young American athletes (under age 35) were analyzed in a 2003 medical review:[3] Cause Incidence Hypertrophic cardiomyopathy 26% Genetically determined Commotio cordis 20% Structurally normal heart, disrupted electrically by a blow to the chest Coronary artery anomalies 14% Exact mechanisms unknown; some association with other congenital CVS abnormalities Left ventricular hypertrophy of undetermined origin 7% Probable variant of hypertrophic cardiomyopathy Myocarditis 5% Acute inflammation Ruptured aortic aneurysm (Marfan syndrome) 3% Genetically determined; also associated with unusual height Arrhythmogenic right ventricular cardiomyopathy 3% Genetically determined Tunneled coronary artery 3% Congenital abnormality Aortic valve stenosis 3% Multiple causes Atherosclerotic coronary artery disease 3% Mainly acquired; dominant cause in older adults Other diagnosis 13% While most causes of sudden cardiac death relate to congenital or acquired cardiovascular disease, an exception is commotio cordis, in which the heart is structurally normal but a potentially fatal loss of rhythm occurs because of the accident of timing of a blow to the chest. Its fatality rate is about 65% even with prompt CPR and defibrillation, and more than 80% without.[4][5] Age 35 serves as an approximate borderline for the likely cause of sudden cardiac death. Before age 35, congenital abnormalities of the heart and blood vessels predominate. These are usually asymptomatic prior to the fatal event, although not invariably so.[6] Congenital cardiovascular deaths are reported to occur disproportionately in African-American athletes.[7] After age 35, acquired coronary artery disease predominates (80%),[6] and this is true regardless of the athlete's former level of fitness.[citation needed] ## Genetics[edit] ### Cardiomyopathies[edit] Arrhythmogenic right ventricular dysplasia, showing fatty infiltration of right and left ventricle, and poor contraction of right ventricle Cardiomyopathies are generally inherited as autosomal dominants, although recessive forms have been described, and dilated cardiomyopathy can also be inherited in an X-linked pattern. Consequently, in addition to tragedy involving an athlete who succumbs, there are medical implications for close relatives. Among family members of index cases, more than 300 causative mutations have been identified. However, not all mutations have the same potential for severe outcomes, and there is not yet a clear understanding of how these mutations (which affect the same myosin protein molecule) can lead to the dramatically different clinical characteristics and outcomes associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).[8] Since HCM, as an example, is typically an autosomal dominant trait, each child of an HCM parent has a 50% chance of inheriting the mutation. In individuals without a family history, the most common cause of the disease is a "de novo" mutation of the gene that produces the β-myosin heavy chain.[citation needed] ### Channelopathies[edit] Sudden cardiac death can usually be attributed to cardiovascular disease or commotio cordis, but about 20% of cases show no obvious cause and remain undiagnosed after autopsy. Interest in these "autopsy-negative" deaths has centered around the "ion channelopathies". These electrolyte channels are pores regulating the movement of sodium, potassium and calcium ions into cardiac cells, collectively responsible for creating and controlling the electrical signals that govern the heart's rhythm. Abnormalities in this system occur in relatively rare genetic diseases such as Long QT syndrome, Brugada syndrome, and Catecholaminergic polymorphic ventricular tachycardia, all associated with sudden death. Consequently, autopsy-negative sudden cardiac deaths (no physical abnormalities identified) may comprise a larger part of the channelopathies than previously anticipated.[9][10] ### Heritable connective tissue diseases[edit] Myxomatous degeneration of the aortic valve, common in Marfan syndrome Heritable connective tissue diseases are rare, each disorder estimated at one to ten per 100,000, of which Marfan syndrome is the most common. It is carried by the FBN1 gene on chromosome 15, which encodes the connective protein fibrillin-1,[11][12] inherited as a dominant trait. This protein is essential for synthesis and maintenance of elastic fibers. Since these fibers are particularly abundant in the aorta, ligaments, and the ciliary zonules of the eye, these areas are among the worst affected. Everyone has a pair of FBN1 genes and, because transmission is dominant, those who have inherited one affected FBN1 gene from either parent will have Marfan syndrome. Although it is most frequently inherited as an autosomal dominant, there is no family history in 25% of cases.[13] Recruiting practices aimed at attracting athletes who are unusually tall or who have an unusually wide arm span (characteristics of Marfan syndrome) can increase the prevalence of the syndrome within sports such as basketball and volleyball. ### DNA testing[edit] After a disease-causing mutation has been identified in an index case (which is not always accomplished conclusively), the main task is genetic identification of carriers within a pedigree, a sequential process known as "cascade testing". Family members with the same mutation may show different severities of disease, a phenomenon known as "variable penetrance". As a result, some may remain asymptomatic, with little lifelong evidence of disease. Nevertheless, their children remain at risk of inheriting the disorder and potentially being more severely affected.[14] ## Screening[edit] See also: Hypertrophic cardiomyopathy screening Echocardiogram showing left ventricle Screening athletes for cardiac disease can be problematic because of low prevalence and inaccurate performance of various tests that have been used. Nevertheless, sudden death among seemingly healthy individuals attracts much public and legislator attention because of its visible and tragic nature. As an example, the Texas Legislature appropriated US$1 million for a pilot study of statewide athlete screening in 2007. The study employed a combination of questionnaire, examination and electrocardiography for 2,506 student athletes, followed by echocardiography for 2,051 of them, including any students with abnormal findings from the first three steps. The questionnaire alone flagged 35% of the students as potentially at risk, but there were many false positive results, with actual disease being confirmed in less than 2%. Further, a substantial number of screen-positive students declined repeated recommendations for follow-up evaluation. (Individuals who are conclusively diagnosed with cardiac disease are usually told to avoid competitive sports.) It should be stressed that this was a single pilot program, but it was indicative of the problems associated with large-scale screening, and consistent with experience in other locations with low prevalence of sudden death in athletes.[15] ## Incidence[edit] Sudden cardiac death occurs in approximately one per 200,000 young athletes per year, usually triggered during competition or practice.[6] The victim is usually male and associated with soccer, basketball, ice hockey, or American football, reflecting the large number of athletes participating in these sustained and strenuous sports.[3] For a normally healthy age group, the risk appears to be particularly magnified in competitive basketball, with sudden cardiac death rates as high as one per 3,000 annually for male basketball players in NCAA Division I.[16] This is still far below the rate for the general population, estimated as one per 1,300–1,600 and dominated by the elderly.[17] However, a population as large as the United States will experience the sudden cardiac death of a competitive athlete at the average rate of one every three days, often with significant local media coverage heightening public attention.[18] ## Notable cases[edit] This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by adding missing items with reliable sources. These athletes, in alphabetical order, experienced sudden cardiac death by age 40. Their notability is established by reliable sources in other Wikipedia articles. * Mohamed Abdelwahab, 22 (2006), soccer * Gaines Adams, 26 (2010), Amer. football * Jaouad Akaddar, 28 (2012), soccer * Davide Astori, 31 (2018), soccer * Víctor Hugo Ávalos, 37 (2009), soccer * Heath Benedict, 24 (2008), Amer. football * Hédi Berkhissa, 24 (1997), soccer * Viktor Blinov, 22 (1968), ice hockey * Gilbert Bulawan, 29 (2016), basketball * J. V. Cain, 28 (1979), Amer. football * Sékou Camara, 27 (2013), soccer * Alexei Cherepanov, 19 (2008), ice hockey * Mitchell Cole, 27 (2012), soccer * Jason Collier, 28 (2005), basketball * Hugo Cunha, 28 (2005), soccer * Renato Curi, 24 (1977), soccer * Alexander Dale Oen, 26 (2012), swimming * Shane del Rosario, 30 (2013), MMA * Ben Idrissa Dermé, 34 (2016), soccer * Lyle Downs, 24 (1921), Austral. football * Patrick Ekeng, 26 (2016), soccer * Bobsam Elejiko, 30 (2011), soccer * Derrick Faison, 36 (2004), Amer. football * Sebastian Faisst, 20 (2009), handball * Miklós Fehér, 24 (2004), soccer * Neil Fingleton, 36 (2017), basketball * Marc-Vivien Foé, 28 (2003), soccer * Matt Gadsby, 27 (2006), soccer * Hank Gathers, 23 (1990), basketball * Cristian Gómez, 27 (2015), soccer * Michael Goolaerts, 23 (2018), cycling * Larry Gordon, 28 (1983), Amer. football * Herb Gorman, 28 (1953), baseball * Rasmus Green, 26 (2006), soccer * Sergei Grinkov, 28 (1995), figure skating * Eddie Guerrero, 38 (2005), wrestling * Frank Hayes, 35 (1923), horse racing * Thomas Herrion, 23 (2005), Amer. football * Cătălin Hîldan, 24 (2000), soccer * Dixie Howell, 40 (1960), baseball * Chuck Hughes, 28 (1971), Amer. football * Flo Hyman, 31 (1986), volleyball * Endurance Idahor, 25 (2010), soccer * Robbie James, 40 (1998), soccer * Daniel Jarque, 26 (2009), soccer * Cristiano Júnior, 25 (2004), soccer * Joe Kennedy, 28 (2007), baseball * Darryl Kile, 33 (2002), baseball * John Kirkby, 23 (1953), soccer * Michael Klein, 33 (1993), soccer * György Kolonics, 36 (2008), canoeing * Wayne Larkin, 29 (1968), ice hockey * Rauli Levonen, 28 (1981), ice hockey * Reggie Lewis, 27 (1993), basketball * José Lima, 37 (2010), baseball * David Longhurst, 25 (1990), soccer * Nikola Mantov, 23 (1973), soccer * Pete Maravich, 40 (1988), basketball * Alex Marques, 20 (2013), soccer * Jesse Marunde, 27 (2007), weightlifting * Scott Mason, 28 (2005), cricket * Stan Mauldin, 27 (1948), Amer. football * Cormac McAnallen, 24 (2004), Gaelic football * Conrad McRae, 29 (2000), basketball * Fab Melo, 26 (2017), basketball * Nilton Pereira Mendes, 30 (2006), soccer * Igor Misko, 23 (2010), ice hockey * Stéphane Morin, 29 (1998), ice hockey * Piermario Morosini, 25 (2012), soccer * Carl Morton, 39 (1983), baseball * Damien Nash, 24 (2007), Amer. football * Frederiek Nolf, 21 (2009), cycling * Chaswe Nsofwa, 28 (2007), soccer * Gábor Ocskay, 33 (2009), ice hockey * Phil O'Donnell, 35 (2007), soccer * Samuel Okwaraji, 25 (1989), soccer * David Oniya, 30 (2015), soccer * Alen Pamić, 23 (2013), soccer * Pavão, 26 (1973), soccer * Bruno Pezzey, 39 (1994), soccer * Pheidippides, c. 40 (490 BC), marathon * Petar Radaković, 29 (1966), soccer * Mickey Renaud, 19 (2008), ice hockey * Bernardo Ribeiro, 26 (2016), soccer * Darcy Robinson, 26 (2007), ice hockey * Brad Rone, 34 (2003), boxing * Omar Sahnoun, 24 (1980), soccer * Serginho, 30 (2004), soccer * Ryan Shay, 28 (2007), marathon * Dave Sparks, 26 (1954), Amer. football * Cheick Tioté, 30 (2017), soccer * Robert Traylor, 34 (2011), basketball * Zeke Upshaw, 26 (2018), basketball * Luciano Vendemini, 24 (1977), basketball * Ginty Vrede, 22 (2008), kickboxing * Frank Warfield, 35 (1932), baseball * Chandler Williams, 27 (2013), Amer. football * David "Soldier" Wilson, 23 (1906), soccer * Sergejs Žoltoks, 31 (2004), ice hockey ## See also[edit] * Cardiac Risk in the Young (UK charity) * Lists of sportspeople who died during their careers ## References[edit] 1. ^ van der Werf C, van Langen IM, Wilde AA (February 2010). "Sudden death in the young: what do we know about it and how to prevent?". Circ Arrhythmia Electrophysiol. 3 (1): 96–104. doi:10.1161/CIRCEP.109.877142. PMID 20160177. 2. ^ Hastings JL, Levine BD (March 2012). "Syncope in the athletic patient". Prog Cardiovasc Dis. 54 (5): 438–44. doi:10.1016/j.pcad.2012.02.003. PMID 22386295. 3. ^ a b Maron, Barry J. (September 11, 2003). "Sudden Death in Young Athletes". New England Journal of Medicine. 349 (11): 1064–1075. doi:10.1056/NEJMra022783. PMID 12968091. 4. ^ Maron, BJ; Estes, NAM III (March 2010). "Commotio cordis". New England Journal of Medicine. 362 (10): 917–927. doi:10.1056/NEJMra0910111. PMID 20220186. 5. ^ "Position Statement on Commotio Cordis". US Lacrosse. January 2008. Retrieved 22 February 2017. 6. ^ a b c Ferreira M, Santos-Silva PR, de Abreu LC, Valenti VE, Crispim V, Imaizumi C, Filho CF, Murad N, Meneghini A, Riera AR, de Carvalho TD, Vanderlei LC, Valenti EE, Cisternas JR, Moura Filho OF, Ferreira C (Aug 3, 2010). "Sudden cardiac death athletes: a systematic review". Sports Med Arthrosc Rehabil Ther Technol. 2: 19. doi:10.1186/1758-2555-2-19. PMC 2923123. PMID 20682064. 7. ^ Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV (March 2003). "Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy". Journal of the American College of Cardiology. 41 (6): 974–980. doi:10.1016/S0735-1097(02)02976-5. 8. ^ Moore JR, Leinwand L, Warshaw DM (Jul 20, 2012). "Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor". Circ Res. 111 (3): 375–85. doi:10.1161/CIRCRESAHA.110.223842. PMC 3947556. PMID 22821910. 9. ^ Westfal RE, Reissman S, Doering G (Jul 1996). "Out-of-hospital cardiac arrests: an 8-year New York City experience". Am J Emerg Med. 14 (4): 364–8. doi:10.1016/S0735-6757(96)90050-9. PMID 8768156. 10. ^ de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, van Ree JW, Daemen MJ, Houben LG, Wellens HJ (Nov 1997). "Out-of-hospital cardiac arrest in the 1990s: a population-based study in the Maastricht area on incidence, characteristics and survival". J Am Coll Cardiol. 30 (6): 1500–5. doi:10.1016/s0735-1097(97)00355-0. PMID 9362408. 11. ^ Kainulainen K, Karttunen L, Puhakka L, Sakai L, Peltonen L (January 1994). "Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome". Nat. Genet. 6 (1): 64–9. doi:10.1038/ng0194-64. PMID 8136837. 12. ^ Dietz HC, Loeys B, Carta L, Ramirez F (November 2005). "Recent progress towards a molecular understanding of Marfan syndrome". Am J Med Genet C Semin Med Genet. 139C (1): 4–9. doi:10.1002/ajmg.c.30068. PMID 16273535. 13. ^ Armon K, Bale P (June 2012). "Identifying heritable connective tissue disorders in childhood". Practitioner. 256 (1752): 19–23, 2–3. PMID 22916581. 14. ^ Raju H, Alberg C, Sagoo GS, Burton H, Behr ER (Nov 21, 2011). "Inherited cardiomyopathies" (PDF). BMJ. 343: d6966. doi:10.1136/bmj.d6966. PMID 22106372. 15. ^ Zeltser I, Cannon B, Silvana L, Fenrich A, George J, Schleifer J, Garcia M, Barnes A, Rivenes S, Patt H, Rodgers G, Scott W (Jun 15, 2012). "Lessons learned from preparticipation cardiovascular screening in a state funded program". Am J Cardiol. 110 (6): 902–8. doi:10.1016/j.amjcard.2012.05.018. PMID 22704711. 16. ^ Harmon KG, Asif IM, Klossner D, Drezner JA (April 2011). "Incidence of sudden cardiac death in National Collegiate Athletic Association athletes". Circulation. 123 (15): 1594–1600. doi:10.1161/CIRCULATIONAHA.110.004622. PMID 21464047. 17. ^ Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, Mariani R, Gunson K, Jui J (Nov–Dec 2008). "Epidemiology of sudden cardiac death: clinical and research implications". Prog Cardiovasc Dis. 51 (3): 213–28. doi:10.1016/j.pcad.2008.06.003. PMC 2621010. PMID 19026856. "For the world (total population approx. 6,540,000,000), the estimated annual burden of sudden cardiac death would be in the range of 4–5 million cases per year." 18. ^ Link, MS; Estes, NAM III (May 2012). "Sudden Cardiac Death in the Athlete". Circulation. 125 (20): 2511–2516. doi:10.1161/CIRCULATIONAHA.111.023861. PMID 22615422. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Sudden cardiac death of athletes	None	3,138	wikipedia	https://en.wikipedia.org/wiki/Sudden_cardiac_death_of_athletes	2021-01-18T18:32:42	{"wikidata": ["Q2099945"]}
Meleda disease Other namesKeratosis palmoplantaris transgrediens of Siemens Meleda disease has an autosomal recessive pattern of inheritance. SpecialtyMedical genetics SymptomsDry, thick patches of skin CausesHereditary; autosomal recessive trait Meleda disease (MDM) or "mal de Meleda", also called Mljet disease, keratosis palmoplantaris and transgradiens of Siemens,[1] (also known as "acral keratoderma",[2] "mutilating palmoplantar keratoderma of the Gamborg-Nielsen type",[2] "palmoplantar ectodermal dysplasia type VIII",[2]:508 and "palmoplantar keratoderma of the Norrbotten type"[3]) is an extremely rare autosomal recessive[4] congenital skin disorder in which dry, thick patches of skin develop on the soles of the hands and feet, a condition known as palmoplantar hyperkeratosis.[5]:214 Meleda Disease is a skin condition which usually can be identified not long after birth. This is a genetic condition but it is very rare. The hands and feet usually are the first to show signs of the disease but the disease can advance to other parts of the body. Signs of the disease include thickening of the skin, on hands and soles of feet, which can turn red in color.[6] There currently is no cure and treatment is limited, but Acitretin can be used in severe cases.[7] ## Contents * 1 Signs and Symptoms * 1.1 Signs * 2 Cause * 3 Pathophysiology * 3.1 Genetic * 4 Diagnosis * 4.1 Palmoplantar keratodermas (PPK) * 4.2 Differential Diagnosis * 5 Treatment * 5.1 Retinoids * 5.1.1 Topical Lotion * 6 Prognosis * 7 Epidemiology * 8 Research Directions * 9 See also * 10 References * 11 Further reading * 12 External links ## Signs and Symptoms[edit] Skin on the palms of hands and soles of feet have dry, thick patches which progress slowly.[8] The skin that is affected may look red in color and then start becoming abnormally thick and scaly.[8] After birth it usually is obvious whether a child is affected with this disease because the hands or feet will appear to be peeling and could be red in color. [6][8] There is not much variation in this disease besides the skin how red the skin will turn and how much skin will turn thicker.[8] The skin that is affected on the hands and feet can start to look like the affected person is wearing gloves or socks, this is because the affected area on the hands and feet go up to the wrists and ankles, respectively.[9] Other symptoms can include excessive sweating due to the thick skin affecting sweat glands on the skin; this excessive sweating can cause a person to have bad odor.[9] Severity of symptoms could increase as a person gets older.[8] ### Signs[edit] * dry skin on hands or feet[6] * skin peeling[6] * thick patches of skin[6] * skin discoloration (red skin)[6] ## Cause[edit] This is a skin disorder that is rare and inherited.[9] It caused by genetics and is an autosomal recessive trait therefore, in order to be affected and present the disease each parent must be a carrier of the mutated allele and pass it to their kids.[6] Inbreeding within families can cause Meleda disease to be prevalent.[9] Meleda disease can be associated with other skin conditions such as skin discoloration, skin thickness, and skin peeling.[6] ## Pathophysiology[edit] Meleda disease is a genetic disease but since it is a rare disease the chances of inheriting the disease are not high.[9] Since this is an autosomal recessive disease, two copies of the gene that contain the mutation must be present for one to show signs and symptoms of the disease.[9] In order for one to be affected with the disease, both parents must contain the affected gene and pass it to their child. Even if a person is not affected by the disease, it is possible for them to be heterozygous, and still carry the affected gene and be able to pass it to their children; there would be a 25% chance that the child would actually be affected if both parents were carriers of the disease but did not actually display symptoms of the disease.[10] ### Genetic[edit] MDM is most common on the Dalmatian island of Mljet (or Meleda), thought to be because of a founder effect. It is of autosomal recessive inheritance. It may be caused by a mutation on the SLURP1 gene, located on chromosome 8.[11] The SLURP1 gene makes a protein called SLURP-1, and this protein is located in cells of the skin.[12] The protein SLURP-1 helps with cell death regulation and help mediate inflammation that is occurring,[13][7] this protein is important in keeping the skin cells at a level of homeostasis.[14] A gene mutation would be caused by the chromosome 8qter,[8][9] which codes for the SLURP1 gene, to be cut, thus causing a mutation in that gene, which would disrupt the way it controls the skin cells.[13] ## Diagnosis[edit] The skin abnormalities can be found on a child at birth or during infancy.[7] The abnormalities on the soles of feet or on the palms of hands can be found by the physician during a full examination.[6] Family medical history can help with diagnosing because this is a genetically inherited disease. Overall, the diagnosis usually happens after birth because the majority of the time the child's hands and feet will be affected, making the condition apparent. Genetic testing can be done to determine whether there are mutations to confirm the disease.[9] There are similar diseases that affect the skin which also have to be taken into consideration before making a diagnosis.[citation needed] ### Palmoplantar keratodermas (PPK)[edit] These are different patterns of disorders that cause the thickening of the skin on the hands and feet: * Diffuse PPK: Symmetric pattern[9] * Focal PPK: Compact masses[9] * Punctate PPK: Distribution of many keratoses[9] ### Differential Diagnosis[edit] * ichtyosis[9] * psoriasis[9] * lichen planus[9] * mycosis fungoides[9] ## Treatment[edit] Treatment can consist of topical lotions, drug therapies, and surgery. Treatment varies from person to person depending on the severity of their symptoms. Treatment has been more successful with oral retinoids than with the use of topical lotions, applied directly to the affected skin.[6] ### Retinoids[edit] Aromatic Retinoid Etretinate used to be prescribed and had effective results in treating Meleda disease, [15] but was taken off of the market in 1998 in America due to toxic effects and the increased risk of birth defects. Aromatic Retinoid Etretinate is still sold in Japan under the name Tigason. In America, Etretinate was replaced by Acitretin, and is only used in severe cases due to the severe side effects.[16] If taking Acitretin it is advised to not donate blood or get pregnant for at least 3 years after taking the drug.[17] #### Topical Lotion[edit] Topical lotions can help keep the skin moisturized, and help reduce flaking of the skin.[9] Generally these are safe to put on skin, but possible side effects can include irritation.[9] * Keratolytics, such as salicylic acid[9] ## Prognosis[edit] With treatment the prognosis can be good for people with this disease.[9] Quality of life can possibly can be decreased, therefore getting treatment is recommended.[6] Too much dry skin can be painful for some and cause discomfort.[8] There is limited data on the life expectancy of an affected person, but this disease alone does not reduce a persons lifespan. ## Epidemiology[edit] Mljet Island located off of Croatia Most cases of Meleda Disease have been reported in and around the former Yugoslavia. It is estimated that there is one case per 100,000 people, who become affected with the disease.[8][7] Symptoms usually show up after birth and there are no differences in gender or ethnicity as to who can become affected.[7] The disease is believed to have started on the Croatian island of Mljet, after people were quarantined on the island for having plague and other diseases in 1826.[9] On the island, inbreeding is believed to have occurred and Meleda disease became apparent.[9] ## Research Directions[edit] Current research is directed to find more treatments, and to see if there is any way to prevent this disease.[6] ## See also[edit] * Palmoplantar keratoderma * List of cutaneous conditions ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 248300 2. ^ a b c Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. 778, 781. ISBN 978-1-4160-2999-1. 4. ^ Fischer J, Bouadjar B, Heilig R, Huber M, Lefèvre C, Jobard F, Macari F, Bakija-Konsuo A, Ait-Belkacem F, Weissenbach J, Lathrop M, Hohl D, Prud'Homme JF (April 2001). "Mutations in the gene encoding SLURP-1 in Mal de Meleda". Human Molecular Genetics. 10 (8): 875–880. doi:10.1093/hmg/10.8.875. ISSN 0964-6906. PMID 11285253. 5. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 6. ^ a b c d e f g h i j k l "Meleda Disease". www.dovemed.com. Retrieved 2019-11-06. 7. ^ a b c d e Perez, Caroline; Khachemoune, Amor (2016-02-01). "Mal de Meleda: A Focused Review". American Journal of Clinical Dermatology. 17 (1): 63–70. doi:10.1007/s40257-015-0157-1. ISSN 1179-1888. PMID 26445964. S2CID 28912068. 8. ^ a b c d e f g h "Meleda Disease". NORD (National Organization for Rare Disorders). Retrieved 2019-11-06. 9. ^ a b c d e f g h i j k l m n o p q r s t u "Diagnosis: Mal de Meleda \| The Dermatologist". www.the-dermatologist.com. Retrieved 2019-12-14. 10. ^ "Autosomal recessive inheritance pattern". Mayo Clinic. Retrieved 2019-12-14. 11. ^ "SLURP1 gene". 12. ^ Reference, Genetics Home. "SLURP1 gene". Genetics Home Reference. Retrieved 2019-12-13. 13. ^ a b Perez, Caroline; Khachemoune, Amor (2016-02-01). "Mal de Meleda: A Focused Review". American Journal of Clinical Dermatology. 17 (1): 63–70. doi:10.1007/s40257-015-0157-1. ISSN 1179-1888. PMID 26445964. S2CID 28912068. 14. ^ Sakabe, Jun-ichi; Kabashima‐Kubo, Rieko; Kubo, Akiharu; Sasaki, Takashi; Tokura, Yoshiki (2014). "A Japanese case of Mal de Meleda with SLURP1 mutation". The Journal of Dermatology. 41 (8): 764–765. doi:10.1111/1346-8138.12539. ISSN 1346-8138. PMID 24985918. S2CID 26539694. 15. ^ Brambilla, L.; Pigatto, P.D.; Boneschi, V.; Altomare, G.F.; Finzi, A.F. (1984). "Unusual Cases of Meleda Keratoderma Treated with Aromatic Retinoid Etretinate". Dermatology. 168 (6): 283–286. doi:10.1159/000249724. ISSN 1421-9832. PMID 6235136. 16. ^ "Etretinate Drug Information, Professional". Drugs.com. Retrieved 2019-12-14. 17. ^ "Drugs & Medications". www.webmd.com. Retrieved 2019-12-14. ## Further reading[edit] * Gjurašić, Marija (June 2010). "Mljetska bolest (Mal de Meleda): promjene identiteta bolesti tijekom povijesti" [Meleda disease (Mal de Meleda): historical shifts in perception] (PDF). Acta Medico-historica Adriatica (in Croatian). Rijeka: Croatian Scientific Society for the History of Health Culture. 8 (1): 17–58. Retrieved 10 August 2017. ## External links[edit] Classification D * ICD-10: Q82.8 (ILDS Q82.834) * OMIM: 248300 External resources * Orphanet: 87503 * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Meleda disease	c0025221	3,139	wikipedia	https://en.wikipedia.org/wiki/Meleda_disease	2021-01-18T19:03:12	{"gard": ["3096", "92"], "mesh": ["D007645"], "umls": ["C0025221"], "orphanet": ["87503"], "wikidata": ["Q4352925"]}
Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinal tract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas. Approximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia, which is an abnormal bleeding disorder caused by a decrease in cells involved in blood clotting called platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritis can occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer. People with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood. There are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms. ## Frequency CVID is estimated to affect 1 in 25,000 to 1 in 50,000 people worldwide, although the prevalence can vary across different populations. ## Causes The cause in CVID is unknown in approximately 90 percent of cases. It is likely that this condition is caused by both environmental and genetic factors. While the specific environmental factors are unclear, the genetic influences in CVID are believed to be mutations in genes that are involved in the development and function of immune system cells called B cells. B cells are specialized white blood cells that help protect the body against infection. When B cells mature, they produce special proteins called antibodies (also known as immunoglobulins). These proteins attach to foreign particles, marking them for destruction. Mutations in the genes associated with CVID result in dysfunctional B cells that cannot make sufficient amounts of antibodies. In about 10 percent of cases, a genetic cause for CVID is known. Mutations in at least 13 genes have been associated with CVID. The most frequent mutations occur in the TNFRSF13B gene. The protein produced from this gene plays a role in the survival and maturation of B cells and in the production of antibodies. TNFRSF13B gene mutations disrupt B cell function and antibody production, leading to immune dysfunction. Other genes associated with CVID are also involved in the function and maturation of immune system cells, particularly of B cells; mutations in these genes account for only a small percentage of cases. All individuals with CVID have a shortage (deficiency) of two or three specific antibodies. Some have a deficiency of the antibodies called immunoglobulin G (IgG) and immunoglobulin A (IgA), while others, in addition to lacking IgG and IgA, are also deficient in immunoglobulin M (IgM). A shortage of these antibodies makes it difficult for people with this disorder to fight off infections. Abnormal and deficient immune responses over time likely contribute to the increased cancer risk. In addition, vaccines for diseases such as measles and influenza do not provide protection for people with CVID because they cannot produce an antibody response. ### Learn more about the gene associated with Common variable immune deficiency * TNFRSF13B Additional Information from NCBI Gene: * CD19 * CD81 * CR2 * ICOS * IKZF1 * IL21 * LRBA * MS4A1 * NFKB1 * NFKB2 * PRKCD * TNFRSF13C ## Inheritance Pattern Most cases of CVID are sporadic and occur in people with no apparent history of the disorder in their family. These cases probably result from a complex interaction of environmental and genetic factors. In rare cases, CVID is inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In a few cases, this condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. When CVID is caused by mutations in the TNFRSF13B gene, it is often sporadic and the result of a new mutation in the gene that occurs during the formation of reproductive cells (eggs or sperm) or in early embryonic development. When TNFRSF13B gene mutations are inherited, they can cause either autosomal dominant CVID or autosomal recessive CVID. Not all individuals who inherit a gene mutation associated with CVID will develop the disease. In many cases, affected children have an unaffected parent who has the same mutation. Additional genetic or environmental factors are likely needed for the disorder to occur. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Common variable immune deficiency	c3809928	3,140	medlineplus	https://medlineplus.gov/genetics/condition/common-variable-immune-deficiency/	2021-01-27T08:25:14	{"gard": ["6140"], "omim": ["615559", "607594", "615577", "615767", "616576", "616873", "240500", "613493", "613494", "613495", "613496", "614699", "614700"], "synonyms": []}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Cerebellopontine angle syndrome" – news · newspapers · books · scholar · JSTOR (December 2015) (Learn how and when to remove this template message) Cerebellopontine angle syndrome Typesneurology The cerebellopontine angle syndrome is a distinct neurological syndrome of deficits that can arise due to the closeness of the cerebellopontine angle to specific cranial nerves.[1] Indications include unilateral hearing loss (85%), speech impediments, disequilibrium, tremors or other loss of motor control. The cerebellopontine angle cistern is a subarachnoid cistern formed by the cerebellopontine angle that lies between the cerebellum and the pons. It is filled with cerebrospinal fluid and is a common site for the growth of acoustic neuromas or schwannomas. ## Contents * 1 Signs and Symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Radiography * 4.2 Traditional protocols * 4.3 Auditory brainstem response audiometry and adjunct tests * 4.4 Magnetic resonance imaging * 5 Management * 5.1 Stereotactic radiosurgery * 5.2 Surgical * 5.2.1 Outcome and complications * 6 See also * 7 References * 8 External links ## Signs and Symptoms[edit] Tumors within the nerve canaliculi initially present with unilateral sensorineural hearing loss, unilateral tinnitus, or disequilibrium (vertigo is rare, on account of the slow growth of neuromas). Speech discrimination out of proportion to hearing loss, difficulty talking on the telephone are frequent accompaniments. Tumors extending into the CPA will likely present with disequilibrium or ataxia depending on the amount of extension on the brainstem. With brainstem extension, midfacial and corneal hypesthesia, hydrocephalus, and other cranial neuropathies become more prevalent. For example, involvement of CN V from a cerebellopontine mass lesion often results in loss of the ipsilateral (same side of the body) corneal reflex (involuntary blink). Patients with larger tumours can develop Bruns nystagmus ('dancing eyes') due to compression of the flocculi.[2] ## Causes[edit] In most cases, the cause of acoustic neuromas is unknown. The only statistically significant risk factor for developing an acoustic neuroma is having a rare genetic condition called neurofibromatosis type 2 (NF2). There are no confirmed environmental risk factors for acoustic neuroma. There are conflicting studies on the association between acoustic neuromas and cellular phone use and repeated exposure to loud noise. In 2011, an arm of the World Health Organization released a statement listing cell phone use as a low grade cancer risk. The Acoustic Neuroma Association recommends that cell phone users use a hands-free device. Meningiomas are significantly more common in women than in men; they are most common in middle-aged women. Two predisposing factors associated with meningiomas for which at least some evidence exists are exposure to ionizing radiation (cancer treatment of brain tumors) and hormone replacement therapy. ## Pathophysiology[edit] Various kinds of tumors, usually primary and benign, are represented in the pathology. Lesions in the area of cerebellopontine angle cause signs and symptoms secondary to compression of nearby cranial nerves, including cranial nerve V (trigeminal), cranial nerve VII (facial), and cranial nerve VIII (vestibulocochlear). The most common cerebellopontine angle (CPA) tumor is a vestibular schwannoma affecting cranial nerve VIII (80%), followed by meningioma (10%). The cranial nerves affected are (from most common to least common) : VIII (cochlear component), VIII (vestibular component), V * Acoustic neuroma/vestibular schwannoma * Meningioma, a tumor of the meninges or membranes that surround the nerves passing through the CPA * Cerebellar astrocytoma, a malignant tumor of star-shaped glial cells called astrocytes in the cerebellum * Intracranial epidermoid cyst * Lipoma * Glomus jugulare associated with the glossopharyngeal nerve * Idiopathic hypertrophic pachymeningitis[3] * IgG4-related hypertrophic pachymeningitis[3] * CPA Metastases in cancer patients with inner ear symptoms (rare) ## Diagnosis[edit] ### Radiography[edit] Subsequent to diagnosis of sensorineural hearing loss, and differential diagnosis of retrocochlear or neural etiologies, radiological assessment of the CPA is performed to assess the presence of anatomical retrocochlear lesions. ### Traditional protocols[edit] Before the advent of MRI, electronystagmography and Computed Tomography were employed for diagnosis of acoustic neuroma. ### Auditory brainstem response audiometry and adjunct tests[edit] The auditory brainstem response (ABR) test gives information about the inner ear (cochlea) and nerve pathways for hearing via ongoing electrical activity in the brain measured by electrodes placed on the scalp. Five different waves (I to V) are measured for each ear. Each waveform represents specific anatomical points along the auditory neural pathway. Delays of one side relative to the other suggest a lesion in cranial nerve VIII between the ear and brainstem or in the brainstem itself. The most reliable indicator for acoustic neuromas from the ABR is the interaural latency differences in wave V: the latency in the impaired ear is prolonged. Different studies have indicated the sensitivity of ABR for detection of acoustic neuromas 1cm or larger to be between 90 and 95%. Sensitivity for neuromas smaller than 1cm are 63-77%. A newer technology, stacked ABR, may have sensitivity as high as 95% with specificity 88% for smaller tumors. ABR is considerably more cost effective, but MRI provides more information. Stapedius reflex (SR) and caloric vestibular response (CVR) are non-invasive otologic tests for auditory neural function. These are not primary diagnostics for CPA neuromas, and are usually used in conjunction with ABR. ### Magnetic resonance imaging[edit] Several different types of magnetic resonance imaging (MRI) may be employed in diagnosis: MRI without contrast, Gd contrast enhanced T1-weighted MRI (GdT1W) or T2-weighted enhanced MRI (T2W or T2W). Non-contrast enhanced MRI is considerably less expensive than any of the contrast enhanced MRI scans. The gold standard in diagnosis is GdT1W MRI. The reliability of non-contrast enhanced MRI is highly dependent on the sequence of scans, and the experience of the operator. ## Management[edit] Acoustic neuromas are managed by either surgery, radiation therapy, or observation with regular MRI scanning. With treatment, the likelihood of hearing preservation varies inversely with the size of the tumor; for large tumors, preservation of hearing is rare. Because acoustic neuromas, meningiomas and most other CPA tumors are benign, slow growing or non-growing, and non-invasive, observation is a viable management option. ### Stereotactic radiosurgery[edit] The objective of irradiation is to halt the growth of the acoustic neuroma tumour, it does not excise it from the body, as the term 'radiosurgery' or 'gammaknife' implies. Radiosurgery is only suitable for small to medium size tumors. ### Surgical[edit] There are three modalities of surgical treatment (excision) depending on where the anatomical location of the incision to access the tumor is made: retrosigmoid (a variant of what was formerly called suboccipital), translabyrinthine, and middle fossa. The goals of surgery are to control the tumor, and preserve hearing as well as facial nerves. Especially in the case of larger tumors, there may be a tradeoff between tumor removal and preservation of nerve functionality. There are different defined degrees of surgical excision, termed 'subtotal resection', 'radical subtotal resection', 'near-total resection', and 'total resection' in order or increasing proportion of tumor removed. Lesser amount of tumor removal may increase likelihood of preservation of nerve function (hence better post-operative hearing), but also likelihood of tumor regrowth, necessitating additional treatment. #### Outcome and complications[edit] The overall complication rate following surgery is around 20%; cerebrospinal fluid leak is the most common. ## See also[edit] Cerebellum * Pons ## References[edit] 1. ^ Rolak LA. Neurology Secrets, 4th Ed. Chapter 10, "Cerebellar Disease." Elsevier. 2. ^ Nedzelski JM (October 1983). "Cerebellopontine angle tumors: bilateral flocculus compression as cause of associated oculomotor abnormalities". Laryngoscope. 93 (10): 1251–60. doi:10.1002/lary.1983.93.10.1251. PMID 6604857. 3. ^ a b E. Rodríguez-Castro; A. Fernández-Lebrero; I.A. López-Dequidt; X. Rodríguez-Osorio; F.J. López-González; J.M. Suárez-Peñaranda; M. Arias (1 October 2015). "[Hypertrophic pachymeningitis secondary to IgG4-related disease: case report and review of the literature]". Revista de Neurología (in Spanish). 61 (7): 308–312. PMID 26411275. ## External links[edit] Classification D * ICD-9-CM: 191.6 \- Neoplasms of brain: Cerebellum NOS: Cerebellopontine angle * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cerebellopontine angle syndrome	c0271518	3,141	wikipedia	https://en.wikipedia.org/wiki/Cerebellopontine_angle_syndrome	2021-01-18T19:08:55	{"umls": ["C0271518"], "icd-9": ["ICD-10-CM D33.1", "191.6"], "wikidata": ["Q640437"]}
Radial deficiency-tibial hypoplasia syndrome is a rare, genetic dysostosis syndrome with combined reduction defects of upper and lower limbs characterized by bilateral radial aplasia, absent thumbs and bilateral tibial hypo/aplasia. Additional bone anomalies (including partial toe hypo/aplasia, short fibula and clubhand) may be associated. There have been no further descriptions in the literature since 1996. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Radial deficiency-tibial hypoplasia syndrome	None	3,142	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1121	2021-01-23T18:00:06	{"icd-10": ["Q73.8"]}
poisoning of humans from pesticide exposure Pesticide toxicity A sign warning about potential pesticide exposure. SpecialtyEmergency medicine, toxicology A pesticide poisoning occurs when pesticides, chemicals intended to control a pest, affect non-target organisms such as humans, wildlife, plant or bees. There are three types of pesticide poisoning. The first of the three is a single and short-term very high level of exposure which can be experienced by individuals who commit suicide, as well as pesticide formulators. The second type of poisoning is long-term high-level exposure, which can occur in pesticide formulators and manufacturers. The third type of poisoning is a long-term low-level exposure, which individuals are exposed to from sources such as pesticide residues in food as well as contact with pesticide residues in the air, water, soil, sediment, food materials, plants and animals.[1][2][3][4] In developing countries, such as Sri Lanka, pesticide poisonings from short-term very high level of exposure (acute poisoning) is the most worrisome type of poisoning. However, in developed countries, such as Canada, it is the complete opposite: acute pesticide poisoning is controlled, thus making the main issue long-term low-level exposure of pesticides.[5] ## Contents * 1 Cause * 1.1 Accidental or suicidal * 1.2 Occupational * 1.3 Residential * 2 Pathophysiology * 2.1 Organochlorines * 2.2 Anticholinesterase compounds * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 Society and culture * 8 Other animals * 9 See also * 10 Notes * 11 References * 11.1 Cited texts * 12 External links ## Cause[edit] The most common exposure scenarios for pesticide-poisoning cases are accidental or suicidal poisonings, occupational exposure, by-stander exposure to off-target drift, and the general public who are exposed through environmental contamination.[6] ### Accidental or suicidal[edit] Share of suicide deaths from pesticide poisoning[7] Self-poisoning with agricultural pesticides represents a major hidden public health problem accounting for approximately one-third of all suicides worldwide.[8] It is one of the most common forms of self-injury in the Global South. The World Health Organization estimates that 300,000 people die from self-harm each year in the Asia-Pacific region alone.[9] Most cases of intentional pesticide poisoning appear to be impulsive acts undertaken during stressful events, and the availability of pesticides strongly influences the incidence of self poisoning. Pesticides are the agents most frequently used by farmers and students in India to commit suicide.[10] ### Occupational[edit] Pesticide poisoning is an important occupational health issue because pesticides are used in a large number of industries, which puts many different categories of workers at risk. Extensive use puts agricultural workers in particular at increased risk for pesticide illnesses.[11][12][13] Exposure can occur through inhalation of pesticide fumes, and often occurs in settings including greenhouse spraying operations and other closed environments like tractor cabs or while operating rotary fan mist sprayers in facilities or locations with poor ventilation systems.[14] Workers in other industries are at risk for exposure as well.[12][13] For example, commercial availability of pesticides in stores puts retail workers at risk for exposure and illness when they handle pesticide products.[15] The ubiquity of pesticides puts emergency responders such as fire-fighters and police officers at risk, because they are often the first responders to emergency events and may be unaware of the presence of a poisoning hazard.[16] The process of aircraft disinsection, in which pesticides are used on inbound international flights for insect and disease control, can also make flight attendants sick.[17][18] Different job functions can lead to different levels of exposure.[6] Most occupational exposures are caused by absorption through exposed skin such as the face, hands, forearms, neck, and chest. This exposure is sometimes enhanced by inhalation in settings including spraying operations in greenhouses and other closed environments, tractor cabs, and the operation of rotary fan mist sprayers.[14] ### Residential[edit] When thinking of pesticide poisoning, one does not take into consideration the contribution that is made of their own household. The majority of households in Canada use pesticides while taking part in activities such as gardening. In Canada, 96 percent of households report having a lawn or a garden.[19] 56 percent of the households who have a lawn or a garden utilize fertilizer or pesticide.[19] This form of pesticide use may contribute to the third type of poisoning, which is caused by long-term low-level exposure.[20] As mentioned before, long-term low-level exposure affects individuals from sources such as pesticide residues in food as well as contact with pesticide residues in the air, water, soil, sediment, food materials, plants and animals.[20] ## Pathophysiology[edit] ### Organochlorines[edit] DDT, an organochlorine The organochlorine pesticides, like DDT, aldrin, and dieldrin, are extremely persistent and accumulate in fatty tissue. Through the process of bioaccumulation (lower amounts in the environment get magnified sequentially up the food chain), large amounts of organochlorines can accumulate in top species like humans.[citation needed] There is substantial evidence to suggest that DDT, and its metabolite DDE, act as endocrine disruptors, interfering with hormonal function of estrogen, testosterone, and other steroid hormones.[citation needed] ### Anticholinesterase compounds[edit] Malathion, an organophosphate anticholinesterase Cholinesterase-inhibiting pesticides, also known as organophosphates, carbamates, and anticholinesterases, are most commonly reported in occupationally related pesticide poisonings globally.[21] Besides acute symptoms including cholinergic crisis, certain organophosphates have long been known to cause a delayed-onset toxicity to nerve cells, which is often irreversible. Several studies have shown persistent deficits in cognitive function in workers chronically exposed to pesticides.[22] ## Diagnosis[edit] Most pesticide-related illnesses have signs and symptoms that are similar to common medical conditions, so a complete and detailed environmental and occupational history is essential for correctly diagnosing a pesticide poisoning. A few additional screening questions about the patient's work and home environment, in addition to a typical health questionnaire, can indicate whether there was a potential pesticide poisoning.[23] If one is regularly using carbamate and organophosphate pesticides, it is important to obtain a baseline cholinesterase test. Cholinesterase is an important enzyme of the nervous system, and these chemical groups kill pests and potentially injure or kill humans by inhibiting cholinesterase. If one has had a baseline test and later suspects a poisoning, one can identify the extent of the problem by comparison of the current cholinesterase level with the baseline level. ## Prevention[edit] Accidental poisonings can be avoided by proper labeling and storage of containers. When handling or applying pesticides, exposure can be significantly reduced by protecting certain parts of the body where the skin shows increased absorption, such as the scrotal region, underarms, face, scalp, and hands.[24] Safety protocols to reduce exposure include the use of personal protective equipment, washing hands and exposed skin during as well as after work, changing clothes between work shifts, and having first aid trainings and protocols in place for workers.[25][26] Personal protective equipment for preventing pesticide exposure includes the use of a respirator, goggles, and protective clothing, which have all have been shown to reduce risk of developing pesticide-induced diseases when handling pesticides.[25] A study found the risk of acute pesticide poisoning was reduced by 55% in farmers who adopted extra personal protective measures and were educated about both protective equipment and pesticide exposure risk.[25] Exposure can be significantly reduced when handling or applying pesticides by protecting certain parts of the body where the skin shows increased absorption, such as the scrotal region, underarms, face, scalp, and hands.[24] Using chemical-resistant gloves has been shown to reduce contamination by 33–86%.[27] ## Treatment[edit] Specific treatments for acute pesticide poisoning are often dependent on the pesticide or class of pesticide responsible for the poisoning. However, there are basic management techniques that are applicable to most acute poisonings, including skin decontamination, airway protection, gastrointestinal decontamination, and seizure treatment.[23] Decontamination of the skin is performed while other life-saving measures are taking place. Clothing is removed, the patient is showered with soap and water, and the hair is shampooed to remove chemicals from the skin and hair. The eyes are flushed with water for 10–15 minutes. The patient is intubated and oxygen administered, if necessary. In more severe cases, pulmonary ventilation must sometimes be supported mechanically.See Note 1 Seizures are typically managed with lorazepam, phenytoin and phenobarbitol, or diazepam (particularly for organochlorine poisonings).[23] Gastric lavage is not recommended to be used routinely in pesticide poisoning management, as clinical benefit has not been confirmed in controlled studies; it is indicated only when the patient has ingested a potentially life-threatening amount of poison and presents within 60 minutes of ingestion.[28] An orogastric tube is inserted and the stomach is flushed with saline to try to remove the poison. If the patient is neurologically impaired, a cuffed endotracheal tube inserted beforehand for airway protection.[23] Studies of poison recovery at 60 minutes have shown recovery of 8%–32%.[29][30] However, there is also evidence that lavage may flush the material into the small intestine, increasing absorption.[31] Lavage is contra-indicated in cases of hydrocarbon ingestion.[23] Activated charcoal is sometimes administered as it has been shown to be successful with some pesticides. Studies have shown that it can reduce the amount absorbed if given within 60 minutes,[32] though there is not enough data to determine if it is effective if time from ingestion is prolonged. Syrup of ipecac is not recommended for most pesticide poisonings because of potential interference with other antidotes and regurgitation increasing exposure of the esophagus and oral area to the pesticide.[33] Urinary alkalinisation has been used in acute poisonings from chlorophenoxy herbicides (such as 2,4-D, MCPA, 2,4,5-T and mecoprop); however, evidence to support its use is poor.[34] ## Epidemiology[edit] Acute pesticide poisoning is a large-scale problem, especially in developing countries. "Most estimates concerning the extent of acute pesticide poisoning have been based on data from hospital admissions which would include only the more serious cases. The latest estimate by a WHO task group indicates that there may be 1 million serious unintentional poisonings each year and in addition 2 million people hospitalized for suicide attempts with pesticides. This necessarily reflects only a fraction of the real problem. On the basis of a survey of self-reported minor poisoning carried out in the Asian region, it is estimated that there could be as many as 25 million agricultural workers in the developing world suffering an episode of poisoning each year."[35] In Canada in 2007 more than 6000 cases of acute pesticide poisoning occurred.[36] Estimating the numbers of chronic poisonings worldwide is more difficult. ## Society and culture[edit] Rachel Carson's 1962 environmental science book Silent Spring brought about the first major wave of public concern over the chronic effects of pesticides.[citation needed] ## Other animals[edit] An obvious side effect of using a chemical meant to kill is that one is likely to kill more than just the desired organism. Contact with a sprayed plant or "weed" can have an effect upon local wildlife, most notably insects. A cause for concern is how pests, the reason for pesticide use, are building up a resistance. Phytophagous insects are able to build up this resistance because they are easily capable of evolutionary diversification and adaptation.[37] The problem this presents is that in order to obtain the same desired effect of the pesticides they have to be made increasingly stronger as time goes on. Repercussions of the use of stronger pesticides on vegetation has a negative result on the surrounding environment, but also would contribute to consumers' long-term low-level exposure. ## See also[edit] * Health effects of pesticides * SENSOR-Pesticides program * WHO Pesticide Evaluation Scheme ## Notes[edit] Note 1. Specific pesticides have special considerations with regard to respiratory support. In anticholinesterase poisoning, adequate tissue oxygenation is essential before administering atropine. In paraquat and diquat poisoning, however, oxygen is contraindicated.[23][38] ## References[edit] 1. ^ Ramesh C. Gupta (28 April 2011). Toxicology of Organophosphate & Carbamate Compounds. Academic Press. pp. 352–353. ISBN 978-0-08-054310-9. 2. ^ Denis Hamilton; Stephen Crossley (14 May 2004). Pesticide Residues in Food and Drinking Water: Human Exposure and Risks. John Wiley & Sons. p. 280. ISBN 978-0-470-09160-9. 3. ^ Lewis A. Owen; Professor Kevin T Pickering; Kevin T. Pickering (1 March 2006). An Introduction to Global Environmental Issues. Routledge. p. 197. ISBN 978-1-134-76919-3. 4. ^ Annalee Yassi (2001). Basic Environmental Health. Oxford University Press. p. 277. ISBN 978-0-19-513558-9. 5. ^ "Archived copy" (PDF). Archived (PDF) from the original on 2015-06-26. Retrieved 2012-03-13.CS1 maint: archived copy as title (link) 6. ^ a b Ecobichon (2001) p. 767 7. ^ "Share of suicide deaths from pesticide poisoning". Our World in Data. Retrieved 4 March 2020. 8. ^ Bertolote, J. M.; Fleischmann, A.; Eddleston, M.; Gunnell, D. "Deaths from pesticide poisoning: a global response". The British Journal of Psychiatry. Archived from the original on 4 March 2015. Retrieved 26 April 2018. 9. ^ WHO. The impact of pesticides on health: preventing intentional and unintentional deaths from pesticide poisoning. 2004: http://www.who.int/mental_health/prevention/suicide/en/PesticidesHealth2.pdf 10. ^ Devendranath Sarkar; Mohammad Shaheduzzaman; Mohammad Ismail Hossain; Mainnudin Ahmed; Nur Mohammad; Ariful Basher (March 2013). "Spectrum of Acute Pharmaceutical and Chemical Poisoning in Northern Bangladesh": 3. Cite journal requires `\|journal=` (help) 11. ^ Reeves, K. S.; Schafer, K. S. (2003). "Greater risks, fewer rights: U.S. Farmworkers and pesticides". International Journal of Occupational and Environmental Health. 9 (1): 30–39. doi:10.1179/107735203800328858. PMID 12749629. 12. ^ a b Calvert, G. M.; Karnik, J.; Mehler, L.; Beckman, J.; Morrissey, B.; Sievert, J.; Barrett, R.; Lackovic, M.; Mabee, L.; Schwartz, A.; Mitchell; Moraga-Mchaley (2008). "Acute pesticide poisoning among agricultural workers in the United States, 1998-2005". American Journal of Industrial Medicine. 51 (12): 883–898. doi:10.1002/ajim.20623. PMID 18666136. 13. ^ a b Calvert, G. M.; Plate, D. K.; Das, R.; Rosales, R.; Shafey, O.; Thomsen, C.; Male, D.; Beckman, J.; Arvizu, E.; Lackovic, M. (2004). "Acute occupational pesticide-related illness in the US, 1998-1999: Surveillance findings from the SENSOR-pesticides program". American Journal of Industrial Medicine. 45 (1): 14–23. doi:10.1002/ajim.10309. PMID 14691965. 14. ^ a b Ecobichon (2001) p. 768 15. ^ Calvert, G. M.; Petersen, A. M.; Sievert, J.; Mehler, L. N.; Das, R.; Harter, L. C.; Romoli, C.; Becker, A.; Ball, C.; Male, D.; Schwartz, A.; Lackovic, M. (2007). "Acute Pesticide Poisoning in the U.S. Retail Industry, 1998–2004". Public Health Reports. 122 (2): 232–244. doi:10.1177/003335490712200213. PMC 1820427. PMID 17357366. 16. ^ Calvert, G. M.; Barnett, M.; Mehler, L. N.; Becker, A.; Das, R.; Beckman, J.; Male, D.; Sievert, J.; Thomsen, C.; Morrissey, B. (2006). "Acute pesticide-related illness among emergency responders, 1993–2002". American Journal of Industrial Medicine. 49 (5): 383–393. doi:10.1002/ajim.20286. PMID 16570258. 17. ^ WHO. World Health Organization Communicable Disease Control, Prevention and Eradication Pesticide Evaluation Scheme (WHOPES) & Protection of the Human Environment Programme on Chemical Safety (PCS). 2005. Safety of pyrethroids for public health use. Archived 2009-11-03 at the Wayback Machine Geneva: WHO. WHO/CDS/WHOPES/GCDPP/2005.10 WHO/PCS/RA/2005.1. 18. ^ Sutton, P. M.; Vergara, X.; Beckman, J.; Nicas, M.; Das, R. (2007). "Pesticide illness among flight attendants due to aircraft disinsection". American Journal of Industrial Medicine. 50 (5): 345–356. doi:10.1002/ajim.20452. PMID 17407145. 19. ^ a b Canada, Government of Canada, Statistics. "CANSIM - 153-0064 - Households and the environment survey, use of fertilizer and pesticides, Canada, provinces and census metropolitan areas (CMA)". www5.statcan.gc.ca. Archived from the original on 26 April 2018. Retrieved 26 April 2018. 20. ^ a b "Long Term Pesticide Poisoning At Home". Archived from the original on 2016-09-13. 21. ^ Kishi, Misa. "Summary of the Main Factors Contributing to Incidents of Acute Toxic Pesticides" (PDF). WHO. WHO. Archived (PDF) from the original on 2015-09-22. 22. ^ Jamal, G. A.; Hansen, S.; Julu, P. O. (2002). "Low level exposures to organophosphorus esters may cause neurotoxicity". Toxicology. 181–182: 23–33. doi:10.1016/S0300-483X(02)00447-X. PMID 12505280. 23. ^ a b c d e f Reigart, J. Routt; Roberts, James R. (1999). Recognition and Management of Pesticide Poisonings (5th ed.). Washington, DC: Environmental Protection Agency. Archived from the original on 2009-05-10. Roberts, James R.; Reigart, J. Routt (2013). Recognition and Management of Pesticide Poisonings (6th ed.). Washington, DC: Office of Pesticide Programs, U.S. Environmental Protection Agency. Full text of the book is freely available from the EPA (15 Mb) 24. ^ a b Feldman RJ, Maiback HI (1974). "Percutaneous penetration of some pesticides and herbicides in man". Toxicol Appl Pharmacol. 28 (1): 126–132. doi:10.1016/0041-008x(74)90137-9. PMID 4853576. 25. ^ a b c Ye, Ming; Beach, Jeremy; Martin, Jonathan; Senthilselvan, Ambikaipakan (28 November 2013). "Occupational Pesticide Exposures and Respiratory Healh". Int J Environ Res Public Health. 10 (12): 6442–6471. doi:10.3390/ijerph10126442. PMC 3881124. PMID 24287863. 26. ^ Fait, A; Iversen, B; Tiramani, M; Visentin, S; Maroni, M. "Preventing Health Risks from Use of Pesticides in Agriculture" (PDF). WHO. International Centre for Pesticide Safety. Archived (PDF) from the original on 19 August 2017. Retrieved 26 October 2017. 27. ^ Bonsall (1985), pp. 13–133. 28. ^ Vale, J. A. (1997). "Position statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists" (PDF). Journal of Toxicology. Clinical Toxicology. 35 (7): 711–719. doi:10.3109/15563659709162568. PMID 9482426. Archived (PDF) from the original on 2016-01-05. 29. ^ Tenenbein, M.; Cohen, S.; Sitar, D. (1987). "Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose". Annals of Emergency Medicine. 16 (8): 838–841. doi:10.1016/S0196-0644(87)80518-8. PMID 2887134. 30. ^ Danel, V.; Henry, J. A.; Glucksman, E. (1988). "Activated charcoal, emesis, and gastric lavage in aspirin overdose". BMJ. 296 (6635): 1507. doi:10.1136/bmj.296.6635.1507. PMC 2546073. PMID 2898963. 31. ^ Saetta, J. P.; March, S.; Gaunt, M. E.; Quinton, D. N. (1991). "Gastric emptying procedures in the self-poisoned patient: are we forcing gastric content beyond the pylorus?". Journal of the Royal Society of Medicine. 84 (5): 274–276. doi:10.1177/014107689108400510. PMC 1293224. PMID 1674963. 32. ^ Chyka, P. A.; Seger, D. (1997). "Position Statement: Single-Dose Activated Charcoal". Clinical Toxicology. 35 (7): 721–741. doi:10.3109/15563659709162569. PMID 9482427. 33. ^ Krenzelok, E. P.; McGuigan, M.; Lheur, P. (1997). "Position statement: ipecac syrup. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists". Journal of Toxicology. Clinical Toxicology. 35 (7): 699–709. doi:10.3109/15563659709162567. PMID 9482425. 34. ^ Roberts DM, Buckley NA (2007). Roberts DM (ed.). "Urinary alkalinisation for acute chlorophenoxy herbicide poisoning". Cochrane Database Syst Rev (1): CD005488. doi:10.1002/14651858.CD005488.pub2. PMID 17253558. 35. ^ Jeyaratnam, J. (1990). "Acute pesticide poisoning: a major global health problem". World Health Statistics Quarterly. Rapport Trimestriel de Statistiques Sanitaires Mondiales. 43 (3): 139–144. PMID 2238694. 36. ^ "www.davidsuzuki.org" (PDF). Archived from the original (PDF) on 2010-05-03. 37. ^ Gassmann Aaron J (2009). "Evolutionary analysis of herbivorous insects in natural and agricultural environments". Pest Management Science. 65 (11): 1174–1181. doi:10.1002/ps.1844. PMID 19757500. 38. ^ Jeyaratnam, J. (1990). "ACUTE PESTICIDE POISONING: A MAJOR GLOBAL HEALTH PROBLEM" (PDF). World Health Statistics Quarterly. 43 (3): 139–144. PMID 2238694. Archived (PDF) from the original on 2015-06-26. ### Cited texts[edit] * Bonsal, J.L. (1985). "Measurement of occupational exposure to pesticides". In Turnbull, G.S. (ed.). Occupational Hazards of Pesticide use. London: Taylor & Francis. ISBN 978-0-85066-325-9. * Ecobichon, D.J. (2001). "Toxic effects of pesticides". In Klaassen, C.D. (ed.). Casarett and Doull's Toxicology: The Basic Science of Poisons, 6th edition. McGraw-Hill Professional. ISBN 978-0-07-134721-1. * Rang, H.P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. ## External links[edit] Classification D * ICD-10: T60 * ICD-9-CM: 989.4 External resources * MedlinePlus: 002430 * eMedicine: article/815051 * v * t * e Pesticides Pesticide types * Acaricide * Bactericide * Biocide * Bioherbicide * Biopesticide * Fungicide * Herbicide * Insecticide * Molluscicide * Nematicide * Piscicide * Rodenticide * Slimicide Related topics * Health effects * Environmental effects * Fumigation * Agricultural spray adjuvant * Biological pest control * Gene silencing * Green pest management * Integrated pest management * Maximum residue limit * Non-pesticide management * Persistent organic pollutant * Pest control * Application * Drift * Formulation * Degradation * Misuse * Paradox of the pesticides * Poisoning * Research * Residue * Resistance * Bee toxicity * Restricted use * Pesticide Action Network * Silent Spring * The Pesticide Question * Toxicity Class By country * Canada * European Union * New Zealand * United States * Integrated 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* Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject Authority control * NDL: 00568731 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pesticide poisoning	c0275009	3,143	wikipedia	https://en.wikipedia.org/wiki/Pesticide_poisoning	2021-01-18T19:04:08	{"icd-9": ["989.4"], "icd-10": ["T60"], "wikidata": ["Q839525"]}
Congenital tufting enteropathy is an inherited disorder of the small intestine that presents with intractable diarrhea in young children. ## Contents * 1 History * 2 Genetics * 3 Pathology * 4 Clinical * 5 Differential diagnosis * 6 Associated conditions * 7 References ## History[edit] The first cases appears to have been reported in 1978 by Davidson et al.[1] These authors reported a five cases of intractable diarrhoea four of whom died. Post mortum showed a thin and dilated intestine with flat small bowel mucosa. A number of jejunal biopsies had been taken during life and these showed partial villous atrophy with by crypt hyperplasia and an increased number of mitotic figures in the crypts. Normal numbers and types of mononuclear cells were present in the lamina propria. Most notably focal epithelial tufts were found on the surface epithelium. These tufts were composed of closely packed enterocytes with apical rounding of the plasma membrane, resulting in a teardrop configuration of the cells. Inclusion bodies or secretory granules were not visualised on transmission electron microscopy within the cytoplasm of the villous enterocytes. Reifen et al reported 2 additional cases in 1994 and coined the name congenital tufting enteropathy.[2] ## Genetics[edit] Two genes have been associated with this condition:[3][4] Epithelial cell adhesion molecule (EpCAM) on chromosome 2 (2p21) and SPINT2 on chromosome 19. SPINT2 is a Kunitz-type protease inhibitor. The mutation in the EpCAM gene in Kuwait and Qatar appears to have originated 5000–6000 years ago.[5] ## Pathology[edit] Histological examination of the small bowel shows varying degrees of villous atrophy, with low or without mononuclear cell infiltration of the lamina propria. The most important feature involves the epithelium where the surface enterocytes are disorganized with focal crowding creating structures resembling tufts. Other features that have been reported include the abnormal deposition of laminin and heparan sulfate proteoglycan within the basement membrane and increased expression of desmoglein. Electron microscopic changes in the desmosomes have been noted as have abnormal distribution of alpha2beta1 integrin adhesion molecules. ## Clinical[edit] The prevalence of this disorder has been estimated to be 1/50,000-100,000 per live births in Western Europe.[6] It appears to be higher in areas with high degree of consanguinity and in patients of Arabic origin. The infants present in the first few days of life with watery diarrhoea. This leads rapidly to dehydration and electrolyte imbalance and metabolic decompensation. Enteral feeding with a protein hydrolysate or amino acid based formulas worsen the diarrhoea and the children rapidly fail to thrive and develop protein energy malnutrition. In the majority of cases the severity of the malabsorption and diarrhoea make them dependent on daily long term total parenteral nutrition. Hepatic fibrosis and cirrhosis are known complications. Bowel transplantation may be an option. ## Differential diagnosis[edit] * Congenital chloride diarrhoea * Congenital sodium diarrhoea * Familial microvillous atrophy * Glucose-galactose malabsorption ## Associated conditions[edit] * Choanal atresia * Nonspecific punctuated keratitis (60%) * Oesophageal atresia * Unperforated anus ## References[edit] 1. ^ Davidson, G.P.; Cutz, E.; Hamilton, J.R.; Gall, D.G. (1978). "Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy". Gastroenterology. 75 (5): 783–790. doi:10.1016/0016-5085(78)90458-4. PMID 100367.. 2. ^ Reifen, R.M.; Cutz, E.; Griffiths, A-M.; Ngan, B.Y.; Sherman, P.M. (April 1994). "Tufting enteropathy: a newly recognized clinicopathological entity associated with refractory diarrhea in infants". Journal of Pediatric Gastroenterology and Nutrition. 18 (3): 379–385. doi:10.1097/00005176-199404000-00022. PMID 8057225. 3. ^ Sivagnanam, Mamata; Mueller, James L.; Lee, Hane; Chen, Zugen; Nelson, Stanley F.; Turner, Dan; Zlotkin, Stanley H.; Pencharz, Paul B.; Ngan, Bo-Yee; Libiger, Ondrej; Schork, Nicholas J.; Lavine, Joel E.; Taylor, Sharon; Newbury, Robert O.; Kolodner, Richard D.; Hoffman, Hal M. (May 15, 2008). "Identification of EpCAM as the gene for congenital tufting enteropathy". Gastroenterology. 135 (2): 429–347. doi:10.1053/j.gastro.2008.05.036. PMC 2574708. PMID 18572020. 4. ^ Sivagnanam, M.; Janecke, A.R.; Müller, T.; Heinz-Erian, P.; Taylor, S; Bird, L.M. (2010). "Case of syndromic tufting enteropathy harbors SPINT2 mutation seen in congenital sodium diarrhea". Clinical Dysmorphology. 19 (1): 48. doi:10.1097/MCD.0b013e328331de38. PMC 6709868. PMID 20009592. 5. ^ Salomon, J.; Espinosa-Parrilla, Y.; Goulet, O.; Al-Qabandi, W.; Guigue, P.; Canioni, D.; Bruneau, J.; Alzahrani, F.; Almuhsen, S.; Cerf-Bensussan, N.; Jeanpierre, M.; Brousse, N.; Lyonnet, S.; Munnich, A.; Smahi, A. (2008). "A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf". European Journal of Medical Genetics. 54 (3): 319–322. doi:10.1016/j.ejmg.2011.01.009. PMID 21315192. 6. ^ Goulet, O; Salomon, J; Ruemmele, F; Patey-Mariaud de Serres, N; Brousse, N (2007). "Intestinal epithelial dysplasia (tufting enteropathy)". Orphanet Journal of Rare Diseases. 2: 20. doi:10.1186/1750-1172-2-20. PMC 1878471. PMID 17448233. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Congenital tufting enteropathy	c2750737	3,144	wikipedia	https://en.wikipedia.org/wiki/Congenital_tufting_enteropathy	2021-01-18T18:54:47	{"gard": ["10630"], "mesh": ["C567703"], "umls": ["C2750737"], "orphanet": ["92050"], "wikidata": ["Q5160453"]}
A number sign (#) is used with this entry because Fanconi anemia of complementation group O (FANCO) is caused by homozygous mutation in the RAD51C gene (602774) on chromosome 17q22. Description Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650. Clinical Features Vaz et al. (2010) reported a consanguineous Pakistani family in which 3 sibs had multiple severe congenital abnormalities characteristic of Fanconi anemia. One girl died at 2 months of age with 1 absent and 1 vestigial thumb, a congenital heart defect, imperforate anus, and hydronephrosis. Her lymphocytes showed elevated chromosome breakage after treatment with the DNA interstrand cross-linking agent mitomycin C, indicating a diagnosis of Fanconi anemia. A son died 2 days after birth with congenital abnormalities similar to those of his sister, and another pregnancy miscarried at 11 weeks. The youngest affected child was age 10 years at the time of the report. He had multiple congenital abnormalities, including short stature, bilateral radial hypoplasia, anal atresia, bilateral cryptorchidism, small genitalia, bilateral cystic dysplasia of the kidneys, and chronic renal failure. Primary cultured fibroblasts showed increased chromosomal breakage after exposure to interstrand cross-linking agents, with pronounced arrest of the cell cycle at G2 associated with impaired RAD51 (179617) focus formation. Since this child had not developed hematologic abnormalities or cancer, Vaz et al. (2010) referred to the phenotype as 'Fanconi anemia-like,' but noted that these features may develop with time. Molecular Genetics By genomewide autozygosity mapping followed by candidate gene sequencing in a Pakistani family with Fanconi anemia, Vaz et al. (2010) identified a homozygous mutation in the RAD51C gene (R258H; 602774.0001). In vitro functional studies showed that the mutation resulted in loss of RAD51 focus formation in response to DNA damage, and that the defect could be rescued by expression of wildtype RAD51C. The authors provisionally designated the locus FANCO. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature CARDIOVASCULAR Heart \- Congenital heart defect ABDOMEN Gastrointestinal \- Imperforate anus \- Duodenal web \- Rectal atresia GENITOURINARY External Genitalia (Male) \- Small genitalia \- Cryptorchidism Kidneys \- Hydronephrosis \- Cystic kidneys \- Chronic renal failure SKELETAL Limbs \- Radial hypoplasia \- Radial anomalies Hands \- Thumb hypoplasia \- Thumb aplasia \- Long, slim fingers LABORATORY ABNORMALITIES \- Increased chromosomal breaks in response to cross-linking agents and ionizing radiation \- Defect in DNA repair \- Cellular arrest at G2 of the cell cycle MOLECULAR BASIS \- Caused by mutation in the C homolog of the S. cerevisiae RAD51 gene (RAD51C, 602774.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	FANCONI ANEMIA, COMPLEMENTATION GROUP O	c0015625	3,145	omim	https://www.omim.org/entry/613390	2019-09-22T15:58:50	{"doid": ["0111096"], "mesh": ["D005199"], "omim": ["613390"], "orphanet": ["84"], "genereviews": ["NBK1401", "NBK5192"]}
A rare subtype of brachydactyly type B characterized by hypoplasia or aplasia of the distal phalanges of digits 2-5 with or without nail dysplasia, in association with fusion of the middle and distal phalanges, a broad or bifid thumb, and occasionally distal and proximal symphalangism or syndactyly. The feet are less severely affected than the hands. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Brachydactyly type B1	c1862112	3,146	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=572385	2021-01-23T18:37:31	{"mesh": ["C566196"], "omim": ["113000"]}
According to the Global Fund, Honduras is the Central American country most adversely affected by the HIV/AIDS epidemic.[1] As of 1998, Honduras had the highest prevalence of HIV out of all seven Central American countries according to a study published by the office of the Honduran Secretary of Public Health. As of that same year, Hondurans made up only 17% of the Central American population, yet Honduras contained 50% of the initial AIDS cases in Central America[2] and 60% of all Central American cases in 2001.[3] In more recent years, new HIV infections have decreased by 29% since 2010 while AIDS-related deaths have increased by 11% since then.[4] HIV/AIDS heavily affects the young, active, working population in Honduras, and HIV/AIDS deaths account for 10% of the overall national mortality rate.[5] As of 2008, AIDS was the leading cause of death among Honduran women of childbearing age and the second-leading cause of hospitalization among both men and women. Sexually transmitted infections are common, and condom use in risky sexual encounters is sporadic and variable.[6] HIV remains a mainly heterosexual epidemic in Honduras, as 90% of emerging infections are attributed to heterosexual transmission.[7] It is estimated that the prevalence of HIV among Honduran adults is 1.5%.[8] ## Contents * 1 First cases * 2 Prevalence and causes * 2.1 Geographical predominance * 2.2 Demographical predominance * 2.3 Proposed national causes * 2.4 Among the Garífuna * 3 National response * 3.1 Early response * 3.2 Recent response and current policies * 4 International response and aid * 5 Access to ARV treatment * 6 Activism * 6.1 Honduran National Association of People Living with HIV (Asociación Nacional de Honduras de Personas que Viven con el VIH) * 7 See also * 8 References ## First cases[edit] According to a 1998 report released by the office of the Honduran Secretary of Public Health, the incubation period, during which HIV/AIDS was first introduced into the Honduran population without being recognized, is estimated to have been during the end of the 1970s and into the early 1980s. In 1984, the first case of HIV/AIDS in Honduras was identified in a man who reported having travelled to San Francisco multiple times in the years preceding his diagnosis, which was confirmed in 1985 when he tested positive for Kaposi's sarcoma and antibodies for HIV. Four men, all reporting having traveled outside of the country, constituted the first cases recognized in Honduras. Three of those men were likely to have contracted HIV from homosexual transmission, while one contracted the virus likely from heterosexual transmission. By 1992, the 100 Honduran cases of HIV/AIDS included almost every risk group associated with HIV/AIDS: men who have sex with men (MSM), men who have sex with men and women (MSM/W), commercial sex workers, children of HIV-positive mothers, intravenous drug users, and blood transfusion recipients. Since spreading to other populations, HIV/AIDS is considered to be transmitted mainly heterosexually in Honduras and thought to have been introduced to the heterosexual population through bisexual transmission. Additionally, groups such as marines and soldiers, who have increased interaction with the exterior and are also more likely to have multiple sexual partners, contributed to the spread of HIV/AIDS throughout Honduras.[2] A 1997 study found prevalence of 6.8% among military recruits.[6] ## Prevalence and causes[edit] ### Geographical predominance[edit] Map of Honduras, delineating its departments, and its capital Tegucigalpa The areas most heavily affected by HIV/AIDS cases tend to be within what is called the Central Corridor of Development (Corridor Central de Desarrollo), affecting urban areas such as Tegucigalpa, San Pedro Sula, La Ceiba, El Progreso, Comayagua, Puerto Cortés, Tela, La Lima, and Choluteca. The disease originated in the northern part of the country, with especially high rates in Tegucigalpa and San Pedro Sula, which was the original epicenter of the disease. In San Pedro Sula, rates of HIV prevalence were estimated to be as high as 14 to 21% of the population at the height of the epidemic in Honduras. HIV/AIDS has since spread to the south, east, and west of Honduras, including the Honduran Bay Islands in the Caribbean, though these regions were affected later.[2] Municipalities with the highest reported incidences of HIV infection are found on the border with neighboring countries El Salvador, Guatemala, and Nicaragua.[1] On the northern coast of Honduras, the Garífuna minority group experiences particularly high rates of HIV prevalence.[8] ### Demographical predominance[edit] HIV/AIDS has most affected young people in Honduras, ranging from 20 to 39 years of age.[2] The main risk groups associated with HIV/AIDS in Honduras are female sex workers (FSWs), men who have sex with men (MSM), the Garífuna community, prisoners, and transgender women.[1] The United Nations Joint Programme on AIDS (UNAIDS) released the following statistics regarding the HIV prevalence among different risk groups in Honduras:[9] * 5.3% among sex workers * 11.7% among gay men and men who have sex with men * 11.9% among transgender people Additionally, prevalence rates among prisoners have been found to be as high as 7.6%.[10] In 2005 the national prevalence among sex workers was 9.68% according to a UNAIDS document on CONASIDA. 47% of the cases of HIV recorded in 2004 were women,[5] and in that same year around 0.5% of women in antenatal surveillance studies were HIV positive.[11] Overall, women account for more of emerging infections than men do.[7] ### Proposed national causes[edit] While it is not known exactly why the epidemic in Honduras became so severe, some experts, such as epidemiologists like Manuel Sierra, attribute its severity to the long incubation period of the disease in the country. Other reasons to which specialists attribute the state of the Honduran epidemic include increased international military presence due to the Cold War, during which Honduras experienced an influx of both international military personnel and also contras from neighboring Nicaragua, who helped to stimulate the commercial sex industry on a national level.[10] ### Among the Garífuna[edit] The Garífuna, of Afro-Caribbean descent, are one of at least eight minority groups within Honduras and one of the few for which HIV prevalence rates are known.[11] Heterosexual transmission rates among the Garífuna are comparable to those of sub-Saharan Africa.[12] As of 2005, the prevalence of HIV among the Garífuna was estimated to be somewhere between 8 and 14% of this population.[5] Among this population, condom use was reported in 2009 to be only 10.6% in stable couples and 41.4% in casual couples.[13] HIV was higher among Garífunas residing in urban areas. In addition to low condom use and urban living, researchers suggest that the high rates of HIV prevalence may be due to the migratory working patterns of Garífuna men, who often travel seasonally to the United States or cities, such as San Pedro Sula where HIV prevalence is particularly high, for their jobs in shipping and fishing. Other possible contributing factors are sexual violence, the inability of women to control their sexual experiences, multiple sex partners, remuneration received for sex, with 6% of subjects reporting having received money for sex in a 2009 study, and first sexual encounters for men at 15 and women at 17.[11] Prevalence among Garífuna was 3.8% among men and 5.1% among women as of 2006, indicating rates more than three times those of the national average. In a 2015 study, men were found to be more than four times as likely to have had multiple sex partners within the last 12 months than women.[7] Garífuna women remain an especially disenfranchised group and have been subject to treatment methods as radical as forced sterilization.[8] Only 9% of Garífuna men were reported to have been circumcised,[11] which is proven to be a successful method at lowering risk of HIV contraction through heterosexual transmission by as much as 60%.[14] High rates of other sexually transmitted infections (STIs) such as syphilis and herpes (HSV-2) were also found among the Garífuna in a 2009 study,[11] and high rates of other STIs are linked to a higher risk of HIV infection.[15] Although traditional health care is available to some within this community, the Garífuna have also developed their own methods of educating their community and spreading knowledge of prevention: utilizing their traditional musical forms to accompany informational plays about HIV/AIDS.[16] Organizations, such as the Pan American Social Marketing Organization (PASMO), have adopted similar education tactics, such as bingo games in which each space on a playing card contains a picture of HIV/AIDS or another STD.[10] ## National response[edit] ### Early response[edit] National efforts to reduce the number of new HIV infections have been in place since the late 1980s. The national response to HIV/AIDS has been led by the Ministry of Health, with collaboration from other ministries and several nongovernmental organizations (NGOs). The Health Secretariat solidified the creation of the National AIDS Control Program (PNS) between 1989 and 1994 in an effort to improve health infrastructure, create a national counseling network, and standardize treatment for Hondurans living with HIV/AIDS. During this same time period, the National AIDS Commission (COMSIDA) was also founded. Since the beginning of its involvement in preventing the spread of HIV, the Honduran government has sought to establish multi-sector programs, such as COMSIDA, which was reorganized in 1999 into CONASIDA, with fifteen national institutions or organizations represented. Similarly, the Strategic Plan for the Fight Against AIDS, in place from 1998 to 2002, included the response capabilities of both governmental and nongovernmental bodies and organizations.[1] By the beginning of the 1990s, blood began to be screened for HIV on a national scale in Honduras, five years after the US began screening blood donations. HIV/AIDS cases due to blood transfusions began to decrease by 1991.[2] ### Recent response and current policies[edit] HIV/AIDS was declared a national priority between 2002 and 2006 under President Ricardo Maduro,[5] who publicly committed himself to support the national response to HIV/AIDS and identified HIV/AIDS as one of five health issues to receive priority government attention. Current programs focus on prevention, education, comprehensive care, and the rights of HIV-positive people. Prevention efforts, executed among various governmental and nongovernmental organizations like NGOs, churches, and schools, have specifically targeted groups especially at risk for HIV/AIDS, such as sex workers, members of the gay and lesbian community, mobile populations, and members of the Garífuna ethnic population. In the education system, teachers were trained in 2005 to educate their students about reproductive health, STIs, and HIV/AIDS, and these topics have become integrated into the national curriculum in Honduran schools.[5] Despite these education and awareness efforts, in 2013, still around half of Hondurans infected were unaware they were living with HIV.[17] Honduras’s long-term plan is to prevent new infections and to provide services to those who are most at risk for HIV infection, including young people, sex workers, men who have sex with men, institutionalized persons, and the Garífuna ethnic group. In 2017, the Ministry of Health resolved to cover all treatment for those living with HIV, regardless of CD4 count, and internal funding covers 95% and 70% of treatment costs and preventative efforts respectively.[4] ## International response and aid[edit] The Global Fund to Fight AIDS, Tuberculosis and Malariahas disbursed US$90,720,054 of the US$96,502,161 originally signed to Honduras for HIV/AIDS programs alone. According to USAIDS, another international body that supports programs addressing HIV/AIDS in Honduras, Global Fund programs have three main goals: to promote the protection of the rights of people living with HIV/AIDS (PLWHA), create awareness surrounding risks and risk-reducing measures among particularly vulnerable populations, and make health services more accessible to these populations.[18] The Joint United Nations Programme on HIV/AIDS (UNAIDS) has been another significant supporter of HIV/AIDS prevention, treatment, and care in Honduras. Other international bodies that have assisted programs in Honduras include the Swedish International Development Agency, Canadian International Development Agency, Department for International Development (United Kingdom), Humanist Institute for Development Cooperation, Christian Aid, Catholic Relief Services, German Cooperation Agency, Cooperative for American Relief Everywhere, Inc. (CARE), and the Red Cross. USAID programs include partnership directly with the Honduran government through projects such as AIDSTAR-One (AIDS Support and Technical Assistance Resources) but also include funding of individual, local organizations and NGOs, such as Fundación para el Fomento en Salud.[19] Doctors Without Borders (Medecins sans Frotieres) has also been active in the country since 1974. Their HIV/AIDS programs in Honduras focus on antenatal care and their servicio prioritario, or priority service, which consists of free and confidential post-exposure prophylaxis and psychological counseling to rape victims. As of 2017, Doctors Without Borders had provided 2,300 mental health consultations, 6,800 antenatal consultations, 800 postnatal consultations, assisted in 400 births, and treated 600 patients after experiences of sexual violence.[20] ## Access to ARV treatment[edit] Antiretroviral therapy was only offered in the Honduran public health system as of 2002. In 2001, 18 million lempiras were allocated to the purchase of ART in 2002, and the Honduran government aims to achieve universal ART access. Currently, the Honduran government spends 40 million lempiras annually to provide this treatment.[21] In 2005, it was estimated that 4,500 people were receiving ART treatment, but CONASIDA estimated that only one-third of people with advanced HIV were actually receiving their drugs.[10] Beyond simply providing the antiretroviral drugs themselves, programs such as the Inter-institutional Alliance for the Improved Nutrition of People Living with HIV/AIDS (IMANAS) have attempted to alleviate among households receiving ART the added stressor of lack of food, which can negatively impact people's ability to adhere to their ART regimens.[5] Despite these efforts, in a study published in 2011, researchers found that 87% of households receiving ART in Honduras were food insecure, which was reflected by the 15% of these households in which ART adherence was inadequate.[22] In 2013, 42% of people were still accessing health care and receiving treatment after 12 months, and one in three patients had reached an undetectable viral load.[17] As of 2016, 51% of Honduras affected by HIV/AIDS were able to receive antiretroviral treatment (ART), and 54% of HIV-positive pregnant women were receiving treatment or had utilized prophylaxis as a means of prevention of mother to child transmission (PMTCT).[4] As of 2018, a total of 12,789 individuals were reported to be receiving ART, according to El Heraldo.[21] ## Activism[edit] The Special Law on HIV/AIDS, passed by Congress and allowing CONASIDA to be formed in order to protect the rights of Hondurans living with HIV/AIDS, is attributed greatly to activism on the part of Hondurans living with HIV/AIDS and civil society workers in a 2005 special report created for the United Nations General Assembly Special Session on HIV/AIDS.[5] ### Honduran National Association of People Living with HIV (Asociación Nacional de Honduras de Personas que Viven con el VIH)[edit] The Honduran National Association of People Living with HIV, in part facilitated by USAID funds, has served to empower those in Honduras living with HIV/AIDS and was established to protect their human rights.[23] It was founded by Allan Dunaway, who also served as its president and give a face to HIV/AIDS in Honduras and essentially all of Latin America, as he was one of the first Latin American HIV/AIDS activists. He and his wife, Rosa González, were the first couple to publicly reveal their HIV-positive status. Together, they also founded Fundación Llaves, and Dunaway worked directly with the National Commission of Human Rights (Comisionado Nacional de los Derechos Humanos). Representing their organization, Dunaway and his wife also traveled to the International AIDS Conference in New York City in 2008.[24] ## See also[edit] * HIV/AIDS in North America * HIV/AIDS in South America ## References[edit] 1. ^ a b c d "Country". www.theglobalfund.org. Retrieved 2018-10-25. 2. ^ a b c d e García Trujillo, Odalys; Paredes, Mayté; Sierra, Manuel (July 1998). "VIH/SIDA: Análisis de la Evolución de la Epidemia en Honduras" (PDF). Universidad de Costa Rica. 3. ^ "Country: Proposal HIV/AIDS R09 (PDF)". www.theglobalfund.org. Retrieved 2018-10-25. 4. ^ a b c "Honduras". www.unaids.org (in Spanish). Retrieved 2018-11-06. 5. ^ a b c d e f g "Honduras: Follow-Up Report to the Commitment on HIV/AIDS" (PDF). UNAIDS. 2005. 6. ^ a b "Health Profile: Honduras" Archived 2008-09-13 at the Wayback Machine. United States Agency for International Development (March 2005). Accessed September 7, 2008. This article incorporates text from this source, which is in the public domain. 7. ^ a b c Gandhi AD, Pettifor A, Barrington C, Marshall SW, Behets F, Guardado ME, Farach N, Ardón E, Paz-Bailey G (September 2015). "Migration, Multiple Sexual Partnerships, and Sexual Concurrency in the Garífuna Population of Honduras". AIDS and Behavior. 19 (9): 1559–70. doi:10.1007/s10461-015-1139-2. PMC 4714585. PMID 26242612. 8. ^ a b c Atkinson HG, Ottenheimer D (May 2018). "Involuntary sterilization among HIV-positive Garifuna women from Honduras seeking asylum in the United States: Two case reports". Journal of Forensic and Legal Medicine. 56: 94–98. doi:10.1016/j.jflm.2018.03.018. PMID 29635207. 9. ^ "Honduras". www.unaids.org. Retrieved 2018-11-08. 10. ^ a b c d Cohen, Jon (2006-07-28). "Why So High? A Knotty Story". Science. 313 (5786): 481–483. doi:10.1126/science.313.5786.481. ISSN 0036-8075. PMID 16873650. S2CID 36511650. 11. ^ a b c d e Paz-Bailey, Gabriela; et al. (2009). "High Rates of STD and Sexual Risk Behaviors Among Garífunas in Honduras". Journal of Acquired Immune Deficiency Syndromes. 51, Supplement 1: S26–34. doi:10.1097/QAI.0b013e3181a2647b. PMID 19384098. S2CID 18623932 – via Ovid. 12. ^ Sabin M, Luber G, Sabin K, Paredes M, Monterroso E (September 2008), "Rapid ethnographic assessment of HIV/AIDS among Garifuna communities in Honduras: informing HIV surveillance among Garifuna women.", Journal of Human Behavior in the Social Environment, 17 (3–4): 237–57, doi:10.1080/10911350802067773, S2CID 72221916 13. ^ "UNAIDS releases report on global AIDS efforts". 2006. doi:10.1037/e672442007-017. Cite journal requires `\|journal=` (help) 14. ^ "Male circumcision for HIV prevention". World Health Organization. Retrieved 2018-11-08. 15. ^ "Detailed STD Facts - HIV/AIDS & STDs". www.cdc.gov. 2018-09-14. Retrieved 2018-11-08. 16. ^ "In Honduras, Fighting HIV/AIDS Through Music And Theater". NPR.org. Retrieved 2018-11-15. 17. ^ a b "Country: Concept Note HIV/AIDS - 2015 (PDF)". www.theglobalfund.org. Retrieved 2018-10-25. 18. ^ Terrell, Stanley (January 2011). "USAID/Honduras: HIV/AIDS Prevention Programs Evaluation" (PDF). unesco.org. Retrieved October 12, 2018. 19. ^ "USAID/Honduras: HIV/AIDS Prevention Programs Evaluation" (PDF). UNESCO. January 2011. Retrieved October 12, 2018. 20. ^ "Honduras \| Médecins Sans Frontières (MSF) International". Médecins Sans Frontières (MSF) International. Retrieved 2018-11-15. 21. ^ a b "Tres personas se infectan a diario con VIH en Honduras - Diario El Heraldo". Diario El Heraldo (in Spanish). Retrieved 2018-10-28. 22. ^ Martinez, Homero; Ramirez, Blanca Yohisy; Palar, Kartika; Adams, Jayne; Farias, Hugo; Green, Hank; Wagner, Glenn; Derose, Katie (2011-04-01). "Food security, nutrition and HIV/AIDS – overview and context in Honduras". The FASEB Journal. 25 (1_supplement): 780.6. doi:10.1096/fasebj.25.1_supplement.780.6 (inactive 2021-01-10).CS1 maint: DOI inactive as of January 2021 (link) 23. ^ "Diagnóstico de los Servicios Ofrecidos por la Asociación Nacional de Personas Viviendo con VIH/SIDA en Honduras". AIDSFree. 2015-09-14. Retrieved 2018-10-29. 24. ^ "En memoria de Allan Dunaway, fundador y presidente de la Asociación Nacional de Honduras de Personas que Viven con el VIH". www.unaids.org (in Spanish). Retrieved 2018-10-29. * v * t * e HIV/AIDS in North America Sovereign states * Antigua and Barbuda * Bahamas * Barbados * Belize * Canada * Costa Rica * Cuba * Dominica * Dominican Republic * El Salvador * Grenada * Guatemala * Haiti * Honduras * Jamaica * Mexico * Nicaragua * Panama * Saint Kitts and Nevis * Saint Lucia * Saint Vincent and the Grenadines * Trinidad and Tobago * United States Dependencies and other territories * Anguilla * Aruba * Bermuda * Bonaire * British Virgin Islands * Cayman Islands * Curaçao * Greenland * Guadeloupe * Martinique * Montserrat * Puerto Rico * Saint Barthélemy * Saint Martin * Saint Pierre and Miquelon * Saba * Sint Eustatius * Sint Maarten * Turks and Caicos Islands * United States Virgin Islands * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HIV/AIDS in Honduras	None	3,147	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Honduras	2021-01-18T19:00:49	{"wikidata": ["Q5629842"]}
Small blue round cells of Ewing Sarcoma Display of small round blue cells characteristic of desmoplastic small round cell tumour. In histopathology, a small-blue-round-cell tumour (abbreviated SBRCT), also known as a small-round-blue-cell tumor (SRBCT) or a small-round-cell tumour (SRCT), is any one of a group of malignant neoplasms that have a characteristic appearance under the microscope, i.e. consisting of small round cells that stain blue on routine H&E stained sections. These tumors are seen more often in children than in adults. They typically represent undifferentiated cells. The predominance of blue staining is because the cells consist predominantly of nucleus, thus they have scant cytoplasm.[1][2] ## Contents * 1 Examples * 2 Conditions mimicking SBRCT * 3 References ## Examples[edit] Tumors that belong to this group are: * Desmoplastic small-round-cell tumour * Ewing's Sarcoma/PNET[3][4] * Neuroblastoma[3] * Medulloblastoma * Rhabdomyosarcoma[3] * Synovial sarcoma * Carcinoid tumor * Mesothelioma * Small cell lung cancer * Wilms' tumour[1] * Retinoblastoma[citation needed] * Small-cell lymphoma[3] * Hepatoblastoma[3]\- only the anaplastic form has round blue cells, the more common fetal and embryonal types do not [5] * Merkel cell carcinoma * Mesenchymal chondrosarcoma ## Conditions mimicking SBRCT[edit] Endometrial stromal condensation may mimic a small-blue-round-cell tumour. Endometrial stromal condensation may mimic a small-blue-round-cell tumour. ## References[edit] 1. ^ a b Gregorio A, Corrias MV, Castriconi R, Dondero A, Mosconi M, Gambini C, et al. (July 2008). "Small round blue cell tumours: diagnostic and prognostic usefulness of the expression of B7-H3 surface molecule". Histopathology. 53 (1): 73–80. doi:10.1111/j.1365-2559.2008.03070.x. PMC 2658025. PMID 18613926. 2. ^ Khan J, Wei J, Saal L, Marc L, Markus R, Peterson C, Chen Y, Meltzer P (April 2001). "Development of a molecular taxonomy of small blue round-cell tumors using cDNA microarrays". Nature Genetics. 27 (4s): 64. doi:10.1038/87150. 3. ^ a b c d e Chen QR, Vansant G, Oades K, Pickering M, Wei JS, Song YK, et al. (February 2007). "Diagnosis of the small round blue cell tumors using multiplex polymerase chain reaction". The Journal of Molecular Diagnostics. 9 (1): 80–8. doi:10.2353/jmoldx.2007.060111. PMC 1867426. PMID 17251339. 4. ^ Grünewald TG, Cidre-Aranaz F, Surdez D, Tomazou EM, de Álava E, Kovar H, et al. (July 2018). "Ewing sarcoma". Nature Reviews. Disease Primers. 4 (1): 5. doi:10.1038/s41572-018-0003-x. PMID 29977059. S2CID 49571421. 5. ^ Gray W, Kocjan G. Diagnostic Cytopathology; . p.307 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Small-blue-round-cell tumor	None	3,148	wikipedia	https://en.wikipedia.org/wiki/Small-blue-round-cell_tumor	2021-01-18T18:55:21	{"wikidata": ["Q7542594"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-33 (RP33) is caused by heterozygous mutation in the SNRNP200 gene (601664) on chromosome 2q11. For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Zhao et al. (2006) reported a Chinese family in which 13 members spanning 4 generations developed retinitis pigmentosa in an autosomal dominant pattern of inheritance. Affected individuals developed night blindness at about 16 to 18 years of age. Subsequently, visual acuity gradually decreased with accompanying progressive loss of peripheral visual fields. Funduscopic findings were variable, but included waxy-pale discs, attenuation of retinal arterioles, bone-spicule pigmentation, and atrophy of the retinal pigment epithelium. Electroretinogram (ERG) responses were decreased. Li et al. (2010) examined 12 affected members of a 4-generation Chinese family segregating nonsyndromic autosomal dominant RP. The average age at onset was 7 to 8 years, although some individuals were affected slightly later, at 10 to 11 years of age. Affected individuals had narrowing of the visual fields and night blindness accompanied by loss of visual acuity; fundus photographs showed changes typical of RP, including a waxy, pale optic disc, attenuation of retinal arteries, and bone spicule pigment deposits in the midperiphery of the retina. The visual fields of affected individuals progressively narrowed with age, eventually leading to loss of peripheral vision with relative preservation of central vision, even in a 14-year-old girl. Affected individuals had typical RP changes on ERG, including loss of both the rod and, in more advanced cases, cone responses. Results from a 45-year-old severely affected man showed little detectable activity under either photopic or scotopic conditions. However, the photopic and 30-MHz flicker response from the more mildly affected 14-year-old girl showed preservation of cone cell function, whereas the rod response decreased under scotopic conditions, consistent with a predominantly rod pathology. A multifocal ERG in the girl also showed functional preservation in the central macular area and decreased signal in the peripheral macular area. Liu et al. (2012) studied 5 affected members of a 4-generation Chinese family with nonsyndromic adRP. Night blindness was always the presenting symptom and the age at onset was between 10 and 15 years. Affected members also reported gradual decline in visual acuity and progressive visual field loss in the fifth decade of life. Funduscopic examination showed typical changes of RP, and ERGs showed reduced or nonrecordable responses. Angle-closure glaucoma was also diagnosed in the fifth decade of life in 2 affected women: examination of 1 of the women revealed a shallow anterior chamber and an enlarged cup-to-disc ratio in both eyes; examination in the other woman could not be performed due to bulbous keratopathy. Mapping By genomewide scan of a Chinese family with autosomal dominant retinitis pigmentosa (adRP), Zhao et al. (2006) identified a candidate disease locus, RP33, on chromosome 2q11.2 (maximum multipoint lod score of 4.69 at marker D2S2222). Haplotype analysis defined a 4.8-cM (9.5-Mb) interval at 2cen-q12.1 between D2S2159 and D2S1343. Molecular analysis excluded mutations in the SEMA4C (604462), CNGA3 (600053), HNK1ST (CHST10; 606376), and MERTK (604705) genes. In a 4-generation Chinese family segregating adRP, Li et al. (2010) performed a screen for 17 known adRP loci, obtaining negative lod scores with all markers except on chromosome 2. Fine mapping with additional markers at chromosome 2q11 yielded maximum 2-point lod scores of 3.5 and 3.46 at D2S2333 and D2S2216, respectively (theta = 0 for both). Haplotype analysis and recombination events narrowed the critical region to an interval between D2S286 proximally and D2S347 distally. Molecular Genetics In a 4-generation Chinese family with adRP mapping to chromosome 2cen-q12.1, previously studied by Zhao et al. (2006), Zhao et al. (2009) analyzed the candidate gene SNRNP200 and identified a heterozygous missense mutation (S1087L; 601664.0001) that segregated fully with the disease and was not found in 400 controls. In a 4-generation Chinese family with adRP mapping to chromosome 2q11, Li et al. (2010) sequenced the SNRNP200 (ASCC3L1) gene and identified a heterozygous missense mutation (R1090L; 601664.0002) that segregated with the disease and was not found in 100 ethnically matched controls. Liu et al. (2012) performed exome sequencing in the proband of a 4-generation Chinese family with adRP and identified a heterozygous missense mutation in the SNRNP200 gene (Q885E; 601664.0003) that segregated with disease in the family and was not found in 100 controls. Two affected individuals were also diagnosed with angle-closure glaucoma; Liu et al. (2012) noted that the association might be fortuitous. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RETINITIS PIGMENTOSA 33	c0035334	3,149	omim	https://www.omim.org/entry/610359	2019-09-22T16:04:41	{"doid": ["0110366"], "mesh": ["D012174"], "omim": ["610359"], "orphanet": ["791"], "genereviews": ["NBK1417"]}
Middle ear disease Mastoiditis Side view of head, showing surface relations of bones. (Mastoid process labeled near center.) SpecialtyOtorhinolaryngology Mastoiditis is the result of an infection that extends to the air cells of the skull behind the ear. Specifically, it is an inflammation of the mucosal lining of the mastoid antrum and mastoid air cell system inside[1] the mastoid process. The mastoid process is the portion of the temporal bone of the skull that is behind the ear. The mastoid process contains open, air-containing spaces.[2][3] Mastoiditis is usually caused by untreated acute otitis media (middle ear infection) and used to be a leading cause of child mortality. With the development of antibiotics, however, mastoiditis has become quite rare in developed countries where surgical treatment is now much less frequent and more conservative, unlike former times.[2] Additionally, there is no evidence that the drop in antibiotic prescribing for otitis media has increased the incidence of mastoiditis, raising the possibility that the drop in reported cases is due to a confounding factor such as childhood immunizations against Haemophilus and Streptococcus. Untreated, the infection can spread to surrounding structures, including the brain, causing serious complications.[4] While the use of antibiotics has reduced the incidence of mastoiditis, the risk of masked mastoiditis, a subclinical infection without the typical findings of mastoiditis has increased with the inappropriate use of antibiotics and the emergence of multidrug-resistant bacteria.[5] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Mastoiditis with subperiostal abscess Some common symptoms and signs of mastoiditis include pain, tenderness, and swelling in the mastoid region. There may be ear pain (otalgia), and the ear or mastoid region may be red (erythematous). Fever or headaches may also be present. Infants usually show nonspecific symptoms, including anorexia, diarrhea, or irritability. Drainage from the ear occurs in more serious cases, often manifest as brown discharge on the pillowcase upon waking.[4][6] ## Pathophysiology[edit] Mastoid cells of Lenoir The pathophysiology of mastoiditis is straightforward: bacteria spread from the middle ear to the mastoid air cells, where the inflammation causes damage to the bony structures. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis are the most common organisms recovered in acute mastoiditis. Organisms that are rarely found are Pseudomonas aeruginosa and other Gram-negative aerobic bacilli, and anaerobic bacteria.[7] P. aeruginosa, Enterobacteriaceae, S. aureus and anaerobic bacteria (Prevotella, Bacteroides, Fusobacterium, and Peptostreptococcus spp. ) are the most common isolates in chronic mastoiditis.[8] Rarely, Mycobacterium species can also cause the infection. Some mastoiditis is caused by cholesteatoma, which is a sac of keratinizing squamous epithelium in the middle ear that usually results from repeated middle-ear infections. If left untreated, the cholesteatoma can erode into the mastoid process, producing mastoiditis, as well as other complications.[4] ## Diagnosis[edit] CT scan: Otitis media (simple arrow) and mastoiditis (double arrow) of the right side (left side in image). The external auditory canal is partially occupied by suppuration (triple arrow). 44-year-old woman. The diagnosis of mastoiditis is clinical—based on the medical history and physical examination. Imaging studies provide additional information; The standard method of diagnosis is via MRI scan although a CT scan is a common alternative as it gives a clearer and more useful image to see how close the damage may have gotten to the brain and facial nerves. Planar (2-D) X-rays are not as useful. If there is drainage, it is often sent for culture, although this will often be negative if the patient has begun taking antibiotics. Exploratory surgery is often used as a last resort method of diagnosis to see the mastoid and surrounding areas.[2][9] ## Treatment[edit] Attack triangle in mastoidectomies If ear infections are treated in a reasonable amount of time, the antibiotics will usually cure the infection and prevent its spread. For this reason, mastoiditis is rare in developed countries. Most ear infections occur in infants as the eustachian tubes are not fully developed and don't drain readily. In all developed countries with up-to-date modern healthcare the primary treatment for mastoiditis is administration of intravenous antibiotics. Initially, broad-spectrum antibiotics are given, such as ceftriaxone. As culture results become available, treatment can be switched to more specific antibiotics directed at the eradication of the recovered aerobic and anaerobic bacteria.[8] Long-term antibiotics may be necessary to completely eradicate the infection.[4] If the condition does not quickly improve with antibiotics, surgical procedures may be performed (while continuing the medication). The most common procedure is a myringotomy, a small incision in the tympanic membrane (eardrum), or the insertion of a tympanostomy tube into the eardrum.[9] These serve to drain the pus from the middle ear, helping to treat the infection. The tube is extruded spontaneously after a few weeks to months, and the incision heals naturally. If there are complications, or the mastoiditis does not respond to the above treatments, it may be necessary to perform a mastoidectomy: a procedure in which a portion of the bone is removed and the infection drained.[4] ## Prognosis[edit] With prompt treatment, it is possible to cure mastoiditis. Seeking medical care early is important. However, it is difficult for antibiotics to penetrate to the interior of the mastoid process and so it may not be easy to cure the infection; it also may recur. Mastoiditis has many possible complications, all connected to the infection spreading to surrounding structures. Hearing loss is likely, or inflammation of the labyrinth of the inner ear (labyrinthitis) may occur, producing vertigo and an ear ringing may develop along with the hearing loss, making it more difficult to communicate. The infection may also spread to the facial nerve (cranial nerve VII), causing facial-nerve palsy, producing weakness or paralysis of some muscles of facial expression, on the same side of the face. Other complications include Bezold's abscess, an abscess (a collection of pus surrounded by inflamed tissue) behind the sternocleidomastoid muscle in the neck, or a subperiosteal abscess, between the periosteum and mastoid bone (resulting in the typical appearance of a protruding ear). Serious complications result if the infection spreads to the brain. These include meningitis (inflammation of the protective membranes surrounding the brain), epidural abscess (abscess between the skull and outer membrane of the brain), dural venous thrombophlebitis (inflammation of the venous structures of the brain), or brain abscess.[2][4] ## Epidemiology[edit] In the United States and other developed countries, the incidence of mastoiditis is quite low, around 0.004%, although it is higher in developing countries. The condition most commonly affects children aged from two to thirteen months, when ear infections most commonly occur. Males and females are equally affected.[3] ## See also[edit] * the case of Simon Guggenheim's son * Pete Browning ## References[edit] 1. ^ Diseases of ear nose & throat by PL dhingra & shruti dhingra. published by elsevier 2. ^ a b c d "Mastoiditis". MedlinePlus Medical Encyclopedia. Retrieved July 30, 2003. 3. ^ a b "Ear Infections – Treatment". webmd.com. Retrieved 24 November 2008. 4. ^ a b c d e f Young, Tesfa. "Mastoiditis". eMedicine. Retrieved June 10, 2005. 5. ^ Omura, T (May 2020). "Meningoencephalitis caused by masked mastoiditis that was diagnosed during a follow-up in an elderly patient with diabetes mellitus: A case report". Geriatr Gerontol Int. 20 (5): 500–01. doi:10.1111/ggi.13904. PMID 32358876. S2CID 218481126. 6. ^ "What to Do About Ear infections". webmd.com. Retrieved 24 November 2008. 7. ^ Nussinovitch M, Yoeli R, Elishkevitz K, Varsano I (2004). "Acute mastoiditis in children: epidemiologic, clinical, microbiologic, and therapeutic aspects over past years". Clin Pediatr (Phila). 43 (3): 261–7. doi:10.1177/000992280404300307. PMID 15094950. S2CID 38653809. 8. ^ a b Brook I (2005). "The role of anaerobic bacteria in acute and chronic mastoiditis". Anaerobe. 11 (5): 252–7. doi:10.1016/j.anaerobe.2005.03.005. PMID 16701580. 9. ^ a b Bakhos D, Trijolet JP, Morinière S, Pondaven S, Al Zahrani M, Lescanne E (April 2011). "Conservative management of acute mastoiditis in children". Arch Otolaryngol Head Neck Surg. 137 (4): 346–50. doi:10.1001/archoto.2011.29. PMID 21502472. ## Further reading[edit] * Durand, Marlene & Joseph, Michael. (2001). Infections of the Upper Respiratory Tract. In Eugene Braunwald, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, & J. Larry Jameson (Eds.), Harrison's Principles of Internal Medicine (15th Edition), p. 191. New York: McGraw-Hill * Cummings CW, Flint PW, Haughey BH, et al. Otolaryngology: Head & Neck Surgery. 4th ed. St Louis, Mo; Mosby; 2005:3019–3020. * Mastoiditis E Medicine ## External links[edit] Classification D * ICD-10: H70 * ICD-9-CM: 383.0-383.1 * MeSH: D008417 * DiseasesDB: 22479 External resources * MedlinePlus: 001034 * eMedicine: emerg/306 ped/1379 * Patient UK: Mastoiditis Wikimedia Commons has media related to Mastoiditis. * v * t * e Diseases of the outer and middle ear Outer ear * Otitis externa * Otomycosis Middle ear and mastoid * Otitis media * Mastoiditis * Bezold's abscess * Gradenigo's syndrome * Tympanosclerosis * Cholesteatoma * Perforated eardrum Symptoms * Ear pain * Hearing loss Tests * Otoscope * pneumatic * tympanometry [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mastoiditis	c0024904	3,150	wikipedia	https://en.wikipedia.org/wiki/Mastoiditis	2021-01-18T18:52:34	{"mesh": ["D008417"], "umls": ["C0024904"], "wikidata": ["Q509389"]}
A number sign (#) is used with this entry because this form of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS1) is caused by a heterozygous hexanucleotide repeat expansion (GGGGCC) in a noncoding region of the C9ORF72 gene (614260) on chromosome 9p21. Unaffected individuals have 2 to 19 repeats, whereas affected individuals have 250 to over 2,000 repeats. However, some individuals can show symptoms with as few as 20 to 22 repeats (summary by Reddy et al., 2013; Gomez-Tortosa et al., 2013). Description Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by Vance et al., 2006). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by Harms et al., 2013). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013; Gomez-Tortosa et al., 2013). For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see 600274. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1 (ALS1; 105400). ### Genetic Heterogeneity of Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis See also FTDALS2 (615911), caused by mutation in the CHCHD10 gene (615903) on chromosome 22q11; FTDALS3 (616437), caused by mutation in the SQSTM1 gene (601530) on chromosome 5q35; and FTDALS4 (616439), caused by mutation in the TBK1 gene (604834) on chromosome 12q14. Clinical Features Pinsky et al. (1975) described amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) as an entity distinct from pure ALS because dementia is absent in the latter condition. They found considerable intrafamilial variability. Lesions in the cerebral cortex had a distinctive frontotemporal distribution. Another family was reported by Finlayson et al. (1973), and the families reported by Dazzi and Finizio (1969) and Robertson (1953) may have had the same condition. Hosler et al. (2000) described several families with ALS and FTD. In family F222, 1 patient was diagnosed with ALS and FTD, while 2 showed only motor neuron symptoms. For 3 other persons, the clinical records and other available information confirmed the diagnosis of ALS accompanied by dementia symptoms but were inconclusive as to the type of dementia. In family F17, 2 patients were diagnosed with ALS and FTD, while 2 had ALS alone. One patient had ALS accompanied by dementia symptoms. The mean age of onset for affected individuals in these 2 families was 53.8 +/- 8.2 years, with a range of 40 to 62 years, and an average duration of 3.8 +/- 4.0 years, with a range of 1.3 to 15 years. Most persons survived 4 years or less, and 1 patient survived 15 years. The dementia specified as FTD in these families was characterized by socially inappropriate, impulsive behavior and general deterioration in ability to perform routine daily tasks. These behavioral changes occurred months before any significant changes in memory. Examination of these patients documented a combination of corticospinal and lower motor neuron features in conjunction with signs of frontal release. Imaging studies were consistent with frontotemporal atrophy. Pathologic studies confirmed the presence of frontotemporal atrophy and also revealed frontotemporal gliosis, vacuolar changes in the corresponding cortex, rare Pick bodies, and a relative paucity of amyloid plaques and neurofibrillary tangles. Hosler et al. (2000) concluded that these combined findings fulfill the Lund-Manchester criteria for a diagnosis of FTD arising concurrently with motor neuron disease. Morita et al. (2006) reported a 4-generation Scandinavian kindred in which 5 individuals were diagnosed with amyotrophic lateral sclerosis and 9 with frontotemporal dementia. No individual had both diagnoses. Those with ALS presented with motor neuron symptoms, but 3 later developed subtle cognitive dysfunction. Those with dementia showed progressive cognitive deficits without significant memory loss and had no signs of motor impairment. Two individuals with FTD showed loss of spinal cord neurons at autopsy. Given the clinical and pathologic overlap of ALS and FTD and the observation that both disorders reflect neurodegenerative processes, Morita et al. (2006) concluded that the disorders in this family represent pleiotropic manifestations of a single gene defect. Vance et al. (2006) reported a large Dutch family in which 10 individuals had ALS. Five had bulbar onset, and 5 had limb onset. Age of onset ranged from 40 to 72 years with a mean survival of 3 years. Inheritance was autosomal dominant with reduced penetrance. Three individuals who presented with motor symptoms of ALS subsequently developed personality and behavioral changes, including apathy, social isolation, emotional lability, and hallucinations. Postmortem examination of 4 individuals showed significant upper and lower motor neuron degeneration. One female individual presented at age 39 with progressive personality changes and dementia and subsequently developed muscle wasting and fasciculations consistent with ALS. She died of respiratory failure after 31 months, and postmortem examination showed frontal lobe atrophy and shrunken motor neurons. Valdmanis et al. (2007) reported 3 unrelated families with ALS and/or FTD. In a Canadian family, 5 individuals had ALS only, and 3 had FTD only. Five individuals from a family of Spanish origin had ALS; 1 of these patients had also shown early signs of FTD. A third family of French Canadian origin included 5 individuals with ALS only and 3 with ALS and FTD. Luty et al. (2008) reported a 3-generation Australian family of Anglo-Celtic origin in which 11 individuals had FTD and/or MND. Five presented with the behavioral variant of FTD, 2 presented with progressive bulbar and limb weakness consistent with MND, 2 presented with a combination of FTD and MND, and 2 had nonspecific dementia, diagnosed as Alzheimer disease (AD; 104300) in 1. The average age at onset was 53 years. Neuropathologic examination of 1 patient with FTD and the patient with a clinical diagnosis of AD showed abnormal TDP43 (TARDBP; 605078)-positive inclusions in neurons of the frontal cortex and hippocampus; examination of a patient with MND showed degeneration of the corticospinal tracts and TDP43-positive inclusions in anterior horn cells. Le Ber et al. (2009) identified 6 new families with FTD and/or motor neuron disease showing linkage to chromosome 9p. The mean age at onset was 57.9 years, and the mean disease duration was 3.6 years. The phenotype was heterogeneous both among and within families: 32% of patients presented with isolated FTD, 29% with isolated MND, and 39% with both disorders. Motor neuron disease presented as upper limb motor deficit and amyotrophy in most patients (68%), and bulbar symptoms were present in 32% of patients. FTD was consistent with a behavioral variant. Brain MRI showed bilateral predominantly frontotemporal atrophy, and neuropathologic examination of 3 patients showed neuronal loss in various brain regions and spinal cord. All patients had cytoplasmic neuronal ubiquitin (UBB; 191339)-positive, tau (MAPT; 157140)-negative cytoplasmic inclusions in the cortex and spinal cord. TDP43-positive neuronal inclusions were also found. Boxer et al. (2011) reported a large 4-generation family of Irish ancestry with FTD and/or ALS. Five individuals had the behavioral variant of FTD, 2 with mild parkinsonism, 2 had limb-onset ALS, and 3 had both disorders. One patient had apraxia and parkinsonism, consistent with a corticobasal syndrome. Age at onset ranged from 35 to 57 years, with a mean of 45.7, and the mean disease duration was 5.4 years. Brain imaging showed reduced cortical volume, particularly affecting the frontal lobes. Neuropathologic study of 3 patients showed chronic degenerative changes with neuronal loss, reactive gliosis, and superficial laminar spongiosis. The corticospinal tracts showed decreased myelin staining. Immunohistochemical studies showed TDP43-immunoreactive cytoplasmic inclusions in neurons, and to a lesser extent, in glial cells. Some neuronal inclusions and neurites stained for p62 (SQSTM1; 601530) and ubiquitin, but not TDP43. Pearson et al. (2011) reported a family originating from South Wales with this disorder. There were 9 affected individuals showing variable phenotypes. The average age at onset was 42.2 years, with a duration of 3.6 years. Five (62.5%) presented with ALS, with bulbar and/or limb onset; 1 also had FTD and 3 later developed FTD. Three (37.5%) patients presented with behavioral variant FTD and later developed ALS. Other variable features included psychosis, hallucinations, delusions, visuospatial dysfunction, extrapyramidal signs, and parkinsonism. One patient had cerebellar ataxia. Neuropathology showed many TDP43-positive neuronal cytoplasmic inclusions. FTDALS, confirmed by the identification of a hexanucleotide repeat expansion in the C9ORF72 gene, was reported in a Brazilian kindred of Italian and Portuguese origin (Takada et al., 2012); in 4 families from Canada and France (Daoud et al., 2012); and in 3 members of a family from the United States (Savica et al., 2012). Three of the families reported by Daoud et al. (2012) had previously been reported by Valdmanis et al. (2007). Intrafamilial phenotypic variation was apparent in all reports. Features included the behavioral variant of FTD, ALS, and parkinsonism: 1 or all 3 of these disorders could be found in an affected individual. Some more variable features included visual hallucinations, focal dystonia, and posterior brain atrophy (Takada et al., 2012); levodopa-unresponsive parkinsonism (Savica et al., 2012); and isolated ALS without dementia (Daoud et al., 2012). Of the 36 affected individuals in the families reported by Daoud et al. (2012), 18 (50%) had ALS, 5 (13.8%) had FTD, 7 (19.4%) had ALS/FTD, and 6 (16.6%) had preliminary signs of dementia. The average age at onset was 60 years. The patients reported by Takada et al. (2012) had expanded alleles of 5 to 23 kb. The exact sizes of the expanded alleles could not be determined by the methods used in the reports of Daoud et al. (2012) and Savica et al. (2012). Lindquist et al. (2013) identified a pathogenic C9ORF72 expansion in 14 (5%) of 280 unrelated hospitalized Danish patients referred for genetic testing for inherited dementia disorders. Ten patients had a diagnosis of FTD or FTD-ALS, 1 had ALS, and 3 had atypical diagnoses, including olivopontocerebellar degeneration, corticobasal syndrome, and atypical Parkinson syndrome with FTD-ALS. All except 1 patient had a family history of a similar disorder. The findings expanded the clinical spectrum associated with C9ORF72 mutations. Gomez-Tortosa et al. (2013) reported 9 Spanish FTD probands with expanded C9ORF72 repeats. Six of the patients had significant psychiatric symptoms, most commonly depression, as long as several decades before the onset of dementia. Brain MRI showed frontotemporal atrophy in 7 of 9 patients. Meisler et al. (2013) reported a parent and child of Northern European ancestry with bipolar disorder associated with a C9ORF72 repeat expansion. The proband was identified from a cohort of 89 patients with bipolar disorder who underwent screening for the C9ORF72 repeat expansion. The 35-year-old proband developed typical bipolar disorder at age 25 years and showed normal executive function and memory ability at age 35. The affected parent developed bipolar disorder and mood irregularities at age 62, and was subsequently diagnosed with FTD. The parent also developed a gait disorder and had parkinsonian features at age 66; the parent died at age 69. Postmortem examination showed frontotemporal atrophy and some neuropathologic changes consistent with Alzheimer disease, including tau pathology and ubiquitinated cytoplasmic inclusions. Southern blot analysis of peripheral blood from the proband identified a 2,600 repeat expansion (between 14 and 20 kb), whereas the parent carried shorter expansions (8.5 to 20 kb). Cultured lymphoblast cell lines from the parent were enriched for the shorter 8.5-kb expansion length, suggesting that there may be selection for the shorter repeat in cultured cells. The genetic and clinical findings were suggestive of genetic anticipation, as well as etiologic relationship between the C9ORF72 expansion and disease progression from bipolar disorder to FTD. Hensman Moss et al. (2014) identified a pathologic C9ORF72 repeat expansion in 10 (1.95%) of 514 patients from the United Kingdom who initially presented with clinical features suggestive of Huntington disease (HD; 143100), but who were negative for a pathologic repeat expansion in the HTT gene (613004). These patients were classified as having an 'HD phenocopy' syndrome. Of these 10 patients, 70% had a positive family history for a neurodegenerative disease. The mean age at onset in these patients was 42.7 years, and 6 presented with psychiatric and/or behavioral problems. Movement disorders, including chorea, dystonia, myoclonus, tremor, rigidity, and bradykinesia, were prominent features. Cognitive impairment, executive dysfunction, and/or memory problems were present in all patients. The expansion size of the repeat could be determined in 8 patients, and ranged from 2,939 to 4,010 repeats. Hensman Moss et al. (2014) concluded that a C9ORF72 repeat expansion is the most common genetic cause of HD phenocopy syndrome in European populations, and that screening for this expansion should be included in an algorithm for the workup of HD. Mapping By genomewide linkage analysis of a large Scandinavian family considering ALS or FTD as different phenotypic manifestations of a single genetic defect, Morita et al. (2006) identified a candidate locus on chromosome 9p21.3-p13.3 (maximum multipoint lod score of 3.00 between D9S1121 and D9S2154). Haplotype analysis delineated a 21.8-cM region between D9S1870 and D9S1791. Sequencing analysis of the VCP (601023) and UBQLN1 (605046) genes showed no abnormalities. In a large Dutch family with ALS and/or FTD, Vance et al. (2006) found linkage to chromosome 9p; fine mapping yielded a maximum multipoint lod score of 3.02 at D9S1874. Haplotype analysis identified a 12-cM region between markers D9S2154 and D9S1874 on chromosome 9p21.3-p13.2. Vance et al. (2006) noted that the report of Morita et al. (2006) overlapped precisely with their locus and reduced the shared region to 9.8 Mb. Valdmanis et al. (2007) found evidence suggesting linkage to chromosome 9p in 3 unrelated families with ALS and/or FTD who were analyzed separately. Combining the results of all 3 families yielded a maximum multipoint lod score of 7.22 for a 15.1-cM interval between D9S1121 and D9S1791. No mutations were identified in the TEK gene (600221). By genomewide linkage analysis of an Australian family with FTD and/or MND, Luty et al. (2008) found significant linkage to a 9.6-cM region on chromosome 9p (2-point lod score of 3.24 and multipoint lod score of 3.41 at D9S1817). The disease haplotype spanned 57 Mb between chromosome 9p21-9q12, and partially overlapped previously reported loci. By linkage analysis of 6 families with FTD and/or MND, Le Ber et al. (2009) found a cumulative multipoint lod score of 8.0 at marker D9S248 between markers D9S1121 and D9S301 on chromosome 9p. Haplotype reconstruction defined a 7.7-Mb region between D9S1817 and AFM218xg11. There were no disease-causing mutations in 29 candidate genes, including IFT74, and no copy number variations in the 9p region. There was no evidence for a founder effect among these families. Van Es et al. (2009) conducted a genomewide association study among 2,323 individuals with sporadic ALS and 9,013 control subjects and evaluated all SNPs with P less than 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Two SNPs at chromosome 9p21.2 showed significant association in the replication phase and genomewide significance in the combined analysis: rs2814707, p = 7.45 x 10(-9) and rs3849942, p = 1.01 x 10(-8). These SNPs are located in a linkage region for familial ALS with frontotemporal dementia found by Valdmanis et al. (2007), Morita et al. (2006), and Vance et al. (2006) in several large pedigrees. By genomewide linkage analysis of a large family with FTD/ALS, Boxer et al. (2011) found linkage to a 28.3-cM region between D9S1808 and D9S251 on chromosome 9p (2-point lod score of 3.01 at D9S1870). Comparison with previous reports allowed refinement of the region to a 3.7-Mb interval. Pearson et al. (2011) identified a 4.8-Mb haplotype on 9p21.2-9p21.1 that was shared by all affected members of a family from Wales with FTD/ALS. Heterogeneity Hosler et al. (2000) conducted a genomewide linkage analysis involving 16 informative pedigrees. In the course of this screening, they identified a locus at chromosome 9q21-q22 in 2 families with FTD and/or ALS. One family, F222, had a lod score of 1.10 at theta of 0.0 for marker D9S922 and a score of 0.48 at theta of 0.0 for marker D9S1122. A second family, F17, had lod scores of 2.08, 0.07, and 3.15 with markers D9S301, D9S1122, and D9S922, respectively, at theta of 0.0. In the other 14 families in this linkage analysis subset, which showed no linkage to these markers on chromosome 9q21-q22, there were no individuals with both ALS and FTD. The locus on 9q identified by Hosler et al. (2000) has not been replicated (Mackenzie and Rademakers, 2007). Diagnosis ### Molecular Diagnosis Akimoto et al. (2014) found significant differences in the accuracy of genetic testing for the pathologic C9ORF72 repeat expansion in a blinded international study of 14 laboratories that tested 78 samples. Using PCR-based techniques, only 5 of the 14 laboratories obtained results in full accordance with Southern blotting results (gold standard). Only 50 of the 78 DNA samples obtained the same genotype result in all 14 laboratories. Sensitivity and specificity greater than 95% was reached in only 7 (50%) of the laboratories. Akimoto et al. (2014) recommended using a combination of amplicon-length analysis and repeat-primed PCR (RP-PCR) as a minimum standard in a research setting. However, Southern blotting techniques should be made obligatory in a clinical diagnostic setting. Using a nonradioactive Southern blot protocol, Dols-Icardo et al. (2014) characterized the C9ORF72 hexanucleotide repeat expansion in 38 ALS and 22 FTD patients who were found by PCR to have over 30 copies of the repeat. Overall, patients with ALS had a significantly higher number of repeats compared to those with FTD, although there was a substantial amount of overlap. There was no correlation between number of repeats and age at onset or disease duration. For ALS and FTD, the median size of the minimum repeat was 1,082 and 916, respectively, and the median size of the maximum repeat was 2,245 and 1,666, respectively. Repeat number in 1 patient with FTD was moderately higher in cerebellar tissue compared to peripheral blood, and repeat number was higher in a monozygotic twin with ALS compared to his twin without ALS. Molecular Genetics In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTD/ALS) mapping to chromosome 9p21, DeJesus-Hernandez et al. (2011) and Renton et al. (2011) simultaneously and independently identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene (614260.0001). The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded to 700 to 1,600 (DeJesus-Hernandez et al., 2011) or 250 repeats (Renton et al., 2011) in patients. DeJesus-Hernandez et al. (2011) identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat. Renton et al. (2011) found the expanded repeat in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases from Finland, as well as in 38.1% of 268 familial ALS probands of European origin. Both DeJesus-Hernandez et al. (2011) and Renton et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of DeJesus-Hernandez et al. (2011), transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. Millecamps et al. (2012) identified expanded repeats in intron 1 of the C9ORF72 gene in 46% of 225 French patients with familial ALS, 7% of 725 French patients with sporadic ALS, and in none of 580 controls. The expanded repeat was shown to segregate with the disorder in 16 families, although there were some unaffected obligate carriers, suggesting incomplete penetrance. An expanded C9ORF72 repeat was defined as greater than 50 repeats. Compared to ALS patients with mutations in other genes, those with the C9ORF72 repeat had later age at onset, showed more frequent bulbar involvement, more often had FTD, and showed shorter disease duration. The findings confirmed that the C9ORF72 repeat expansion plays a major role in ALS. Belzil et al. (2013) identified a hexanucleotide repeat expansion in the C9ORF72 gene in 13 (52%) of 25 patients of Caucasian origin with ALS who had a family history of cognitive impairment. Gomez-Tortosa et al. (2013) identified expanded C9ORF72 repeats in 9 (8.2%) of 109 Spanish probands with FTD. Four patients had more than 30 repeats, whereas 4 had 20 repeats and 1 had 22 repeats. None of the other 100 cases had greater than 13 repeats, and none of 216 controls had more than 14 repeats. In 4 families, the expanded 20- or 22-repeat alleles segregated consistently in all affected sibs, with the unaffected sibs having wildtype alleles (2-9 repeats). The 20- or 22-repeat allele was associated with the surrogate marker of the founder haplotype in all cases. Most of the 9 expansion carriers had extended periods with psychiatric symptoms and subjective cognitive complaints before clear neurologic deterioration, and there was no phenotypic difference between those with longer or shorter expansions. These findings suggested that short C9ORF72 hexanucleotide expansions in the 20- to 22-repeat range are also related to FTD. Harms et al. (2013) found C9ORF72 hexanucleotide expansions in 55 (6.9%) of 797 patients with sporadic ALS from the United States. The frequency of expansions was significantly higher in the Midwest (9.2%) compared to the Pacific Northwest (3.0%). Mutation carriers had an earlier age at onset compared to nonmutation carriers (55.9 versus 59.2 years), and were more likely than noncarriers to have a family history of dementia. Two (0.4%) of 526 neurologically normal Caucasian controls also carried an expansion. Repeat expansions were also found in 22 (43%) of 51 patients with familial ALS. Fibroblast cell lines available from 9 patients showed expanded repeats between 600 and 800 units. Two individuals had additional smaller expanded alleles, suggesting somatic instability. DNA derived from occipital cortex was available for 2 additional patients and showed much larger expansions (1,600 repeat units), suggesting that expansions are larger within neuronal tissues. Sequencing of the coding exons of the C9ORF72 gene in 389 ALS patients yielded no pathogenic mutations, suggesting a gain-of-function mechanism rather than a loss-of-function mechanism. Van Blitterswijk et al. (2013) detected C9ORF72 repeat expansions in 4 (1.2%) of 334 individuals who carried pathogenic mutations in genes associated with a neurodegenerative disease. Three of the patients carried mutations in the GRN gene (138945) and 1 had a mutation in the MAPT gene (157140). All 4 patients had the behavioral variant of FTD. Postmortem examination of 1 of the patients who carried both a GRN mutation and a C9ORF72 expansion showed mixed neuropathology with characteristics of both genetic defects. The findings indicated that some cases of FTD may be due to an oligogenic effect, and suggested that the cooccurrence of 2 pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. Van Blitterswijk et al. (2013) concluded that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. Using Southern blot analysis, Nordin et al. (2015) investigated the size of the C9ORF72 repeat expansion in different tissues from 18 autopsied patients with ALS and/or FTD who had repeat expansions in peripheral blood. There was tissue-specific variability in all patients, suggesting that certain properties of each tissue could influence the size of the expansion. In 2 patients, the size variation was extreme: repeats in all nonneural tissues examined were below 100, whereas expansions in neural tissues were 20 to 40 times greater. There was no correlation between expansion size in the frontal lobe and occurrence of cognitive impairment. ### Associations Pending Confirmation In affected members of the family with FTD and/or MND reported by Luty et al. (2008), Luty et al. (2010) identified a putative pathogenic heterozygous G-to-T transversion (67251G-T) in the 3-prime untranslated region (UTR) of the SIGMAR1 gene (601978) on chromosome 9p13. In vitro functional expression studies in human neuroblastoma, HEK293 cells, and patient lymphocytes showed that the substitution resulted in about 2-fold increased expression of SIGMAR1 compared to wildtype, and neuropathologic study of affected individuals showed increased SIGMAR1 protein in frontal cortex tissue. Studies of brain tissue from controls and from individuals with unrelated form of FTLD showed that sigma-1 was localized on membranes within the cytoplasm of most neurons, astrocytes, and oligodendroglia, whereas in 2 patients with the 67251G-T mutation, it was concentrated within the nucleus of degenerating neurons. Patients with the SIGMAR1 mutation also had TDP43- and FUS-positive inclusions in affected brain regions, although in different neuronal populations. Overexpression of SIGMAR1 in cell lines resulted in increased levels of TDP43 protein, but not TDP43 transcripts, and caused a change in localization of TDP43 from the nucleus to the cytoplasm. Luty et al. (2010) postulated that the 67251G-T transversion, which occurs in the 3-prime UTR of the SIGMAR1 gene, alters transcript stability and increases gene expression, resulting in increased pathogenic alterations of TDP43 and FUS. However, the authors noted that the SIGMAR1 gene may not represent the major locus for FTLD/MND that maps to chromosome 9p. Luty et al. (2010) also reported an unrelated patient from another Australian family (AUS-47) with frontotemporal dementia without motor neuron disease who carried a heterozygous c.67226C-T transition in the SIGMAR1 gene, and an unrelated patient from a Polish family (POL-1) with a diagnosis of Alzheimer disease and aphasia who carried a heterozygous c.67247G-A transition. Both variants occurred in the 3-prime UTR of the SIGMAR1 gene and were absent from 169 elderly controls and 1,110 normal controls, but segregation analysis in these 2 families was not possible. Neither patient had motor neuron disease. Dobson-Stone et al. (2013) noted that the AUS-14 family reported by Luty et al. (2010) also carried a pathogenic expansion in the C9ORF72 gene (614260.0001) that segregated with the disorder and was thus likely responsible for the phenotype. However, Dobson-Stone et al. (2013) excluded a pathogenic expansion of the C9ORF72 gene in the proband of the AUS-47 family. Pickering-Brown and Hardy (2015) commented that the disease in the AUS-14 family reported by Luty et al. (2010) was likely caused by the C9ORF72 expansion rather than the SIGMAR1 variant, and questioned the role of SIGMA1 variants in FTD/MND. Belzil et al. (2013) did not identify any coding or noncoding variants in the SIGMAR1 gene among 25 patients with ALS and a family history of dementia. A G-to-T transversion (67243G-T) in the 3-prime untranslated region was found in 1 patient, but this was also found in 1 of 190 controls. Moreover, the C9ORF72 repeat expansion was subsequently identified in this patient and in 52% of the entire cohort. Belzil et al. (2013) suggested that the SIGMAR1 variants identified by Luty et al. (2010) actually segregated with C9ORF72 expansions, and that SIGMAR1 variants are not a cause of ALS with dementia. Xi et al. (2014) reported a pair of Caucasian Semitic monozygotic twin sisters with an expanded C9ORF72 repeat who were discordant for ALS. One twin developed bulbar-onset ALS at age 57 years and had no cognitive impairment. At age 62, the other twin had no symptoms of ALS but did have mild cognitive deficits on testing, particularly in verbal fluency, abstraction, and executive function, which could represent early signs of dementia. Southern blot analysis of blood samples showed expanded C9ORF72 repeats of 800 and 1,350, with the difference likely due to somatic instability. Neither twin had increased methylation at the 5-prime CpG island. Xi et al. (2015) reported a British Canadian family in which a clinically unaffected 89-year-old man had a 70-repeat mildly expanded C9ORF72 allele that expanded significantly to about 1,750 repeats during transmission to 4 of his offspring, who ranged in age from 51 to 65 years of age. However, only 2 of the 4 sibs with the expanded allele were affected with FTDALS, which Xi et al. (2015) attributed to clinical variability and variable age at onset. Epigenetic and RNA-expression analyses showed that the large expansions in the offspring were methylated and associated with decreased C9ORF72 expression, whereas the 70-repeat allele in the father was unmethylated and associated with upregulation of C9ORF72. Fibroblasts from the offspring with large expansions showed RNA foci, which were not found in the father. Postmortem tissue from 1 of the affected offspring showed variation in the expansion among tissues studied, suggesting somatic instability. Xi et al. (2015) concluded that the 70-repeat expansion allele is not pathogenic and suggested that there should be a better low cut-off for a pathogenic repeat number. However, small expansions could be considered premutations because of the potential instability during transmission. In addition, the findings supported a hypothesis of multiple origins for the expansion rather than a single founder effect. Pathogenesis Using 2 methods, Xi et al. (2013) investigated the CpG methylation profile of genomic DNA from the blood of individuals with ALS, including 37 G4C2 expansion carriers and 64 noncarriers, 76 normal controls, and family members of 7 ALS patients with the expansion. Hypermethylation of the CpG island 5-prime of the G4C2 repeat was associated with the presence of the expansion (p less than 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p less than 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Methylation changes were not detected in either normal or intermediate alleles (up to 43 repeats), raising the question of whether the cutoff of 30 repeats for pathologic alleles was adequate. The findings suggested that pathogenic repeat expansion of the G4C2 allele in C9ORF72 may lead to epigenetic changes, such as gene expression silencing, that may be associated with disease. Using electrophoresis, Reddy et al. (2013) found that nonpathogenic lengths of the C9ORF72 repeat RNA r(GGGGCC) (2 to 19 units) form extremely stable uni- and multimolecular structures called G-quadruplexes. Increasing concentration of RNA or number of repeats increased the formation of the G-quadruplexes. The r(GGGGCC)4 repeat bound the splicing factor SRSF1 (600812) in vivo. The complementary C-rich r(CCCCGG) did not form such complexes. G-quadruplex structures are associated with several biologic processes, including gene regulation, splicing, and RNA translation regulation. The location of the r(GGGGCC) repeat within a noncoding region of the C9ORF72 gene suggests that it may play a role in the normal function of the transcript. Pathogenic expansion of the repeat may contribute to the formation of toxic ribonuclear foci via the formation of hairpin structures or abnormal binding of additional proteins. Donnelly et al. (2013) generated induced pluripotent stem cells (iPSCs) from fibroblasts derived from ALS patients with a pathogenic expanded C9ORF72 repeat and reprogrammed them to differentiate into neuronal cells. These neuronal cells, which retained the expanded repeat, showed decreased levels of C9ORF72 RNA compared to controls, as well as toxic intranuclear expanded GGGGCC RNA foci. Decreased C9ORF72 RNA and toxic RNA foci were also found in brain tissue derived from patients with the mutation. Toxic cytoplasmic protein foci were also observed in cells and tissue, indicating that the expanded repeat RNA undergoes non-ATG-initiated translation. A proteome array and immunofluorescence analysis showed that the RNA-binding protein ADARB2 (602065) interacts with the C9ORF72 GGGGCC repeat; toxic foci in patient cells comprised the expanded pathogenic repeat and sequestered ADARB2. Patient iPSCs showed enhanced glutamate sensitivity, which may have been related to ADARB2 sequestration. Transcriptome analysis of patient cells and tissue showed dysregulation of several genes compared to controls. Treatment of the cells with antisense oligonucleotides to C9ORF72 reduced the number of toxic RNA foci, attenuated nuclear accumulation of ADARB2, normalized the dysregulated gene expression of some targeted candidate biomarker genes, and partially rescued the glutamate toxicity of these cells. These findings indicated that RNA toxicity plays a key role in C9ORF72 ALS. Ciura et al. (2013) found decreased C9ORF72 gene expression in cells and tissue derived from ALS/FTD patients carrying the pathogenic expanded repeat. Decreased C9ORF72 expression was also found in brain samples of 8 patients with ALS/FTD who did not carry the C9ORF72 expansion, suggesting that this gene may play a wider role in the etiology of this neurodegenerative disorder. Haeusler et al. (2014) identified a molecular mechanism by which structural polymorphism of the C9ORF72 hexanucleotide repeat expansion (HRE) leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (164035) preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Haeusler et al. (2014) concluded that distinct C9ORF72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases. Both the sense and antisense transcripts of the GGGGCC repeats associated with C9ORF72 can be translated in an ATG-independent manner (without an ATG start codon) known as repeat-associated non-ATG (RAN) translation (Mori et al., 2013). The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9ORF72 gene altered in neurodegenerative disease encode glycine:arginine (GR(n)) and proline:arginine (PR(n)) repeat polypeptides, respectively. Kwon et al. (2014) found that both peptides bound to hnRNPA2 (see 600124) hydrogels. When applied to cultured cells, both GR(20) and PR(20) peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death. Mizielinska et al. (2014) developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted 'RNA-only' repeats, in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine; GR) and poly-(proline-arginine; PR) proteins caused neurodegeneration. Mizielinska et al. (2014) concluded that their findings were consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9ORF72-mediated neurodegeneration. To discover RNA-binding proteins that genetically modify GGGGCC (G4C2)-mediated neurogenesis, Zhang et al. (2015) performed a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats. They identified RanGAP (the Drosophila ortholog of human RanGAP1, 602362), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppressed neurodegeneration. RanGAP physically interacted with HRE RNA and was mislocalized in HRE-expressing flies, neurons from C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9ORF72 ALS patient brain tissue. Nuclear import was impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Zhang et al. (2015) suggested that nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. Freibaum et al. (2015) generated transgenic flies expressing 8, 28, or 58 G4C2 repeat-containing transcripts that did not have a translation start site but contained an open reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. Freibaum et al. (2015) showed that these transgenic animals display dosage-dependent, repeat length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat proteins, as observed in patients with C9ORF72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, Freibaum et al. (2015) found morphologic abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, the authors identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged iPSC-derived neurons from patients with C9ORF72-related disease. Freibaum et al. (2015) concluded that their studies showed that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease (143100), spinocerebellar ataxia (e.g., 164400), myotonic dystrophy (e.g., 160900), and FTDALS1. In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease. Clinical Management Kramer et al. (2016) found that targeting Spt4 (orthologous to SUPT4H1; 603555) selectively decreased production of both sense and antisense expanded transcripts of C9orf72, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1 similarly decreased production of sense and antisense RNA foci and DPR proteins in patient cells. The authors argued that single-factor targeting has advantages over targeting sense and antisense repeats separately. Population Genetics In a genomewide association analysis of 442 Finnish ALS patients and 521 controls, Laaksovirta et al. (2010) identified a disease association with SNP rs3849942 on chromosome 9p21 (p = 9.11 x 10(-11)). A 42-SNP haplotype was associated with a significantly increased risk of ALS (odds ratio of 21.0, p = 7.47 x 10(-33)) when those with familial ALS were compared to controls. For familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9%. About 3% of the patients with this risk haplotype developed FTD. The findings were consistent with a founder effect in this homogeneous population. Mok et al. (2012) found that a smaller founder disease haplotype, located within that identified in the Finnish population by Laaksovirta et al. (2010), was present in ALS families from other populations of northern European descent, including Irish, UK, and US, but not in Italians. The findings suggested that most individuals with the disease carry the same pathogenic variant. Ishiura et al. (2012) identified a pathogenic repeat expansion in the C9ORF72 gene in 3 (20%) of 15 patients with ALS from the southernmost Kii peninsula of Japan in the Wakayama prefecture neighboring the Koza River. The patients did not have parkinsonism, and only 1 had moderate cognitive decline. Haplotype analysis indicated a founder effect, with a shared haplotype spanning 3.3-63 Mb; this haplotype overlapped the Finnish founder haplotype by 130 kb and was shared by another Japanese patient with ALS from another area of Japan. C9ORF72 expansions were not found in 6 ALS patients from a more northern Wakayama region or in 16 patients with ALS and 16 patients with parkinsonism-dementia complex (PDC) in the more northern Mie prefecture/Hohara district of the Kii peninsula. The findings suggested that part of the known ALS-PDC phenotype prevalent among Japanese from the Kii peninsula (105500) is caused by an expanded C9ORF72 repeat. In a large population-based study of Caucasian individuals from the Netherlands, van Rheenen et al. (2012) identified an expanded C9ORF72 hexanucleotide repeat (over 30 repeats) in 33 (37%) of 78 probands with familial ALS, 87 (6.1%) of 1,422 patients with sporadic ALS, 4 (1.6%) of 246 patients with a diagnosis of progressive muscular atrophy, and 1 (0.9%) of 110 patients with a diagnosis of primary lateral sclerosis. None of 768 control individuals carried a repeat expansion. Patients with ALS due to the expansion had a higher incidence of family members with dementia compared to all patients with ALS or to controls. All patients had tested negative for mutations in the SOD1 (147450), TARDBP (605078), and FUS (137070) genes, and the C9ORF72 repeat expansions were determined by a repeat primed PCR method. Garcia-Redondo et al. (2013) identified a pathogenic intron 1 C9ORF72 hexanucleotide repeat expansion (defined as more than 30 repeats) (614260.0001) in 42 (27.1%) of 155 Spanish patients with familial ALS and in 25 (3.2%) of 781 Spanish patients with sporadic ALS. Thus, this mutation was the most common genetic cause of ALS in the Spanish population, followed by SOD1 (147450) mutations, which account for 18% of familial ALS and 1% of sporadic ALS. Haplotype analysis indicated a founder effect for the pathogenic expansion allele. One ALS patient with 28 repeats was identified, and his allele was on the founder disease haplotype. The most common nonpathogenic allele in both patients and controls was 2 repeats; none of 248 controls carried the expansion mutation. C9ORF72 mutation carriers had a lower age at onset, frequent concurrence with FTD, and shorter survival when compared to ALS patients without the expansion. Analysis of other ethnic populations showed that this haplotype was present in 5.6% Yoruba African, 8.9% European CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes. Van der Zee et al. (2013) assessed the distribution of C9ORF72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort of 1,205 individuals ascertained by the European Early-Onset Dementia (EOD) consortium. A metaanalysis of the data and that of other European studies, including a total of 2,668 patients from 15 countries, showed that the frequency of C9ORF72 expansions in western Europe was 9.98% in FTLD, with 18.52% in familial and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of 29.33% and 20.73%, respectively, consistent with the hypothesis of a Scandinavian founder effect. However, Spain also showed a high frequency of the expansion, at 25.49%. In contrast, the prevalence in Germany was low, at 4.82%. The phenotype was most often characterized by behavioral disturbances (95.7%). Postmortem examination of a small number of cases showed TDP43 (605078) and p62 (601530) deposits in the brain. Intermediate repeats (7 to 24 repeat units) were found to be strongly correlated with the risk haplotype tagged by a T allele of SNP rs2814707. In vitro reporter gene expression studies showed significantly decreased transcriptional activity of C9ORF72 with increasing number of normal repeat units, consistent with a loss of function. This was also observed with intermediate repeats, suggesting that they might act as predisposing alleles. There was also a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the expanded repeat in expansion carriers, suggesting that pathologic expansion may be due to replication slippage. Smith et al. (2013) identified the expanded hexanucleotide repeat in C9ORF72 in 226 (17%) of 1,347 patients with ALS with or without FTD collected from 5 European populations in whom known ALS genes had been excluded. The expansion was also observed in 3 (0.3%) of 856 controls, yielding an odds ratio (OR) of 57 (p = 4.12 x 10(-47)), but also indicating incomplete penetrance. The highest frequency of the mutation was in familial cases of ALS+FTD (48/67, 72%), but it was also prevalent in pure ALS families (89/228, 39%), with the total familial frequency being 46% (OR of 244, p = 6.13 x 10(-89)). Frequencies of the expansion in familial ALS+FTD showed variation by country: 19/22 (86%) in Belgium, 30/41 (73%) in Sweden, 10/27 (37%) in the Netherlands, 73/185 (39%) in England, and 4/20 (20%) in Italy. Haplotype analysis identified a common 82-SNP disease haplotype in the majority of 137 cases studied, indicating a single common founder in these European populations. The mutation was estimated to have arisen 6,300 years ago. The disease haplotype was found in almost 15% of European controls. The average number of pathogenic repeats on the disease haplotype was 8, with a spread of expanded alleles up to 26. The most prevalent number of repeats on other haplotypes was 2. The findings suggested that the background disease haplotype is intrinsically unstable, tending to generate longer repeats. In a subset of 296 ALS patients with or without FTD from London, the C9ORF72 expanded repeat was found in 26%, followed by mutations in SOD1 (147450) (24%), FUS (137070) (4%), and TARDPB (605078) (1%). Overall, the findings showed that the C9ORF72 expanded repeat is the most common genetic cause of ALS with or without FTD across Europe. Using repeat-primed PCR, Beck et al. (2013) identified 96 repeat-primed PCR expansions in a large population- and patient-based cohort: there were 85 (2.9%) expansions among 2,974 patients with various neurodegenerative diseases and 11 (0.15%) expansions among 7,579 controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in patients was 800 to 4,400. Large expansions were also detected in the population controls. There were some differences in expansion size and morphology between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. The findings suggested that there may be a higher prevalence of expanded C9ORF72 repeat carriers than previously thought. Animal Model Ciura et al. (2013) found expression of the C9orf72 gene in the brain and spinal cord of zebrafish embryos. Morpholino knockdown of C9orf72 in zebrafish resulted in disrupted neuronal arborization and shortening of the motor neuron axons compared to controls, as well as motor deficits. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. These results revealed a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Supranuclear gaze palsy (less common) MUSCLE, SOFT TISSUES \- Muscle weakness \- Muscle atrophy NEUROLOGIC Central Nervous System \- Frontotemporal dementia \- Amytrophic lateral sclerosis \- Paraparesis \- Quadriparesis \- Motor neuron disease \- Parkinsonism \- Extrapyramidal signs \- Delusions \- Hallucinations \- Apraxia \- Dyscalculia \- Dysarthria \- Brain atrophy, particularly of the frontal and temporal lobes \- Neuropathology shows neuronal degeneration \- Neuronal loss \- Gliosis \- Superficial laminar spongiosis \- Myelin loss in the corticospinal tracts \- TDP43-positive neuronal and glial cytoplasmic inclusions Behavioral Psychiatric Manifestations \- Executive dysfunction \- Apathy \- Poor judgement \- Depression MISCELLANEOUS \- Onset in adulthood \- Rapidly progressive \- Patients can have ALS, FTD, or both \- Intrafamilial variability MOLECULAR BASIS \- Caused by an expanded hexanucleotide repeat (GGGGCC)n in the chromosome 9 open reading frame 72 gene (C9ORF72, 614260.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 1	c3888102	3,151	omim	https://www.omim.org/entry/105550	2019-09-22T16:45:11	{"doid": ["0060213"], "mesh": ["C566288"], "omim": ["105550"], "orphanet": ["275872"], "synonyms": ["Alternative titles", "FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS", "FRONTOTEMPORAL DEMENTIA AND/OR MOTOR NEURON DISEASE", "AMYOTROPHIC LATERAL SCLEROSIS AND/OR FRONTOTEMPORAL DEMENTIA"], "genereviews": ["NBK268647", "NBK1450"]}
A number sign (#) is used with this entry because of evidence that nonautoimmune hyperthyroidism is caused by heterozygous mutation in the thyroid-stimulating hormone receptor gene (TSHR; 603372) on chromosome 14q31. Mutation in the TSHR gene can also cause thyrotropin resistance and nonautoimmune hypothyroidism (275200). Congenital nonautoimmune hyperthyroidism is distinct from autoimmune hyperthyroidism, or Graves disease (275000), and from transient neonatal hyperthyroidism due to passive transfer of maternal autoantibodies. Clinical Features Graves disease in the neonate is usually described as a transient disorder in the newborn offspring of women who have or have had hyperthyroidism. Hollingsworth and Mabry (1976) reported a subset of patients with 'congenital Graves disease' in whom the disorder was not caused by immunoglobulins. The authors favored autosomal dominant inheritance with female predilection. They quoted an experience of Dr. A. M. DiGeorge (Philadelphia) who had seen affected father and son. The father had symptoms from age 3 years and the son from birth; both had required antithyroid medication. Thomas et al. (1982) reported a large family in which 9 of 34 members had hyperthyroidism associated with diffuse goiter. Exophthalmos was absent, and there were no antithyroid antibodies. Examination of thyroid tissue showed rare lymphocytic infiltration and absence of immune complexes. Kopp et al. (1995) described a boy in whom hyperthyroidism was suspected at birth because of tachycardia, tachypnea, and a diffuse goiter. Laboratory tests confirmed the diagnosis and did not demonstrate any antithyroid antibodies. The patient was initially treated with propylthiouracil, and later had a subtotal thyroidectomy at the age of 8 years. Although almost all thyroid tissue was removed, the patient remained hyperthyroid after surgery and radioiodine therapy was administered at the age of 9 years. Thereafter, the patient became euthyroid. Neuropsychologic testing revealed hyperactivity and mental retardation with an IQ between 75 and 85. The patient's mother was euthyroid, and repeated tests for thyroid antibodies were always negative. De Roux et al. (1996) reported a newborn who presented with severe hyperthyroidism, diffuse goiter, eyelid retraction, and possibly proptosis. The absence of thyroid pathology in the parents and the lack of antithyroid antibodies in the mother and the patient suggested a nonimmune etiology. In a review, Paschke and Ludgate (1997) noted that the thyroid gland was enlarged in most patients with nonautoimmune hyperthyroidism, but that features of Graves disease, such as thyroid-associated ophthalmopathy, pretibial myxedema, lymphocytic infiltration of the thyroid, and thyroid antibodies, were absent. Hyperthyroidism occurred at any time from the neonatal period to adulthood; the variability in age at onset probably resulted from other genetic components and environmental factors such as iodine intake and dietary goitrogens. Patients required ablative treatment (surgery or radioiodine) because there had been reports in many families of recurrent hyperthyroidism after subtotal thyroidectomy, mandating a second thyroidectomy or radioiodine treatment. Molecular Genetics In affected members of 2 large unrelated kindreds from northern France with autosomal dominant nonautoimmune hyperthyroidism, Duprez et al. (1994) identified 2 different heterozygous mutations in the TSHR gene (603372.0019; 603372.0020). One of the families had been reported by Thomas et al. (1982). In a boy with nonautoimmune congenital hyperthyroidism, Kopp et al. (1995) identified a heterozygous mutation in the TSHR gene (603372.0004) that resulted in constitutive activation of the receptor. In an infant with nonautoimmune hyperthyroidism, de Roux et al. (1996) identified a heterozygous mutation in the TSHR gene (603372.0007). INHERITANCE \- Autosomal dominant GROWTH Weight \- Low birth weight HEAD & NECK Eyes \- Absence of exophthalmos CARDIOVASCULAR Heart \- Tachycardia SKELETAL \- Advanced bone age SKIN, NAILS, & HAIR Skin \- Absence of dermopathy \- Absence of pretibial myxedema NEUROLOGIC Central Nervous System \- Delayed motor development \- Delayed speech development \- Mental retardation \- Sleep difficulties Behavioral Psychiatric Manifestations \- Hyperactivity ENDOCRINE FEATURES \- Hyperthyroidism \- Goiter \- Thyroid hyperplasia \- Absence of immune complexes and lymphocytes in thyroid tissue IMMUNOLOGY \- Absence of anti-thyroid antibodies PRENATAL MANIFESTATIONS Delivery \- Premature delivery of affected infants LABORATORY ABNORMALITIES \- Decreased serum thyroid-stimulating hormone (TSH) \- Increased serum levels of free plasma thyroid hormones MISCELLANEOUS \- De novo mutation (in some patients) \- Age at onset ranges from neonatal to adulthood \- Phenotypic variation \- Patients usually require total thyroidectomy \- Distinct disorder from transient neonatal hyperthyroidism due to maternal Graves disease (see 275000 ) MOLECULAR BASIS \- Caused by mutation in the thyroid-stimulating hormone receptor gene (TSHR, 603372.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPERTHYROIDISM, NONAUTOIMMUNE	c1836706	3,152	omim	https://www.omim.org/entry/609152	2019-09-22T16:06:35	{"doid": ["7998"], "mesh": ["C563786"], "omim": ["609152"], "orphanet": ["424"], "synonyms": ["HYPERTHYROIDISM, CONGENITAL NONAUTOIMMUNE", "Resistance to thyroid stimulating hormone", "Alternative titles", "Familial non-immune hyperthyroidism", "HYPERTHYROIDISM, NONAUTOIMMUNE, AUTOSOMAL DOMINANT", "TOXIC THYROID HYPERPLASIA, AUTOSOMAL DOMINANT"]}
Nevus sebaceus Nevus sebaceus or sebaceous nevus (the first term is its Latin name, the second term is its name in English; also known as an "organoid nevus"[1]:661 and "nevus sebaceus of Jadassohn"[2]:773) is a congenital, hairless plaque that typically occurs on the face or scalp.[3] Such nevi are classified as epidermal nevi and can be present at birth, or early childhood, and affect males and females of all races equally.[4] The condition is named for an overgrowth of sebaceous glands in the area of the nevus. Skin growths such as benign tumors and basal cell carcinoma can arise in sebaceous nevi, usually in adulthood. Rarely, sebaceous nevi can give rise to sebaceous carcinoma.[5] However, the rate of such malignancies is now known to be less than had been estimated. For this reason, excision is no longer automatically recommended.[6] ## See also[edit] * Phakomatosis pigmentokeratotica * List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Kovich O, Hale E (2005). "Nevus sebaceus". Dermatology Online Journal. 11 (4): 16. PMID 16403388. 4. ^ Teng, Joyce M.C. Nevus sebaceous Archived 30 May 2009 at the Wayback Machine, University of Wisconsin Hospitals and Clinics Authority, last updated 16 November 2007. 5. ^ Izumi M, Tang X, Chiu CS, et al. (November 2008). "Ten cases of sebaceous carcinoma arising in nevus sebaceus". J. Dermatol. 35 (11): 704–11. doi:10.1111/j.1346-8138.2008.00550.x. PMID 19120764. 6. ^ Santibanez-Gallerani A, Marshall D, Duarte AM, Melnick SJ, Thaller S (September 2003). "Should nevus sebaceus of Jadassohn in children be excised? A study of 757 cases, and literature review". J. Craniofac. Surg. 14 (5): 658–60. doi:10.1097/00001665-200309000-00010. PMID 14501324. ## External links[edit] Classification D * ICD-O: M8410/0, M8410/3 * v * t * e Cancers of skin and associated structures Glands Sweat gland Eccrine * Papillary eccrine adenoma * Eccrine carcinoma * Eccrine nevus * Syringofibroadenoma * Spiradenoma Apocrine * Cylindroma * Dermal cylindroma * Syringocystadenoma papilliferum * Papillary hidradenoma * Hidrocystoma * Apocrine gland carcinoma * Apocrine nevus Eccrine/apocrine * Syringoma * Hidradenoma or Acrospiroma/Hidradenocarcinoma * Ceruminous adenoma Sebaceous gland * Nevus sebaceous * Muir–Torre syndrome * Sebaceous carcinoma * Sebaceous adenoma * Sebaceoma * Sebaceous nevus syndrome * Sebaceous hyperplasia * Mantleoma Hair * Pilomatricoma/Malignant pilomatricoma * Trichoepithelioma * Multiple familial trichoepithelioma * Solitary trichoepithelioma * Desmoplastic trichoepithelioma * Generalized trichoepithelioma * Trichodiscoma * Trichoblastoma * Fibrofolliculoma * Trichilemmoma * Trichilemmal carcinoma * Proliferating trichilemmal cyst * Giant solitary trichoepithelioma * Trichoadenoma * Trichofolliculoma * Dilated pore * Isthmicoma * Fibrofolliculoma * Perifollicular fibroma * Birt–Hogg–Dubé syndrome Hamartoma * Basaloid follicular hamartoma * Folliculosebaceous cystic hamartoma * Folliculosebaceous-apocrine hamartoma Nails * Neoplasms of the nailbed This Epidermal nevi, neoplasms, cysts article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nevus sebaceous	c4552097	3,153	wikipedia	https://en.wikipedia.org/wiki/Nevus_sebaceous	2021-01-18T18:45:19	{"mesh": ["D054000"], "icd-9": ["238.2"], "icd-10": ["Q82.5"], "wikidata": ["Q1574843"]}
Relapsing fever SpecialtyInfectious disease Relapsing fever is a vector-borne disease caused by infection with certain bacteria in the genus Borrelia,[1] which is transmitted through the bites of lice or soft-bodied ticks (genus Ornithodoros).[2] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Louse-borne relapsing fever * 2.2 Tick-borne relapsing fever * 3 Diagnosis * 4 Treatment * 5 Research * 6 History * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Most people who are infected develop sickness between 5 and 15 days after they are bitten. The symptoms may include a sudden fever, chills, headaches, muscle or joint aches, and nausea. A rash may also occur. These symptoms usually continue for 2 to 9 days, then disappear. This cycle may continue for several weeks if the person is not treated.[3] ## Causes[edit] ### Louse-borne relapsing fever[edit] Along with Rickettsia prowazekii and Bartonella quintana, Borrelia recurrentis is one of three pathogens of which the body louse (Pediculus humanus humanus) is a vector.[4] Louse-borne relapsing fever is more severe than the tick-borne variety.[citation needed] Louse-borne relapsing fever occurs in epidemics amid poor living conditions, famine and war in the developing world.[5] It is currently prevalent in Ethiopia and Sudan. Mortality rate is 1% with treatment and 30–70% without treatment. Poor prognostic signs include severe jaundice, severe change in mental status, severe bleeding and a prolonged QT interval on ECG.[citation needed] Lice that feed on infected humans acquire the Borrelia organisms that then multiply in the gut of the louse. When an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. B. recurrentis infects the person via mucous membranes and then invades the bloodstream. No non-human, animal reservoir exists. ### Tick-borne relapsing fever[edit] Tick-borne relapsing fever is found primarily in Africa, Spain, Saudi Arabia, Asia, and certain areas of Canada and the western United States. Other relapsing infections are acquired from other Borrelia species, which can be spread from rodents, and serve as a reservoir for the infection, by a tick vector.[citation needed] * Borrelia crocidurae – occurs in Egypt, Mali, Senegal, Tunisia; vectors – Carios erraticus, Ornithodoros sonrai; animal host – shrew (Crocidura stampflii) * Borrelia duttoni, transmitted by the soft-bodied African tick Ornithodoros moubata, is responsible for the relapsing fever found in central, eastern, and southern Africa. * Borrelia hermsii * Borrelia hispanica * Borrelia miyamotoi[6] * Borrelia parkeri * Borrelia turicatae * Borrelia persica B. hermsii and B. recurrentis cause very similar diseases. However, one or two relapses are common with the disease associated with B. hermsii, which is also the most common cause of relapsing disease in the United States. (Three or four relapses are common with the disease caused by B. recurrentis, which has longer febrile and afebrile intervals and a longer incubation period than B. hermsii.) ## Diagnosis[edit] The diagnosis of relapsing fever can be made on blood smear as evidenced by the presence of spirochetes. Other spirochete illnesses (Lyme disease, syphilis, leptospirosis) do not show spirochetes on blood smear. Although considered the gold standard, this method lacks sensitivity and has been replaced by PCR in many settings.[7] ## Treatment[edit] Relapsing fever is easily treated with a one- to two-week-course of antibiotics, and most people improve within 24 hours. Complications and death due to relapsing fever are rare. Tetracycline-class antibiotics are most effective. These can, however, induce a Jarisch–Herxheimer reaction in over half those treated, producing anxiety, diaphoresis, fever, tachycardia and tachypnea with an initial pressor response followed rapidly by hypotension. Recent studies have shown tumor necrosis factor-alpha may be partly responsible for this reaction. ## Research[edit] Currently, no vaccine against relapsing fever is available, but research continues. Developing a vaccine is very difficult because the spirochetes avoid the immune response of the infected person (or animal) through antigenic variation. Essentially, the pathogen stays one step ahead of antibodies by changing its surface proteins. These surface proteins, lipoproteins called variable major proteins, have only 30–70% of their amino acid sequences in common, which is sufficient to create a new antigenic "identity" for the organism. Antibodies in the blood that are binding to and clearing spirochetes expressing the old proteins do not recognize spirochetes expressing the new ones. Antigenic variation is common among pathogenic organisms. These include the agents of malaria, gonorrhea, and sleeping sickness. Important questions about antigenic variation are also relevant for such research areas as developing a vaccine against HIV and predicting the next influenza pandemic.[citation needed] ## History[edit] Relapsing fever has been described since the days of the ancient Greeks.[8] After an outbreak in Edinburgh in the 1840s, relapsing fever was given its name, but the etiology of the disease was not better understood for a decade.[8] Physician David Livingstone is credited with the first account in 1857 of a malady associated with the bite of soft ticks in Angola and Mozambique.[9] In 1873, Otto Obermeier first described the disease-causing ability and mechanisms of spirochetes, but was unable to reproduce the disease in inoculated test subjects and thereby unable to fulfill Koch's postulates.[8] The disease was not successfully produced in an inoculated subject until 1874.[8] In 1904 and 1905, a series of papers outlined the cause of relapsing fever and its relationship with ticks.[10][11][12][13] Both Joseph Everett Dutton and John Lancelot Todd contracted relapsing fever by performing autopsies while working in the eastern region of the Congo Free State. Dutton died there on February 27, 1905. The cause of tick-borne relapsing fever across central Africa was named Spirillum duttoni.[14] In 1984, it was renamed Borrelia duttoni.[15] The first time relapsing fever was described in North America was in 1915 in Jefferson County, Colorado.[16] Sir William MacArthur suggested that relapsing fever was the cause of the yellow plague, variously called pestis flava, pestis ictericia, buidhe chonaill, or cron chonnaill, which struck early Medieval Britain and Ireland, and of epidemics which struck modern Ireland in the famine.[17][18] This is consistent with the description of the symptoms suffered by King Maelgwn of Gwynedd as recorded in words attributed to Taliesin and with the "great mortality in Britain" in 548 CE noted in the Annales Cambriae. ## See also[edit] * Lyme disease * Typhus * Continuous fever * Intermittent fever * Remittent fever ## References[edit] 1. ^ Schwan T (1996). "Ticks and Borrelia: model systems for investigating pathogen-arthropod interactions". Infect Agents Dis. 5 (3): 167–81. PMID 8805079. 2. ^ Schwan T, Piesman J; Piesman (2002). "Vector interactions and molecular adaptations of Lyme disease and relapsing fever spirochetes associated with transmission by ticks". Emerg Infect Dis. 8 (2): 115–21. doi:10.3201/eid0802.010198. PMC 2732444. PMID 11897061. 3. ^ Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. pp. 432–4. ISBN 978-0-8385-8529-0.CS1 maint: multiple names: authors list (link) CS1 maint: extra text: authors list (link) 4. ^ Fournier, Pierre-Edouard (2002). "Human Pathogens in Body and Head Lice". Emerging Infectious Diseases. 8 (12): 1515–8. doi:10.3201/eid0812.020111. PMC 2738510. PMID 12498677. Retrieved October 17, 2010. 5. ^ Cutler S (2006). "Possibilities for relapsing fever reemergence". Emerg Infect Dis. 12 (3): 369–74. doi:10.3201/eid1203.050899. PMC 3291445. PMID 16704771. 6. ^ McNeil, Donald (19 September 2011). "New Tick-Borne Disease Is Discovered". The New York Times. pp. D6. Retrieved 20 September 2011. 7. ^ Fotso Fotso A, Drancourt M (2015). "Laboratory Diagnosis of Tick-Borne African Relapsing Fevers: Latest Developments". Frontiers in Public Health. 3: 254. doi:10.3389/fpubh.2015.00254. PMC 4641162. PMID 26618151. 8. ^ a b c d Cutler, S.J. (April 2010). "Relapsing fever – a forgotten disease revealed". Journal of Applied Microbiology. 108 (4): 1115–1122. doi:10.1111/j.1365-2672.2009.04598.x. ISSN 1365-2672. PMID 19886891. S2CID 205322810. 9. ^ Livingstone D (1857) Missionary travels and researches in South Africa. London: John Murray 10. ^ Cook AR (1904). "Relapsing fever in Uganda". J Trop Med Hyg. 7: 24–26. 11. ^ Ross, P. H.; Milne, A. D. (1904). "Tick Fever". British Medical Journal. 2 (2291): 1453–4. doi:10.1136/bmj.2.2291.1453. PMC 2355890. PMID 20761784. 12. ^ Dutton JE, Todd JL (1905). "The nature of human tick-fever in the eastern part of the Congo Free State with notes on the distribution and bionomics of the tick". Liverpool School Trop Med Mem. 17: 1–18. 13. ^ Wellman FC (1905). "Case of relapsing fever, with remarks on its occurrence in the tropics and its relation to "tick fever"". J Trop Med. 8: 97–99. 14. ^ Novy, F. G.; Knapp, R. E. (1906). "Studies on Spirillum obermeieri and related organisms". Journal of Infectious Diseases. 3 (3): 291–393. doi:10.1093/infdis/3.3.291. hdl:2027/hvd.32044106407547. JSTOR 30071844. 15. ^ Kelly RT (1984) "Genus IV. Borrelia Swellengrebel 1907" in Krieg NR (ed.) Bergey's Manual of Systematic Bacteriology. Baltimore: Williams & Wilkins 16. ^ Davis, Gordon E. (1940-01-01). "Ticks and Relapsing Fever in the United States". Public Health Reports. 55 (51): 2347–2351. doi:10.2307/4583554. JSTOR 4583554. 17. ^ Bonser, Wilfrid; MacArthur, Wm (1944). "Epidemics during the Anglo-Saxon period, with appendix: Famine fevers in England and Ireland". Journal of the British Archaeological Association. 9: 48–71. doi:10.1080/00681288.1944.11894687. 18. ^ MacArthur, W (1947). "Famine fevers in England and Ireland". Postgraduate Medical Journal. 23 (260): 283–6. doi:10.1136/pgmj.23.260.283. PMC 2529527. PMID 20248471. ## External links[edit] * CDC: Relapsing Fever * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill fever) * v * t * e Tick-borne diseases and infestations Diseases Bacterial infections Rickettsiales * Anaplasmosis * Boutonneuse fever * Ehrlichiosis (Human granulocytic, Human monocytotropic, Human E. ewingii infection) * Scrub typhus * Spotted fever rickettsiosis * Pacific Coast tick fever * American tick bite fever * rickettsialpox * Rocky Mountain spotted fever) Spirochaete * Baggio–Yoshinari syndrome * Lyme disease * Relapsing fever borreliosis Thiotrichales * Tularemia Viral infections * Bhanja virus * Bourbon virus * Colorado tick fever * Crimean–Congo hemorrhagic fever * Heartland bandavirus * Kemerovo tickborne viral fever * Kyasanur Forest disease * Omsk hemorrhagic fever * Powassan encephalitis * Severe fever with thrombocytopenia syndrome * Tete orthobunyavirus * Tick-borne encephalitis Protozoan infections * Babesiosis Other diseases * Tick paralysis * Alpha-gal allergy * Southern tick-associated rash illness Infestations * Tick infestation Species and bites Amblyomma * Amblyomma americanum * Amblyomma cajennense * Amblyomma triguttatum Dermacentor * Dermacentor andersoni * Dermacentor variabilis Ixodes * Ixodes cornuatus * Ixodes holocyclus * Ixodes pacificus * Ixodes ricinus * Ixodes scapularis Ornithodoros * Ornithodoros gurneyi * Ornithodoros hermsi * Ornithodoros moubata Other * Rhipicephalus sanguineus Authority control * NDL: 00564580 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Relapsing fever	c0035021	3,154	wikipedia	https://en.wikipedia.org/wiki/Relapsing_fever	2021-01-18T18:37:51	{"mesh": ["D012061"], "umls": ["C0035021"], "orphanet": ["91547"], "wikidata": ["Q690032"]}
Bannayan–Riley–Ruvalcaba syndrome Other namesBRRS Autosomal dominant is the manner in which this condition is inherited SpecialtyOncology, medical genetics SymptomsEnlarged head[1] CausesMutations in the PTEN gene [2] Diagnostic methodBased on signs and symptoms[3] TreatmentBased on symptoms[3] Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth syndrome and hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. The disease is inherited in an autosomal dominant manner.[4] The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz–Jeghers syndrome, juvenile polyposis and Cowden syndrome. Mutation of the PTEN gene underlies this syndrome, as well as Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, these four syndromes are referred to as PTEN Hamartoma-Tumor Syndromes.[5] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] Bannayan–Riley–Ruvalcaba syndrome is associated with enlarged head and benign mesodermal hamartomas (multiple hemangiomas, and intestinal polyps). Dysmorphy as well as delayed neuropsychomotor development can also be present.[1][5] The head enlargement does not cause widening of the ventricles or raised intracranial pressure; these individuals have a higher risk of developing tumors, as the gene involved in BRRs is phosphatase and tensin homologue.[medical citation needed] Some individuals have thyroid issues consistent with multinodular goiter, thyroid adenoma, differentiated non-medullary thyroid cancer, most lesions are slowly growing. Visceral as well as intracranial involvement may occur in some cases, and can cause bleeding and symptomatic mechanical compression[6][7] ## Genetics[edit] PTEN The genetics of the Bannayan–Riley–Ruvalcaba syndrome is determined, in the majority of cases, via the PTEN gene which presents about 30 mutations in this condition. This gene which regulates cell growth, when not working properly can lead to hamartomas. PTEN chromosomal location is 10q23.31, while the molecular location is 87,863,438 to 87,971,930 [2][7] There are many syndromes that are linked to PTEN aside from Bannayan–Riley–Ruvalcaba Syndrome.[8] The syndrome combines Bannayan–Zonana syndrome, Riley–Smith syndrome, and Ruvalcaba–Myhre–Smith syndrome.[9] Bannayan–Zonana syndrome is named for George A. Bannayan and Jonathan Zonana[10] ## Diagnosis[edit] In terms of diagnosing Bannayan–Riley–Ruvalcaba syndrome there is no current method outside the physical characteristics that may be present as signs/symptoms.[3] There are, however, multiple molecular genetics tests (and cytogenetic test) to determine Bannayan–Riley–Ruvalcaba syndrome.[11] ### Differential diagnosis[edit] The differential diagnosis for BRRS consists of the following:[12] * Juvenile polyposis syndrome * Peutz–Jeghers syndrome * Proteus syndrome * Neurofibromatosis 1 * Cowden syndrome ## Treatment[edit] Kidney In terms of treatment/management one should observe what signs or symptoms are present and therefore treat those as there is no other current guideline. The affected individual should be monitored for cancer of:[3] * Thyroid * Breast * Renal ## See also[edit] * List of cutaneous conditions * List of cutaneous neoplasms associated with systemic syndromes ## References[edit] 1. ^ a b Disorders, ed. by the National Organization for Rare (2003). NORD guide to rare disorders. Philadelphia: Lippincott Williams & Wilkins. p. 240. ISBN 9780781730631. Retrieved 9 December 2016.CS1 maint: extra text: authors list (link) 2. ^ a b Reference, Genetics Home. "PTEN gene". Genetics Home Reference. Retrieved 9 December 2016. 3. ^ a b c d "Bannayan-Riley-Ruvalcaba syndrome \| Genetic and Rare Diseases Information Center(GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 9 December 2016. 4. ^ Reference, Genetics Home. "Bannayan-Riley-Ruvalcaba syndrome". Genetics Home Reference. Retrieved 9 December 2016. 5. ^ a b Eng, Charis (1 January 1993). "PTEN Hamartoma Tumor Syndrome". GeneReviews. Retrieved 9 December 2016.update 2016 6. ^ Hobert, Judith A; Eng, Charis (6 August 2009). "PTEN hamartoma tumor syndrome: An overview". Genetics in Medicine. 11 (10): 687–694. doi:10.1097/GIM.0b013e3181ac9aea. PMID 19668082. 7. ^ a b "OMIM Entry - # 153480 - BANNAYAN-RILEY-RUVALCABA SYNDROME; BRRS". www.omim.org. Retrieved 9 December 2016. 8. ^ Edmondson, Andrew C.; Kalish, Jennifer M. (9 December 2016). "Overgrowth Syndromes". Journal of Pediatric Genetics. 4 (3): 136–143. doi:10.1055/s-0035-1564440. ISSN 2146-4596. PMC 4918719. PMID 27617124. 9. ^ Hannigan, Steve, ed. (2007). Inherited Metabolic Diseases: A Guide to 100 Conditions. Radcliffe Publishing. p. 101. ISBN 978-1-84619-099-5. 10. ^ Bannayan, G. A. (1 July 1971). "Lipomatosis, angiomatosis, and macrencephalia. A previously undescribed congenital syndrome". Archives of Pathology. 92 (1): 1–5. ISSN 0363-0153. PMID 5091590. 11. ^ "Bannayan-Riley-Ruvalcaba syndrome - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 9 December 2016. 12. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Bannayan Riley Ruvalcaba syndrome". www.orpha.net. Retrieved 9 December 2016. ## Further reading[edit] * Gilbert-Barness, Enid; Kapur, Raj P.; Oligny, Luc Laurier; Siebert, Joseph R. (2007). Potter's Pathology of the Fetus and Infant: 2-Volume Set. Edinburgh: Elsevier Health Sciences. ISBN 9780323076166. Retrieved 9 December 2016. * (eds.), Martino Ruggieri, Ignacio Pascual-Castroviejo, Concezio Di Rocco; Castroviejo, Ignacio Pascual; Rocco, Concezio Di (2008). Neurocutaneous disorders phakomatoses and hamartoneoplastic syndromes (revised. ed.). Wien: Springer. ISBN 9783211695005. Retrieved 9 December 2016.CS1 maint: extra text: authors list (link) ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 153480 * MeSH: D006223 * DiseasesDB: 31337 Scholia has a topic profile for Bannayan–Riley–Ruvalcaba syndrome. * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome * v * t * e Phakomatosis Angiomatosis * Sturge–Weber syndrome * Von Hippel–Lindau disease Hamartoma * Tuberous sclerosis * Hypothalamic hamartoma (Pallister–Hall syndrome) * Multiple hamartoma syndrome * Proteus syndrome * Cowden syndrome * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease Neurofibromatosis * Type I * Type II Other * Abdallat–Davis–Farrage syndrome * Ataxia telangiectasia * Incontinentia pigmenti * Peutz–Jeghers syndrome * Encephalocraniocutaneous lipomatosis * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bannayan–Riley–Ruvalcaba syndrome	c0265326	3,155	wikipedia	https://en.wikipedia.org/wiki/Bannayan%E2%80%93Riley%E2%80%93Ruvalcaba_syndrome	2021-01-18T18:33:14	{"gard": ["5887"], "mesh": ["D006223"], "umls": ["C0265326"], "orphanet": ["109"], "wikidata": ["Q474254"]}
A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-4 (LCCS4) can be caused by homozygous mutation in the MYBPC1 gene (160794) on chromosome 12q23. For a general phenotypic description and discussion of genetic heterogeneity of LCCS, see LCCS1 (253310). Molecular Genetics Markus et al. (2012) studied 2 consanguineous families from apparently unrelated Bedouin tribes in southern Israel in which affected individuals had a clinical phenotype 'identical to that of LCCS3' (611369) but were negative for mutation in the PIP5K1C gene (606102) as well as in the 2 other genes known to cause LCCS. After homozygosity mapping of 1 affected individual from each family proved unsuccessful, whole-exome sequencing was performed, which revealed homozygosity for a nonsense mutation in the MYBPC1 gene (R318X; 160794.0003) in both probands as well as the affected sister of 1 of the probands. The mutation, confirmed by Sanger sequencing, was present in heterozygosity in both sets of parents as well as unaffected sibs, and was not found in 150 unrelated Bedouin controls. Markus et al. (2012) noted that heterozygous mutation in the MYBPC1 gene had previously been shown to cause the much less severe phenotype of distal arthrogryposis type 1B (DA1B; 614335). INHERITANCE \- Autosomal recessive RESPIRATORY \- Respiratory insufficiency at birth, lethal SKELETAL Limbs \- Severe multiple joint contractures MUSCLE, SOFT TISSUES \- Muscle wasting, severe, primarily in the legs \- Muscle atrophy, primarily in the legs MISCELLANEOUS \- Clinical details not provided beyond a statement that the phenotype is 'identical to that of LCCS3' ( 611369 ) \- Death due to respiratory insufficiency within minutes to hours after birth MOLECULAR BASIS \- Caused by mutation in the slow-type myosin-binding protein-C gene (MYBPC1, 160794.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	LETHAL CONGENITAL CONTRACTURE SYNDROME 4	c1969655	3,156	omim	https://www.omim.org/entry/614915	2019-09-22T15:53:44	{"mesh": ["C566961"], "omim": ["614915"], "orphanet": ["137783"]}
Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematous (SLE), commonly known as lupus. The symptoms of lupus nephritis include blood in the urine, a foamy appearance to the urine, high blood pressure, and swelling in any part of the body. This condition typically occurs in people aged 20 to 40 years. Treatment may involve medications to suppress the immune system, dialysis, or a kidney transplant. Visit our Web page on lupus for more information and resources. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lupus nephritis	c0024143	3,157	gard	https://rarediseases.info.nih.gov/diseases/10747/lupus-nephritis	2021-01-18T17:59:18	{"mesh": ["D008181"], "umls": ["C0024143"], "synonyms": []}
MEGDEL syndrome is an inherited disorder that affects multiple body systems. It is named for several of its features: 3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E), and Leigh-like disease (L). MEGDEL syndrome is characterized by abnormally high levels of an acid, called 3-methylglutaconic acid, in the urine (3-methylglutaconic aciduria). MEGDEL syndrome is one of a group of metabolic disorders that can be diagnosed by presence of this feature. People with MEGDEL syndrome also have high urine levels of another acid called 3-methylglutaric acid. In infancy, individuals with MEGDEL syndrome develop hearing loss caused by changes in the inner ear (sensorineural deafness); the hearing problems gradually worsen over time. Another feature of MEGDEL syndrome is brain dysfunction (encephalopathy). In infancy, encephalopathy leads to difficulty feeding, an inability to grow and gain weight at the expected rate (failure to thrive), and weak muscle tone (hypotonia). Infants with MEGDEL syndrome later develop involuntary muscle tensing (dystonia) and muscle stiffness (spasticity), which worsen over time. Because of these brain and muscle problems, affected babies have delayed development of mental and movement abilities (psychomotor delay), or they may lose skills they already developed. Individuals with MEGDEL syndrome have intellectual disability and never learn to speak. People with MEGDEL syndrome have changes in the brain that resemble those in another condition called Leigh syndrome. These changes, which can be seen with medical imaging, are referred to as Leigh-like disease. Other features that occur commonly in MEGDEL syndrome include low blood sugar (hypoglycemia) in affected newborns; liver problems (hepatopathy) in infancy, which can be serious but improve by early childhood; and episodes of abnormally high amounts of lactic acid in the blood (lactic acidosis). The life expectancy of individuals with MEGDEL syndrome is unknown. Because of the severe health problems caused by the disorder, some affected individuals do not survive past infancy. ## Frequency MEGDEL syndrome is a rare disorder; its prevalence is unknown. At least 40 affected individuals have been mentioned in the medical literature. ## Causes MEGDEL syndrome is caused by mutations in the SERAC1 gene. The function of the protein produced from this gene is not completely understood, although research suggests that it is involved in altering (remodeling) certain fats called phospholipids, particularly a phospholipid known as phosphatidylglycerol. Another phospholipid called cardiolipin is made from phosphatidylglycerol. Cardiolipin is a component of the membrane that surrounds cellular structures called mitochondria, which convert the energy from food into a form that cells can use, and is important for the proper functioning of these structures. SERAC1 gene mutations involved in MEGDEL syndrome lead to little or no SERAC1 protein function. As a result, phosphatidylglycerol remodeling is impaired, which likely alters the composition of cardiolipin. Researchers speculate that the abnormal cardiolipin affects mitochondrial function, reducing cellular energy production and leading to the neurological and hearing problems characteristic of MEGDEL syndrome. It is unclear how SERAC1 gene mutations lead to abnormal release of 3-methylglutaconic acid in the urine, although it is thought to be related to mitochondrial dysfunction. ### Learn more about the gene associated with MEGDEL syndrome * SERAC1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MEGDEL syndrome	c3553597	3,158	medlineplus	https://medlineplus.gov/genetics/condition/megdel-syndrome/	2021-01-27T08:25:30	{"gard": ["12963"], "omim": ["614739"], "synonyms": []}
Laryngeal papillomatosis Other namesAdult papillomatosis, Juvenile papillomatosis, Recurrent respiratory papillomatosis, Squamous cell papillomatosis, Nonkeratinized papillomatosis Volumetric CT rendering of multiple tracheal papilloma (arrow). SpecialtyOtorhinolaryngology ComplicationsSquamous cell carcinoma CausesHPV infection Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis (RRP) or glottal papillomatosis, is a rare medical condition in which benign tumors (papilloma) form along the aerodigestive tract.[1][2] There are two variants based on the age of onset: juvenile and adult laryngeal papillomatosis.[3] The tumors are caused by human papillomavirus (HPV) infection of the throat. The tumors may lead to narrowing of the airway, which may cause vocal changes or airway obstruction.[4][5] Laryngeal papillomatosis is initially diagnosed through indirect laryngoscopy upon observation of growths on the larynx and can be confirmed through a biopsy.[6][7][8] Treatment for laryngeal papillomatosis aims to remove the papillomas and limit their recurrence.[9] Due to the recurrent nature of the virus, repeated treatments usually are needed.[7][9][2][10] Laryngeal papillomatosis is primarily treated surgically, though supplemental nonsurgical and/or medical treatments may be considered in some cases.[7][10] The evolution of laryngeal papillomatosis is highly variable.[4][1] Though total recovery may be observed, it is often persistent despite treatment.[11][8][1] The number of new cases of laryngeal papillomatosis cases is at approximately 4.3 cases per 100,000 children and 1.8 cases per 100,000 adults annually.[1][6][7][12] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Treatment * 5.1 Surgery * 5.2 Nonsurgical adjuvant treatment * 6 Outcomes * 7 Epidemiology * 8 Costs * 9 Research * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] A common symptom of laryngeal papillomatosis is a change in voice quality. More specifically, hoarseness is observed.[4][5] As a consequence of the narrowing of the laryngeal or tracheal parts of the airway, shortness of breath, chronic cough and stridor (i.e. noisy breathing which can sound like a whistle or a snore), can be present.[4][5] As the disease progresses, occurrence of secondary symptoms such as dysphagia, pneumonia, acute respiratory distress syndrome, failure to thrive, and recurrent upper respiratory infections can be diagnosed.[4][5] The risk of laryngeal papillomatosis spreading to the lungs is higher in the juvenile-onset than the adult-onset.[3] In children, symptoms are usually more severe and often mistaken for manifestations of other diseases such as asthma, croup or bronchitis. Therefore, diagnosis is usually delayed.[8][5] ## Cause[edit] Laryngeal papillomatosis is caused by human papillomavirus (HPV) infection, most frequently genotypes 6 and 11[13] although genotypes 16, 18, 31, and 33 have also been implicated.[7] HPV-11 is associated with more aggressive forms of papillomatosis, which may involve more distal parts of the tracheobronchial tree.[7] The mode of viral inoculation is hypothesized to vary according to age of disease onset.[13][14] The presence of HPV in the respiratory tract does not necessarily result in the development of laryngeal papillomatosis. Other factors that could be involved include immunodeficiency or other similar infections. For example, laryngeal papillomatosis may become more aggressive due to the presence of certain viruses (e.g., herpes simplex virus, Epstein-Barr virus).[2] The disease is typically separated into two forms, juvenile and adult papillomatosis, based on whether it develops before or after 20 years of age.[1][7] The juvenile form is generally transmitted through contact with a mother's infected vaginal canal during childbirth.[14] Less is known about transmission in the adult form of this disease, though oral sex has been implicated as a potential mode of transmission.[13][14] However, it is uncertain whether oral sex would directly transmit the virus[14] or activate the dormant virus that was transmitted at childbirth.[14][13] In general, physicians are unsure why only certain people who have been exposed to the HPV types implicated in the disease develop laryngeal papillomatosis. In the case of the juvenile form of the disease, the likelihood of a child born of an infected mother developing laryngeal papillomatosis is low (between 1 in 231 to 1 in 400),[15] even if the mother's infection is active.[13] Risk factors for a higher likelihood of transmission at childbirth include the first birth, vaginal birth, and teenage mother.[14][13] There are three big risk factors that contribute to the acquirement of the juvenile variant. These include:[16] * Birth history (e.g., increased time spent in vaginal delivery) and the presence of HPV in the vaginal canal. It is important to note that it is still uncertain whether caesarean delivery is a protective factor. * Genotype of the HPV (e.g., HPV-11) * Individual factors (e.g., being younger when diagnosed, which may be due to a less developed immune system). ## Diagnosis[edit] Laryngeal papillomatosis can be diagnosed through visualization of the lesions using one of several indirect laryngoscopy procedures.[6][8] In indirect laryngoscopy, the tongue is pulled forward and a laryngeal mirror or a rigid scope is passed through the mouth to examine the larynx.[12][6] Another variation of indirect laryngoscopy involves passing a flexible scope, known as a fiberscope or endoscope, through the nose and into the throat to visualize the larynx from above.[12][8] This procedure is also called flexible fiberoptic laryngoscopy.[12] The appearance of papillomas has been described as multiple or rarely, single, white growths with a lumpy texture similar to cauliflower.[12][7] Papillomas usually present in the larynx, especially on the vocal folds and in the space above the vocal folds called the ventricles.[17][18][1] They can spread to other parts of the larynx and throughout the aerodigestive tract, from the mouth to the lower respiratory tract.[1][7][17] Spread to regions beyond the larynx is more common in children than adults.[17] Growths tend to be located at normal junctions in squamous and ciliated epithelium or at tissue junctions arising from injury.[1][17][18] A confirmatory diagnosis of laryngeal papillomatosis can only be obtained through a biopsy, involving microscopic examination and HPV testing of a sample of the growth.[7][6] Biopsy samples are collected under general anesthesia, either through direct laryngoscopy or fiberoptic bronchoscopy.[6][7] ## Prevention[edit] Little is known in terms of effective means of prevention, if the mother is infected with HPV. (HPV vaccination can prevent these infections in the mother, and thereby eliminate the possibility of the virus infecting the baby.[19]) Due to the low likelihood of transmission even from an infected mother, it is not recommended to expose the mother and child to the additional risks of caesarean section to prevent the transmission of this disease during vaginal childbirth.[13] Opting for a caesarean section does not guarantee that transmission will not still occur.[14] ## Treatment[edit] As of 2014 there was no permanent cure for laryngeal papillomatosis, and treatment options aimed to remove and limit the recurrence of the papillomas.[9] Repeated treatments are often needed because of the recurrent nature of the virus, especially for children, as the juvenile form of laryngeal papillomatosis often triggers more aggressive relapses than the adult form.[9][2][7][10] Between recurrences, voice therapy may be used to restore or maintain the person's voice function.[12] ### Surgery[edit] The first line of treatment is surgery to remove papillomas.[7][10] Typically performed using a laryngeal endoscopy, surgery can protect intact tissues and the individual's voice, as well as ensure that the airway remains unobstructed by the disease.[2] However, surgery does not prevent recurrences, and can lead to a number of serious complications.[9][7][10] Laser technology, and carbon dioxide laser surgery in particular, has been used since the 1970s for the removal of papillomas; however, laser surgery is not without its risks, and has been associated with a higher occurrence of respiratory tract burns, stenosis, severe laryngeal scarring, and tracheoesophagyeal fistulae.[9][2][7][10] Tracheotomies are offered for the most aggressive cases, where multiple debulking surgery failures have led to airways being compromised.[2][7] The tracheotomies use breathing tubes to reroute air around the affected area, thereby restoring the person's breathing function. Although this intervention is usually temporary, some people must use the tube indefinitely.[8] This method should be avoided if at all possible, since the breathing tube may serve as a conduit for spread of the disease as far down as the tracheobronchial tree.[2][7] A microdebrider is a tool that can suction tissue into a blade, which then cuts the tissue. Microdebriders are gradually replacing laser technology as the treatment of choice for laryngeal papillomatosis, due to their ability to selectively suction papillomas while relatively sparing unaffected tissue.[2][10] In addition to the lower risk of complications, microdebrider surgery also is reportedly less expensive, less time-consuming, and more likely to give the person a better voice quality than the traditional laser surgery approaches.[10] ### Nonsurgical adjuvant treatment[edit] For about 20% of people, surgery is not sufficient to control their laryngeal papillomatosis, and additional nonsurgical and/or medical treatments are necessary.[7] As of 2015[update], these treatments alone are not sufficient to cure laryngeal papillomatosis, and can only be considered supplemental to surgery.[2] Some varieties of nonsurgical treatments include interferon, antiviral drugs (especially cidofovir, but also ribavirin and acyclovir), and photodynamic therapy.[9][2][7][10][12] The monoclonal antibody against Vascular Endothelial Growth Factor (VEGF), Bevacizumab has shown promising result as an adjuvant therapy in the management of recurrent respiratory papillomatosis.[20][21] Although vaccines are normally used to prevent infections from happening, HPV vaccines can be used therapeutically (after the infection has occurred).[22][23] For most patients, the HPV vaccine significantly increases the length of time needed between surgeries.[19][22][23] ## Outcomes[edit] The evolution of laryngeal papillomatosis is highly unpredictable and is characterized by modulation of its severity and variable rate of progression across individuals.[4][1] While instances of total recovery are observed, the condition is often persistent and lesions can reappear even after treatment.[8][1][11] Factors that might affect the clinical course of the condition include: the HPV genotype, the age at onset, the elapsed time between the diagnosis and first treatment in addition to previous medical procedures.[7][17][1] Other factors, albeit controversial, such as smoking or the presence of gastroesophageal reflux disease might also play a role in the progression of the disease.[17][3] The papillomas can travel past the larynx and infect extralaryngeal sites.[4] In more aggressive cases, infection of the lungs can occur with progressive airway obstruction.[4][5] Although rare (less than 1% of people with laryngeal papillomatosis), transformation from a benign form to a malignant form is also observed.[4][5] Death can result from these complications (morbidity rate is around 1-2%).[4] ## Epidemiology[edit] Laryngeal papillomatosis is a rare disease with a bimodal distribution based on age of incidence.[1] The incidence, or number of new cases, of laryngeal papillomatosis cases is at approximately 4.3 cases per 100 000 children and 1.8 cases per 100 000 adults annually.[7][6][12][1] The incidence of laryngeal papillomatosis in children peaks before the age of 5, though the term juvenile papillomatosis refers to all cases occurring before the age of 20.[1][7] The incidence of adult laryngeal papillomatosis, which has an onset after the age of 20, peaks between the ages of 20 and 40.[7][1] While there are no gender differences in the incidence of laryngeal papillomatosis in children, adult laryngeal papillomatosis occurs more frequently in males than in females.[7][17][1] The incidence of laryngeal papillomatosis also varies according to factors such as socioeconomic status, such that higher rates are observed in groups having a lower socioeconomic status.[7] ## Costs[edit] Because of its relative commonness and the cost of treatments, more money is spent on treating RRP than on any other benign airway tumor.[22] ## Research[edit] As of 2015 use of the measles-mumps-rubella vaccine to reduce rate of recurrences had been investigated, but had not yielded significant results.[2] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ a b c d e f g h i j k l m n o p El-Naggar, Adel K.; Chan, John K. C.; Grandis, Jennifer R.; Takashi, Takata; Slootweg, Pieter J., eds. (2017). "Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space". World Health Organization Classification of Head and Neck Tumours. Lyon: International Agency for Research on Cancer. pp. 93–95. ISBN 9789283224389. OCLC 990147303. 2. ^ a b c d e f g h i j k l Carifi, M; Napolitano, D; Morandi, M; Dall'Olio, D (2015). "Recurrent respiratory papillomatosis: current and future perspectives". Therapeutics and Clinical Risk Management. 11: 731–8. doi:10.2147/TCRM.S81825. PMC 4427257. PMID 25999724. 3. ^ a b c Taliercio, Sal; Cespedes, Michelle; Born, Hayley; Ruiz, Ryan; Roof, Scott; Amin, Milan R.; Branski, Ryan C. (January 2015). "Adult-onset recurrent respiratory papillomatosis: a review of disease pathogenesis and implications for patient counseling". JAMA Otolaryngology–Head & Neck Surgery. 141 (1): 78–83. doi:10.1001/jamaoto.2014.2826. ISSN 2168-619X. PMID 25393901. 4. ^ a b c d e f g h i j Diseases of the central airways : a clinical guide. Mehta, Atul C.,, Jain, Prasoon,, Gildea, Thomas R. Springer. 2016. pp. 215–218. ISBN 9783319298283. OCLC 945577007.CS1 maint: others (link) 5. ^ a b c d e f g Venkatesan, Naren N.; Pine, Harold S.; Underbrink, Michael P. (June 2012). "Recurrent respiratory papillomatosis". Otolaryngologic Clinics of North America. 45 (3): 671–694, viii–ix. doi:10.1016/j.otc.2012.03.006. ISSN 1557-8259. PMC 3682415. PMID 22588043. 6. ^ a b c d e f g Grimes, MD, Jill; Fagerberg, MD, Kristyn; Smith, MD, Lori, eds. (2014). "Laryngeal Papillomatosis". Sexually Transmitted Disease : An Encyclopedia of Diseases, Prevention, Treatment, and Issues. Greenwood. pp. 401–403. ISBN 9781440801341. OCLC 880530919. 7. ^ 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 Fortes, HR; von Ranke, FM; Escuissato, DL; Araujo Neto, CA; Zanetti, G; Hochhegger, B; Souza, CA; Marchiori, E (May 2017). "Recurrent respiratory papillomatosis: A state-of-the-art review". Respiratory Medicine. 126: 116–121. doi:10.1016/j.rmed.2017.03.030. PMID 28427542. 8. ^ a b c d e f g "Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis". NIDCD. 2015-08-18. Retrieved 2017-10-21. 9. ^ a b c d e f g Alfano, DM (2014). "Human papillomavirus laryngeal tracheal papillomatosis". Journal of Pediatric Health Care. 28 (5): 451–5. doi:10.1016/j.pedhc.2014.04.003. PMID 24882788. 10. ^ a b c d e f g h i Avelino, Melissa Ameloti Gomes; Zaiden, Tallyta Campos Domingues Teixeira; Gomes, Raquel Oliveira (September 2013). "Surgical treatment and adjuvant therapies of recurrent respiratory papillomatosis". Brazilian Journal of Otorhinolaryngology. 79 (5): 636–642. doi:10.5935/1808-8694.20130114. ISSN 1808-8686. PMID 24141682. 11. ^ a b Drejet, Sarah; Halum, Stacey; Brigger, Matthew; Skopelja, Elaine; Parker, Noah P. (March 2017). "A Systematic Review". Otolaryngology–Head and Neck Surgery. 156 (3): 435–441. doi:10.1177/0194599816683384. ISSN 1097-6817. PMID 28072562. S2CID 4406970. 12. ^ a b c d e f g h Colton, Raymond H.; Casper, Janina K.; Leonard, Rebecca (2011). Understanding Voice Problems : A Physiological Perspective for Diagnosis and Treatment (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 171–172, 224–228. ISBN 9781609138745. OCLC 660546194. 13. ^ a b c d e f g Larson, Daniel A.; Derkay, Craig S. (June 2010). "Epidemiology of recurrent respiratory papillomatosis". APMIS. 118 (6–7): 450–454. doi:10.1111/j.1600-0463.2010.02619.x. ISSN 1600-0463. PMID 20553527. S2CID 193686. 14. ^ a b c d e f g Barnes, Leon (2005). Pathology and genetics of head and neck tumours (PDF). IARC Press Lyon. pp. 144–145. 15. ^ Derkay, Craig S.; Wiatrak, Brian (July 2008). "Recurrent respiratory papillomatosis: a review". The Laryngoscope. 118 (7): 1236–1247. doi:10.1097/MLG.0b013e31816a7135. ISSN 1531-4995. PMID 18496162. S2CID 12467098. 16. ^ Niyibizi, Joseph; Rodier, Caroline; Wassef, Maggy; Trottier, Helen (2014). "Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review". International Journal of Pediatric Otorhinolaryngology. 78 (2): 186–197. doi:10.1016/j.ijporl.2013.11.036. ISSN 0165-5876. PMID 24367938. 17. ^ a b c d e f g Wenig, Bruce M. (2013). "Tumors of the Upper Respiratory Tract". In Fletcher, MD, Christopher D. M. (ed.). Diagnostic Histopathology of Tumors. Fletcher, Christopher D. M. (4th ed.). Philadelphia, PA: Saunders/Elsevier. pp. 92–98. ISBN 9781455737543. OCLC 846903109. 18. ^ a b Grant, David G.; Mirchall, Martin A.; Bradley, Patrick J. (2010). "Surgery for Benign Tumors of the Adult Larynx". In Remacle, Marc; Eckel, Hans Edmund (eds.). Surgery of Larynx and Trachea. Berlin: Springer-Verlag Berlin Heidelberg. pp. 91–112. ISBN 9783540791355. OCLC 567327912. 19. ^ a b Ivancic, Ryan; Iqbal, Hassan; deSilva, Brad; Pan, Quintin; Matrka, Laura (February 2018). "Current and future management of recurrent respiratory papillomatosis". Laryngoscope Investigative Otolaryngology. 3 (1): 22–34. doi:10.1002/lio2.132. ISSN 2378-8038. PMC 5824106. PMID 29492465. 20. ^ Mohr M, Schliemann C, Biermann C, Schmidt L-H, Kessler T, Schmidt J, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014 Nov;8(5):1912–8. 21. ^ Sidell DR, Nassar M, Cotton RT, Zeitels SM, de Alarcon A. High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2014 Mar;123(3):214–21. 22. ^ a b c Derkay, Craig S.; Bluher, Andrew E. (December 2018). "Recurrent respiratory papillomatosis: update 2018". Current Opinion in Otolaryngology & Head and Neck Surgery. 26 (6): 421–425. doi:10.1097/MOO.0000000000000490. ISSN 1531-6998. PMID 30300210. S2CID 52947478. 23. ^ a b Pham, Christine T.; Juhasz, Margit; Sung, Calvin; Mesinkovska, Natasha Atanaskova (2020). "The Human Papillomavirus Vaccine as a Treatment 1 for HPV-related Dysplastic and Neoplastic Conditions: A Literature Review". Journal of the American Academy of Dermatology. 82 (1): 202–212. doi:10.1016/j.jaad.2019.04.067. ISSN 1097-6787. PMID 31085272. ## External links[edit] Classification D * ICD-10: D14.1 * ICD-9-CM: 212.1 * MeSH: C535297 External resources * Orphanet: 60032 * v * t * e Skin infections, symptoms and signs related to viruses DNA virus Herpesviridae Alpha HSV * Herpes simplex * Herpetic whitlow * Herpes gladiatorum * Herpes simplex keratitis * Herpetic sycosis * Neonatal herpes simplex * Herpes genitalis * Herpes labialis * Eczema herpeticum * Herpetiform esophagitis Herpes B virus * B virus infection VZV * Chickenpox * Herpes zoster * Herpes zoster oticus * Ophthalmic zoster * Disseminated herpes zoster * Zoster-associated pain * Modified varicella-like syndrome Beta * Human herpesvirus 6/Roseolovirus * Exanthema subitum * Roseola vaccinia * Cytomegalic inclusion disease Gamma * KSHV * Kaposi's sarcoma Poxviridae Ortho * Variola * Smallpox * Alastrim * MoxV * Monkeypox * CPXV * Cowpox * VV * Vaccinia * Generalized vaccinia * Eczema vaccinatum * Progressive vaccinia * Buffalopox Para * Farmyard pox: Milker's nodule * Bovine papular stomatitis * Pseudocowpox * Orf * Sealpox Other * Yatapoxvirus: Tanapox * Yaba monkey tumor virus * MCV * Molluscum contagiosum Papillomaviridae HPV * Wart/plantar wart * Heck's disease * Genital wart * giant * Laryngeal papillomatosis * Butcher's wart * Bowenoid papulosis * Epidermodysplasia verruciformis * Verruca plana * Pigmented wart * Verrucae palmares et plantares * BPV * Equine sarcoid Parvoviridae * Parvovirus B19 * Erythema infectiosum * Reticulocytopenia * Papular purpuric gloves and socks syndrome Polyomaviridae * Merkel cell polyomavirus * Merkel cell carcinoma RNA virus Paramyxoviridae * MeV * Measles Togaviridae * Rubella virus * Rubella * Congenital rubella syndrome ("German measles" ) * Alphavirus infection * Chikungunya fever Picornaviridae * CAV * Hand, foot, and mouth disease * Herpangina * FMDV * Foot-and-mouth disease * Boston exanthem disease Ungrouped * Asymmetric periflexural exanthem of childhood * Post-vaccination follicular eruption * Lipschütz ulcer * Eruptive pseudoangiomatosis * Viral-associated trichodysplasia * Gianotti–Crosti syndrome * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor * v * t * e Human papillomavirus Related diseases Cancers * Cervical cancer * cancers * Anal * Vaginal * Vulvar * Penile * Head and neck cancer (HPV-positive oropharyngeal cancer) Warts * * genital * plantar * flat * Laryngeal papillomatosis * Epidermodysplasia verruciformis * Focal epithelial hyperplasia * Papilloma Others Acrochordon (skin tags) Vaccine * HPV vaccines * Cervarix * Gardasil Screening * Pap test: * stain * Bethesda system * Cytopathology * Cytotechnology * Experimental techniques: * Speculoscopy * Cervicography Colposcopy Biopsy histology * Cervical intraepithelial neoplasia (CIN) * Koilocyte * Vaginal intraepithelial neoplasia (VAIN) * Vulvar intraepithelial neoplasia (VIN) Treatment * Cervical conization * Loop electrical excision procedure (LEEP) History * Georgios Papanikolaou * Harald zur Hausen [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Laryngeal papillomatosis	c1168198	3,159	wikipedia	https://en.wikipedia.org/wiki/Laryngeal_papillomatosis	2021-01-18T18:42:24	{"gard": ["111", "6864"], "mesh": ["C535297"], "umls": ["C1168198"], "icd-9": ["212.1"], "icd-10": ["D14.1"], "orphanet": ["60032"], "wikidata": ["Q3497004"]}
Rare eating disorder caused by injury to the frontal lobe or limbic structures Gourmand syndrome Frontal lobe (at right) SpecialtyNeurology Gourmand syndrome is a very rare and benign eating disorder that usually occurs six to twelve months after an injury to the frontal lobe.[1][2][3][4] Those with the disorder usually have suffered from a right hemisphere frontal or temporal brain lesion typically affecting the cortical areas, basal ganglia or limbic structures.[3][2][5][6] These people develop a new, post-injury passion for gourmet food.[3][2][5][4] There are two main aspects of gourmand syndrome: first, the fine dining habits and changes to taste, and second, the obsessive component, which may result in craving and preservation.[2] Gourmand syndrome can be related to, and shares biological features with, addictive and obsessive disorders.[2][3] The syndrome was first characterised in 1997.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 History * 4 References * 5 Further reading ## Signs and symptoms[edit] * A new-found obsession for fine foods[2][4][3][6][5][1][excessive citations] * Wanting to write, talk, eat, about refined foods[2][1][3][4][5][6][excessive citations] ## Causes[edit] It is believed that the frontotemporal circuits, normally involved in healthy eating, can, when injured, cause gourmand syndrome in patients.[4] ## History[edit] Only 36 people had been diagnosed with gourmand syndrome as of 2001.[6] In many of these cases, the patient did not have any interest in food beforehand nor had any family history with eating disorders.[5][2][3] The first, most famous case was seen in 1997 by Regard and Landis in the journal Neurology:[2][3] after a Swiss stroke patient was released from the hospital, he immediately quit his job as a political journalist and took up the profession of food critic.[3] Regard and Landis also observed an athletic businessman with this condition whose family was shocked to see such a sudden, drastic change in his diet.[3] Only one case of gourmand syndrome has been reported in a child. He was born with issues with his right temporal lobe; at eight years old he began to experience seizures, within the year of the seizures beginning, his behavior began to change to the symptoms of gourmand syndrome.[2] In 2014, a man that was once interested in marathon running now was only interested in gastronomy, traveling hundreds or thousands of miles to eat gourmet food. He became a famous gastronomic critic and gained 50 kg (110 pounds).[5] ## References[edit] 1. ^ a b c Pascual-Leone, Alvaro; Alonso-Alonso, Miguel (2007-04-25). "The Right Brain Hypothesis for Obesity". JAMA. 297 (16): 1819–1822. doi:10.1001/jama.297.16.1819. ISSN 0098-7484. PMID 17456824. 2. ^ a b c d e f g h i j Kurian, M.; Schmitt-Mechelke, T.; Korff, C.; Delavelle, J.; Landis, T.; Seeck, M. (2008). ""Gourmand syndrome" in a child with pharmacoresistant epilepsy". Epilepsy & Behavior. 13 (2): 413–415. doi:10.1016/j.yebeh.2008.04.004. PMID 18502182. 3. ^ a b c d e f g h i j k Regard, Marianne; Landis, Theodor (1997). ""Gourmand syndrome": Eating passion associated with right anterior lesions". Neurology. 48 (5): 1185–1190. doi:10.1212/WNL.48.5.1185. PMID 9153440. 4. ^ a b c d e Uher, R.; Treasure, J. (2004). "Brain lesions and eating disorders". J Neurol Neurosurg Psychiatry. 76 (6): 852–857. doi:10.1136/jnnp.2004.048819. PMC 1739667. PMID 15897510. 5. ^ a b c d e f Gallo, M.; Gámiz, F.; Perez-Garíca, M.; Morals, R.; Rolls, T. (2014). "Taste and olfactory status in a gourmand with a right amygdala lesion". Neurocase. 20 (4): 421–433. doi:10.1080/13554794.2013.791862. PMID 23668221. 6. ^ a b c d Cummings, Jeffery L.; Lichter, David G. (2001). Frontal-Subcortical Circuits in Psychiatric and Neurological Disorders. New York, London: Guliford Press. pp. 167–169. ISBN 1-57230-623-8. ## Further reading[edit] * Uher, R (2005). "Brain lesions and eating disorders". Journal of Neurology, Neurosurgery & Psychiatry. 76 (6): 852–7. doi:10.1136/jnnp.2004.048819. PMC 1739667. PMID 15897510. * Bramen, Lisa (2011-07-06). "Gourmand Syndrome – First identified by neuroscientists in the 1990s, the disorder is marked by "a preoccupation with food and a preference for fine eating". Smithsonian.com. Retrieved 27 April 2015. * v * t * e Neurotrauma Traumatic brain injury * Intracranial hemorrhage * Intra-axial * Intraparenchymal hemorrhage * Intraventricular hemorrhage * Extra-axial * Subdural hematoma * Epidural hematoma * Subarachnoid hemorrhage * Brain herniation * Cerebral contusion * Cerebral laceration * Concussion * Post-concussion syndrome * Second-impact syndrome * Dementia pugilistica * Chronic traumatic encephalopathy * Diffuse axonal injury * Abusive head trauma * Penetrating head injury Spinal cord injury * Anterior spinal artery syndrome * Brown-Séquard syndrome * Cauda equina syndrome * Central cord syndrome * Paraplegia * Posterior cord syndrome * Spinal cord injury without radiographic abnormality * Tetraplegia (Quadriplegia) Peripheral nerves * Nerve injury * Peripheral nerve injury * classification * Wallerian degeneration * Injury of accessory nerve * Brachial plexus injury * Traumatic neuroma This article about a medical condition affecting the nervous system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Gourmand syndrome	None	3,160	wikipedia	https://en.wikipedia.org/wiki/Gourmand_syndrome	2021-01-18T18:43:56	{"wikidata": ["Q5588436"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive epidermolysis bullosa simplex-2 (EBSB2) is caused by homozygous mutation in the DST (BPAG1) gene (113810) on chromosome 6p12. Description EBSB2 is a mild autosomal recessive dermatologic disorder characterized by trauma-induced blistering mainly occurring on the feet and ankles. Ultrastructural analysis of skin biopsy shows abnormal hemidesmosomes with poorly formed inner plaques (summary by Liu et al., 2012). Clinical Features Groves et al. (2010) reported a 38-year-old Kuwaiti man, born of consanguineous parents, with epidermolysis bullosa simplex. He had a lifelong history of trauma-induced spontaneous blisters and erosions particularly affecting his ankles and feet, although the face, trunk, and more proximal limbs were also affected. Blisters and erosions healed without delay, scarring, or milia formation. He also had nail dystrophy and moderate dental caries, but hair was normal and there was no history of mucosal blistering. Electron microscopic analysis of a skin biopsy showed discrete abnormalities of hemidesmosomes, with poorly formed inner plaques leading to a lucent zone between keratin filaments and outer hemidesmosomal plaques, which showed no gross abnormalities. Immunofluorescence staining showed absence of BPAG1-e at the dermal-epidermal junction and in keratinocytes. There was also decreased immunoreactivity for beta-4-integrin (ITGB4; 147557), PLEC1 (601282), and COL17A1 (113811). The patient's 4 sibs, parents, and 2 children had no skin abnormalities. In addition to skin blistering, the patient had CADASIL (125310) resulting from a heterozygous mutation in the NOTCH3 gene (600276). Liu et al. (2012) reported a 34-year-old Iranian woman with a lifelong skin blistering disorder that was worse during the summer and after trauma, such as at sites of friction from clothing. Blistering occurred mainly on the ankles, feet, dorsal aspects of the hands, and elbows. She had no hair, nail, mucosal, or genital involvement. Subtle atrophic scarring was present on the shins, ankles, elbows, dorsal aspects of the hands, and lower back. Electron microscopy of skin biopsy showed abnormal hemidesmosomes with poorly formed inner plaques and a lucent zone between keratin filament sand outer hemidesmosomal plaques. The keratin filaments extended to where the inner plaques should be, but did not associate with any attachment structures. Immunostaining for BPAG1-e showed complete absence of the protein in the patient's skin sample. Her father and 2 of her 3 children also had mild blistering, but skin biopsies and DNA were not available from those individuals. None of the individuals had neurologic abnormalities. Inheritance The transmission pattern of EBSB2 in the family reported by Groves et al. (2010) was consistent with autosomal recessive inheritance. Molecular Genetics In a Kuwaiti man with epidermolysis bullosa simplex, Groves et al. (2010) identified a homozygous truncating mutation in the DST gene (Q1124X; 113810.0002). In a 34-year-old Iranian woman from a consanguineous family with epidermolysis bullosa simplex, Liu et al. (2012) identified a homozygous truncating mutation in the DST gene (R1249X; 113810.0003). INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Blistering, mild (occurs mainly on ankles and feet and in response to trauma) \- Atrophic scars Skin Histology \- Decreased immunostaining for BPAG1-e Electron Microscopy \- Hemidesmosomes show poorly formed inner plaques \- Lucent zone between keratin filaments and outer hemidesmosomal plaques Nails \- Nail dystrophy (1 patient) MISCELLANEOUS \- Two unrelated families have been reported (last curated September 2013) \- Onset in childhood \- Blistering may worsen during the summer MOLECULAR BASIS \- Caused by mutation in the dystonin gene (DST, 113810.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 2	c3809470	3,161	omim	https://www.omim.org/entry/615425	2019-09-22T15:52:10	{"doid": ["4644"], "omim": ["615425"], "orphanet": ["412181"], "synonyms": ["DST-related epidermolysis bullosa simplex", "EBS-AR BP230"]}
Nonbullous congenital ichthyosiform erythroderma (NBCIE) is a condition that mainly affects the skin. Many infants with this condition are born with a tight, clear sheath covering their skin called a collodion membrane. Constriction by the membrane may cause the lips and eyelids to be turned out so the inner surface is exposed. The collodion membrane is usually shed during the first few weeks of life. Following shedding of the collodion membrane, the skin is red (erythroderma) and covered with fine, white scales (ichthyosis). Infants with NBCIE may develop infections, an excessive loss of fluids (dehydration), and respiratory problems early in life. Some people with NBCIE have thickening of the skin on the palms of the hands and soles of the feet (palmoplantar keratoderma), decreased or absent sweating (anhidrosis), and abnormal nails (nail dystrophy). In severe cases, there is an absence of hair growth (alopecia) in certain areas, often affecting the scalp and eyebrows. In individuals with NBCIE, some of the skin problems may improve by adulthood. Life expectancy is normal in people with NBCIE. ## Frequency NBCIE is estimated to affect 1 in 200,000 to 300,000 individuals in the United States. This condition is more common in Norway, where an estimated 1 in 90,000 people are affected. ## Causes Mutations in several genes can cause NBCIE. Mutations in the ABCA12, ALOX12B, or ALOXE3 gene are responsible for most of cases of NBCIE. Mutations in other genes are each found in only a small percentage of cases. All of the genes associated with NBCIE provide instructions for making proteins that are found in the outermost layer of the skin (the epidermis). The epidermis forms a protective barrier between the body and its surrounding environment. Gene mutations impair the respective protein's function or structure within the epidermis, which prevents this outermost layer of skin from being an effective barrier before and after birth. The abnormal skin cannot protect against fluid loss (dehydration) or the outside environment, leading to problems controlling body temperature; dry skin; the formation of fine, white scales; and increased risk of infections in people with NBCIE. The skin scales can impair the function of sweat glands under the skin, causing anhidrosis. In some people with NBCIE, the cause of the disorder is unknown. Researchers are looking for additional genes that are associated with NBCIE. ### Learn more about the genes associated with Nonbullous congenital ichthyosiform erythroderma * ABCA12 * ALOX12B * ALOXE3 Additional Information from NCBI Gene: * CASP14 * CERS3 * CYP4F22 * NIPAL4 * PNPLA1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nonbullous congenital ichthyosiform erythroderma	c3554355	3,162	medlineplus	https://medlineplus.gov/genetics/condition/nonbullous-congenital-ichthyosiform-erythroderma/	2021-01-27T08:25:08	{"gard": ["9736"], "omim": ["615024", "617320", "242100", "606545", "601277", "604777", "612281", "615023"], "synonyms": []}
Neuroendocrine hyperplasia Other namesNeuroendocrine cell hyperplasia of infancy SpecialtyPulmonology Neuroendocrine hyperplasia is rare and poorly understood lung condition which causes abnormal growth pulmonary neuroendocrine cells in the lungs. It is a progressive hyperplastic process that ultimately results in obliterative fibrosis of predominantly the pulmonary tree (the lungs). It is characterized by tachypnea, hypoxemia, and retractions.[1] It is predominantly found in infants and children younger than 2 years of age.[2] There is no currently recognized treatment for the relentless progression of this disorder. ## Contents * 1 Signs and Symptoms * 2 Causes * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Current Research * 9 References * 10 External links ## Signs and Symptoms[edit] X-Ray of Chest with Pneumonia People with this diagnosis may have no obvious symptoms, they may present with shortness of breath or wheezing.Infants and children present with symptoms of heavy breathing at a rate greater than 20 breath/min. Oxygen levels are lower due to hypoxia, and chest x-rays show signs of pneumonia. NEHI typically presents in otherwise healthy infants during the first months to year of life. Severe cases may risk permanent damage to the lungs and death from severe tachypnea. * Tachypnea * Hypoxemia * retractions * crackles (in lungs) * exercise intolerance ## Causes[edit] There is not cause of Neuroendocrine hyperplasia, however some known causes are a rapid increase of pulmonary endocrine cells in the lungs in children under the age of 2. An increase in pulmonary endocrine cells is usually seen in adults with a history of smoking, COPD, or cystic fibrosis. Children under the age of 2 may present with signs of interstitial lung disease and be diagnosed with NEH following severe progression.[2] ## Mechanism[edit] Neuroendocrine hyperplasia is a rare condition amongst chILD. This condition is characterized as an overgrowth of pulmonary endocrine cells in the lungs. These cells receive signals from neurons to produce hormones. With this rapid increase of PNC (pulmonary endocrine cells), this can affect the airways of children.[3] Furthermore, this increase can be a precursor of pulmonary carcinoid tumors.[4] ## Diagnosis[edit] To diagnose neuroendocrine hyperplasia after a referral is made for fast breathing (tachypnea) or need for extra oxygen. There are several tests that are commonly performed to confirm the diagnosis.[2] Chest CT gives a better look at the lungs to see signs of pneumonia. [5] With a bronchoscopy, a scope (small camera) is passed from the mouth or nose, through the windpipe, and into the lungs to check for other causes of breathing problems. [5] A lung biopsy may be the only way to diagnose the disease if the chest CT does not show the characteristic findings. In a biopsy, a small portion of lung tissue is removed to determine if lung disease is present. ## Treatment[edit] There is no consensus on the therapy for NEHI, and management generally consists of supportive care: supplemental oxygen for chronic hypoxemia, adequate nutrition, proper immunization, avoidance of environmental pollutants, and treatment of recurrent infections .[1] To relieve symptoms of NEH, there are not any methods yet proven effective in infants. [2] Supportive care and adequate nutrition may be considerate in improve quality of life as NEH in most cases is not treatable. [2] ## Prognosis[edit] Most outcomes in neuroendocrine hyperplasia leads to failure to thrive due to the restrictions of oxygen flow in lungs. [5] The long-term outcome of NEHI is generally favourable with most patients gradually improving over time, although persistent airway obstruction mimicking severe asthma and relapse with respiratory infection. [4] ## Epidemiology[edit] The incidence and prevalence of NEHI are unknown, but it is clearly rare. Available data derive from small to moderate sized case series. The original report of this disorder in 2005 included 15 cases.[4] A study from a large referral center identified 19 cases (14 percent) from among 138 lung biopsy cases accrued over a 10-year period.[1] Twenty-three NEH cases were included in a separate study testing chest CAT scan. The largest report to date includes 37 cases in a manuscript focusing on infant pulmonary function testing (PFT) ## Current Research[edit] The research being done on neuroendocrine hyperplasia consists of a criterion to distinguish its characteristics from similar cHILD cases.[6] A recent study in November, 2020 helped identify pathologic features of NEH, and used clinical patients to support their data.[7] Another study reviewed the various supplemental oxygen use in NEH patients. They identified factors in NEH to help in clinical course. As well as, reviewed failure to thrive patients who would have an increased use of supplemental oxygen.[8] Other than its associations with chILD, researchers do not know much about this condition. [1] ## References[edit] 1. ^ a b c Brody AS, Crotty EJ (December 2006). "Neuroendocrine cell hyperplasia of infancy (NEHI)". Pediatric Radiology. 36 (12): 1328. doi:10.1007/s00247-006-0302-3. PMID 16957891. 2. ^ a b c d e Caimmi S, Licari A, Caimmi D, Rispoli A, Baraldi E, Calabrese F, Marseglia GL (September 2016). "Neuroendocrine cell hyperplasia of infancy: an unusual cause of hypoxemia in children". Italian Journal of Pediatrics. 42 (1): 84. doi:10.1186/s13052-016-0295-y. PMC 5024443. PMID 27629751. 3. ^ "Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia". rarediseases.info.nih.gov. Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Retrieved 2020-12-18. 4. ^ a b c Spagnolo P, Bush A (June 2016). "Interstitial Lung Disease in Children Younger Than 2 Years". Pediatrics. 137 (6). doi:10.1542/peds.2015-2725. PMID 27245831. 5. ^ a b c "Neuroendocrine cell hyperplasia of infancy (NEHI)". www.childrenshospitalvanderbilt.org. Vanderbilt Children's Nashville, TN. Retrieved 2020-11-12. 6. ^ Sazonova O, Manem V, Béland C, Hamel MA, Lacasse Y, Lévesque MH, et al. (July 2020). "Development and Validation of Diffuse Idiopathic Pulmonary Neuroendocrine Hyperplasia (DIPNECH) Diagnostic Criteria". JTO Clinical and Research Reports. 24: 100078. doi:10.1016/j.jtocrr.2020.100078. 7. ^ "Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia". rarediseases.info.nih.gov. Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Retrieved 2020-11-13. 8. ^ Nevel RJ, Garnett ET, Schaudies DA, Young LR (May 2018). "Growth trajectories and oxygen use in neuroendocrine cell hyperplasia of infancy". Pediatric Pulmonology. 53 (5): 656–663. doi:10.1002/ppul.23958. PMC 5903936. PMID 29393588. ## External links[edit] Classification D External resources * Orphanet: 217560 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Neuroendocrine hyperplasia	c3161105	3,163	wikipedia	https://en.wikipedia.org/wiki/Neuroendocrine_hyperplasia	2021-01-18T19:04:13	{"umls": ["C3161105"], "orphanet": ["217560"], "wikidata": ["Q16946826"]}
Phallophobia SpecialtyPsychology Phallophobia in its narrower sense is a fear of the erect penis[1][2][3] and in a broader sense an excessive aversion to masculinity.[4] ## Contents * 1 Terminology * 2 Scope * 3 Cause * 4 Behavior * 5 References ## Terminology[edit] Alternative terms for this condition include ithyphallophobia[5] or medorthophobia.[6] An individual who has the condition is a phallophobe.[7][8] The term is derived from the word phallo in Greek meaning penis and at times denoting masculinity, coupled with the suffix phobia.[9][10] Medomalacuphobia, the fear of losing an erection or acquiring erectile dysfunction, is its antonym.[11] At its most extreme, phallophobia when coupled with a psychiatric condition may result in issues such as Klingsor Syndrome or ederacinism.[12] ## Scope[edit] In its broadest sense the term can be used metaphorically, for example in regards to pro-feminists.[13] However, in its narrower sense it has been described as a symptom that is more likely to be exhibited by women.[14] In sources that appear to use it in the original sense, it is sometimes nuanced as a byproduct or hyponym of an aversion, dislike or fear of the protruding appendage resemblance of the male erection, and how this symbolizes an accompanying aggression or assertiveness. This may occur in an aesthetic setting,[15] or in a sociological setting.[16] Such an aversion is sometimes extended to an unattributale cognitive process while at other times men's self and own experience.[17] In such a scenario, due to the essentiality of such reflexes for men, some correspondents have posited the feasibility of such a diagnosis if a man has relatively frequent nocturnal penile tumescence since he will probably not notice his erections then.[18] In cultures that discuss the male genitalia as a singular unit, the phenomenon of castration anxiety may overlap with phallophobia from a linguistic standpoint.[19] Although usually referring to ordinary erections, the term has also been used in toxicological and therapeutic contexts.[20] ## Cause[edit] Sigmund Freud has footnoted the possibility that this fear may be derived from a lack of ingenuity allowing one to ornamentally distance the copulatory organs from the excretory organs.[21] Such a condition can affect both men and women.[22] For others, symptoms include what characterizes a panic attack. It does not necessarily have to be induced by an uncovered penis, but may also result from seeing the manbulging outline or curvature of the penis, perhaps through clothes consisting of thin fabric. In more extreme cases it has been likened to the fight or flight response ingrained within the human body wherein an individual ceases to be intimate with their male partner and is unable to visit mixed gender establishments where people are likely to wear more revealing clothing, such as a gym, beach, cinema or livingrooms with a switched on monitor. The fear can recur through any of the senses including accidental touch, sight, hearing the word penis or thinking about an erection. The phobia may have developed from a condition such as dyspareunia,[23] a trauma (usually sexual) that occurred during childhood, but can also have a fortuitous origin.[3] In literature covering human sexuality, it is used as an adjective only to negatively allude to penetrative sex acts.[24] Men who have the phobia may try to avoid wearing sweatpants and other light fabrics, especially in public. Some analysts have purported that the condition may be inherited or may be a combination of genetic inheritance and life experiences.[25] For men with the condition, one of the byproducts is difficulty consummating with a partner due to a sense of vulnerability. This vulnerability may have developed during childhood if they grew up being told by their parents that sex and its physiological functions be evil, sinful and dirty, but were subsequently unable to detach such shameful feelings nor reverse it upon reaching adulthood, even when romantic initiatives were subsequently approved of or encouraged by their parents.[26][27] ## Behavior[edit] Sometimes the word is used in a sense wherein it is metaphorical and unrelated to its etymological origins, as in for instance when a man sees another man as a rival and a potential source of infidelity for his spouse.[28] Other reviews have applied the term as a euphemism or allegory to indicate that society is in contemporary times less willing to be objective and straightforward in discussions of the physiological aspects of the young male body in general due to prudery, or a celibacist and puritan standpoint that in particular targets men and boys. For instance, Ken Corbett has theorized the fact of widespread absence of the penis as an object of discussion in children's books and parenting books as evidencing that "a kind of phallophobia has crept into our cultural theorizing".[29] In other writings it has been used as an epithet to describe the lesbian or female asexual aversion to male sexuality.[30][31] Author Fawzi Boubia defines phallophobia as a hostility towards the stronger male gender.[32] The term has also been used as a substitute to indirectly express an aversion to procreation.[33] Phallophobia has also been used as an algorithm in studies of heuristics in robotic decision making in themes related to sexual temperance.[2] In criticisms of anti-male sexism, phallophobia is used as an epithet to deride double standards and hypocrisy in the legal system, all down to the set of genitalia one possesses.[34] One of the byproducts of this phobia among women is that it may result in them faking an orgasm to mask their feeling of revulsion around their male spouse.[35] Forms of treatment may include intensive counselling and therapy sessions.[36] ## References[edit] 1. ^ Basavanna, M (2000). Dictionary of Psychology. p. 310. 2. ^ a b Izbicki, M (2012). What if Aristotle had been a robot? (PDF). 3. ^ a b http://www.thedebrief.co.uk/sex/sex-stories/what-its-like-to-have-phallophobia-a-phobia-of-penises-20150541887 4. ^ Corbett, Ken (2009). Boyhoods: Rethinking Masculinities. pp. 213–20. 5. ^ "Cure Ithyphallophobia, How To Do It?". Retrieved 2018-06-25. 6. ^ "Medorthophobia", The Free Dictionary, retrieved 2018-06-25 7. ^ Center for the Study of Popular Culture (1992). Heterodoxy: Articles and Animadiversions on Political Correctness and Other Follies, Volumes 1-2. p. 219. 8. ^ Scott, Jay (1987). Midnight matinees: movies and their makers, 1975-1985. p. 124. 9. ^ Kirkpatrick, Kathryn (2015). Animals in Irish Literature and Culture. p. 5. 10. ^ Colman, Andrew M. (2008). Phobias and phobic stimuli - Oxford Reference. doi:10.1093/acref/9780199534067.001.0001. ISBN 9780199534067. Retrieved 2018-06-25. 11. ^ Semua, Lihat (12 April 2013). "9 Fobia Seksual yang Bikin Orang Takut dengan Hubungan Intim". Liputan 6. Retrieved 21 January 2016. "Medomalacuphobia ... the opposite of medorthophobia" 12. ^ Schweitzer, Isaac. "Genital self-amputation and the Klingsor syndrome." Australian and New Zealand journal of psychiatry 24.4 (1990): 566-569 13. ^ Duke, Michael (1989). Modern Chinese Women Writers: Critical Appraisals. p. 253. 14. ^ Goldblatt, Howard (1990). Worlds Apart: Recent Chinese Writing and Its Audiences. p. 56. 15. ^ Calenza, A (2014). Erotic revelations: Clinical applications and perverse scenarios. p. 7. 16. ^ Corbett, K (2013). "Shifting sexual cultures, the potential space of online relations, and the promise of psychoanalytic listening". Journal of the American Psychoanalytic Association. 61 (1): 25–44. doi:10.1177/0003065112470562. PMID 23269855. 17. ^ Kahn, Ada (2009). The Encyclopedia of Phobias, Fears, and Anxieties, Third Edition. p. 308. 18. ^ Cutler, Tom (2012). Slap and Tickle: The Unusual History of Sex and the People Who Have it. 19. ^ Campbell, Jill (1995). Natural Masques: Gender and Identity in Fielding's Plays and Novels. p. 260. 20. ^ Davies, Will (2014-06-09). "Brazil: No Fun for Arachnophobes". Wall Street Journal. ISSN 0099-9660. Retrieved 2018-06-25. 21. ^ O'Neill, John (2010). The Domestic Economy of the Soul: Freud's Five Case Studies. p. 54. 22. ^ Ngo, Denise (2010). "12 Crazy Phobias That Make Sex Sound Terrifying". Tango Magazine. 23. ^ Reamy, Kenneth J. "Meeting Sexual Dysfunction Again for the First Time." Journal of Sex & Marital Therapy 27.2 (2001): 197-201. 24. ^ Whitechapel, Simon (1997). Intense Device: A Journey Through Lust, Murder & the Fires of Hell. p. 29. 25. ^ "Cele mai ciudate fobii sexuale". Ele.ro (Comunicat de Presă). Retrieved 21 January 2016. 26. ^ Adnamazida, Rizqi. "9 Fobia seksual teraneh yang pernah ada \| merdeka.com". merdeka.com. Retrieved 2018-06-25. 27. ^ "Waduh, Banyak Wanita Gemetaran saat Melihat Mr P Ereksi! - Tribun Lampung". Tribun Lampung (in Indonesian). 2014-12-25. Retrieved 2018-06-25. 28. ^ Balbert, Peter (2013). "From Panophilia to Phallophobia: Sublimation and Projection in D. H. Lawrence's St. Mawr". Papers on Language & Literature. 49 (1): 37. 29. ^ Lubart, WD (2011). "Can We Speak of the Penis?". Contemporary Psychoanalysis. 47 (3): 447–454. doi:10.1080/00107530.2011.10746470. 30. ^ Keesey, D (2011). "Intertwinings of death and desire in Michele Soavi's Dellamorte Dellamore". Horror Studies. 2. CiteSeerX 10.1.1.1014.6473. doi:10.1386/host.2.1.105_1. 31. ^ Hetchegoyen, Horacio (2005). The Fundamentals of Psychoanalytic Technique. p. 194. 32. ^ Boubia, Fawzi (1997). Hegal's Internationalism: World History and Exclusion. "All of this leads to the belief that Hegel is haunted not only by the monstrosities of this “Feminine State,” but equally, by this “phallophobia,” this hostility declared toward its “strong” sex." 33. ^ The Cincinnati Lancet-clinic - Volume 76. 1896. p. 446. 34. ^ Barnes, Alexander (2000). The Book Read Backwards: The Deconstruction of Patriarchy and the Wombanization of Being. p. 430. 35. ^ "Ithyphallophobia, Fobia Melihat Penis yang Ereksi - Banjarmasin Post". Banjarmasin Post (in Indonesian). 2015-06-04. Retrieved 2018-06-25. 36. ^ "SEXUAL HEALTH: A most unusual phobia". Daily Nation. Retrieved 2018-06-25. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Phallophobia	None	3,164	wikipedia	https://en.wikipedia.org/wiki/Phallophobia	2021-01-18T18:45:25	{"wikidata": ["Q22162415"]}
Oculopalatocerebral syndrome is characterised by the association of four anomalies: intellectual deficit, microcephaly, palate anomalies and ocular abnormalities. ## Epidemiology It has been described in five patients (three boys and two girls). ## Clinical description Maternal hypertension, oligoamnios and intrauterine growth retardation (IUGR) are often noted during pregnancy. The clinical manifestations are evident from birth. The palate anomaly is usually cleft palate. In the majority of cases, postnatal growth is marked by statural (between -2.5 and -4 SD) and ponderal retardation. Microcephaly is present in all patients (between -2 and -5.6 SD). Persistent hyperplastic primary vitreous (uni- or bilateral) was present in all cases reported so far and may be associated with microphthalmia, cataract or optic atrophy. Facial dysmorphology is characterised by full cheeks, a bulbous nasal tip, and long ears with thickened helices. Hands and feet are small. Anomalies of the external genitalia were reported in some of the male patients, with two of the boys displaying cryptorchidism. Skeletal anomalies include pectus excavatum, joint hyperlaxity and kyphoscoliosis. Intellectual deficit (moderate to severe) is a constant feature and is associated with cerebral atrpohy or quadriplegia in some cases. Hearing difficulties may also be present and a tendency for atopy is often noted. ## Etiology So far, neither a causative gene nor locus has been identified. ## Diagnostic methods Diagnosis is based in the clinical manifestations, in particular on the presence of a persistent hyperplastic primary vitreous in association with other malformations. ## Differential diagnosis Differential diagnosis should include cerebro-oculo-nasal syndrome (see this term) and other syndromes associated with a persistent hyperplastic primary vitreous. ## Antenatal diagnosis Prenatal diagnosis is possible but relies on detection of the malformations and growth retardation by foetal ultrasound. ## Genetic counseling Familial reoccurrence and evidence of consanguinity in two of the three reported families are suggestive of autosomal recessive inheritance. Genetic counselling of families with an affected child should take into account a risk of reoccurrence of 25%. ## Management and treatment Treatment should include surgical correction of the palate anomalies and management of the visual problems. Physical and speech therapy should also be recommended. ## Prognosis Although no data are available on the long-term prognosis, the nature of the anomalies suggests that life expectancy for these patients is normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Oculo-palato-cerebral syndrome	c1850338	3,165	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2714	2021-01-23T18:22:10	{"mesh": ["C564935"], "omim": ["257910"], "umls": ["C1850338"], "icd-10": ["Q87.1"], "synonyms": ["Oculo-palato-cerebral dwarfism"]}
## Clinical Features The pigment dispersion syndrome with open-angle glaucoma usually affects individuals under the age of 30 years. In addition to the typical optic nerve degeneration seen in all forms of glaucoma, the pigment dispersion syndrome is characterized by distinctive clinical features. One feature is the deposition of pigment granules from the iris epithelium on various ocular structures, including the trabecular meshwork. This disorder frequently affects young myopic individuals. In the early stages of the disease, affected individuals may have clinical evidence of dispersed pigment without an associated elevation of intraocular pressure and optic-nerve degeneration. However, as the disease progresses, approximately 50% of patients develop increased intraocular pressure and degeneration of the optic nerve, causing permanent loss of sight (Richter et al., 1986). Siddiqui et al. (2003) reviewed the results from 113 patients newly diagnosed with pigment dispersion syndrome over a 24-year period. The risk of developing pigmentary glaucoma from pigment dispersion syndrome was 10% at 5 years and 15% at 15 years. Young myopic men were most likely to have pigmentary glaucoma. An intraocular pressure greater than 21 mm Hg at initial examination was associated with an increased risk of conversion. Pigment dispersion syndrome and pigmentary glaucoma result from iridozonular friction causing disruption of the iris epithelium and deposition of iris pigment on the anterior segment structures. Tesser (2003) reported a 48-year-old patient with congenital bilateral iris colobomas (see 120200). Elevated intraocular pressure was present in the eye with a partial iris coloboma and iris transillumination defects but pigment deposition on the ipsilateral corneal endothelium (Krukenberg spindle). The other eye was diagnosed as having mild ocular hypertension, without pigment dispersion or glaucoma, in association with a complete iris coloboma. Tesser (2003) concluded that pigment dispersion was prevented in the eye with the complete iris coloboma. Grassi et al. (2004) reported an 8-year-old boy with atypical PDS. In addition to iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure, he had emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae. Dorairaj et al. (2007) reported 3 unrelated children with PDS: an 11-year-old girl with bilateral PDS with elevated intraocular pressure whose mother had PDS, and two 12-year-old boys, 1 with a more severe phenotype and both parents affected, and the other with a less severe phenotype and 1 parent affected. Inheritance Autosomal dominant inheritance of the pigment dispersion syndrome was documented by Scheie and Cameron (1981) and Mandelkorn et al. (1983), among others. Mapping Andersen et al. (1997) performed a genomewide screen using microsatellite repeat markers in 4 pedigrees containing 28 patients showing clinical evidence of the pigment dispersion syndrome. Of these, 14 also had elevated intraocular pressures requiring medical or surgical treatment or both. Linkage was observed between the disease phenotype and markers located on the telomere region of 7q, 7q35-q36. The maximum 2-point lod score for a single pedigree was 5.72 at theta = 0.0 for markers D7S2546 and D7S550. Analysis of affected recombinant individuals demonstrated that the responsible gene is located in a 10-cM interval between markers D7S2462 and D7S2423. ### Exclusion Studies The pigment dispersion syndrome shares several clinical features with the form of autosomal dominant juvenile open-angle glaucoma that shows linkage mapping to 1q21-q31 (137750). The 2 disorders share a similar age of onset and a high prevalence of myopia in affected individuals. Paglinauan et al. (1995) observed a family in which several sibs had severe juvenile glaucoma without clinical features of the pigment dispersion syndrome. The juvenile glaucoma in these patients segregated with markers located on 1q21-q31. One individual in the family had the pigment dispersion syndrome but lacked elevated intraocular pressure or optic nerve damage. This individual had not inherited the 1q21-q31 haplotype from his glaucoma-affected father, suggesting that the pigment dispersion syndrome and chromosome 1-linked juvenile glaucoma are separate entities. In a linkage study involving 3 pigment dispersion syndrome pedigrees, Paglinauan et al. (1995) excluded linkage to the 1q21-q31 region, confirming that these are distinct entities. Wiggs et al. (1995) studied 3 pedigrees in which the pigment dispersion syndrome was not linked to the 1q21-q31 region. Animal Model John et al. (1998) characterized the DBA/2J mouse that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between DBA/2J and C57BL/6J mice, Chang et al. (1999) demonstrated that there are 2 chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the DBA/2J allele (ipd) of one locus on mouse chromosome 6 developed an iris pigment dispersion similar to human pigment dispersion syndrome (GPDS1), which maps to human chromosome 7q, a region with homology of synteny to mouse chromosome 6. Progeny homozygous for the DBA/2J allele (isa) of a different locus on chromosome 4 develop an iris stromal atrophy phenotype. Chang et al. (1999) suggested that the Tyrp1 gene (115501) is a candidate for isa and likely causes iris stromal atrophy via a mechanism involving pigment production. Progeny homozygous for both the isa and ipd alleles develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy. Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure and glaucoma (Sugar, 1966). Using high-resolution mapping techniques, sequencing, and functional genetic tests, Anderson et al. (2002) further pursued the DBA/2J model of pigmentary glaucoma. They showed that iris pigment dispersion (ipd) and iris stromal atrophy (isa) result from mutations in related genes encoding melanosomal proteins. Ipd is caused by a premature stop codon mutation (arg150 to ter; R150X) in the Gpnmb gene (604368), as proved by the occurrence of Ipd only in mice homozygous with respect to this mutation; otherwise, similar mice that are not homozygous for the R150X mutation of Gpnmb do not develop Ipd. Anderson et al. (2002) found that Isa is caused by a recessive mutant allele of the Tyrp1 gene and rescued by the transgenic introduction of wildtype Tyrp1. They hypothesized that Ipd and Isa alter melanosomes, allowing toxic intermediates of pigment production to leak from melanosomes, causing iris disease and subsequent pigmentary glaucoma. This is supported by the rescue of Ipd and Isa in the DBA/2J strain with substantially decreased pigment production. The data suggested that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. The fact that hypopigmentation profoundly alleviates the disease in DBA/2J mice indicates that therapeutic strategies designed to decrease pigment production may be beneficial in human pigmentary glaucoma. Lu et al. (2011) used quantitative trait locus mapping methods and gene set analysis to evaluate Gpnmb coexpression networks in wildtype and mutant cohorts. Covariates of wildtype Gpnmb were involved in melanin synthesis and cell migration, whereas the covariates of mutant Gpnmb were involved in posttranslational modification, stress activation, and sensory processing. Lu et al. (2011) showed that the R150X mutation in Gpnmb dramatically modified its list of genetic covariates, which might explain the associated ocular pathology in pigment dispersion syndrome. Reichstein et al. (2007) used annexin-V (131230) labeling to determine the in vivo time course and spatial distribution of retinal ganglion cells (RGCs) undergoing apoptotic death in DBA/2 mice. Apoptotic RGC death was maximal between 12 and 15 months of age and occurred in clusters. The clusters were initially located in the midperipheral retina and progressively occurred closer to the optic nerve head with increasing age. Retrograde axonal transport in the glaucomatous mouse retina was functional until at least 2 to 3 days prior to initiation of apoptotic RGC cell death. Marneros and Olsen (2003) found that abnormalities in the iris and ciliary body of Col18a1 (120328) -/- mice demonstrated the important role of collagen XVIII in the function of ocular basement membranes. The absence of collagen XVIII altered the properties of basement membranes and led to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome. In addition, loss of collagen XVIII created changes that allowed clump cells to migrate out of the iris. These cells had not been well characterized previously. The authors showed that clump cells are macrophage-like cells and are able to penetrate the internal limiting membrane in mutant mice. The disease mechanism of human pigment dispersion syndrome was not well understood, but Col18a1 -/- mice might serve as a model and demonstrate the potential importance of alterations in extracellular matrix components in this disease. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Pigment-dispersion type open-angle glaucoma \- Optic-nerve degeneration \- Pigment granule deposition from iris epithelium to other ocular structures \- Myopia \- Permanent loss of sight MISCELLANEOUS \- Usual onset under age 30 years ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GLAUCOMA-RELATED PIGMENT DISPERSION SYNDROME	c1271398	3,166	omim	https://www.omim.org/entry/600510	2019-09-22T16:16:04	{"doid": ["0060680"], "mesh": ["C563184"], "omim": ["600510"], "synonyms": ["Alternative titles", "GLAUCOMA, PIGMENT-DISPERSION TYPE", "PIGMENT DISPERSION SYNDROME"]}
Janeway lesion Specialty * Cardiology * Dermatology SymptomsPainless red flat papules on palms and soles. Usual onsetSudden DurationDays to weeks CausesInfective endocarditis Differential diagnosisOsler's nodes Janeway lesions are rare, non-tender, small erythematous or haemorrhagic macular, papular or nodular lesions on the palms or soles only a few millimeters in diameter that are associated with infective endocarditis and often indistinguishable from Osler's nodes.[1][2] ## Contents * 1 Definition * 2 Differential * 3 Pathophysiology * 4 Diagnosis * 5 History * 6 See also * 7 References * 8 External links ## Definition[edit] Janeway lesions are painless, frequently haemorrhagic lesions seen most commonly on the palms and soles, particularly on the base of the thumb and little finger, and seen in infective endocarditis.[1] ## Differential[edit] Osler's nodes and Janeway lesions are similar and point to the same diagnostic conclusion. The only noted difference between the two is that Osler's nodes present with tenderness, while Janeway lesions do not.[2] ## Pathophysiology[edit] Pathologically, the lesion is described to be a microabscess of the dermis with marked necrosis and inflammatory infiltrate not involving the epidermis.[2] They are caused by septic emboli which deposit bacteria, forming microabscesses.[3] Organisms may be cultured from the lesions.[4] ## Diagnosis[edit] Janeway lesions present as red, painless macules and papules on the palms and soles.[1] They are not common and are frequently indistinguishable from Osler's nodes. Rarely, they have been reported in cases of Systemic lupus erythematosis (SLE), Gonococcemia (disseminated gonorrhoea), haemolytic anaemia and typhoid fever.[1] They may last days to weeks before completely resolving.[1] ## History[edit] Janeway lesions are named after Edward Janeway (1841–1911), a prominent American physician, pathologist and contemporary of Sir William Osler, who initially described "peculiar skin lesions" in some people with endocarditis, in a paper published in 1899. The term was first used by internist and pathologist Emanuel Libman, who reported the lesions in his paper of 1906 and explained his reasoning for using the term "Janeway lesions" in a footnote in 1923. Osler never mentioned Janeway lesions. The inclusion into Osler's 1925 textbook came six years after Osler died.[5] ## See also[edit] * Roth's spots * Osler's node ## References[edit] 1. ^ a b c d e "Osler nodes and Janeway lesions \| DermNet NZ". www.dermnetnz.org. Retrieved 2 October 2019. 2. ^ a b c Farrior, J.B.; Silverman M.E. (1976). "A consideration of the differences between a Janeway's lesion and an Osler's node in infectious endocarditis". Chest. 70 (2): 239–243. doi:10.1378/chest.70.2.239. PMID 947688. 3. ^ Mandell, Douglas, Bennett's Principles and Practice of Infectious Diseases, 7th ed., Churchill Livingstone (2009). 4. ^ Patterson, James W. (2016). "8. The Vasculopathic Reaction Pattern". Weedon's Skin Pathology (4th ed.). Churchill Livingston. pp. 239–240. ISBN 9780702051838. 5. ^ Jordan Prutkin, W. Bruce Fye (2006). "Edward G. Janeway, Clinician and Pathologist". Clinical Cardiology. 29 (8): 376–377. doi:10.1002/clc.4960290815. PMC 6654287. PMID 16933584.CS1 maint: uses authors parameter (link) ## External links[edit] Classification D * ICD-10: A41.8 (ILDS A41.820) * v * t * e Symptoms and signs relating to the circulatory system Chest pain * Referred pain * Angina * Levine's sign Auscultation * Heart sounds * Split S2 * S3 * S4 * Gallop rhythm * Heart murmur * Systolic * Functional murmur * Still's murmur * Diastolic * Pulmonary insufficiency * Graham Steell murmur * Continuous * Carey Coombs murmur * Mitral insufficiency * Presystolic murmur * Pericardial friction rub * Heart click * Bruit * carotid Pulse * Tachycardia * Bradycardia * Pulsus paradoxus * doubled * Pulsus bisferiens * Pulsus bigeminus * Pulsus alternans Other * Palpitations * Apex beat * Cœur en sabot * Jugular venous pressure * Cannon A waves * Hyperaemia * Shock * Cardiogenic * Obstructive * Hypovolemic * Distributive * See further Template:Shock Cardiovascular disease Aortic insufficiency * Collapsing pulse * De Musset's sign * Duroziez's sign * Müller's sign * Austin Flint murmur * Mayne's sign Other endocardium * endocarditis: Roth's spot * Janeway lesion/Osler's node * Bracht–Wachter bodies Pericardium * Cardiac tamponade/Pericardial effusion: Beck's triad * Ewart's sign Other * rheumatic fever: * Anitschkow cell * Aschoff body * EKG * J wave * Gallavardin phenomenon Vascular disease Arterial * aortic aneurysm * Cardarelli's sign * Oliver's sign * pulmonary embolism * Right heart strain * radial artery sufficiency * Allen's test * pseudohypertension * thrombus * Lines of Zahn * Adson's sign * arteriovenous fistula * Nicoladoni sign Venous * Friedreich's sign * Caput medusae * Kussmaul's sign * Trendelenburg test * superior vena cava syndrome * Pemberton'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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Janeway lesion	c1532713	3,167	wikipedia	https://en.wikipedia.org/wiki/Janeway_lesion	2021-01-18T18:31:57	{"umls": ["C1532713"], "icd-10": ["A41.8"], "wikidata": ["Q1149382"]}
Hangman's fracture CT scan of hangman's fracture SpecialtyOrthopedic Hangman's fracture is the colloquial name given to a fracture of both pedicles, or pars interarticulares, of the axis vertebra (C2). ## Contents * 1 Causes * 2 Mechanisms * 3 Prevention * 3.1 Car crashes * 3.2 Contact sports * 4 Treatment * 4.1 Non-surgical or surgical * 4.2 Benefits of surgical hangman's fracture treatment * 4.3 Result of the surgical treatment * 5 Epidemiology * 6 Society * 7 See also * 8 References * 9 External links ## Causes[edit] X-ray of the cervical spine with a Hangman's fracture. Left without, right with annotation. It can be seen clearly that C2 (red outline) is moved forward with respect to C3 (blue outline). The injury mainly occurs from falls, usually in elderly adults, and motor accidents mainly due to impacts of high force causing extension of the neck and great axial load onto the C2 vertebra.[1] In a study based in Norway, 60% of reported cervical fractures came from falls and 21% from motor-related accidents.[2] According to the Agency for Healthcare Research and Quality (AHRQ), the group under the highest risk of C2 fractures are elderly people within the age group of 65-84 (39.02%) at risks of falls (61%) or motor accidents (21%) in metropolitan areas (94%). There were 203 discharges from the age group 1-17; 1,843 from 18- to 44-year-olds; 2,147 from 45- to 64-year-olds, 4,890 from 65- to 84-year-olds, and 3440 from 85+-year-olds. Females accounted for 54.45% of occurrences while males accounted for the other 45.38%.[3] ## Mechanisms[edit] A demonstration of a common mechanism of a hangman's fracture in a car accident. The mechanism of the injury is forcible hyperextension of the head, usually with distraction of the neck. Traditionally this would occur during judicial hanging, when the noose was placed below the condemned subject's chin. When the subject was dropped, the head would be forced into hyperextension by the full weight of the body, a sufficient force to cause the fracture. However, despite its long association with judicial hangings, one study of a series of such hangings showed that only a small minority of hangings produced a hangman's fracture.[4] Apart from hangings, the mechanism of injury—a sudden forceful hyperextension centered just under the chin—occurs mainly with deceleration injuries in which the victim's face or chin strike an unyielding object with the neck in extension. The most common scenario is a frontal motor vehicle accident with an unrestrained passenger or driver, with the person striking the dashboard or windshield with their face or chin. Other scenarios include falls, diving injuries, and collisions between players in contact sports.[citation needed] Although a hangman's fracture is unstable, survival from this fracture is relatively common, as the fracture itself tends to expand the spinal canal at the C2 level. It is not unusual for patients to walk in for treatment and have such a fracture discovered on X-rays. Only if the force of the injury is severe enough that the vertebral body of C2 is severely subluxed from C3 does the spinal cord become crushed, usually between the vertebral body of C3 and the posterior elements of C1 and C2.[citation needed] ## Prevention[edit] ### Car crashes[edit] Most commonly this can occur during a car accident. A person involved in a car crash, especially with no seat belt, can slam his chin against the steering wheel, dashboard, or windshield, causing the hyperextension to occur.[citation needed] ### Contact sports[edit] Falling and colliding with other people in a contact sport can also cause this fracture. Falling causes the weight of the body to force hyperextension. In full-contact sports such as American football and Rugby, diving for the ball can lead a player to land on his head, forcing the neck into hyperextension. The further piling of players on top of an injured player adds more weight and can lead to further occurrences of this fracture.[citation needed] ## Treatment[edit] ### Non-surgical or surgical[edit] Hangman's fractures treatments are both non-surgical and surgical.[5][6] ### Benefits of surgical hangman's fracture treatment[edit] Sasso[5] also observed that people who underwent surgical treatment will not be affected by pin site infections, brain abscesses, facet joint stiffness, loss of spinal alignment, and skin breakdown. Another study concerns the surgical treatment of the ring of axis conducted by Barsa et al. (2006)[7] based on 30 cases within 41 patients treated by using anterior cervical fixation and fusion and 11 cases treated by a posterior CT.[citation needed] ### Result of the surgical treatment[edit] As a result, Barsa et al.[8] showed that the result of fracture fusion reduced after one year but only one patient died of other disease during the follow-up. Hakalo and Wronski (2008)[9] showed the benefits of operative treatment such as using transoral C2-C3 discectomy with plate-cage stabilization or posterior direct pars screw repair for the reducing and healing process.In deliberate or suicidal hanging, asphyxia is much more likely to be the cause of death due to associated prevertebral swelling.A common sign is a constricted pupil (Horner's syndrome) on the ipsilateral side due to loss of sympathetic innervation to the eye, caused by damage to the sympathetic trunk in the neck.[citation needed] ## Epidemiology[edit] The pie chart shows the incidence of C2 fractures according to age groups. For the <17 age group, there were 203 incidents. For ages 18-44 there were 1843. For 45-64 there were 2147. For 65-84 there were 4890 and for 85+ there were 3440 incidents. A total of 12,532 discharges in America were reported in 2010. The C2 fracture accounts for nearly 19% of spinal fractures[10] and 55% of cervical fractures (in patients with head injury). Within C2 fractures, the hangman's fracture accounts for 23% of occurrences while the odontoid or dens fracture accounts for 55% of them.[1] ## Society[edit] The graph shows the trend of hospital charges and number of discharges over the span of 12 years in the U.S.A. In 1998, hospital costs were $24,423 with 4,991 discharged. In 2010 hospital charges increased to 59,939 with 12,532 discharged. Statistics from the AHRQ show that there were 12,532 hospital discharges from C2 fractures in the US during 2010. The mean healthcare costs were $17,015 and the "national bill" or the aggregate charges were $749,553,403. Only 460 in-hospital deaths related to the C2 fracture occurred. From 2000 to 2010, the number of discharges has increased from 4,875 to 12,532, almost a 250 percent increase. Mean health care costs went from $24,771 to $59,939.[3] ## See also[edit] * Cervical fracture * Cervical vertebrae ## References[edit] 1. ^ a b Ryan, MD.; Henderson, JJ. (1992). "The epidemiology of fractures and fracture-dislocations of the cervical spine". Injury. 23 (1): 38–40. doi:10.1016/0020-1383(92)90123-a. PMID 1541497. 2. ^ Pratt, H.; Davies, E.; King, L. (2008). "Traumatic injuries of the c1/c2 complex: computed tomographic imaging appearances". Curr Probl Diagn Radiol. 37 (1): 26–38. doi:10.1067/j.cpradiol.2007.07.001. PMID 18054664. 3. ^ a b "Healthcare Cost and Utilization Project". HCUP Home. 4. ^ James R, Nasmyth-Jones R (Apr 1992). "The occurrence of cervical fractures in victims of judicial hanging". Forensic Science International. 54 (1): 81–91. doi:10.1016/0379-0738(92)90083-9. 5. ^ a b Sasso Rick C (2001). "C2 Dens Fractures: Treatment Options". Journal of Spinal Disorders. 14 (5): 455–463. doi:10.1097/00002517-200110000-00015. 6. ^ Li, Xin-Feng; Dai, Li-Yang; Lu, Hua; Chen, Xiao-Dong (19 October 2005). "A systematic review of the management of hangman's fractures". European Spine Journal. 15 (3): 257–269. doi:10.1007/s00586-005-0918-2. PMC 3489291. PMID 16235100. 7. ^ Barsa P; Buchvald P; Frohlich R; Hradil J; Lukas R; Suchomel P; & Taller S.(2006). Surgical treatment of fracture of the ring of axis - "hangman's fracture". 73(5): 321-8. 8. ^ Barsa P; Buchvald P; Frohlich R; Hradil J; Lukas R; Suchomel P; & Taller S.(2006). Surgical treatment of fracture of the ring of axis \- "hangman's fracture". 73(5): 321-8. 9. ^ Hakalo J; Wronski J.(2008). Operative treatment of hangman's fractures of C2. Posterior direct pars screw repair or anterior plate-cage stabilization? 42(1): 28-36. 10. ^ Mulligan, RP.; Friedman, JA.; Mahabir, RC. (Mar 2010). "A nationwide review of the associations among cervical spine injuries, head injuries, and facial fractures". J Trauma. 68 (3): 587–92. doi:10.1097/TA.0b013e3181b16bc5. PMID 19996802. ## External links[edit] Classification D * ICD-10: S12.1 * ICD-9-CM: 805.02 * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hangman's fracture	c0434858	3,168	wikipedia	https://en.wikipedia.org/wiki/Hangman%27s_fracture	2021-01-18T18:44:52	{"mesh": ["D016103"], "icd-9": ["805.02"], "icd-10": ["S12.1"], "wikidata": ["Q2365851"]}
See also: Poisoning of Sergei and Yulia Skripal 2018 Amesbury poisonings LocationAmesbury, Wiltshire, England Date30 June 2018 WeaponsA-234 (suspected chemical weapon used) DeathsDawn Sturgess (8 July 2018, aged 44, after being admitted to hospital) InjuredCharlie Rowley (45; admitted to hospital; discharged 20 July 2018) CoronerHM Coroner for Wiltshire and Swindon On 30 June 2018, in Amesbury, two British nationals, Charlie Rowley and Dawn Sturgess, were admitted to Salisbury District Hospital in Wiltshire, England. Police determined that they were poisoned by a Novichok nerve agent of the same kind used in the poisoning of Sergei and Yulia Skripal in Salisbury, 8 miles (13 km) away, almost four months prior.[1][2][3] Sturgess died on 8 July, and Rowley regained consciousness two days after. ## Contents * 1 Hospital admissions and subsequent death of Sturgess * 2 Investigation * 2.1 Inquest * 3 Government response * 4 Interview with Rowley * 5 Fate of flat * 6 References ## Hospital admissions and subsequent death of Sturgess[edit] According to the subsequent press report released by the Metropolitan Police, at 10:15 on Saturday 30 June 2018, the South Western Ambulance Service was called to a residential address in Amesbury after Dawn Sturgess had collapsed. She was subsequently taken to hospital and admitted. At 15:30, the ambulance service was again called to that address, after Charlie Rowley had fallen ill. He was taken to hospital, and Wiltshire Police were informed of both admissions. On 8 July, Sturgess died at Salisbury District Hospital after doctors took the decision to switch off her life support.[4][5] On 10 July, Rowley regained consciousness and there was a "small but significant improvement to his condition" according to the hospital.[6] On 11 July, he was no longer in critical condition and the hospital downgraded his condition to "serious but stable".[7] The same day, officers from the investigation team spoke with Rowley.[7] He told his brother Matthew the nerve agent had been in a small perfume or aftershave bottle, which they had found in a park about nine days before spraying themselves with it. The police later closed and fingertip-searched Queen Elizabeth Gardens, a riverside park in central Salisbury, which the couple had visited the day before they fell ill.[8] The funeral of Sturgess took place at Salisbury crematorium on 30 July 2018.[9] On 20 July, Rowley was discharged from the hospital.[10] Over the weekend of 18/19 August 2018, Rowley was re-admitted to hospital with sight problems.[11] On 4 September 2018 he was reported to be ill with meningitis but was expected to leave hospital "within a month".[12] ## Investigation[edit] The incident was investigated by the Specialist Operations Directorate of the Metropolitan Police, assisted nationally by the National Counter Terrorism Policing Network and locally by Wiltshire Police, in a multi-agency response named Operation Fortis.[13] According to the Metropolitan Police, there was nothing in either of the victims' backgrounds to suggest that they were deliberately targeted, and there were no other reports of people presenting with similar symptoms. The couple were believed to have been near the roads that were sealed off during the investigation of the Skripal poisoning in Salisbury.[14] During initial assessment, medical staff believed that the patients' illness was caused by the use of contaminated illegal drugs. But on 2 July, hospital staff had concerns over the symptoms the couple were displaying, and sent samples from both patients to the Government's Defence Science and Technology Laboratory (DSTL) at Porton Down for analysis. On 4 July the laboratory confirmed that the patients were exposed to Novichok nerve agent.[2][15] According to BBC News, the "most likely hypothesis" was that the Novichok was left over from the attack on the Skripals and that the contaminated item which poisoned the couple "could be a vial or syringe because of the couple's lifestyle", as it is believed the Novichok was disposed of "in a haphazard way".[16] Friends of the couple told The Guardian that Rowley frequently scavenged recycling bins for objects that he could sell, and that the couple's houses contained "loads of household things" they had picked up.[17] Sites in both Amesbury and Salisbury which were believed to have been visited by the couple were cordoned off. These sites are the local Boots Pharmacy, the Baptist Centre, and Muggleton Road in Amesbury, and the Queen Elizabeth Gardens in Salisbury.[15] Local residents were warned of an increased police presence, including officers wearing protective equipment.[15] On 6 July, police announced that officers had identified and spoken to several key witnesses and were trawling through more than 1,300 hours of CCTV footage which has been collected so far.[18] On 13 July a police cordon closed the north end of Rollestone Street, Salisbury to enable members of the Counter Terrorism Policing Network to search John Baker House, a hostel for the homeless where Dawn Sturgess lived. On 24 July the cordon was lifted and the police announced that no contamination was found in John Baker House.[19] The Metropolitan Police announced on 13 July 2018[20][21] that they had identified the source of the nerve agent that poisoned Sturgess and Rowley as being a "small bottle" discovered at Rowley's house in Amesbury which was confirmed by analysis at DSTL Porton Down to contain Novichok. Matthew Rowley, brother of the victim, said Charlie told him that he had picked up "the perfume bottle". The Metropolitan Police refused to confirm this claim.[22] Also on 13 July, the intergovernmental Organisation for the Prohibition of Chemical Weapons (OPCW) received a request from the UK for technical assistance on the incident in Amesbury. The OPCW sent a team of specialists who collected the samples and sent them to two laboratories. By 18 July, preliminary work was completed and the team left the UK.[23] On 7 August 2018, the Foreign Office announced that OPCW experts would return to Amesbury to collect further samples. A spokesman said: "During their visit, the OPCW's experts will collect more samples to inform their work following their visit in July. The samples will be analysed at highly reputable international laboratories designated by the OPCW."[24] The poison was confirmed on 4 September by the OPCW to be the same kind of nerve agent as that used on the Skripals, but the OPCW also said that it could not determine if it was from the same batch.[25] On 5 September 2018 Assistant Commissioner Neil Basu said the police had "no doubt" that this incident was connected to the poisoning of Sergei and Yulia Skripal. He said, "we do not believe Dawn and Charlie were deliberately targeted, but became victims as a result of the recklessness in which such a toxic nerve agent was disposed of."[26] The Met Police released a detailed description of the Salisbury poisoning and named the suspects wanted. This went on to state that the investigation into the Amesbury poisoning was ongoing by the Police and the CPS, and further charges relating to Sturgess and Rowley would follow.[27] ### Inquest[edit] The inquest for Sturgess was opened and adjourned by HM Coroner for Wiltshire and Swindon in Salisbury on 19 July 2018, with a Pre-Inquest Review listed for 16 January 2019.[28][29] This was delayed, in part because the Crown Prosecution Service requested a suspension in view of the ongoing criminal investigation.[30] The Senior Coroner, David Ridley, issued a 31-page ruling[30] on the scope of the inquest on 20 December 2019, but no date for the full inquest was given.[31] ## Government response[edit] On 5 July 2018, Home Secretary Sajid Javid chaired a meeting of the COBR committee to discuss the incident.[32] In the House of Commons later that day, Javid stated the most likely hypothesis was that the Novichok was in an item discarded after the Skripal attack. He accused Russia of using Britain as a "dumping ground for poison".[33] ## Interview with Rowley[edit] Rowley gave an interview to ITV News on 24 July 2018, stating that he believed a sealed box of a recognisable brand of perfume, which he had found and given to Sturgess, was the source of the Novichok. His partner became sick "within 15 minutes" after spraying the "oily substance" onto her wrists before rubbing them together, under the assumption that it was perfume.[34][35][36] He also stated that he came into contact with the chemical agent after some tipped onto his hands while attaching the plastic spray dispenser to the bottle, but had washed his hands soon after. They had used a knife to open the sealed packaging.[34][35] ## Fate of flat[edit] In June 2020 it was announced that the flat the poisonings happened in, together with the one below it, would be demolished.[37] Both Dawn Sturgess’ family and partner supported the demolition and liked the idea of it being turned into a green space.[37] Dawn's father, Stan Sturgess, said "It’s a shame that it is being lost but I can imagine that people wouldn’t want to live there."[37] Rowley said "I think it's for the best. There would always be a stigma around it."[37] ## References[edit] 1. ^ "Two collapse near spy poisoning site". BBC News. 4 July 2018. Retrieved 4 July 2018. 2. ^ a b "Amesbury pair poisoned by Novichok". BBC News. Retrieved 4 July 2018. 3. ^ "Amesbury substance: Paramedics wore hazmat suits". Sky News. Retrieved 4 July 2018. 4. ^ "UPDATE: Woman dies following exposure to nerve agent in Amesbury". Metropolitan Police. Retrieved 8 July 2018. 5. ^ "Novichok victim's sister recalls 'goodbye'". 19 July 2018. Retrieved 24 July 2018 – via www.bbc.co.uk. 6. ^ Morris, Steven; Bannock, Caroline (10 July 2018). "Man poisoned by novichok regains consciousness". the Guardian. Retrieved 10 July 2018. 7. ^ a b Morris, Steven; Dodd, Vikram (11 July 2018). "Amesbury novichok victim 'reveals doctors feared he would die'". the Guardian. Retrieved 15 July 2018. 8. ^ Steven Morris (18 July 2018). "Novichok poisonings: police search Salisbury park visited by couple". The Guardian. 9. ^ "Amesbury poisoning: 'Very emotional' funeral held for novichok victim Dawn Sturgess". Retrieved 7 August 2018. 10. ^ Bullen, Jamie (20 July 2018). "Novichok victim Charlie Rowley discharged from Salisbury hospital three weeks after poisoning". Retrieved 24 July 2018 – via www.telegraph.co.uk. 11. ^ Morris, Steven (20 August 2018). "Novichok victim back in hospital with sight problems, says brother". The Guardian. Retrieved 22 August 2018. 12. ^ "Novichok victim Charlie Rowley 'feeling positive' and 'hoping to get out of hospital in next two or three weeks'". Retrieved 5 September 2018. 13. ^ Marlow, Jeremy (27 September 2018). "Annual Board statement by the Accountable Emergency Officer" (PDF). NHS Improvement. Retrieved 10 March 2020. 14. ^ Agerholm, Harriet (4 July 2018). "Amesbury incident latest: Wiltshire couple were exposed to novichok nerve agent, police confirm". The Independent. Retrieved 5 July 2018. 15. ^ a b c "Wiltshire pair poisoned by Novichok nerve agent". BBC News. 4 July 2018. Retrieved 5 July 2018. 16. ^ "Poisoned pair 'handled contaminated item'". BBC News. 5 July 2018. Retrieved 5 July 2018. 17. ^ Bannock, Caroline; Dodd, Vikram; Morris, Steven (6 July 2018). "Novichok poisonings: search intensifying to find contaminated item". The Guardian. Retrieved 6 July 2018. 18. ^ "Updated statement re: Amesbury". Metropolitan Police. 6 July 2018. Archived from the original on 13 July 2018. 19. ^ "No contamination found at John Baker House in Salisbury". Spire FM. 24 July 2018. Retrieved 28 July 2018. 20. ^ "UPDATE: Source of nerve agent contamination identified". Metropolitan Police. 13 July 2018. Retrieved 19 July 2018. 21. ^ Dodd, Vikram; Morris, Steven (13 July 2018). "Novichok that killed woman came from bottle, police believe". The Guardian. Retrieved 13 July 2018. 22. ^ "Amesbury: Novichok found in perfume bottle, says victim's brother". BBC News. 15 July 2018. Retrieved 16 July 2018. 23. ^ "OPCW Provides Technical Assistance for Amesbury, UK Incident". Organisation for the Prohibition of Chemical Weapons. 18 July 2018. Retrieved 2 August 2018. 24. ^ "Chemical weapons inspectors returning to UK to gather new novichok samples". Retrieved 7 August 2018. 25. ^ "Nerve agent used on Skripals 'same one that killed Dawn Sturgess'". South China Morning Post. 4 September 2018. 26. ^ Tobin, Olivia (5 September 2018). "Novichok poisoning probe: Police say there is 'no doubt' Novichok victims are linked and Charlie Rowley and Dawn Sturgess were innocent tragic victims". Evening Standard. Retrieved 5 September 2018. 27. ^ "Archived copy". Archived from the original on 27 September 2018. Retrieved 6 September 2018.CS1 maint: archived copy as title (link) 28. ^ Hudson, Rebecca (19 July 2018). "Dawn Sturgess inquest opens in Salisbury". Salisbury Journal. Archived from the original on 19 July 2018. Retrieved 19 July 2018. 29. ^ Tryhorn, Faye (19 July 2018). "Inquest into Novichok victim Dawn Sturgess opened". Spire FM. Archived from the original on 21 July 2018. Retrieved 21 July 2018. 30. ^ a b Ridley, David (20 December 2019). "The Inquest touching upon the death of Dawn Kelly Sturgess: Scope Ruling" (PDF). Wiltshire Council. Retrieved 10 March 2020. 31. ^ Morris, Steven (14 January 2020). "Dawn Sturgess death from novichok: duty to protect public 'not breached' says coroner". The Guardian. ISSN 0261-3077. Retrieved 10 March 2020. 32. ^ "Amesbury poisoning - LIVE: Government to hold emergency Cobra meeting after novichok nerve agent leaves Wiltshire couple fighting for their life". Independent. Retrieved 5 July 2018. 33. ^ "Amesbury poisoning: Russia using UK as 'dumping ground", BBC News, 5 July 2018 34. ^ a b Evelyn, Rupert (24 July 2018). "Exclusive: Novichok poisoning victim Charlie Rowley reveals perfume gift he gave to partner contained deadly nerve agent". ITV News. Retrieved 25 July 2018. 35. ^ a b Steven Morris; Kevin Rawlinson (24 July 2018). "Novichok victim found substance disguised as perfume in sealed box". The Guardian. Retrieved 25 July 2018. 36. ^ "Novichok: Victim found poison bottle in branded box". BBC News. 24 July 2018. Retrieved 25 July 2018. 37. ^ a b c d Morris, Steven (9 June 2020). "Wiltshire flat where novichok victim fell ill to be demolished". The Guardian. Retrieved 14 July 2020. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	2018 Amesbury poisonings	None	3,169	wikipedia	https://en.wikipedia.org/wiki/2018_Amesbury_poisonings	2021-01-18T18:31:57	{"wikidata": ["Q55381117"]}
A very rare subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by late-onset and slowly progressive cerebellar signs (gait ataxia) and eye movement abnormalities. ## Epidemiology To date, only 23 affected patients have been described from one American family of Norwegian descent. ## Clinical description Spinocerebellar ataxia type 26 (SCA26) onset occurs between the ages of 26-60 with a mean age of onset of 42 years. Slowly progressive gait ataxia and dysarthria were reported in all patients. Nystagmus, impaired pursuit, and dysmetric saccades were described in majority of patitents. Left-sided pyramidal signs (hyperreflexia with positive Babinski sign) were reported in one patient. The disease duration is unknown. ## Etiology A candidate gene for SCA26 has recently been identified as the eukaryotic translation elongation factor 2 (EEF2) gene, located on chromosome 19p13.3. Further confirmatory studies are still required in order to determine if a mutation in this gene directly causes SCA26. ## Diagnostic methods Diagnosis is based on the clinical findings of pure cerebellar ataxia as well as molecular findings. Head magnetic resonance imaging (MRI) usually demonstrates the presence of atrophy of the cerebellum sparing the brainstem and is helpful in excluding other causes of ataxia. Molecular genetic testing identifies a mutation in the EEF2 gene, confirming a diagnosis of SCA26. ## Differential diagnosis Differential diagnoses include other forms of ADCA type III, in particular SCA5, SCA6, SCA11, SCA30 and SCA31. ## Antenatal diagnosis Antenatal diagnosis is possible in families with a known disease causing mutation. ## Genetic counseling SCA26 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring. ## Management and treatment There is no cure for SCA26 and treatment is supportive. Neurological follow-up is recommended to monitor the progression of ataxia. ## Prognosis Disease progression is very slow, but precise prognosis is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Spinocerebellar ataxia type 26	c1836395	3,170	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101112	2021-01-23T17:31:31	{"gard": ["9995"], "mesh": ["C537203"], "omim": ["609306"], "umls": ["C1836395"], "icd-10": ["G11.2"], "synonyms": ["SCA26"]}
Waltman Walter syndrome Waltman Walters syndrome[1] is characterized by accumulation of bile in the right subphrenic or subhepatic space, even when provision for drainage appears to have been adequate after a cholecystectomy. It is named for Dr. Waltman Walters, an abdominal surgeon at the Mayo Clinic in Rochester, MN. ## Contents * 1 Symptoms and signs * 2 Diagnosis * 3 Treatment * 4 References ## Symptoms and signs[edit] Upper abdominal or chest pain associated with tachycardia and persistently low blood pressure due to compression on IVC are cardinal signs and are mistaken for coronary thrombosis. ## Diagnosis[edit] Ultrasonography will show collection in subphrenic or subhepatic space. ## Treatment[edit] Abdominal reexploration and drainage of bile is curative. ## References[edit] 1. ^ McNair TJ (1972). "The Waltman Walters syndrome". J R Coll Surg Edinb. 17 (3): 185–9. PMID 5072924. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Waltman Walter syndrome	None	3,171	wikipedia	https://en.wikipedia.org/wiki/Waltman_Walter_syndrome	2021-01-18T18:31:50	{"wikidata": ["Q7966693"]}
A number sign (#) is used with this entry because of evidence that early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS) is caused by homozygous or compound heterozygous mutation in the TRAPPC12 gene (614139) on chromosome 2p25. Clinical Features Milev et al. (2017) reported 3 children from 2 unrelated families with severe early-onset progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss. One patient, born of consanguineous Palestinian parents, presented with brief flexion seizures at age 5 months and subsequently showed developmental regression and stagnation with loss of smiling, visual tracking, and social overtures. EEG showed hypsarrhythmia. Family history in this patient was notable for the mother having 5 previous pregnancies ending in spontaneous abortions, a sixth terminated for multiple anomalies, and another child born at 24 weeks' gestation who died soon after birth. In the second family, 2 sisters were similarly affected. Both had small developmental gains in infancy, but then plateaued or showed regression and had severe global developmental deficits. Additional features in all patients included truncal hypotonia, appendicular spasticity, dystonia and/or myoclonus, optic atrophy or cortical visual impairment, scoliosis, and dysphagia, necessitating G-tube placement in the sisters. Brain MRI in all patients showed a similar pattern of pontine hypoplasia, partial agenesis of the corpus callosum, simplified frontal gyri, and diffuse cortical atrophy with enlarged ventricles and relative sparing of the cerebellum. Two of the 3 patients had seizures. One of the sisters died of respiratory insufficiency at age 4 years, 9 months. Inheritance The transmission pattern of PEBAS in the families reported by Milev et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 patients from 2 unrelated families with PEBAS, Milev et al. (2017) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene (614139.0001-614139.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from all 3 individuals showed a fragmented Golgi that could be rescued by expression of wildtype TRAPPC12. Patient cells also showed delayed mitosis and delayed transport of proteins from the endoplasmic reticulum to and through the Golgi, suggesting that defects in membrane protein transport are causative of the disorder. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (-3 to -4 SD) Ears \- Hearing loss Eyes \- Cortical visual impairment \- Loss of tracking \- Optic atrophy ABDOMEN Gastrointestinal \- Dysphagia \- Reflux \- Poor feeding SKELETAL Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Truncal hypotonia NEUROLOGIC Central Nervous System \- Encephalopathy \- Global developmental delay, severe \- Developmental regression in infancy \- Appendicular spasticity \- Dystonia \- Myoclonus \- Seizures (in some patients) \- Hypsarrhythmia \- Cortical atrophy \- Enlarged ventricles \- Agenesis of the corpus callosum \- Simplified frontal gyri \- Pontine hypoplasia \- Relative sparing of the cerebellum MISCELLANEOUS \- Onset at birth \- Progressive disorder \- Three patients from 2 unrelated families have been reported (last curated September 2017) MOLECULAR BASIS \- Caused by mutation in the trafficking protein particle complex, subunit 12 gene (TRAPPC12, 614139.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH BRAIN ATROPHY AND SPASTICITY	c4540059	3,172	omim	https://www.omim.org/entry/617669	2019-09-22T15:45:13	{"omim": ["617669"], "orphanet": ["500144"], "synonyms": []}
Primary anetoderma is a rare skin disease characterized by loss of elastin tissue resulting in localized areas of flaccid skin in the absence of a secondary cause. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Primary anetoderma	c0406550	3,173	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228272	2021-01-23T16:59:33	{"mesh": ["D057088"], "umls": ["C0406550"], "icd-10": ["L90.1", "L90.2"], "synonyms": ["Primary macular atrophy"]}
Rhinosporidiosis Rhinosporidiosis in oropharynx SpecialtyInfectious disease Rhinosporidiosis is an infection caused by Rhinosporidium seeberi.[1][2] ## Contents * 1 Classification * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 References * 7 External links ## Classification[edit] This organism was previously considered to be a fungus, and rhinosporidiosis is classified as a fungal disease under ICD-10. It is now considered to be a protist[3] classified under Mesomycetozoea.[4] Authors of detailed studies have revealed superficial similarities between Dermocystidium and Rhinosporidium when using light microscopy, but substantial morphological differences between the groups exist.[5] There is some evidence that DNA extracted from purified uncontaminated round bodies (Rhinosporidium seeberi) is of cyanobacterial origin.[6] ## Pathophysiology[edit] Rhinosporidiosis is a granulomatous disease affecting the mucous membrane of nasopharynx, oropharynx, conjunctiva, rectum and external genitalia. Through the floor of the nose and inferior turbinate are the most common sites, the lesions may appear elsewhere too. Traumatic inoculation from one site to others is common. Laryngeal rhinosporidiosis,[7] too, has been described and may be due to inoculation from the nose during endotracheal intubation. After inoculation, the organism replicates locally, resulting in hyperplasia of host tissue and localised immune response. * infection of nose and nasopharynx - 70% * infection of palpebral conjunctiva - 15% ## Diagnosis[edit] * History * Unilateral nasal obstruction * Epistaxis * Local pruritus * Rhinorrhea * Coryza (rhinitis) with sneezing * Post nasal discharge with cough * Foreign body sensation * History of exposure to contaminated water * Increased tearing and photo phobia in cases of infection of palpebral conjunctiva * On examination * Pink to deep red polyps * Strawberry like appearance * Bleeds easily upon manipulation * Diagnosis * confirmed by biopsy and histopathology - several round or oval sporangia and spores which may be seen bursting through its chitinous wall ## Treatment[edit] * Surgical excision - wide excision with wide area electro-coagulation of the lesion base * Medical treatment is not so effective but treatment with a year-long course of dapsone has been reported * Recurrence is common ## Epidemiology[edit] Disease endemic in Chhattisgarh South India, Sri Lanka, South America and Africa. It is presumed to be transmitted by exposure to the pathogen when taking a bath in stagnant water pools where animals also bathe. ## References[edit] 1. ^ Arseculeratne SN (2002). "Recent advances in rhinosporidiosis and rhinosporidium seeberi". Indian J Med Microbiol. 20 (3): 119–31. PMID 17657050. 2. ^ Arseculeratne SN (April 2005). "Rhinosporidiosis: what is the cause?". Curr. Opin. Infect. Dis. 18 (2): 113–8. doi:10.1097/01.qco.0000160898.82115.e8. PMID 15735413. 3. ^ Morelli L, Polce M, Piscioli F, et al. (2006). "Human nasal rhinosporidiosis: an Italian case report". Diagn Pathol. 1 (1): 25. doi:10.1186/1746-1596-1-25. PMC 1560165. PMID 16945122. 4. ^ "Rhinosporidiosis". 5. ^ Pekkarinen, Low, Murphy, Ragan and Dykova. 2003. Phylogenetic position and ultrastructure of two Dermocystidium species are(Ichthyosporea) from the common perch (Perca fluviatilis) Archived 2007-10-10 at the Wayback Machine. Acta Protozoologica Vol. 42:287-307 6. ^ Dhaulakhandi, Ahluwalia, Ravi and Garg. 2006. Detection of 16S rRNA gene in round bodies isolated from polyps of rhinosporidiosis. Infection, Genetics and Evolution Vol. 6:331-336 7. ^ Ajit Daharwal, Hansa Banjara, Digvijay Singh, Anuj Gupta, Surjeet Singh. 2011. A rare case of laryngeal rhinosporidiosis. J Laryngol Voice 2011;1:30-2 ## External links[edit] Classification D * ICD-10: B48.1 * ICD-9-CM: 117.0 * MeSH: D012227 * DiseasesDB: 31328 External resources * eMedicine: med/2029 * v * t * e Fungal infection and mesomycetozoea Superficial and cutaneous (dermatomycosis): Tinea = skin; Piedra (exothrix/ endothrix) = hair Ascomycota Dermatophyte (Dermatophytosis) By location * Tinea barbae/tinea capitis * Kerion * Tinea corporis * Ringworm * Dermatophytids * Tinea cruris * Tinea manuum * Tinea pedis (athlete's foot) * Tinea unguium/onychomycosis * White superficial onychomycosis * Distal subungual onychomycosis * Proximal subungual onychomycosis * Tinea corporis gladiatorum * Tinea faciei * Tinea imbricata * Tinea incognito * Favus By organism * Epidermophyton floccosum * Microsporum canis * Microsporum audouinii * Trichophyton interdigitale/mentagrophytes * Trichophyton tonsurans * Trichophyton schoenleini * Trichophyton rubrum * Trichophyton verrucosum Other * Hortaea werneckii * Tinea nigra * Piedraia hortae * Black piedra Basidiomycota * Malassezia furfur * Tinea versicolor * Pityrosporum folliculitis * Trichosporon * White piedra Subcutaneous, systemic, and opportunistic Ascomycota Dimorphic (yeast+mold) Onygenales * Coccidioides immitis/Coccidioides posadasii * Coccidioidomycosis * Disseminated coccidioidomycosis * Primary cutaneous coccidioidomycosis. Primary pulmonary coccidioidomycosis * Histoplasma capsulatum * Histoplasmosis * Primary cutaneous histoplasmosis * Primary pulmonary histoplasmosis * Progressive disseminated histoplasmosis * Histoplasma duboisii * African histoplasmosis * Lacazia loboi * Lobomycosis * Paracoccidioides brasiliensis * Paracoccidioidomycosis Other * Blastomyces dermatitidis * Blastomycosis * North American blastomycosis * South American blastomycosis * Sporothrix schenckii * Sporotrichosis * Talaromyces marneffei * Talaromycosis Yeast-like * Candida albicans * Candidiasis * Oral * Esophageal * Vulvovaginal * Chronic mucocutaneous * Antibiotic candidiasis * Candidal intertrigo * Candidal onychomycosis * Candidal paronychia * Candidid * Diaper candidiasis * Congenital cutaneous candidiasis * Perianal candidiasis * Systemic candidiasis * Erosio interdigitalis blastomycetica * C. auris * C. glabrata * C. lusitaniae * C. tropicalis * Pneumocystis jirovecii * Pneumocystosis * Pneumocystis pneumonia Mold-like * Aspergillus * Aspergillosis * Aspergilloma * Allergic bronchopulmonary aspergillosis * Primary cutaneous aspergillosis * Exophiala jeanselmei * Eumycetoma * Fonsecaea pedrosoi/Fonsecaea compacta/Phialophora verrucosa * Chromoblastomycosis * Geotrichum candidum * Geotrichosis * Pseudallescheria boydii * Allescheriasis Basidiomycota * Cryptococcus neoformans * Cryptococcosis * Trichosporon spp * Trichosporonosis Zygomycota (Zygomycosis) Mucorales (Mucormycosis) * Rhizopus oryzae * Mucor indicus * Lichtheimia corymbifera * Syncephalastrum racemosum * Apophysomyces variabilis Entomophthorales (Entomophthoramycosis) * Basidiobolus ranarum * Basidiobolomycosis * Conidiobolus coronatus/Conidiobolus incongruus * Conidiobolomycosis Microsporidia (Microsporidiosis) * Enterocytozoon bieneusi/Encephalitozoon intestinalis Mesomycetozoea * Rhinosporidium seeberi * Rhinosporidiosis Ungrouped * Alternariosis * Fungal folliculitis * Fusarium * Fusariosis * Granuloma gluteale infantum * Hyalohyphomycosis * Otomycosis * Phaeohyphomycosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Rhinosporidiosis	c0035469	3,174	wikipedia	https://en.wikipedia.org/wiki/Rhinosporidiosis	2021-01-18T18:51:01	{"mesh": ["D012227"], "umls": ["C0035469"], "wikidata": ["Q4845643"]}
X-Linked Myopathy with Excessive Autophagy (XMEA) is a type of inherited myopathy (muscle disease) that mainly affects males. It is characterized by muscle weakness that begins in childhood that slowly worsens over time. Weakness involving the upper legs is typically noticed first, affecting activities such as running and climbing stairs. As the condition progresses, men with XMEA may experience weakness in their lower legs and arms. Some people with XMEA remain able to walk as they get older, while others require assistance in adulthood. This disorder is caused by mutations in the VMA21 gene and is inherited in an X-linked recessive fashion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-linked myopathy with excessive autophagy	c1839615	3,175	gard	https://rarediseases.info.nih.gov/diseases/3892/x-linked-myopathy-with-excessive-autophagy	2021-01-18T17:57:02	{"mesh": ["C564093"], "omim": ["310440"], "umls": ["C1839615"], "orphanet": ["25980"], "synonyms": ["XMEA", "Myopathy, X-linked, with excessive autophagy"]}
Joubert syndrome Other namesCPD IV[1] Joubert syndrome is inherited via an autosomal recessive manner SpecialtyMedical genetics Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination. Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa.[2] The syndrome was first identified in 1969 by pediatric neurologist Marie Joubert in Montreal, Quebec, Canada, while working at the Montreal Neurological Institute and McGill University.[3] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Research * 7 References * 8 External links ## Signs and symptoms[edit] Most of the signs and symptoms of the Joubert syndrome appear very early in infancy with most children showing delays in gross motor milestones.[4] Although other signs and symptoms vary widely from individual to individual, they generally fall under the hallmark of cerebellum involvement or in this case, lack thereof. Consequently, the most common features include ataxia (lack of muscle control), hyperpnea (abnormal breathing patterns), sleep apnea, abnormal eye and tongue movements, and hypotonia in early childhood. Other malformations such as polydactyly (extra fingers and toes), cleft lip or palate, tongue abnormalities, and seizures may also occur. Developmental delays, including cognitive, are always present to some degree.[5] Severe forms have been noted to include hypoplasia of the corpus callosum.[6][7][8] Those suffering from this syndrome often exhibit specific facial features such as a broad forehead, arched eyebrows, ptosis (droopy eyelids), hypertelorism (widely spaced eyes), low-set ears and a triangle shaped mouth. Additionally, this disease can include a broad range of other abnormalities to other organ systems such as retinal dystrophy, kidney diseases, liver diseases, skeletal deformities and endocrine (hormonal) problems.[9] ## Genetics[edit] A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes.[citation needed] This disorder can be caused by mutations in more than 30 genes within genetic makeup. The primary cilia play an important role in the structure and function of cells. When primary cilia are mutated and defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus.[citation needed] Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. The remaining cases, the cause is unknown if isn't linked to a mutation of known genes.[10] Type OMIM Gene Locus Inheritance Remarks JBTS1 213300 INPP5E 9q34.3 Autosomal recessive Also known as Cerebellooculorenal syndrome 1 (CORS1) JBTS2 608091 TMEM216 11q12.2 Autosomal recessive Also known as Cerebellooculorenal syndrome 2 (CORS2) JBTS3 608629 AHI1 6q23.3 Autosomal recessive JBTS4 609583 NPHP1 2q13 JBTS5 610188 CEP290 NPHP6 12q21.32 Autosomal recessive JBTS6 610688 TMEM67 8q22.1 Autosomal recessive JBTS7 611560 RPGRIP1L 16q12.2 JBTS8 612291 ARL13B 3q11.1 JBTS9 612285 CC2D2A 4p15.32 Autosomal recessive JBTS10 300804 OFD1 Xp22.2 X-linked recessive JBTS11 – TTC21B 2q24.3 JBTS12 – KIF7 15q26.1 JBTS13 614173 TCTN1 12q24.11 JBTS14 614424 TMEM237 2q33.1 Autosomal recessive JBTS15 614464 CEP41 7q32.2 Autosomal recessive JBTS16 614465 TMEM138 11q12.2 Autosomal recessive JBTS17 614615 C5ORF42 5p13.2 JBTS18 614815 TCTN3 10q24.1 JBTS19 – ZNF423 16q12.1 Autosomal dominant JBTS20 614970 TMEM231 16q23.1 Autosomal recessive 611654 CSPP1,[11][12][13] 8q13.2 Autosomal recessive \- ARMC9 2q37.1 Autosomal recessive FAM149B1 10q22.2 Autosomal recessive ## Diagnosis[edit] The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a transverse view of head MRI scan.[14] Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.[4] Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive - in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern. In these cases, males are more commonly affected because affected males must have one X chromosome mutated, while affected females must have mutated genes on both X chromosomes.[10] ## Treatment[edit] Treatment for Joubert syndrome is symptomatic and supportive. Infants with abnormal breathing patterns should be monitored. The syndrome is associated with progressive worsening for kidneys, the liver and the eyes and thus requires regular monitoring.[5] Delays in gross motor skills, fine motor skills and speech development are seen in almost all individuals with Joubert syndrome. Delays can be due to low muscle tone as well as impaired motor coordination. Some children have also been noted to have visual impairment due to abnormal eye movements. Developmental delays are usually treated with physical therapy, occupational therapy, and speech therapy interventions. Most children diagnosed with Joubert syndrome are able to achieve standard milestones, although often at a much later age.[15] ## Prognosis[edit] In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with developmental quotients from 60 to 85.[16] ## Research[edit] Research has revealed that a number of genetic disorders, not previously thought to be related, may indeed be related as to their root cause. Joubert syndrome is one such disease. It is a member of an emerging class of diseases called ciliopathies.[citation needed] The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases.[citation needed] Currently recognized ciliopathies include Joubert syndrome, primary ciliary dyskinesia (also known as Kartagener Syndrome), Bardet–Biedl syndrome, polycystic kidney disease and polycystic liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.[17] Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent.[18] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Joubert syndrome". www.orpha.net. Retrieved 24 October 2019. 2. ^ Saraiva, JM; Baraitser, M (1992). "Joubert syndrome: a review". American Journal of Medical Genetics. 43 (4): 726–731. doi:10.1002/ajmg.1320430415. PMID 1341417. 3. ^ Joubert M, Eisenring JJ, Robb JP, Andermann F (September 1969). "Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation". Neurology. 19 (9): 813–25. doi:10.1212/wnl.19.9.813. PMID 5816874. 4. ^ a b "Joubert Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-12-19. 5. ^ a b Parisi, Melissa A.; Doherty, Dan; Chance, Phillip F.; Glass, Ian A. (2007-03-21). "Joubert syndrome (and related disorders) (OMIM 213300)". European Journal of Human Genetics. 15 (5): 511–521. doi:10.1038/sj.ejhg.5201648. ISSN 1018-4813. PMID 17377524. 6. ^ "OMIM Entry - # 213300 - JOUBERT SYNDROME 1; JBTS1". www.omim.org. Retrieved 2019-12-22. 7. ^ Zamponi, N.; Rossi, B.; Messori, A.; Polonara, G.; Regnicolo, L.; Cardinali, C. (2002). "Joubert syndrome with associated corpus callosum agenesis". European Journal of Paediatric Neurology. 6 (1): 63–66. doi:10.1053/ejpn.2001.0542. ISSN 1090-3798. PMID 11993957. 8. ^ Bader, Ingrid; Decker, E.; Mayr, J. A.; Lunzer, V.; Koch, J.; Boltshauser, E.; Sperl, W.; Pietsch, P.; Ertl-Wagner, B.; Bolz, H.; Bergmann, C. (August 2016). "MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum". European Journal of Medical Genetics. 59 (8): 386–391. doi:10.1016/j.ejmg.2016.06.007. ISSN 1878-0849. PMID 27377014. 9. ^ Reference, Genetics Home. "Joubert syndrome". Genetics Home Reference. Retrieved 2016-12-19. 10. ^ a b Reference, Genetics Home. "Joubert syndrome". Genetics Home Reference. Retrieved 2017-09-13. 11. ^ Shaheen, R.; Shamseldin, H. E.; Loucks, C. M.; Seidahmed, M. Z.; Ansari, S.; Ibrahim Khalil, M.; Al-Yacoub, N.; Davis, E. E.; Mola, N. A.; Szymanska, K.; Herridge, W.; Chudley, A. E.; Chodirker, B. N.; Schwartzentruber, J.; Majewski, J.; Katsanis, N.; Poizat, C.; Johnson, C. A.; Parboosingh, J.; Boycott, K. M.; Innes, A. M.; Alkuraya, F. S. (2013). "Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans". The American Journal of Human Genetics. 94 (1): 73–9. doi:10.1016/j.ajhg.2013.11.010. PMC 3882732. PMID 24360803. 12. ^ Akizu, N.; Silhavy, J. L.; Rosti, R. O.; Scott, E.; Fenstermaker, A. G.; Schroth, J.; Zaki, M. S.; Sanchez, H.; Gupta, N.; Kabra, M.; Kara, M.; Ben-Omran, T.; Rosti, B.; Guemez-Gamboa, A.; Spencer, E.; Pan, R.; Cai, N.; Abdellateef, M.; Gabriel, S.; Halbritter, J.; Hildebrandt, F.; Van Bokhoven, H.; Gunel, M.; Gleeson, J. G. (2013). "Mutations in CSPP1 Lead to Classical Joubert Syndrome". The American Journal of Human Genetics. 94 (1): 80–6. doi:10.1016/j.ajhg.2013.11.015. PMC 3882909. PMID 24360807. 13. ^ Tuz, K.; Bachmann-Gagescu, R.; o’Day, D. R.; Hua, K.; Isabella, C. R.; Phelps, I. G.; Stolarski, A. E.; o’Roak, B. J.; Dempsey, J. C.; Lourenco, C.; Alswaid, A.; Bönnemann, C. G.; Medne, L.; Nampoothiri, S.; Stark, Z.; Leventer, R. J.; Topçu, M.; Cansu, A.; Jagadeesh, S.; Done, S.; Ishak, G. E.; Glass, I. A.; Shendure, J.; Neuhauss, S. C. F.; Haldeman-Englert, C. R.; Doherty, D.; Ferland, R. J. (2013). "Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy". The American Journal of Human Genetics. 94 (1): 62–72. doi:10.1016/j.ajhg.2013.11.019. PMC 3882733. PMID 24360808. 14. ^ Brancati F, Dallapiccola B, Valente EM (2010). "Joubert Syndrome and related disorders". Orphanet J Rare Dis. 5: 20. doi:10.1186/1750-1172-5-20. PMC 2913941. PMID 20615230. 15. ^ "Joubert Syndrome \| MedLink Neurology". www.medlink.com. Retrieved 3 April 2020. 16. ^ Steinlin, M.; Schmid, M.; Landau, K.; Boltshauser, E. (1997-08-01). "Follow-Up in Children with Joubert Syndrome". Neuropediatrics. 28 (4): 204–211. doi:10.1055/s-2007-973701. ISSN 0174-304X. PMID 9309710. 17. ^ Badano, Jose L.; Norimasa Mitsuma; Phil L. Beales; Nicholas Katsanis (September 2006). "The Ciliopathies : An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7: 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. 18. ^ Gutkind, Lee; Kennedy, Pagan (10 October 2013). An Immense New Power to Heal: The Promise of Personalized Medicine. Underland Press. p. 36. ISBN 978-1-937163-07-5. ## External links[edit] Classification D * ICD-10: Q04.3 * ICD-9-CM: 742.2 * OMIM: 213300 * DiseasesDB: 30688 External resources * GeneReviews: Joubert Syndrome and Related Disorders * Orphanet: 475 * NINDS Joubert Syndrome Information Page * Researchers Identify Joubert Syndrome Genes * GeneReviews: Joubert syndrome * NCBI Joubert Syndrome * v * t * e Diseases of cilia Structural * receptor: Polycystic kidney disease * cargo: Asphyxiating thoracic dysplasia * basal body: Bardet–Biedl syndrome * mitotic spindle: Meckel syndrome * centrosome: Joubert syndrome Signaling * Nephronophthisis Other/ungrouped * Alström syndrome * Primary ciliary dyskinesia * Senior–Løken syndrome * Orofaciodigital syndrome 1 * McKusick–Kaufman syndrome * Autosomal recessive polycystic kidney See also: ciliary proteins * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Joubert syndrome	c0431399	3,176	wikipedia	https://en.wikipedia.org/wiki/Joubert_syndrome	2021-01-18T18:34:20	{"gard": ["6802"], "mesh": ["C536293"], "umls": ["C0431399"], "icd-9": ["742.2"], "orphanet": ["475"], "wikidata": ["Q1101694"]}
Terminal osseous dysplasia with pigmentary defects SpecialtyDermatology Terminal osseous dysplasia with pigmentary defects is a cutaneous condition characterized by hyperpigmented, atrophic facial macules.[1] It has been associated with FLNA.[2] ## See also[edit] * Corneodermatosseous syndrome * Osseous choristoma of the tongue * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 897. ISBN 978-1-4160-2999-1. 2. ^ Sun Y, Almomani R, Aten E, et al. (July 2010). "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene". Am. J. Hum. Genet. 87 (1): 146–53. doi:10.1016/j.ajhg.2010.06.008. PMC 2896768. PMID 20598277. ## External links[edit] Classification D * OMIM: 300244 * MeSH: C564554 * v * t * e Cytoskeletal defects Microfilaments Myofilament Actin * Hypertrophic cardiomyopathy 11 * Dilated cardiomyopathy 1AA * DFNA20 * Nemaline myopathy 3 Myosin * Elejalde syndrome * Hypertrophic cardiomyopathy 1, 8, 10 * Usher syndrome 1B * Freeman–Sheldon syndrome * DFN A3, 4, 11, 17, 22; B2, 30, 37, 48 * May–Hegglin anomaly Troponin * Hypertrophic cardiomyopathy 7, 2 * Nemaline myopathy 4, 5 Tropomyosin * Hypertrophic cardiomyopathy 3 * Nemaline myopathy 1 Titin * Hypertrophic cardiomyopathy 9 Other * Fibrillin * Marfan syndrome * Weill–Marchesani syndrome * Filamin * FG syndrome 2 * Boomerang dysplasia * Larsen syndrome * Terminal osseous dysplasia with pigmentary defects IF 1/2 * Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1 * Striate palmoplantar keratoderma 3 * Epidermolytic hyperkeratosis * IHCM * KRT2E (Ichthyosis bullosa of Siemens) * KRT3 (Meesmann juvenile epithelial corneal dystrophy) * KRT4 (White sponge nevus) * KRT5 (Epidermolysis bullosa simplex) * KRT8 (Familial cirrhosis) * KRT10 (Epidermolytic hyperkeratosis) * KRT12 (Meesmann juvenile epithelial corneal dystrophy) * KRT13 (White sponge nevus) * KRT14 (Epidermolysis bullosa simplex) * KRT17 (Steatocystoma multiplex) * KRT18 (Familial cirrhosis) * KRT81/KRT83/KRT86 (Monilethrix) * Naegeli–Franceschetti–Jadassohn syndrome * Reticular pigmented anomaly of the flexures 3 * Desmin: Desmin-related myofibrillar myopathy * Dilated cardiomyopathy 1I * GFAP: Alexander disease * Peripherin: Amyotrophic lateral sclerosis 4 * Neurofilament: Parkinson's disease * Charcot–Marie–Tooth disease 1F, 2E * Amyotrophic lateral sclerosis 5 * Laminopathy: LMNA * Mandibuloacral dysplasia * Dunnigan Familial partial lipodystrophy * Emery–Dreifuss muscular dystrophy 2 * Limb-girdle muscular dystrophy 1B * Charcot–Marie–Tooth disease 2B1 * LMNB * Barraquer–Simons syndrome * LEMD3 * Buschke–Ollendorff syndrome * Osteopoikilosis * LBR * Pelger–Huet anomaly * Hydrops-ectopic calcification-moth-eaten skeletal dysplasia Microtubules Kinesin * Charcot–Marie–Tooth disease 2A * Hereditary spastic paraplegia 10 Dynein * Primary ciliary dyskinesia * Short rib-polydactyly syndrome 3 * Asphyxiating thoracic dysplasia 3 Other * Tauopathy * Cavernous venous malformation Membrane * Spectrin: Spinocerebellar ataxia 5 * Hereditary spherocytosis 2, 3 * Hereditary elliptocytosis 2, 3 Ankyrin: Long QT syndrome 4 * Hereditary spherocytosis 1 Catenin * APC * Gardner's syndrome * Familial adenomatous polyposis * plakoglobin (Naxos syndrome) * GAN (Giant axonal neuropathy) Other * desmoplakin: Striate palmoplantar keratoderma 2 * Carvajal syndrome * Arrhythmogenic right ventricular dysplasia 8 * plectin: Epidermolysis bullosa simplex with muscular dystrophy * Epidermolysis bullosa simplex of Ogna * plakophilin: Skin fragility syndrome * Arrhythmogenic right ventricular dysplasia 9 * centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II) Related topics: Cytoskeletal proteins 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Terminal osseous dysplasia with pigmentary defects	c1846129	3,177	wikipedia	https://en.wikipedia.org/wiki/Terminal_osseous_dysplasia_with_pigmentary_defects	2021-01-18T18:59:56	{"mesh": ["C564554"], "umls": ["C1846129"], "orphanet": ["88630"], "wikidata": ["Q7702740"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Uterine hypoplasia" – news · newspapers · books · scholar · JSTOR (September 2019) Uterine hypoplasia Other namesNaive uterus or Infantile uterus SpecialtyReproductive Endocrinologist Uterine hypoplasia, also known as naive uterus or infantile uterus, is a reproductive disorder characterized by hypoplasia of the uterus. It is usually due to pubertal failure/hypogonadism and may be treated with puberty induction using estrogens and/or progestogens. ## See also[edit] * Uterine hyperplasia * Uterine malformation ## References[edit] * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder This medical symptom article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Uterine hypoplasia	c0266399	3,178	wikipedia	https://en.wikipedia.org/wiki/Uterine_hypoplasia	2021-01-18T18:42:21	{"umls": ["C0266399"], "icd-9": ["752.32"], "orphanet": ["180139"], "wikidata": ["Q16636845"]}
Kindler syndrome (KS) is the fourth major type of epidermolysis bullosa (EB), besides simplex, junctional and dystrophic forms, and is characterized by skin fragility and blistering at birth followed by development of photosensitivity and progressive poikilodermatous skin changes. ## Epidemiology Prevalence is unknown. More than 250 cases have been reported to date. ## Clinical description The disease usually manifests at birth with trauma-induced skin blistering that is more prominent on extremities and tends to regress with age, becoming rare in adulthood. Healing of blisters occurs with minimal scarring. With age, additional skin findings are observed: (i) in most patients, photosensitivity with erythema and photo-induced blisters is obvious since early childhood and often diminishes after adolescence, (ii) progressive skin poikiloderma (atrophy, telangiectases, and reticular pigmentation) manifests from childhood and is predominantly localized to the face and neck, and (iii) skin atrophy is localized to hands and feet in the first years of life but becomes generalized by adolescence. Blisters also affect the mucosae. In the oral cavity, chronic gingivitis and periodontitis are frequent and prominent features in adulthood. Esophageal strictures, causing dysphagia and requiring repeated dilatations, frequently develop in adulthood. Anal (bleeding, stenosis), urogenital (urethral bleeding, meatal stenosis), and ocular (ectropion) involvement has also been described. The frequency of these manifestations increases with age. An additional frequent feature is digit webbing/partial pseudosyndactyly. Laryngeal and intestinal involvement, the latter manifesting with severe colitis, are rare. Other features may include: skin xerosis and fine scaling, palmoplantar hyperkeratosis, milia formation, nail dystrophy, constricting bands of pseudoainhum type, orogenital leukokeratosis. Finally, KS patients present an increased susceptibility to the development of squamous cell carcinomas (SCC): in a recent case series skin cancer affected 70% of the patients older than 45 years. ## Etiology Kindler syndrome is caused by loss-of-function mutations in the kindlin-1 gene (FERMT1; 20p12.3) causing the defective expression of the fermitin family homologue 1 (kindlin-1), a component of cell adhesive focal contacts. ## Diagnostic methods Diagnosis is based on clinical examination and determination by biopsy of the level within which blisters develop following minor traction. Biopsy of blistered skin samples by immunofluorescence antigen mapping and transmission electron microscopy, shows single or multiple cleavage planes at the level of the cutaneous basement membrane zone as well as an extensive reduplication of the lamina densa. Blister formation can occur below the lamina densa, within the lamina lucida or within basal keratinocytes. The diagnosis is confirmed by molecular genetic testing, particularly during the first years of life. ## Differential diagnosis The differential diagnosis includes all forms of inherited EB, in particular dystrophic EB and EB simplex with mottled pigmentation (see these terms), as well as congenital diseases with photosensitivity and poikiloderma, such as Rothmund-Thomson syndrome, Bloom syndrome, dyskeratosis congenita, poikiloderma with neutropenia or xeroderma pigmentosum (see these terms). ## Antenatal diagnosis Prenatal diagnosis can be performed by DNA mutational analysis if the causal mutation has been identified in the family. ## Genetic counseling The condition follows an autosomal recessive pattern of inheritance. ## Management and treatment Management is based on the avoidance of blistering by protective padding of the skin. Preventive measures should also be adopted for photosensitivity. Esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. Early diagnosis of SCC requires a rigorous and regular follow-up in adulthood. ## Prognosis In the majority of cases, life expectancy is normal. However, there are reports of few patients with fatal aggressive SCC. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Kindler syndrome	c0406557	3,179	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2908	2021-01-23T18:29:42	{"gard": ["4391"], "mesh": ["C536321"], "umls": ["C0406557"], "icd-10": ["Q81.8"], "synonyms": ["Congenital bullous poikiloderma", "Poikiloderma of Kindler"]}
Brain-lung-thyroid syndrome is a group of conditions that affect the brain, lungs, and thyroid gland (a butterfly-shaped gland in the lower neck). Brain-lung-thyroid syndrome historically included problems with all three organs, although the designation now encompasses a combination of brain, lung, and thyroid problems. About 50 percent of affected individuals have problems with all three organs, about 30 percent have brain and thyroid problems, and about 10 percent have brain and lung problems. The brain alone is affected in 10 to 20 percent of people with the condition. Such cases are sometimes called isolated benign hereditary chorea. Nearly everyone with brain-lung-thyroid syndrome has brain-related movement abnormalities. Benign hereditary chorea is the most common feature of the syndrome. This feature is associated with involuntary jerking movements (chorea) of the face, torso, and limbs; writhing movements (athetosis) of the limbs; and other movement problems. Individuals with brain-lung-thyroid syndrome can have other abnormalities, such as difficulty coordinating movements (ataxia), muscle twitches (myoclonus), and involuntary muscle contractions that result in twisting and repetitive movements (dystonia). The movement problems typically begin around age 1, although they can begin in early infancy or later in life, and are often preceded by weak muscle tone (hypotonia). They can delay the development of walking. The movement problems usually remain stable and can improve over time. Some affected individuals also have learning difficulties or intellectual disability. Thyroid problems are the next most common feature of brain-lung-thyroid syndrome. The thyroid gland makes hormones that help regulate a wide variety of critical body functions, including growth, brain development, and the rate of chemical reactions in the body (metabolism). Many affected individuals have reduced thyroid function from birth (congenital hypothyroidism), resulting in lower-than-normal levels of thyroid hormones. Others have a milder condition called compensated or subclinical hypothyroidism, in which thyroid hormone levels are within the normal range, even though the thyroid is not functioning properly. While most people with brain-lung-thyroid syndrome have a normal-sized thyroid, the gland is reduced in size (hypoplastic) or absent (aplastic) in some affected individuals. Although a shortage of thyroid hormones can cause intellectual disability and other neurological problems, it is unclear whether such issues in individuals with brain-lung-thyroid syndrome are due to hypothyroidism or to the brain abnormalities related to the condition. Lung problems are common in brain-lung-thyroid syndrome. Some affected newborns have respiratory distress syndrome, which causes extreme difficulty breathing and can be life-threatening. Other affected individuals develop widespread lung damage (interstitial lung disease) or scarring in the lungs (pulmonary fibrosis), both of which can also lead to breathing problems. Recurrent lung infections, which can be life-threatening, also occur in people with brain-lung-thyroid syndrome. People with brain-lung-thyroid syndrome have a higher risk of developing lung cancer than do people in the general population. ## Frequency Brain-lung-thyroid syndrome is a rare disorder; its prevalence is unknown. ## Causes Brain-lung-thyroid syndrome is caused by genetic changes that affect the NKX2-1 gene, which provides instructions for making a protein called homeobox protein Nkx-2.1. This protein functions as a transcription factor, which means it attaches to DNA and controls the activity (expression) of other genes. By regulating the expression of certain genes during embryonic development, homeobox protein Nkx-2.1 helps direct the development of the brain, lungs, and thyroid gland and promotes their normal function. Mutations in or deletion of the NKX2-1 gene lead to a reduction in the amount of homeobox protein Nkx-2.1 or impair its function. As a result, the expression of genes controlled by homeobox protein Nkx-2.1 is altered, which impedes the normal development and function of the brain, lungs, or thyroid gland. Problems with these organs underlie benign hereditary chorea, respiratory distress syndrome, congenital hypothyroidism, and other features of brain-lung-thyroid syndrome. It is unclear why all three organs are affected in some individuals with the condition, while only one or two are affected in others. ### Learn more about the gene associated with Brain-lung-thyroid syndrome * NKX2-1 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Brain-lung-thyroid syndrome	c1970269	3,180	medlineplus	https://medlineplus.gov/genetics/condition/brain-lung-thyroid-syndrome/	2021-01-27T08:25:24	{"gard": ["1305", "12163"], "mesh": ["C567034"], "omim": ["610978"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that Gerstmann-Straussler disease (GSD) and a form of cerebral amyloid angiopathy are caused by heterozygous mutation in the prion protein gene (PRNP; 176640) on chromosome 20p13. Creutzfeldt-Jakob disease (CJD; 123400) and familial fatal insomnia (FFI; 600072) are 2 other allelic inherited prion diseases caused by mutation in the PRNP gene. Description Gerstmann-Straussler disease is a rare inherited prion disease characterized by adult onset of memory loss, dementia, ataxia, and pathologic deposition of amyloid-like plaques in the brain (Gerstmann et al., 1936). Gerstmann-Straussler disease typically presents with progressive limb and truncal ataxia, dysarthria, and cognitive decline in the thirties and forties, and the average disease duration is 7 years. GSD can be distinguished from CJD by earlier age at onset, longer disease duration, and prominent cerebellar ataxia (Masters et al., 1981). On the basis of clinical and pathologic criteria, Hsiao et al. (1989) suggested that Gerstmann-Straussler syndrome could be classified into 3 forms: an 'ataxic' form, a 'dementing' form, and a dementing form that is accompanied by pathologic quantities of neurofibrillary tangles (NFTs). However, these distinctions may only underscore the phenotypic variability in presentation and progression of the disease (Panegyres et al., 2001). PRNP-related amyloid angiopathy is usually not a feature of CJD, GSD, or FFI. However, PRNP-immunoreactive amyloid deposits within the walls of cerebral vessels have been observed in patients with truncating mutations in the PRNP gene. Data suggest that C-terminal-truncated PRNP proteins lacking the glycosylphosphatidylinositol (GPI) anchor required to attach the protein to the plasma membrane may readily form amyloid fibrils that result in cerebrovascular amyloid deposition (summary by Revesz et al., 2009). Clinical Features Seitelberger (1962) described a kindred with a unique neurologic disorder traced through 5 generations. Plaque-like deposits were found in the cerebral cortex, basal ganglia, and (most extremely) all layers of the cerebellum. Clinically and pathologically the disorder most closely resembled kuru, although the authors noted some differences in the plaque distribution. Kretzschmar et al. (1991) noted that the family reported by Seitelberger (1962) was the same family originally reported by Gerstmann et al. (1936). Peiffer (1982) described a family of sheepbreeders in which a father and 2 sons had GSD. All 3 also had congenital hip dysplasia, as did at least 3 other members of the kindred, all females. The main clinical features included ataxia, dysarthria, and personality changes. Peiffer (1982) noted that GSD was characterized neuropathologically by large plaques distributed throughout the cerebral cortex, basal ganglia, and white matter. Hudson et al. (1983) reported a family in which Gerstmann-Straussler disease occurred in 3 members of 2 generations. The clinical picture included visual loss in 1 patient and sensory loss in another patient. Dementia only occurred late in the illness in 2 patients. Neuropathologic examination showed multicentric amyloid plaques in the cerebral and cerebellar cortices, basal ganglia, and white matter, as well as degeneration of the corticospinal tract, spinocerebellar tract, and dorsal columns. Spongiform changes were limited to the superficial cerebral cortex. Vinters et al. (1986) presented the postmortem neuropathologic findings in 1 of the patients reported by Hudson et al. (1983). The disorder had lasted 8 years. There were severe spongy changes in the neocortex, extensive and often large amyloid deposits throughout the cerebral hemispheres and cerebellum, and severe astrocytic gliosis throughout all areas of gray and white matter within the brain. The degree of cortical spongy change was much greater than that in relatives who died with a similar clinical history. Farlow et al. (1989) reported a large kindred from Indiana with Gerstmann-Straussler disease inherited in an autosomal dominant pattern. Sixty-four patients showed progressive ataxia, dementia, and parkinsonism with onset in the late thirties to early sixties. Early features included impaired smooth pursuit eye movements, impaired short-term memory, and clumsiness of the hands. In late stages of the disease, there was dementia, psychosis, and/or severe depression with weight loss. Death occurred 6 months to 2 years after onset. Farlow et al. (1989) noted that the neuropathologic findings in affected members of the Indiana kindred included widespread amyloid plaques in the cerebrum and cerebellum as well as widespread Alzheimer (104300)-like neurofibrillary tangles composed of paired helical filaments in the cerebral cortex and subcortical nuclei. The amyloid core of plaques was immunolabeled with antibodies raised to PrP, but not with antibodies raised to beta-amyloid (APP; 104760). Spongiform changes were mild. The disease in the Indiana kindred was traced to the year 1792 (Farlow et al., 1989; Ghetti et al., 1989). In each of the generations since 1792, affected members had been identified by either history or clinical examination. Yamada et al. (1999) found intense deposition of prion protein in the posterior horn of the spinal cord but not in the dorsal root ganglia or peripheral nerves in an autopsy of a 38-year-old woman with GSD confirmed by mutation in the PRNP gene (P102L; 176640.0002). The findings seemed to account for the painful dysesthesias and arreflexia seen in this variant of the disorder. Panegyres et al. (2001) reported a man with GSD confirmed by mutation in the PRNP gene (176640.0021). He had no family history of neurologic disease. At disease onset in his forties, he developed impaired short-term memory function, reduced learning capacity, and personality changes, including emotional immaturity, anxiety, and increasing anger. Neurologic examination showed apraxia, tremor, rigidity, and hyperreflexia, but no ataxia. Eventually he developed ataxia and his dementia progressed. He died at age 51, 9 years after symptom onset. Neuropathologic examination showed mild cerebral and cerebellar atrophy. There were numerous congophilic amyloid plaques throughout the brain that were immunoreactive to PrP. There was no spongiform degeneration; occasional neurofibrillary tangles were seen. Arata et al. (2006) reported detailed clinical features of 11 individuals from 9 families with GSS, all of whom had the common P102L mutation of the PRNP gene. Age at onset ranged from 38 to 70 years, with an average of 60.2 years. Nine patients presented with gait disturbance, 1 with dysarthria, and 1 with dysesthesia of the lower limbs. Common features of the early stage of disease were unsteady gait, truncal ataxia, painful dysesthesias of the lower limbs, weakness of the proximal lower limbs, loss of deep tendon reflexes, and mild dysarthria. Ten of the 11 patients were initially evaluated by orthopedic surgeons on the suspicion of lumbar spine disease, none of whom diagnosed GSS. Only 1 patient had clear dementia on initial examination. Brain MRIs were normal during the initial stages and no patients had cerebellar changes. However, all patients developed cortical and diffuse brain atrophy with disease progression and onset of dementia. Brain SPECT studies of 5 patients showed hypoperfusion of the occipital lobes and patchy decreased blood flow in the cerebrum, with normal flow in the cerebellum. Arata et al. (2006) concluded that the sites of pathology in this group of patients were in the cerebrum and spinal cord, including the posterior horn and spinocerebellar tracts, instead of the cerebellum proper. Yamamoto et al. (2007) reported a 72-year-old man with GSS who presented with a 1-year history of progressive limb weakness, aphasia, and apathy. Diffusion-weighted brain MRI at the initial examination showed hyperintense signal changes in the frontal, temporal, occipital, and parietal cortical gyri of both hemispheres, although CT scan showed no abnormalities. His condition deteriorated over the next 8 months, resulting in mutism, akinesia, and spastic tetraplegia. CT scans performed at 2 and 8 months after the initial examination showed remarkable progression of cortical atrophy in the bilateral frontotemporal lobes and hypodense lesions in frontal subcortical areas. Rowe et al. (2007) reported a 62-year-old woman with a phenotype most consistent with Gerstmann-Straussler disease. The phenotype was somewhat unusual in that she exhibited supranuclear gaze palsy early in the disease course and had absence of myoclonus, lack of 14-3-3 proteins (see 113508) in the CSF, and no significant EEG or MRI findings. The patient later developed more typical features of the disorder with rapid progression to death 4 months after presentation. Postmortem examination showed typical diffuse spongiform encephalopathy with amyloid-like plaques restricted to the cerebellum. Genetic analysis identified a heterozygous mutation in the PRNP gene (176640.0026). ### PRNP-Related Amyloid Angiopathy Ghetti et al. (1996) reported a Japanese woman who developed progressive dementia at age 38 resulting in death at age 59 years and associated with PrP-immunoreactive cerebral amyloid angiopathy. Family history was not contributory. Neuropathologic examination showed severe cortical atrophy with amyloid deposits in the parenchymal and leptomeningeal blood vessels and in the perivascular neuropil, as well as marked tau (MAPT; 157140)-immunoreactive neurofibrillary tangles, similar to those observed in Alzheimer disease. Amyloid was also present in the surrounding parenchyma. Amyloid was immunoreactive to PrP, and immunoblot analysis detected mainly a 7.5-kD peptide that was truncated at the N- and C-termini, with immunoreactivity between residues 90 and 147. Amyloid-laden vessels were also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele was also involved in the pathologic process. Genetic analysis revealed a heterozygous truncating mutation in the PRNP gene (Y145X; 176640.0031). Ghetti et al. (1996) noted that abnormal PRNP truncation at a similar site (between residues 144 and 150) occurs in GSS variants in which the amyloid protein has been analyzed, suggesting that this truncated PrP peptide is important for amyloid formation. Jansen et al. (2010) reported a 57-year-old Dutch woman with PRNP-related cerebral amyloid angiopathy. She presented at age 55 years with a 12-month history of increasing cognitive impairment, forgetfulness, and decreased concentration associated with hallucinations. She also had aphasia, but no extrapyramidal signs, ataxia, or myoclonic jerks. EEG showed generalized slowing with a typical pattern of periodic synchronous wave complexes. The disorder progressed, and she developed parkinsonism as a result of neuroleptic treatment, mutism, akinesia, and myoclonic jerks. She died 27 months after onset. Neuropathologic examination showed severe PRNP-reactive amyloid angiopathy and parenchymal plaques; neurofibrillary tangles were not present, but there were focal tau accumulations. Her mother was diagnosed with probable CJD on the basis of comparable symptoms and signs. Genetic analysis identified a heterozygous truncating mutation in the PRNP gene (Y226X; 176640.0033). The patient was heterozygous for M129V (176640.0005). An unrelated patient had a similar truncating PRNP mutation, Q227X (176640.0034), associated with amyloid plaques and extensive neurofibrillary tangles, but not amyloid angiopathy. Both Y226X and Q227X result in C-terminally truncated proteins lack the GPI anchor and thus cannot localize to the plasma membrane, suggesting that absence of this anchor predisposes to amyloid formation. Jayadev et al. (2011) reported a woman with onset of progressive memory impairment and depression beginning at age 39 years and resulting in death at age 47. The patient was initially diagnosed with Alzheimer disease. Neuropathologic examination showed frontotemporal atrophy, severe tau-immunoreactive neurofibrillary tangles, and amyloid plaques that were immunoreactive to PRNP. The prion deposits were immunopositive to residues 90-102, but not to 220-231, consistent with C-terminal truncation. Western blot analysis showed a smear of proteinase K-resistant PrP, the most prominent of which was 11 kD. PrP-immunoreactive amyloid angiopathy was observed. There was also immunoreactivity to alpha-synuclein (SNCA; 163890), in the form of Lewy bodies and Lewy neurites. Spongiform changes were not observed. The patient's deceased mother had a history of a similar disorder with later onset and accompanied by severe chronic diarrhea. She was diagnosed with Alzheimer disease, but reexamination of her pathology showed the same abnormalities as observed in her daughter. Genetic analysis identified a heterozygous mutation in the PRNP gene (Q160X; 176640.0032) in the proband and her mother. The proband was heterozygous for M129V, whereas her mother was homozygous for M129. Jayadev et al. (2011) postulated a link between truncating PRNP mutations and the development of a disorder with a relatively prolonged clinical course and features similar to AD. Pathogenesis Masters et al. (1981) reported that inoculation of brain tissue from 3 patients with GSD resulted in spongiform encephalopathy in nonhuman primates, supporting a relation to Creutzfeldt-Jakob disease. One of these patients was a member of the family reported by Adam et al. (1982) as an instance of familial cerebral amyloidosis. Prusiner (1987) reviewed the possible role of prions in GSD as well as in other diseases such as CJD and kuru. Brown et al. (1993) examined the question of whether 'prion dementia' should replace 'spongiform encephalopathy' to accommodate the existence of atypical forms of these 'prion protein' cerebral amyloidoses that may not show spongiform changes in the brain. They tested for the presence of PrP in brain tissue extracts from 46 cases, including 13 familial cases, of nonspongiform dementias with a variety of associated neurologic signs. None of the cases transmitted disease to primates, and none had PrP detectable by Western immunoblots. Brown et al. (1993) concluded that the clinicopathologic limits of prion dementias are, except for a small number of previously reported familial cases, essentially those of spongiform encephalopathy. Molecular Genetics In affected members of 2 unrelated families with autosomal dominant inheritance of Gerstmann-Straussler disease, Hsiao et al. (1989) identified a heterozygous mutation in the PRNP gene (P102L; 176640.0002). In a 36-year-old woman who belonged to the original family reported by Gerstmann et al. (1936) and Seitelberger (1962), Kretzschmar et al. (1991) identified a heterozygous P102L mutation in the PRNP gene. In affected members of a large Indiana kindred with Gerstmann-Straussler disease reported by Ghetti et al. (1989), Hsiao et al. (1992) identified a mutation in the PRNP gene (176640.0011). Dlouhy et al. (1992) showed absolute linkage of the PRNP mutation to the clinical phenotype in the Indiana kindred. Their studies suggested that patients who were heterozygous for the PRNP met/val129 (176640.0005) polymorphism had a later age of onset of the disease than individuals who were either met129 or val129 homozygotes. In a patient with GSD, Peoc'h et al. (2012) identified a heterozygous mutation in the PRNP gene (E211D; 176640.0029). The patient was homozygous for val129 (176640.0005). Neuropathologic studies showed typical features of GSS, including multicentric amyloid PrP-immunoreactive plaques, spongiform changes, mild gliosis, and neurofibrillary tangles. Proteinase K-resistant prion protein was found, and immunochemical studies showed accumulation of a C-terminal-truncated PrP fragment (roughly covering residues 80 to 150). Biophysical studies showed that the mutant protein had an increased tendency to aggregate, with a different effect on the PrP structural dynamics compared to the E211Q mutation (176640.0030), which was found in a patient with CJD. ### PRNP-Related Amyloid Angiopathy In a Japanese woman with PrP-immunoreactive cerebral amyloid angiopathy, Ghetti et al. (1996) identified a heterozygous truncating mutation in the PRNP gene (Y145X; 176640.0031). Ghetti et al. (1996) noted that abnormal PRNP truncation at a similar site (between residues 144 and 150) occurs in GSS variants in which the amyloid protein has been analyzed, suggesting that this truncated PrP peptide is important for amyloid formation. In a patient with PRNP-related cerebral amyloid angiopathy, Revesz et al. (2009) reported a tyr163-to-ter (Y163X) substitution in the PRNP gene. Clinical data was not provided, but neuropathologic studies showed vascular and parenchymal PRNP-immunoreactive amyloid deposition and extensive neurofibrillary tangle pathology. Jansen et al. (2010) identified a heterozygous truncating mutation in the PRNP gene (Y226X; 176640.0033) in a 57-year-old Dutch woman with PRNP-related cerebral amyloid angiopathy. Animal Model Telling et al. (1996) showed that the presence of wildtype PRNP genes, the level of PRNP transgene expression, and the sequence of the transgene can profoundly modify experimental prion disease in a transgenic mouse model with a murine P101L mutation in the Prnp gene, which is homologous to the human P102L mutation. They produced a homozygous animal for the mutant transgene array which caused spontaneous disease in a consistently shorter period of time than in the hemizygous animal. The authors concluded that the murine P101L mutation is required for CNS degeneration, that the clinical and neuropathic phenotypes of transgenic mice can be dramatically altered by ablation of the wildtype Prnp gene, and that this mouse model recapitulated virtually all features of human GSD. Choi et al. (2010) established a Drosophila model of GSD by expressing mouse prion protein (PrP) with a leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wildtype MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expressed MoPrP(P101L) in Drosophila was differentially glycosylated, localized at the synaptic terminals, and mainly present as deposits in adult brains. Behavioral defects and early death of MoPrP(P101L) flies were not due to caspase-3 (CASP3; 600636)-dependent programmed cell death signaling. In addition, type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrP(P101L) flies showed significantly increased numbers of satellite synaptic boutons. The amount of bruchpilot and discs large (DLG1; 601014) in MoPrP(P101L) flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS (ERC1; 607127), an active zone matrix marker, compared with control mice. The authors proposed that altered active zone structures at the molecular level may be involved in the pathogenesis of GSD in Drosophila and scrapie-infected mice. INHERITANCE \- Autosomal dominant GROWTH Weight \- Rapid weight loss late in the disease HEAD & NECK Eyes \- Impaired smooth pursuit NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Gait ataxia \- Truncal ataxia \- Limb ataxia \- Lower limb weakness \- Dysarthria \- Memory loss \- Dementia (later onset) \- Extrapyramidal signs (less common) \- Parkinsonism \- Rigidity \- Bradykinesia \- Tremor \- Apraxia \- Spasticity \- Hyperreflexia \- Myoclonus \- Perseveration \- Amyloid-like plaques, immunoreactive to PrP, predominantly in the cerebellum \- Amyloid-like plaques are not immunoreactive to APP ( 104760 ) \- PRNP-immunoreactive cerebral amyloid angiopathy (in some patients) \- Neurofibrillary tangles may be present \- Spongiform changes are mild or may not be present \- Some patients have periodic wave complexes on EEG \- Cerebellar atrophy Peripheral Nervous System \- Dysesthesias of the lower limbs \- Loss of deep tendon reflexes Behavioral Psychiatric Manifestations \- Personality changes \- Aggressive behavior \- Emotional lability \- Depression \- Psychosis MISCELLANEOUS \- Adult onset, usually 30's to 40's, but up to early 60's \- Rapidly progressive, but slower than Creutzfeldt-Jakob disease ( 123400 ) \- Average disease duration of 7 years \- Longer disease duration than Creutzfeldt-Jakob disease \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the prion protein gene (PRNP, 176640.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GERSTMANN-STRAUSSLER DISEASE	c0017495	3,181	omim	https://www.omim.org/entry/137440	2019-09-22T16:40:44	{"doid": ["4249"], "mesh": ["D016098"], "omim": ["137440"], "icd-9": ["046.71"], "icd-10": ["A81.82"], "orphanet": ["356"], "synonyms": ["Alternative titles", "ENCEPHALOPATHY, SUBACUTE SPONGIFORM, GERSTMANN-STRAUSSLER TYPE", "GERSTMANN-STRAUSSLER-SCHEINKER DISEASE", "CEREBELLAR ATAXIA, PROGRESSIVE DEMENTIA, AND AMYLOID DEPOSITS IN CNS", "AMYLOIDOSIS, CEREBRAL, WITH SPONGIFORM ENCEPHALOPATHY", "PRION DEMENTIA"], "genereviews": ["NBK1229"]}
STEAP3/TSAP6-related sideroblastic anemia is a very rare severe non-syndromic hypochromic anemia, which is characterized by transfusion-dependent hypochromic, poorly regenerative anemia, iron overload, resembling non-syndromic sideroblastic anemia (see this term) except for increased erythrocyte protoporphyrin levels. ## Epidemiology It has been reported in 3 siblings to date. ## Etiology STEAP3/TSAP6-related sideroblastic anemia is caused by a nonsense heterozygous mutation in the STEAP3/TSAP6 gene. Transmission is most likely recessive with a low expression allele. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Severe congenital hypochromic anemia with ringed sideroblasts	c3808920	3,182	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300298	2021-01-23T17:11:18	{"omim": ["615234"], "icd-10": ["D64.0"], "synonyms": ["Severe congenital hypochromic sideroblastic anemia"]}
Homocystinuria due to MTHFR deficiency is a genetic condition that results from poor metabolism of folate (also called vitamin B9), due to a lack of working enzyme called MTHFR. The gene that tells our body how to make the enzyme is also called MTHFR. At least 40 rare MTHFR gene variants have been found in people with decreased or no working enzyme. Very common gene variants (C677T and A1298C) can cause some decrease in enzyme function. People with homocystinuria due to MTHFR deficiency tend to have two rare variants or sometimes a rare variant and a common variant. Very rarely people inherit a combination of three or four common variants from their parents (for example two C677T variants and two A1298C variants) and may also develop very high levels of homocystine in their body. Homocystinuria usually does not show symptoms in a newborn baby. If untreated, children show signs and symptoms of severe homocystinuria in infancy. Newborn screening in most states includes a screening test for homocystinuria so that newborn infants can be treated early in their lives. However, homocystinuria due to MTHFR variants can be milder, presenting in later childhood or in adulthood. Symptoms may include abnormal clotting, developmental delay, seizures, intellectual disability, and microcephaly. Severe homocystinuria can also be caused by gene variants in other genes besides MTHFR. For more information about other causes of homocystinuria, see the GARD page: https://rarediseases.info.nih.gov/diseases/10770/homocystinuria For more information on having two common MTHFR gene variants (specifically, C677T and A1298C) visit our page: MTHFR gene variant [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Homocystinuria due to MTHFR deficiency	c1856061	3,183	gard	https://rarediseases.info.nih.gov/diseases/2734/homocystinuria-due-to-mthfr-deficiency	2021-01-18T17:59:58	{"mesh": ["C537357"], "omim": ["236250"], "orphanet": ["395"], "synonyms": ["Homocysteinemia due to methylenetetrahydro-folate reductase deficiency", "Methylenetetrahydro-folate reductase deficiency", "Homocysteinuria due to methylenetetrahydro-folate reductase deficiency", "5,10-alpha-methylenetetrahydro-folate reductase deficiency", "5,10 alpha methylenetetrahydro-folate reductase deficiency"]}
With less than 0.1 percent of the population estimated to be HIV-positive, Bangladesh is a low HIV-prevalence country. ## Contents * 1 Prevalence * 2 Preventive programs * 3 Tuberculosis * 4 National response * 5 References ## Prevalence[edit] The country faces a concentrated epidemic, and its very low HIV-prevalence rate is partly due to prevention efforts, focusing on men who have sex with men, female sex workers, and intravenous drug users. Four years before the disease's 1989 appearance in the country, the government implemented numerous prevention efforts targeting the above high-risk populations as well as migrant workers. Although these activities have helped keep the incidence of HIV down, the number of HIV-positive individuals has increased steadily since 1994 to approximately 7,500 people in 2005 according to the International Center for Diarrhoeal Disease Research, Bangladesh. UNAIDS estimates the number to be slightly higher at 11,000 people.[1] While HIV prevalence is very low in the general population, among most at risk populations it rises to 0.7%. In some cases it is as high as 3.7%, for instance among casual sex workers in Hili, a small border town in northwest Bangladesh.[2] Many of the estimated 11,000 people living with HIV are migrant workers. The 2006 National AIDS/STD programme estimated that 67% of identified HIV positive cases in the country were returnee migrant workers and their spouses.[2] This is similar to findings from other organisations. According to the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B), 47 of 259 cases of people living with HIV during the period 2002–2004 were identified during the migration process.[2] Other data from 2004 (from the National AIDS/Sexually Transmitted Disease (STD) programme of the Ministry of Health and Family Welfare (MoHFW)) shows that 57 of 102 newly reported HIV cases were among returning migrants.[2] While HIV prevalence among male homosexuals and sex workers has remained below 1 percent, unsafe practices among drug users, particularly needle sharing, have caused a sharp increase in the number of people infected. Measurements at one central surveillance point showed that between 2001 and 2005, incidence of HIV in IDUs more than doubled – from 1.4 percent to 4.9 percent, according to UNAIDS. In 2004, 9 percent of IDUs at one location in Dhaka were HIV-positive. Compounding the risk of an epidemic, a large proportion of IDUs (up to 20 percent in some regions) reported buying sex, fewer than 10 percent of whom said they consistently used a condom.[1] ## Preventive programs[edit] HIV/AIDS prevention programs have successfully reached 71.6 percent of commercial sex workers (CSWs) in Bangladesh, according to the 2005 United Nations General Assembly Special Session (UNGASS) Country Report. However, only 39.8 percent of sex workers reported using a condom with their most recent client, and just 23.4 percent both correctly identified ways of preventing the sexual transmission of HIV and rejected major misconceptions about HIV transmission. Other factors contributing to Bangladesh's HIV/AIDS vulnerability include cross-border interaction with high-prevalence regions in Burma and northeast India, low condom use among the general population, and a general lack of knowledge about HIV/AIDS and other sexually transmitted infections (STIs).[1] For instance, a study in 2008 found poor HIV knowledge among female migrant workers who were flying for an overseas job.[3] Research performed by Islam & Conigrave (2007) found that there were substantial gaps between current needs and the ongoing prevention efforts.[4][5] The authors stressed the importance of developing a pre-departure and post-departure program for international migrants; increased co-ordination among intervening agencies and equitable coverage of prevention programs. ## Tuberculosis[edit] Bangladesh also has a high tuberculosis (TB) burden, with 102 new cases per 100,000 people in 2005, according to the World Health Organization. HIV infects about 0.1 percent of adult TB patients in Bangladesh and HIV-TB co-infections complicate treatment and care for both diseases.[1] ## National response[edit] Bangladesh's HIV/AIDS prevention program started in 1985, when the Minister of Health and Family Welfare established the National AIDS and Sexually Transmitted Diseases Program under the overall policy support of the National AIDS Council (NAC), headed by the President and chaired by the Minister of Health and Family Welfare. The National AIDS/STD Program has set in place guidelines on key issues including testing, care, blood safety, sexually transmitted infections, and prevention among youth, women, migrant populations, and sex workers. In 2004, a six-year National Strategic Plan (2004–2010) was approved. The country's HIV policies and strategies are based on other successful family planning programs in Bangladesh and include participation from schools, as well as religious and community organisations. The AIDS Initiative Organization was launched in 2007 to fund for those without proper medication to combat the virus. The National HIV and AIDS Communication Strategy (2006–2010) was also developed and launched.[1] Since 2000, the Government of Bangladesh has worked with the World Bank on the HIV/AIDS Prevention Project, a $26 million program designed to prevent HIV from spreading within most-at-risk populations and into the general population. The program is being integrated into the country's Health, Nutrition and Population Program, which is supported by the government and external donors. In 2003, a national youth policy was established on reproductive health, including HIV/AIDS awareness. Since 2006, students in 21,500 secondary and upper-secondary schools have been taught about HIV/AIDS issues. The educational program introduces a "life skills" curriculum, including a chapter on HIV/AIDS drafted with assistance from the United Nations Children's Fund (UNICEF).[1] Bangladesh developed its first Antiretroviral Therapy (ART) treatment guidelines in 2006, with PLHIV able to buy subsidised antiretroviral drugs from specified pharmacies.[2] Unfortunately, most HIV diagnostic facilities are provided by NGOs based in Dhaka and most rural and cross-border migrants miss out on ART, HIV testing and other associated care and support services. If they seek private care, the cost is often beyond their means.[2] Currently, the program funded by the Global Fund is leading the national response to fight HIV and AIDS. Bangladesh had received 3 grants on HIV/AIDS from The Global Fund to fight AIDS, Tuberculosis and Malaria: Round 2 from 2004 to 2009, Round 6 from 2007 to 2012 and Rolling Continuation Channel (RCC) from 2009 to 2015. The Round 2 grant focused mainly on prevention of HIV among young people with strategies including: 1. HIV/AIDS prevention messages dissemination through information campaign in mass and print media 2. HIV/AIDS orientation, training and services via Life skills education, Youth Friendly Health services and accessing condom 3. Integration of HIV/AIDS in school and college curriculum 4. Advocacy and sensitisation of religious leaders, parents and policy makers 5. Generating information for policies and programs. The main focus of the Round 6 grant was on most at risk populations and scaling up of the Round 2 project including interventions with vulnerable youth. The interventions for High Risk population and vulnerable young people includes essential services for injecting drug users and female sex workers; treatment, care and support for PLHIV; and awareness and prevention strategy for vulnerable young people including garment industry workers. National level capacity building, strengthening district co-ordination, support to networks and self-help groups are also among the strategies. Round 2 and Round 6 have been implemented through Public–Private Partnership where the Economic Relations Division of the Government of Bangladesh worked as Principal Recipient and Save the Children USA managed the grants as Management Agency in collaboration with Ministry of Health and Family Welfare. Based on the satisfactory level of completion of the Round 2 project, Global Fund awarded Bangladesh with the 6 year fund termed as "Rolling Continuation Channel (RCC)" from 2009 to 2015, which is consolidated with the Round 6 grant. For high level of performance the Project is appreciated as a "best practice" example in Asia and is rated as "A" by the Global Fund. The program is being implemented through 13 technical packages by 13 consortiums comprising 61 organisations nationwide. Save the Children, as a Principle Recipient of the grant is facilitating implementation through technical and compliance related support to all the consortia. Other Principal Recipients are National AIDS/STD Program and ICDDR B. The main objectives of RCC Program are: 1. Increase the scale of prevention services for key populations at higher risk: Injecting Drug Users (IDUs), Sex Workers (FSWs), hijras (transgender people) & Men who have Sex with Men (MSM) 2. Increase the scale of the most effective HIV/AIDS activities conducted through Round 2 3. Build capacity of partners to increase scale of national response to the HIV/AIDS epidemic Some significant achievements of the HIV/AIDS program funded by the Global Fund are: 1. Overall HIV Prevalence remains <1% 2. HIV/AIDS information is included in text books of secondary and higher secondary level education, from grades VI to XII, in both Bangla and English 3. HIV/AIDS prevention, care & support related information now mainstreamed within the training curriculum of five different Ministries 4. National standards for Youth Friendly Health Services (YFHS) have been established, now practised in public, NGO & private health service facilities countrywide 5. Standard Operating Procedures (SOP) for services to PLHIV have been endorsed by the government 6. Public–private partnership has been proved to be an effective model for fighting AIDS 7. Over 300 people living with HIV and AIDS (PLHIV) are receiving anti-retroviral treatment (ARV) per year 8. Workplace policy on Life Skills-based Education (LSE) on HIV/AIDS endorsed by Bangladesh Garments Manufacturers' association (BGMEA) 9. Under the Ministry of Religious Affairs, 4 booklets on HIV/AIDS have been published for the 4 major practising religions in the country ## References[edit] 1. ^ a b c d e f "Health Profile: Bangladesh" Archived 17 August 2008 at the Wayback Machine. United States Agency for International Development (March 2008). Accessed 25 August 2008. This article incorporates text from this source, which is in the public domain. 2. ^ a b c d e f Fiona Samuels and Sanju Wagle 2011. Population mobility and HIV and AIDS: review of laws, policies and treaties between Bangladesh, Nepal and India. London: Overseas Development Institute 3. ^ Islam, M. M., Conigrave, K. M., Miah, M. S., Kalam, K. A. (2010). "HIV awareness of outgoing female migrant workers of Bangladesh: a pilot study". Journal of Immigrant and Minority Health. 12: 940–946. doi:10.1007/s10903-010-9329-5. PMID 20155324.CS1 maint: multiple names: authors list (link) 4. ^ Islam, M. M., Conigrave, K. M. (2007). "Increasing prevalence of HIV, and persistent high-risk behaviours among drug users in Bangladesh: need for a comprehensive harm reduction programme". Drug and Alcohol Review. 26: 445–454. doi:10.1080/09595230701373925. PMID 17564883.CS1 maint: multiple names: authors list (link) 5. ^ Islam, M. M., Conigrave, K. M. (2008). "HIV and sexual risk behaviors among recognized high-risk groups in Bangladesh: need for a comprehensive prevention program". International Journal of Infectious Diseases. 12: 363–370. doi:10.1016/j.ijid.2007.12.002. PMID 18325810.CS1 maint: multiple names: authors list (link) * v * t * e HIV/AIDS in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HIV/AIDS in Bangladesh	None	3,184	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Bangladesh	2021-01-18T19:01:47	{"wikidata": ["Q5629816"]}
2p15-16.1 microdeletion syndrome Other namesMonosomy 2p15-p16.1 Chromosome 2(where deletion for this condition occurs) SpecialtyMedical genetics 2p15-16.1 microdeletion is an extremely rare genetic disorder caused by a small deletion in the short arm of human chromosome 2. First described in two patients in 2007,[1] by 2013 only 21[citation needed] people have been reported as having the disorder in the medical literature.[2][3][4][5] ## Contents * 1 Presentation * 2 Cause * 2.1 Affected genes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Presentation[edit] Only 21 patients with 2p15-16.1 microdeletion have been described as of 2013. The clinical similarities between the individuals resulted in the classification of a new genetic syndrome.[1][2][3] The shared clinical features include moderate to severe intellectual disability and similar facial features including telecanthus, drooping eyelids, downslanting, short palpebral fissures, a prominent nasal bridge, high palate with long, smooth philtrum and an everted lower lip. Some of the patients also had feeding problems in infancy, microcephaly, optic nerve hypoplasia and hydronephrosis, wide-spaced nipples, short stature, cortical dysplasia, camptodactyly and pigeon toe.[1][2][3] ## Cause[edit] Human chromosome 2. The short arm where the deletion occurs is to the top Three of the patients reported had a consistent proximal breakpoint on chromosome 2, but varying distal breakpoints.[1][2] The patients have 2p15–16.1 deletions of 5.7 megabases (Mb), 4.5 Mb, 3.9 Mb, 3.35Mb 3.3Mb and 570 kilobases, respectively.[4] In all 21 patients the deletions are de novo — neither parent possessed nor transmitted the mutation to the affected individual. One patient is a genetic mosaic, having some cells with the deletion and others without.[2] ### Affected genes[edit] The largest deletion encompasses approximately 15 protein-coding genes, 6 pseudogenes and a number of other as yet uncharacterised candidates, including:[2][6] * AHSA2, activator of heat shock 90kDa protein ATPase homolog * BCL11A, B-cell lymphoma/leukemia 11A * C2orf74, Uncharacterized protein C2orf74 * FANCL, E3 ubiquitin-protein ligase FANCL * KIAA1841, Uncharacterized protein KIAA1841 * PAPOLG, Poly(A) polymerase gamma * PEX13, Peroxisomal membrane protein Peroxin-13 * PUS10, Pseudouridylate synthase 10 * REL, C-Rel proto-oncogene protein * SNORA70B, small nucleolar RNA, H/ACA box 70B * USP34, Ubiquitin carboxyl-terminal hydrolase 34 * VRK2, Serine/threonine-protein kinase VRK2 * XPO1, Exportin-1 ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (December 2017) ## References[edit] 1. ^ a b c d Rajcan-Separovic E, Harvard C, Liu X, McGillivray B, Hall JG, Qiao Y, Hurlburt J, Hildebrand J, Mickelson EC, Holden JJ, Lewis ME (2007). "Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15-16.1". J Med Genet. 44 (4): 269–76. doi:10.1136/jmg.2006.045013. PMC 2598046. PMID 16963482. 2. ^ a b c d e f de Leeuw N, Pfundt R, Koolen DA, Neefs I, Scheltinga I, Mieloo H, Sistermans EA, Nillesen W, Smeets DF, de Vries BB, Knoers NV (2008). "A newly recognised microdeletion syndrome involving 2p15p16.1: narrowing down the critical region by adding another patient detected by genome wide tiling path array comparative genomic hybridisation analysis". J Med Genet. 45 (2): 122–4. doi:10.1136/jmg.2007.054049. PMID 18245392. S2CID 972258. 3. ^ a b c Chabchoub E, Vermeesch JR, de Ravel T, de Cock P, Fryns JP (2008). "The facial dysmorphy in the newly recognised microdeletion 2p15-p16.1 refined to a 570 kb region in 2p15". J Med Genet. 45 (3): 189–92. doi:10.1136/jmg.2007.056176. PMID 18310269. S2CID 32961901. 4. ^ a b Liang JS, Shimojima K, Ohno K, Sugiura C, Une Y, Ohno K, et al. (2009). "A newly recognised microdeletion syndrome of 2p15-16.1 manifesting moderate developmental delay, autistic behaviour, short stature, microcephaly, and dysmorphic features: a new patient with 3.2 Mb deletion". J Med Genet. 46 (9): 645–7. doi:10.1136/jmg.2008.059220. PMID 19724011. S2CID 5128199. 5. ^ Félix TM, Petrin AL, Sanseverino MT, Murray JC (2010). "Further characterization of microdeletion syndrome involving 2p15-p16.1". Am J Med Genet A. 152A (10): 2604–8. doi:10.1002/ajmg.a.33612. PMC 2946431. PMID 20799320. 6. ^ "2p15-16.1 microdeletion syndrome". Wellcome Trust Sanger Institute. Retrieved 24 May 2011. ## External links[edit] Classification D * ICD-10: Q93.5 * OMIM: 612513 * MeSH: C567289 External resources * Orphanet: 261349 * DECIPHER database entry for 2p15-16.1 microdeletion syndrome * Orphanet entry for 2p15-16.1 microdeletion syndrome * Online Mendelian Inheritance in Man (OMIM): 612513 * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	2p15-16.1 microdeletion syndrome	c2675875	3,185	wikipedia	https://en.wikipedia.org/wiki/2p15-16.1_microdeletion_syndrome	2021-01-18T19:02:11	{"gard": ["13391"], "mesh": ["C567289"], "umls": ["C2675875"], "orphanet": ["261349"], "wikidata": ["Q4633988"]}
In this condition the spinal cord is divided longitudinally in the anteroposterior plane by a fibrous or bony structure. The cases are usually isolated but affected sisters were reported by Kapsalakis (1964). Gardner (1973) described a family in which 3 sisters had diastematomyelia and other dysraphic malformations in various combinations. Balci et al. (1999) reported 2 sisters with diastematomyelia with variable expressivity. They suggested that X-linked dominant inheritance with lethality in hemizygous males or female sex preference of a multifactorial trait may explain the fact that all reported familial cases have been female. Inheritance \- Possibly autosomal recessive Neurologic \- Diastematomyelia \- Divided spinal cord \- Spinal cord dysraphism ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DIASTEMATOMYELIA	c0011999	3,186	omim	https://www.omim.org/entry/222500	2019-09-22T16:28:43	{"mesh": ["D009436"], "omim": ["222500"], "icd-9": ["742.51"], "icd-10": ["Q06.2"], "orphanet": ["1671"]}
A number sign (#) is used with this entry because congenital nongoitrous hypothyroidism-5 (CHNG5) is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35. For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see 275200. Molecular Genetics Dentice et al. (2006) screened for mutations in the coding region of the NKX2-5 gene (600584) in 241 patients with congenital nongoitrous hypothyroidism, including 53 with athyreosis, 99 with thyroid ectopy, and 15 with hypoplasia, and identified 3 different heterozygous missense mutations in 4 of the patients: 2 of the mutations were novel (600584.0015-600584.0016) and the other had previously been identified in patients with congenital heart disease (600584.0004). Functional characterization of the 3 mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wildtype NKX2-5. INHERITANCE \- Autosomal dominant GROWTH Other \- Growth retardation, severe (if untreated) NEUROLOGIC Central Nervous System \- Mental retardation, severe (if untreated) ENDOCRINE FEATURES \- Hypothyroidism, nongoitrous \- Hypoplastic thyroid gland \- Ectopic thyroid gland LABORATORY ABNORMALITIES \- Increased TSH \- Decreased free T(3)/free T(4) MOLECULAR BASIS \- Caused by mutation in the E homolog of the Drosophila NK2 transcription factor (NKX2E, 600584.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 5	c0151516	3,187	omim	https://www.omim.org/entry/225250	2019-09-22T16:28:24	{"doid": ["0070125"], "mesh": ["D050033"], "omim": ["225250"], "orphanet": ["95720", "95713", "95712"]}
Purple urine bag syndrome Purple urine bag syndrome usually presents as urine with a purplish discoloration accumulating in a catheterized person's collection bag. Purple urine bag syndrome (PUBS) is a medical syndrome where purple discoloration of urine occurs in people with urinary catheters and co-existent urinary tract infection. Bacteria in the urine produce the enzyme indoxyl sulfatase. This converts indoxyl sulfate in the urine into the red and blue colored compounds indirubin and indigo.[1] The most commonly implicated bacteria are Providencia stuartii, Providencia rettgeri, Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli, Morganella morganii, and Pseudomonas aeruginosa.[2] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 References ## Signs and symptoms[edit] People with purple urine bag syndrome usually do not complain of any symptoms. Purple discoloration of urine bag is often the only finding, frequently noted by caregivers. It is usually considered a benign condition, although in the setting of recurrent or chronic urinary tract infection, it may be associated with drug-resistant bacteria.[3] ## Pathophysiology[edit] Tryptophan in the diet is metabolized by bacteria in the gastrointestinal tract to produce indole. Indole is absorbed into the blood by the intestine and passes to the liver. There, indole is converted to indoxyl sulfate, which is then excreted in the urine. In purple urine bag syndrome, bacteria that colonize the urinary catheter convert indoxyl sulfate to the colored compounds indirubin and indigo.[1] ## Diagnosis[edit] Purple urine bag syndrome is a clinical diagnosis, the cause of which may be investigated using a variety of laboratory tests or imaging. ## Treatment[edit] Antibiotics such as ciprofloxacin should be administered and the catheter should be changed. If constipation is present, this should also be treated.[4] ## Epidemiology[edit] Purple urine bag syndrome is more common in female nursing home residents. Other risk factors include alkaline urine, constipation, and polyvinyl chloride catheter use.[5] ## History[edit] The syndrome was first described by Barlow and Dickson in 1978.[6] ## References[edit] 1. ^ a b Tan, CK; Wu YP; Wu HY; Lai CC (August 2008). "Purple urine bag syndrome". Canadian Medical Association Journal. 179 (5): 491. doi:10.1503/cmaj.071604. PMC 2518199. PMID 18725621. 2. ^ Lin, CH; Huang HT; Chien CC; et al. (December 2008). "Purple urine bag syndrome in nursing homes: ten elderly case reports and a literature review". Clinical Interventions in Aging. 3 (4): 729–734. doi:10.2147/cia.s3534. PMC 2682405. PMID 19281065. 3. ^ Bhattarai, M; Mukhtar HB; Davis TW; et al. (2013). "Purple urine bag syndrome may not be benign: a case report and brief review of the literature". Case Reports in Infectious Diseases. 2013: 863853. doi:10.1155/2013/863853. PMC 3705812. PMID 23864970. 4. ^ Kalsi, DS; Ward, J; Lee, R; Handa, A (November 2017). "Purple urine bag syndrome: a rare spot diagnosis". Disease Markers. 2017: 9131872. doi:10.1155/2017/9131872. PMC 5727662. PMID 29317791. 5. ^ Su, FH; Chung SY; Chen MH; et al. (September 2005). "Case analysis of purple urine-bag syndrome at a long-term care service in a community hospital". Chang Gung Medical Journal. 28 (9): 636–642. PMID 16323555. 6. ^ Barlow, GB; Dickson JAS (March 1978). "Purple urine bags". Lancet. 1 (8062): 502. doi:10.1016/s0140-6736(78)90163-0. PMID 76045. S2CID 54340615. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Purple urine bag syndrome	c4324366	3,188	wikipedia	https://en.wikipedia.org/wiki/Purple_urine_bag_syndrome	2021-01-18T19:00:13	{"umls": ["CL519275"], "wikidata": ["Q7261489"]}
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: "Nasolacrimal duct obstruction" – news · newspapers · books · scholar · JSTOR (August 2012) (Learn how and when to remove this template message) Nasolacrimal duct obstruction Other namesDacryocystitis Tear system consists of lacrimal gland (a), punctums (b,e), canalicules (c,f), lacrimal sac (g,d). Tear is then drained through nasolacrimal duct (not shown in the image) into nasal cavity SpecialtyOphthalmology Differential diagnosisTears arising from lacrimal sac fistula.[1] See also: Dacryocystitis Nasolacrimal duct obstruction is the obstruction of the nasolacrimal duct and may be either congenital or acquired. Obstruction of the nasolacrimal duct leads to the excess overflow of tears called epiphora.[2] ## Contents * 1 Sign and symptoms * 2 Cause * 2.1 Involutional stenosis * 2.2 Dacryolith * 2.3 Sinus disease * 2.4 Trauma * 2.5 Inflammatory disease * 2.6 Lacrimal plugs * 2.7 Neoplasm * 2.8 Congenital * 3 Diagnosis * 3.1 Dye disappearance test * 3.2 Irrigation test * 4 Management * 4.1 Intubation and stenting * 4.2 Dacryocystorhinostomy * 5 See also * 6 References * 7 External links ## Sign and symptoms[edit] Excessive tearing is the most common complaint of patients with nasolacrimal duct obstruction, followed by acute or chronic infections.[3] Pain at the side of the nose suggests dacryocystitis. Nasolacrimal duct obstruction is more common with increasing age and more common in females than males.[3] ## Cause[edit] ### Involutional stenosis[edit] Involutional stenosis is probably the most common cause of nasolacrimal duct obstruction in older people. It affects women twice as frequently as men. Although the inciting event in this process is unknown, clinicopathologic study suggests that compression of the lumen of the nasolacrimal duct is caused by inflammatory infiltrates and edema. This may be the result of an unidentified infection or possibly an autoimmune disease.[citation needed] ### Dacryolith[edit] Dacryoliths or cast formation, within the lacrimal sac can also produce obstruction of the nasolacrimal duct. ### Sinus disease[edit] Sinus disease often occurs in conjunction with, and in other instances may contribute to the development of nasolacrimal duct obstruction. Patients should be asked about previous sinus surgery, as the nasolacrimal duct is sometimes damaged when the maxillary sinus ostium is being enlarged anteriorly. ### Trauma[edit] Naso-orbital fractures may involve the nasolacrimal duct. Early treatment by fracture reduction with stenting of the entire lacrimal drainage system should be considered. However, such injuries are often not recognized or are initially neglected as more serious injuries are managed. In such cases, late treatment of persistent epiphora usually requires dacryocystorhinostomy. ### Inflammatory disease[edit] Granulomatous disease, including sarcoidosis, granulomatosis with polyangiitis, and midline granuloma, may also lead to nasolacrimal duct obstruction. ### Lacrimal plugs[edit] As with similar cases of canalicular obstruction, dislodged punctual and canalicular plugs can migrate to and occlude the nasolacrimal duct. ### Neoplasm[edit] Neoplasm should be considered in any patient presenting with nasolacrimal duct obstruction. In patients with atypical presentations, including younger age and male gender, further workup is appropriate. Bloody punctual discharge or lacrimal sac distension above the medial canthal tendon is also highly suggestive of neoplasm. ### Congenital[edit] Congenital nasolacrimal duct obstruction, or dacryostenosis, occurs when the lacrimal duct has failed to open at the time of birth, most often due to an imperforate membrane at the valve of Hasner.[4] Around 6% of infants have congenital nasolacrimal duct obstruction, or dacryostenosis, usually experiencing a persistent watery eye even when not crying. If a secondary infection occurs (Dacryocystitis), purulent (yellow / green) discharge may be present. Most cases resolve spontaneously, with antibiotics reserved only if conjunctivitis occurs. Lacrimal sac massage has been proposed as helping to open the duct, though this is not always successful.[5] The aim of massage is to generate enough hydrostatic pressure (downward, toward the nose) to "pop" open any obstruction. Additional massage may then be performed up toward the lacrimal punctum, in order to express any infectious material out of the nasolacrimal sac. When discharge or crusting is present, the lids should be gently cleaned using cooled pre-boiled water or saline. Referral to an ophthalmologist is indicated if symptoms are still present at 12 months, or sooner if significant symptoms or recurrent infections occur. Nasolacrimal duct probing may be performed in the office setting (usually from 4 to 8 months of age) or under general anesthesia in an operating room for older patients. The success rate of probing is higher for younger children. A silastic tube or stent may be employed along with probing to maintain tear duct patency.[6] A systematic review comparing immediate probing with deferred probing found that in children with unilateral nasolacrimal duct obstruction, immediate probing resulted in a higher success rate of treatment compared to deferred probing.[7] ## Diagnosis[edit] Evaluation is in the form of a dye disappearance test followed by irrigation test. By using this sequence (with modifications) as a guide, the physician can frequently streamline diagnostic testing. ### Dye disappearance test[edit] The dye disappearance test is useful for assessing the presence or absence of adequate lacrimal outflow, especially in unilateral cases. It is more heavily relied upon in children, in whom lacrimal irrigation is impossible without deep sedation. Using a drop of sterile 2% fluorescein solution or a moistened fluorescein strip, the examiner instills fluorescein into the conjunctival fornices of each eye and then observes the tear film, preferably with the cobalt blue filter of the slit lamp. Persistence of significant dye and, particularly asymmetric clearance of the dye from the tear meniscus over a 5-minute period indicate an obstruction. If the dye disappearance test result is normal, severe lacrimal drainage dysfunction is highly unlikely. The Jones tests are variations of the dye disappearance test. ### Irrigation test[edit] Flushing the nasolacrimal duct in a cat. In irrigation test, a lacrimal irrigation cannula is passed into the punctum and advanced through the canaliculus to the lacrimal fossa. Clear water or saline is then irrigated through the cannula. If fluid passes into the nose without reflux out of the opposite canaliculus, the system is patent. If no fluid passes but it all comes back through either punctum, nasolacrimal duct obstruction is present. ## Management[edit] ### Intubation and stenting[edit] Some clinicians believe that partial stenosis of the nasolacrimal duct with symptomatic epiphora sometimes responds to surgical intubation of the entire lacrimal drainage system. This procedure should be performed only if the tubes can be passed easily. In complete nasolacrimal duct obstruction, intubation alone is not effective, and a dacryocystorhinostomy should be considered. ### Dacryocystorhinostomy[edit] A dacryocystorhinostomy is the treatment of choice for most patients with acquired nasolacrimal duct obstruction. Surgical indications include recurrent dacryocystitis, chronic mucoid reflux, painful distension of the lacrimal sac, and bothersome epiphora. For patients with dacryocystitis, active infection should be cleared, if possible, before a dacryocystorhinostomy is performed.[2] ## See also[edit] * Nasolacrimal duct * Lacrimal apparatus * Imperforate lacrimal punctum ## References[edit] 1. ^ Nerad, Jeffrey A.; Carter, Keith D.; Alford, Mark (2008). "Disorders of the Lacrimal System: Congenital Obstruction". Oculoplastic and Reconstructive Surgery. Elsevier. pp. 131–137. doi:10.1016/b978-0-323-05386-0.50010-7. ISBN 978-0-323-05386-0. "This tearing is different (from Dacryocystitis), as it originates from the fistula located below the eyelid on the cheek (may be associated with nasolacrimal duct obstruction)." 2. ^ a b Myron Yanoff; Jay S. Duker (2009). Ophthalmology (3rd ed.). Mosby Elsevier. pp. 1482–1487. ISBN 9780323043328. 3. ^ a b Jawaheer L, MacEwen CJ, Anijeet D (2017). "Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction". Cochrane Database Syst Rev. 2: CD007097. doi:10.1002/14651858.CD007097.pub3. PMC 6464401. PMID 28231605.CS1 maint: uses authors parameter (link) 4. ^ Blocked tear ducts in infants, Pediatric Views, June 2006 http://www.childrenshospital.org/views/june06/blocked_tear_ducts.html Archived 2012-07-08 at the Wayback Machine 5. ^ Young JD, MacEwen CJ (1997). "Managing congenital lacrimal obstruction in general practice". BMJ. 315 (7103): 293–6. doi:10.1136/bmj.315.7103.293. PMC 2127215. PMID 9274552. 6. ^ Engel JM, Hichie-Schmidt C, Khammar A, Ostfeld BM, Vyas A, Ticho BH (2007). "Monocanalicular silastic intubation for the initial correction of congenital nasolacrimal duct obstruction". J AAPOS. 11 (2): 183–186. doi:10.1016/j.jaapos.2006.09.009. PMID 17307001. 7. ^ Petris C, Liu D (2017). "Probing for congenital nasolacrimal duct obstruction". Cochrane Database of Systematic Reviews. 7: CD011109. doi:10.1002/14651858.CD011109.pub2. PMC 5580992. PMID 28700811.CS1 maint: uses authors parameter (link) ## External links[edit] Classification D * ICD-10: H04.5 * ICD-9-CM: 375.56 * MeSH: D007767 External resources * MedlinePlus: 001016 * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nasolacrimal duct obstruction	c0022906	3,189	wikipedia	https://en.wikipedia.org/wiki/Nasolacrimal_duct_obstruction	2021-01-18T19:02:38	{"mesh": ["D007767"], "umls": ["C0022906", "C1281931"], "wikidata": ["Q5797309"]}
## Clinical Features Zhao et al. (1995) reported a 4-generation Chinese family in which retinitis pigmentosa affected only males. All sons of affected males were affected, but all 4 daughters of affected males (and all children of these daughters) were healthy. Inheritance According to Zhao et al. (1995) the probability of autosomal dominant inheritance in the family they reported is only 1:8,192. Therefore, the authors proposed Y-linked inheritance as a possible explanation for the pattern in this family. INHERITANCE \- Y-linked HEAD & NECK Eyes \- Retinitis pigmentosa MISCELLANEOUS \- Based on 1 4-generation Chinese family \- Limited clinical information provided ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RETINITIS PIGMENTOSA, Y-LINKED	c0035334	3,190	omim	https://www.omim.org/entry/400004	2019-09-22T16:17:02	{"doid": ["0110418"], "mesh": ["D012174"], "omim": ["400004"], "orphanet": ["791"]}
A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most cancers develop at their primary site but then go on to metastasize or spread to other parts of the body. These further tumors are secondary tumors. Most cancers continue to be called after their primary site, as in breast cancer or lung cancer for example, even after they have spread to other parts of the body. Cancer of unknown primary origin is cancer in which secondary tumors are found but the original primary site cannot be decided. ## References[edit] * Weinberg, Robert. The Biology of Cancer, 2007. * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea This article about a neoplasm is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Primary tumor	c1306459	3,191	wikipedia	https://en.wikipedia.org/wiki/Primary_tumor	2021-01-18T18:49:42	{"umls": ["C1306459"], "wikidata": ["Q2110267"]}
A calciumopathy is a disease caused by disruption to the use of calcium within a cell. To a large extent, a calciumopathy is a type of channelopathy, or a disease caused by disturbed function of ion channel subunits or the proteins that regulate them; calciumopathies also include dysfunctions of regulatory pathways and mitochondria. Many calciumopathies are complex polygenic diseases; clues to their understanding are coming from the rarer monogenic forms of common symptoms such as seizures, ataxia, and migraine.[1] ## References[edit] 1. ^ Gargus JJ (2009). "Genetic calcium signaling abnormalities in the central nervous system: seizures, migraine, and autism". Ann N Y Acad Sci. 1151 (1): 133–56. Bibcode:2009NYASA1151..133G. doi:10.1111/j.1749-6632.2008.03572.x. PMID 19154521. This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Calciumopathy	None	3,192	wikipedia	https://en.wikipedia.org/wiki/Calciumopathy	2021-01-18T18:49:55	{"wikidata": ["Q5018845"]}
A rare, genetic disorder of amino acid absorption and transport, characterized by generalized hypotonia at birth, neonatal/infantile failure to thrive (followed by hyperphagia and rapid weight gain in late childhood), cystinuria type 1, nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypotonia-cystinuria syndrome	c1848030	3,193	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163690	2021-01-23T18:24:21	{"mesh": ["C564710"], "omim": ["606407"], "umls": ["C1848030"], "icd-10": ["E72.0"], "synonyms": ["HCS"]}
Total recorded alcohol per capita consumption (15+), in litres of pure alcohol.[1] Alcoholic beverages are classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen (carcinogenic to humans). IARC classifies alcoholic beverage consumption as a cause of female breast, colorectal, larynx, liver, esophagus, oral cavity, and pharynx cancers; and as a probable cause of pancreatic cancer.[2] 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol (specifically, ethanol).[3][needs update] Even light and moderate alcohol consumption increases cancer risk in individuals.[4][5] Some nations have introduced alcohol packaging warning messages that inform consumers about alcohol and cancer.[6] The alcohol industry has tried to actively mislead the public about the risk of cancer due to alcohol consumption,[7] in addition to campaigning to remove laws that require alcoholic beverages to have cancer warning labels.[8] ## Contents * 1 Mortality from alcohol-related cancers * 2 Alcohol as a carcinogen and cocarcinogen * 3 Mechanisms * 3.1 Acetaldehyde * 3.2 Reviews * 3.3 Local carcinogenic effect of ethanol * 3.4 Epithelial-mesenchymal transition * 3.5 Effect of alcohol on the progress of cancer when established * 4 Genetic variation and cancer risk * 5 Risk factor for specific cancers * 5.1 Moderate consumption increases risk * 5.1.1 Cancers of the mouth, esophagus, pharynx, and larynx * 5.1.2 Breast cancer * 5.1.3 Colorectal cancer * 5.1.4 Liver cancer * 5.1.5 Lung cancer * 5.1.6 Skin cancer * 5.1.7 Stomach cancer * 5.2 Consumption of 50g or more per day increases risk * 5.2.1 Endometrial cancer * 5.2.2 Gallbladder cancer * 5.2.3 Ovarian cancer * 5.2.4 Prostate cancer * 5.2.5 Small intestine cancer * 5.3 Evidence is mixed * 5.3.1 Leukemia * 5.3.2 Multiple myeloma (MM) * 5.3.3 Pancreatic cancer * 5.4 Not suspected to increase risk * 5.4.1 Childhood astrocytoma * 5.4.2 Bile duct cancer * 5.4.3 Bladder cancer * 5.4.4 Cervical cancer * 5.4.5 Ductal carcinoma in situ (DCIS) breast cancer * 5.4.6 Ependymoma * 5.4.7 Intraocular and uveal melanomas * 5.4.8 Nasopharynageal cancer / Nasopharyngeal carcinoma (NPC) * 5.4.9 Neuroblastoma * 5.4.10 Salivary gland cancer (SGC) * 5.4.11 Testicular cancer * 5.4.12 Thyroid cancer * 5.4.13 Vaginal cancer * 5.4.14 Vulvar cancer * 5.5 Might reduce risk * 5.5.1 Hodgkin's lymphoma (HL) * 5.5.2 Kidney cancer (Renal cell carcinoma) (RCC) * 5.5.3 Non-Hodgkin lymphoma (NHL) * 6 Recommended maximum alcohol intake * 7 Alcohol industry manipulation of the science on alcohol and cancer * 8 References * 9 External links ## Mortality from alcohol-related cancers[edit] Australia: A 2009 study found that 2,100 Australians die from alcohol-related cancer each year.[9] Europe: A 2011 study found that one in 10 of all cancers in men and one in 33 in women were caused by past or current alcohol intake.[10][11] ## Alcohol as a carcinogen and cocarcinogen[edit] The International Agency for Research on Cancer (Centre International de Recherche sur le Cancer) of the World Health Organization has classified alcohol as a Group 1 carcinogen, similar to arsenic, benzene, and asbestos. Its evaluation states, "There is sufficient evidence for the carcinogenicity of alcoholic beverages in humans. …Alcoholic beverages are carcinogenic to humans (Group 1)."[12] ## Mechanisms[edit] ### Acetaldehyde[edit] Acetaldehyde is produced by the liver as it breaks down ethanol. The liver then normally eliminates 99% of the acetaldehyde. An average liver can process 7 grams of ethanol per hour. For example, it takes 12 hours to eliminate the ethanol in a bottle of wine, giving 12 hours or more of acetaldehyde exposure. A study of 818 heavy drinkers found that those who are exposed to more acetaldehyde than normal through a defect in the gene for alcohol dehydrogenase are at greater risk of developing cancers of the upper gastrointestinal tract and liver.[13] There are many associations between alcohol drinking and different types of cancer. Data from 2009 indicated 3.5 percent of cancer deaths in the U.S. were due to consumption of alcohol.[14] ### Reviews[edit] In a review, Pöschl and Seitz[15] list some possible mechanisms of alcohol as a carcinogen: * local effects of alcohol * metabolism to acetaldehyde (which may be mutagenic at physiologically meaningful levels[16]) * induction of CYP2E1 * nutritional deficiencies * interactions with retinoids * alcohol and methylation * alcohol and immune surveillance Purohita et al. propose an overlapping list: 1. production of acetaldehyde, which is a weak mutagen and carcinogen 2. induction of cytochrome P450 2E1 and associated oxidative stress and conversion of procarcinogens to carcinogens 3. depletion of S-adenosylmethionine and, consequently, induction of global DNA hypomethylation; 4. induction of increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase–mitogen-activated protein kinase signaling 5. accumulation of iron and associated oxidative stress 6. inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness (primarily in breast) 7. impairment of retinoic acid metabolism.[17] Boffetta and Hashibe list plausible mechanisms as including: * a genotoxic effect of acetaldehyde * increased oestrogen concentration * a role as solvent for tobacco carcinogens * production of reactive oxygen species and nitrogen species * changes in folate metabolism[18] Individuals who both smoke and drink are at a much higher risk of developing mouth, tracheal, and esophageal cancer. Research has shown their risk of developing these cancers is 35 times higher than in individuals who neither smoke nor drink. This evidence may suggest that there is a cocarcinogenic interaction between alcohol and tobacco-related carcinogens.[19][20] ### Local carcinogenic effect of ethanol[edit] The risk of cancer associated with alcohol consumption is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. This is explained by the fact that ethanol is a proven mutagen and in addition, metabolite of ethanol (acetaldehyde) produced in the liver is highly carcinogenic, thus explaining both local (mouth, throat, esophageal cancers) as well as distant (skin, liver, breast) cancers. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages. Few cells survive a one-hour exposure to 5–10% ethanol or a 15-second exposure to 30–40% ethanol in cell culture, where surviving cells might undergo genomic changes leading to carcinogenesis. But recent evidence suggests that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of DNA-damaging agents (e.g., acetaldehyde and tobacco carcinogens). Alcohol consumption probably increases the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Because the cytotoxic activity of ethanol is concentration-dependent, the risk of these cancers will not only increase with increasing amounts of ethanol, but also with increasing concentrations; an ounce of whisky is probably more carcinogenic when taken undiluted than when taken mixed with non-alcoholic beverages. The local cytotoxic effect of ethanol may also explain the known synergistic effect of alcohol and tobacco use on the risk of these cancers.[21] ### Epithelial-mesenchymal transition[edit] A study found that alcohol stimulates the epithelial-mesenchymal transition (EMT), in which ordinary cancer cells change into a more aggressive form and begin to spread throughout the body.[22][23] ### Effect of alcohol on the progress of cancer when established[edit] A study of the influence of alcohol intake on tumor growth of hepatocellular carcinoma (HCC) in patients with type C cirrhosis, found that alcohol influenced tumor volume doubling time (TVDT).[24] A study of chick embryos suggests that alcohol stimulates their tumor growth by fueling the production of a growth factor that stimulates blood vessel development in tumors.[25] A 2006 study in mice showed moderate drinking resulted in larger and stronger tumors via a process known as angiogenesis.[26][27] A study where high amounts of alcohol were given to mice suggests that it accelerates their cancer growth by speeding up the loss of body fat and depressing immune activity.[28] ## Genetic variation and cancer risk[edit] A study found that "the ADH1C1 allele and genotype ADH1C1/1 were significantly more frequent in patients with alcohol-related cancers…"[13] A European study has found two gene variants which offer "significant" protection against mouth and throat cancers.[29] Alcohol is a known porphyrinogenic chemical. Several European studies have linked the inherited hepatic porphyrias with a predisposition to hepatocellular carcinoma. Typical risk factors for HCC need not be present with the acute hepatic porphyrias, specifically acute intermittent porphyria, variegate porphyria and hereditary coproporphyria. Porphyria cutanea tarda is also associated with HCC, but with typical risk factors including evidence of hepatotropic viruses, hemochromatosis and alcoholic cirrhosis. Tyrosinemia Type I, an inherited disorder in tyrosine metabolism impacting the second enzyme in the heme metabolic pathway is associated with a high risk of developing HCC in younger populations, including children.[30] ## Risk factor for specific cancers[edit] ### Moderate consumption increases risk[edit] A study found that, "Increasing but moderate alcohol consumption in women was determined to be associated with an increased risk of cancers of the oral cavity and pharynx, esophagus, larynx, rectum, breast, and liver…".[31] #### Cancers of the mouth, esophagus, pharynx, and larynx[edit] Main articles: Oral cancer, Esophageal cancer, Head and neck cancer, and Laryngeal cancer Endoscopic image of patient with esophageal adenocarcinoma seen at gastro-esophageal junction. Alcohol consumption at any quantity is a risk factor for cancers of the mouth, esophagus, pharynx and larynx. The U.S. National Cancer Institute states "Drinking alcohol increases the risk of cancers of the mouth, esophagus, pharynx, larynx, and liver in men and women, … In general, risks increases above baseline with any alcohol intake (mild; <2 glass of wine per week) and increases significantly with moderate alcohol intake (one glass of wine per day) with highest risk in those with greater than 7 glasses of wine per week. (A drink is defined as 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of 80-proof liquor.) … Also, using alcohol with tobacco is riskier than using either one alone, because it further increases the chances of getting cancers of the mouth, throat, and esophagus."[32] The federal government’s Dietary Guidelines for Americans 2010 defines moderate alcohol drinking as up to one drink per day for women and up to two drinks per day for men. Heavy alcohol drinking is defined as having more than three drinks on any day or more than seven drinks per week for women and more than four drinks on any day or more than 14 drinks per week for men. The International Head and Neck Cancer Epidemiology (INHANCE) Consortium co-ordinated a meta-study on the issue.[33] A study looking at laryngeal cancer and beverage type concluded, "This study thus indicates that in the Italian population characterized by frequent wine consumption, wine is the beverage most strongly related to the risk of laryngeal cancer."[34] A review of the epidemiological literature published from 1966 to 2006 concluded that: * The risk of esophageal cancer nearly doubled in the first two years following alcohol cessation, a sharp increase that may be due to the fact that some people only stop drinking when they are already experiencing disease symptoms. However, risk then decreased rapidly and significantly after longer periods of abstention. * Risk of head and neck cancer only reduced significantly after 10 years of cessation. * After more than 20 years of alcohol cessation, the risks for both cancers were similar to those seen in people who never drank alcohol.[35][36] A study concluded that for every additional drink regularly consumed per day, the incidence of oral cavity and pharynx cancers increases by 1 per 1000. The incidence of cancers of the esophagus and larynx increase by 0.7 per 1000.[31] A 2008 study suggests that acetaldehyde (a breakdown product of alcohol) is implicated in oral cancer.[37][38] #### Breast cancer[edit] Mastectomy specimen containing a very large cancer of the breast (in this case, an invasive ductal carcinoma). Main article: Alcohol and breast cancer Alcohol is a risk factor for breast cancer in women.[39][40][41][42][43] A woman drinking an average of two units of alcohol per day has an 8% higher risk of developing breast cancer than a woman who drinks an average of one unit of alcohol per day.[44] A study concluded that for every additional drink regularly consumed per day, the incidence of breast cancer increases by 11 per 1000.[31] Approximately 6% (between 3.2% and 8.8%) of breast cancers reported in the UK each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week).[44] Moderate to heavy consumption of alcoholic beverages (at least three to four drinks per week) is associated with a 1.3-fold increased risk of the recurrence of breast cancer. Further, consumption of alcohol at any quantity is associated with significantly increased risk of relapse in breast cancer survivors.[45][46] #### Colorectal cancer[edit] Main article: Colorectal cancer Colectomy specimen containing an invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor). Drinking may be a cause of earlier onset of colorectal cancer.[47] The evidence that alcohol is a cause of bowel cancer is convincing in men and probable in women.[48] The National Institutes of Health,[49] the National Cancer Institute,[50] Cancer Research,[51] the American Cancer Society,[52] the Mayo Clinic,[53] and the Colorectal Cancer Coalition,[54] American Society of Clinical Oncology[55] and the Memorial Sloan-Kettering Cancer Center[56] list alcohol as a risk factor. A WCRF panel report finds the evidence "convincing" that alcoholic drinks increase the risk of colorectal cancer in men at consumption levels above 30 grams of absolute alcohol daily.[57] The National Cancer Institute states, "Heavy alcohol use may also increase the risk of colorectal cancer"[58] A 2011 meta-analysis found that alcohol consumption was associated with an increased risk of colorectal cancer.[59] #### Liver cancer[edit] Main article: Liver cancer Hepatocellular carcinoma in an individual that was hepatitis C positive. Autopsy specimen. Alcohol is a risk factor for liver cancer, through cirrhosis.[60][61][62] "Cirrhosis results from scar formation within the liver, most commonly due to chronic alcohol use."[63] "Approximately 5 percent of people with cirrhosis develop liver cancer. Cirrhosis is a disease that develops when liver cells are replaced with scar tissue after damage from alcohol abuse, …"[64] The NIAAA reports that "Prolonged, heavy drinking has been associated in many cases with primary liver cancer." However, it is liver cirrhosis, whether caused by alcohol or another factor, that is thought to induce the cancer."[65][66] "The chances of getting liver cancer increase markedly with five or more drinks per day" (NCI). A study concluded that for every additional drink regularly consumed per day, the incidence of liver cancer increases by 0.7 per 1000.[31] In the United States, liver cancer is relatively uncommon, afflicting approximately 2 people per 100,000, but excessive alcohol consumption is linked to as many as 36% of these cases by some investigators[19][67] "Overall, 61% of HCC were attributable to HCV [hepatitis C virus], 13% to HBV [hepatitis B virus], and 18% to heavy alcohol drinking."[68] A study in the province of Brescia, northern Italy concluded, "On the basis of population attributable risks (AR), heavy alcohol intake seems to be the single most relevant cause of HCC in this area (AR: 45%), followed by HCV (AR: 36%), and HBV (AR: 22%) infection."[69] #### Lung cancer[edit] Main article: Lung cancer Alcohol intake of more than 2 drinks per day is associated with a small increased risk of lung cancer.[70] Commenting on a study by Freudenheim et al., R. Curtis Ellison MD writes, "This study, like others, suggests a weak, positive association between consuming larger amounts of alcohol (>2 drinks a day) and lung cancer risk."[71] #### Skin cancer[edit] Main article: Melanoma Any alcohol intake is associated with the development of malignant melanoma.[72] #### Stomach cancer[edit] Main article: Stomach cancer "Statistically significant increases in risk also existed for cancers of the stomach, colon, rectum, liver, female breast, and ovaries."[73] "While alcohol has been extensively studied as a cause of stomach cancer there is no conclusive evidence that it increases risk. However, results from at least three studies suggest that heavy alcohol consumption may increase the risk of stomach cancer in heavy smokers."[74][75][76][77] A Taiwanese study concluded, "…cigarette smoking may play the most harmful role in the initial development of gastric cancer, and that drinking alcohol may promote the process."[74] A Norwegian study found that, "No statistically significant associations between various degrees of exposure to alcohol and risk of gastric cancer was revealed, but combined high use of cigarettes (>20/day) and alcohol (>5 occasions/14 days) increased the risk of noncardia gastric cancer nearly 5-fold (HR = 4.90 [95% CI = 1.90–12.62]), compared to nonusers."[76] ### Consumption of 50g or more per day increases risk[edit] #### Endometrial cancer[edit] Main article: Endometrial cancer An endometrial adenocarcinoma invading the uterine muscle. Alcohol has been identified as a risk factor for endometrial cancer.[78] Data however, on the association of alcohol intake and endometrial cancer is conflicting. Where data exists for an association low to moderate intake of alcohol, (less than two drinks per day) is not associated with an increased risk but an association has been suggested for higher alcohol intake.[79][80] "Our results suggest that only alcohol consumption equivalent to 2 or more drinks per day increases risk of endometrial cancer in postmenopausal women."[81] "In conclusion, our results suggest that low alcohol consumption (up to one drink per day) is unlikely to substantially influence risk of endometrial cancer."[82] #### Gallbladder cancer[edit] Main article: Gallbladder cancer Alcohol has been suggested as a risk factor for gallbladder cancer.[83] Evidence suggests that a high intake of alcohol is associated with gallbladder cancer.[84][85] Men may be at a higher risk of alcohol-related gallbladder cancer than women.[86] #### Ovarian cancer[edit] Main article: Ovarian cancer "Thus, the results of this study suggest that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk.".[87] "Associations were also found between alcohol consumption and cancers of the ovary and prostate, but only for 50 g and 100 g a day."[88] "Statistically significant increases in risk also existed for cancers of the stomach, colon, rectum, liver, female breast, and ovaries."[73] "Thus, this pooled analysis does not provide support for an association between moderate alcohol intake and ovarian cancer risk."[89] #### Prostate cancer[edit] Main article: Prostate cancer "Data from the Health Professionals Follow-Up Study showed only a weak association between overall alcohol intake and prostate cancer risk, and no association at all between red wine intake and prostate cancer risk."[90] A meta-analysis published in 2001 found a small but significant increased risk for men drinking more than 50 g/day of alcohol, with a slightly higher risk for men consuming more than 100 g/day.[91] Since that analysis, cohort studies in America have found increased risks for men drinking moderate amounts of spirits, and for 'binge drinkers,[92] but moderate consumption of beer or wine has not been linked to an increased risk.[93][94][95] Alcohol consumption of 50 g and 100 g per day is also associated with cancers of the ovary and prostate.[88] However, one study concludes, that moderate alcohol consumption increases the risk of prostate cancer. Liquor, but not wine or beer, consumption was positively associated with prostate cancer."[93] The Fred Hutchinson Cancer Research Center found that men who consumed four or more glasses of red wine per week had a 50 percent reduction in the risk of developing prostate cancer. They "found no significant effects – positive nor negative – associated with the consumption of beer or hard liquor and no consistent risk reduction with white wine, which suggests that there must be a beneficial compound in red wine that other types of alcohol lack. That compound … may be an antioxidant called resveratrol, which is abundant in the skins of red grapes.".[94][96] A meta analysis of studies published in 2009 found that consumption of only 2 standard drinks per day increased the cancer risk by 20%.[97][98] #### Small intestine cancer[edit] Endoscopic image of adenocarcinoma of duodenum seen in the post-bulbar duodenum. Main article: Small intestine cancer A study of small intestine cancer patients reported that alcohol consumption was associated with adenocarcinomas and malignant carcinoid tumors.[99] "In men and women combined, a significant 3-fold increased risk in heavy drinkers (80+g ethanol/day) relative to more moderate drinkers and non-drinkers was observed."[100] "Alcohol and tobacco consumption did not increase the risk of adenocarcinoma of the small intestine. … While the present data are inconsistent with a major effect of tobacco or alcohol, a moderate association between these factors and small bowel cancer may have been obscured by the play of chance."[101] ### Evidence is mixed[edit] #### Leukemia[edit] Main article: Leukemia Intake of alcohol during pregnancy has been associated with childhood leukemia.[102] A review published by the National Cancer Institute placed maternal alcohol consumption during pregnancy in the category of "suggestive" but concluded that the risk was not important.[103] Acute Lymphocytic Leukemia (ALL) For ALL in children, maternal alcohol consumption during pregnancy is "unlikely to be an important risk factor for ALL"[103] Acute myeloid leukemia (AML) Main article: Acute myeloid leukemia A study concluded, "In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose-response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive."[104] Childhood AML "Three studies have reported an increased risk (approximately 1.5-2 fold) in mothers who drank alcoholic beverages during pregnancy. These associations have been particularly apparent in children diagnosed younger than three years of age.".[103] "Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML."[105] Acute non-lymphocytic leukemia (ANLL) A study found that intrauterine exposure to alcohol doubled the risk for childhood ANLL.[106] Chronic Lymphocytic Leukemia (CLL) Main article: Chronic Lymphocytic Leukemia A study concluded, "In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose-response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive."[104] Chronic myeloid leukemia (CML) Main article: Chronic myelogenous leukemia A population-based case-control study in Italy found a non-significant positive association between drinking and CML.[104] Hairy cell leukemia Main article: Hairy cell leukemia A study concluded, "There was no association found for cigarette smoking, alcohol or coffee consumption and hairy cell leukemia."[107] #### Multiple myeloma (MM)[edit] Main article: Multiple myeloma Alcohol has been suggested as a possible cause of multiple myeloma,[108] although a study found no association between MM in a comparison study between drinkers and non-drinkers.[109] #### Pancreatic cancer[edit] Whilst the association between alcohol abuse and pancreatitis is well established the association between alcohol consumption and pancreatic cancer is less clear. Overall the evidence suggests a slightly increased risk of pancreatic cancer with chronic heavy alcohol consumption but the evidence remains conflicting with a number of studies finding no association.,[110][111] but no increased risk for people consuming up to 30g of alcohol a day[112] Overall, the association is consistently weak and the majority of studies have found no association.[19][112][113] Although drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, chronic pancreatitis associated with alcohol consumption is less frequently a precursor for pancreatic cancer than other types of chronic pancreatitis.[114] Some studies suggest a relationship,[115] the risk increasing with increasing amount of alcohol intake.[116][117] The risk is greatest in heavy drinkers,[110][111][118] mostly on the order of four or more drinks per day.[119] There appears to be no increased risk for people consuming up to 30g of alcohol a day,[112][120][121] which is approximately 2 alcoholic beverages/day,[121] so most people who take alcohol do so at a level that "is probably not a risk factor for pancreatic cancer".[111] A pooled analysis concluded, "Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day".[121] Several studies caution that their findings could be due to confounding factors.[110][122] Even if a link exists, it "could be due to the contents of some alcoholic beverages"[123] other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.[124] "About 7 out of 10 cases of chronic pancreatitis are due to long term heavy drinking. Chronic pancreatitis is a known risk factor for cancer of the pancreas. But chronic pancreatitis that is due to alcohol doesn't increase risk as much as other types of chronic pancreatitis. So if there is a link with alcohol and pancreatic cancer risk, it is only very slight."[114] "Our findings indicate that alcohol drinking at the levels typically consumed by the general population of the United States is probably not a risk factor for pancreatic cancer. Our data suggest, however, that heavy alcohol drinking may be related to pancreatic cancer risk."[111] "Relative risks of pancreatic cancer increased with the amount of alcohol consumed (Ptrend = 0.11) after adjustment for age, smoking status, and pack-years of smoking."[125] "Alcoholics had only a modest 40% excess risk of pancreatic cancer … The excess risk for pancreatic cancer among alcoholics is small and could conceivably be attributed to confounding by smoking."[110] "It was shown that the relative risk of cancer of the pancreas increases with fat and alcohol intakes, … Alcohol may be not directly involved in the aetiology of cancer of the pancreas: its effect could be due to the contents of some alcoholic beverages."[126] "When compared with data from non-drinkers, the cumulative lifetime consumption of all types of alcohol in grams of ethanol… beer, spirits, red wine and fortified wine was not related to risk. The consumption of white wine was inversely associated with risk…. The uniformly reduced risk estimates for the lifetime number of drinks of white wine were based on small numbers…."[127] "For the most part, consumption of total alcohol, wine, liquor and beer was not associated with pancreatic cancer."[128] "Data from these two large cohorts do not support any overall association between coffee intake or alcohol intake and risk of pancreatic cancer."[112] "Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day."[129] ### Not suspected to increase risk[edit] This section lists cancers where alcohol is not listed as a risk factor and where papers have been published. #### Childhood astrocytoma[edit] Main article: Astrocytoma A study concluded that foetal exposure to alcohol is not associated with childhood astrocytoma.[130] #### Bile duct cancer[edit] Main article: Bile duct cancer A review of the literature found that there is no association between alcohol use and bile duct cancer.[131] #### Bladder cancer[edit] Main article: Bladder cancer "Epidemiological data on alcohol drinking and bladder cancer are suggestive of no association, although findings were not always consistent. For both habits, an explanation of the moderate increase in risk observed in some investigations might be attributed to residual confounding by smoking, or to an association between alcohol, coffee, and yet unidentified risk factors for bladder cancer."[132] #### Cervical cancer[edit] Main article: Cervical cancer A study concluded "that alcoholic women are at high risk for in situ and invasive cervical cancer" but attributed this to indirect, lifestyle-related reasons.[133] #### Ductal carcinoma in situ (DCIS) breast cancer[edit] "DCIS patients and control subjects did not differ with respect to oral contraceptive use, hormone replacement therapy, alcohol consumption or smoking history, or breast self-examination. Associations for LCIS were similar."[134] #### Ependymoma[edit] Main article: Ependymoma A review of the basic literature[135] found that consumption of beer was associated with increased risk in one study[136] but not in another[137] #### Intraocular and uveal melanomas[edit] See also: Uveal melanoma A study found no association between alcohol and uveal melanoma.[138] #### Nasopharynageal cancer / Nasopharyngeal carcinoma (NPC)[edit] Main article: Nasopharyngeal carcinoma A systematic review found evidence that light drinking may decrease the risk of nasopharyngeal carcinoma whereas high intake of alcohol may increase the risk.[139] #### Neuroblastoma[edit] Main article: Neuroblastoma A few studies have indicated an increased risk of neuroblastoma with use of alcohol during pregnancy.[140] #### Salivary gland cancer (SGC)[edit] Main article: Salivary gland cancer Alcohol use is associated with an increased risk of salivary gland cancer.[141] #### Testicular cancer[edit] Main article: Testicular cancer A review concluded that "There is no firm evidence of a causal relation between behavior risks [tobacco, alcohol and diet] and testicular cancer."[142] #### Thyroid cancer[edit] Main article: Thyroid cancer A 2009 review found that alcohol intake does not affect the risk of developing thyroid cancer.[143] However, a 2009 study of 490,000 men and women concluded that alcohol may reduce the risk of thyroid cancer.[144] A 2009 study of 1,280,296 women in the United Kingdom concluded, "The decreased risk for thyroid cancer that we find to be associated with alcohol intake is consistent with results from some studies, although a meta-analysis of 10 case–control studies and two other cohort studies reported no statistically significant associations."[145] #### Vaginal cancer[edit] Main article: Vaginal cancer A Danish study found that "Abstinence from alcohol consumption was associated with low risk for both VV-SCCvagina and VV-SCCvulva in our study."[146] A study concluded that alcoholic women are at high risk for cancer of the vagina.[133] In both studies, indirect, lifestyle-related reasons were cited. #### Vulvar cancer[edit] Main article: Vulvar cancer One study reported "No consistent association emerged between milk, meat, liver, alcohol and coffee consumption and risk of vulvar cancer."[147] A Danish study found the reverse, that alcohol consumption is significantly associated with VV-SCCvagina and VV-SCCvulva cancer.[146] A Swedish study concluded that alcoholic women are at no higher risk for cancer of the vulva.[133] ### Might reduce risk[edit] #### Hodgkin's lymphoma (HL)[edit] Main article: Hodgkin's lymphoma A study concluded, "The results of this large-scale European study … suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries."[148] A population based case-control study in Germany found that alcohol reduced the risk of HL for both men and women but more so for men, whose risk was lowered by 53%.[149] A population-based case-control study in Italy reported a protective effect of alcohol consumption on risk of HL among non-smokers.[109] Analysis of data from a series of case-control studies in Northern Italy revealed a modest positive effect of alcohol on lowering risk of HL among both smokers and non-smokers.[150] #### Kidney cancer (Renal cell carcinoma) (RCC)[edit] Main article: Renal cell carcinoma "Moderate alcohol consumption was associated with a lower risk of renal cell cancer among both women and men in this pooled analysis"[151] "This pooled analysis found an inverse association between alcohol drinking and RCC. Risks continued to decrease even above eight drinks per day (i.e. >100 g/day) of alcohol intake, with no apparent levelling in risk."[152] A study concluded, "Results from our prospective cohort study of middle-aged and elderly women indicate that moderate alcohol consumption may be associated with decreased risk of RCC."[153] Researchers who conducted a study in Iowa reported that "In this population-based case-control investigation, we report further evidence that alcohol consumption decreases the risk of RCC among women but not among men. Our ability to show that the association remains after multivariate adjustment for several new confounding factors (i.e., diet, physical activity, and family history) strengthens support for a true association.[154] Another study found no relationship between alcohol consumption and risk of kidney cancer among either men or women.[155] A Finnish study concluded, "These data suggest that alcohol consumption is associated with decreased risk of RCC in male smokers. Because most of the risk reductions were seen at the highest quartile of alcohol intake and alcohol is a risk factor for a number of cancers particularly among smokers, these data should be interpreted with caution."[156] "Our data suggest an inverse association between alcohol intake and risk of renal cell cancer…"[157] Compared with nondrinkers, men who drank one or more drinks per day had a 31% lower risk of kidney cancer among 161,126 Hawaii-Los Angeles Multiethnic Cohort participants.[158] #### Non-Hodgkin lymphoma (NHL)[edit] Main article: Non-Hodgkin lymphoma A study concluded, "People who drink alcoholic beverages might have a lower risk of NHL than those who do not, and this risk might vary by NHL subtype."[159] "Compared with nondrinkers, alcohol consumers had a lower risk for non-Hodgkin's lymphoma overall … and for its main subtypes."[160] A study concluded, "Nonusers of alcohol had an elevated NHL risk compared with users…"[161] Some studies have found a protective effect on NHL of drinking some forms of alcoholic beverage or in some demographic groups. A study of men in the US found that consumption of wine, but not beer or spirits, was associated with a reduced NHL risk[162] and a large European study found a protective effect of alcohol among men and in non-Mediterranean countries.."[163] A study of older women in Iowa found alcohol to reduce the risk of NHL and the amount of alcohol consumed, rather than the type of alcoholic beverages, appeared to be the main determinant in reducing risk."[164] A possible mechanism has been suggested.[165] Some studies have not found a protective effect from drinking. British research found no association between frequency of drinking and NHL[166] and research in Sweden found that total beer, wine, or liquor intake was not associated with any major subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia.."[167] One study of NHL patients concluded, "Our findings strongly encourage physicians to advise NHL patients to stop smoking and diminish alcohol consumption to obtain improvements in the course of NHL."[168] ## Recommended maximum alcohol intake[edit] Main article: Recommended maximum intake of alcoholic beverages As outlined above, there is no recommended alcohol intake with respect to cancer risk alone as it varies with each individual cancer. See Recommended maximum intake of alcoholic beverages for a list of governments' guidances on alcohol intake which, for a healthy man, range from 140–280g per week. One meta-analysis suggests that risks of cancers may start below the recommended levels. "Risk increased significantly for drinkers, compared with non-drinkers, beginning at an intake of 25 g (< 2 standard drinks) per day for the following: cancers of the oral cavity and pharynx (relative risk, RR, 1.9), esophagus (RR 1.4), larynx (RR 1.4), breast (RR 1.3), liver (RR 1.2), colon (RR 1.1), and rectum (RR 1.1)"[169][170] World Cancer Research Fund recommends that people aim to limit consumption to less than two drinks a day for a man and less than one drink a day for a woman. It defines a "drink" as containing about 10–15 grams of ethanol.[171] ## Alcohol industry manipulation of the science on alcohol and cancer[edit] A study published in 2017 has found that front organisations set up by the world's leading alcohol companies are actively misleading the public about the risk of cancer due to alcohol consumption. 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"A meta-analysis of alcohol consumption and the risk of 15 diseases". Preventive Medicine. 38 (5): 613–9. doi:10.1016/j.ypmed.2003.11.027. PMID 15066364. 171. ^ World Cancer Research Fund, Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, http://www.dietandcancerreport.org/ ## External links[edit] International: International Agency for Research on Cancer home page * International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 44 Alcohol Drinking: Summary of Data Reported and Evaluation * IARC Alcoholic beverages (Group 1) Ethanol in alcoholic beverages (Group 1) VOL.: 96 5. 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Sulfonic acids: Acamprosate Religion and alcohol * Christian views on alcohol * alcohol in the Bible * Islam and alcohol History * Bratt System Related * Index of alcohol-related articles * Austrian syndrome * Ban on caffeinated alcoholic beverages * Brief intervention * Gateway drug effect * Last call * Mood disorder * Non-alcoholic fatty liver disease * Self-medication * Spins * Sober companion * Sober living houses * Sobering center * Town drunk * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Alcohol and cancer	None	3,194	wikipedia	https://en.wikipedia.org/wiki/Alcohol_and_cancer	2021-01-18T18:38:27	{"wikidata": ["Q4713253"]}
Autosomal recessive spastic paraplegia type 77 is a rare, pure or complex hereditary spastic paraplegia characterized by an infancy to childhood onset of slowly progressive lower limb spasticity, delayed motor milestones, gait disturbances, hyperreflexia and various muscle abnormalities, including weakness, hypotonia, intention tremor and amyotrophy. Ocular abnormalities (e.g. strabismus, ptosis) and other neurological abnormalities, such as dysarthria, seizures and extensor plantar responses, may also be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal recessive spastic paraplegia type 77	c4310750	3,195	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=466722	2021-01-23T17:00:59	{"omim": ["617046"], "icd-10": ["G11.4"], "synonyms": ["SPG77"]}
Neuromyelitis optica is an autoimmune disorder that affects the nerves of the eyes and the central nervous system, which includes the brain and spinal cord. Autoimmune disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. In neuromyelitis optica, the autoimmune attack causes inflammation of the nerves, and the resulting damage leads to the signs and symptoms of the condition. Neuromyelitis optica is characterized by optic neuritis, which is inflammation of the nerve that carries information from the eye to the brain (optic nerve). Optic neuritis causes eye pain and vision loss, which can occur in one or both eyes. Neuromyelitis optica is also characterized by transverse myelitis, which is inflammation of the spinal cord. The inflammation associated with transverse myelitis damages the spinal cord, causing a lesion that often extends the length of three or more bones of the spine (vertebrae). In addition, myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses, can be damaged. Transverse myelitis causes weakness, numbness, and paralysis of the arms and legs. Other effects of spinal cord damage can include disturbances in sensations, loss of bladder and bowel control, uncontrollable hiccupping, and nausea. In addition, muscle weakness may make breathing difficult and can cause life-threatening respiratory failure in people with neuromyelitis optica. There are two forms of neuromyelitis optica, the relapsing form and the monophasic form. The relapsing form is most common. This form is characterized by recurrent episodes of optic neuritis and transverse myelitis. These episodes can be months or years apart, and there is usually partial recovery between episodes. However, most affected individuals eventually develop permanent muscle weakness and vision impairment that persist even between episodes. For unknown reasons, approximately nine times more women than men have the relapsing form. The monophasic form, which is less common, causes a single episode of neuromyelitis optica that can last several months. People with this form of the condition can also have lasting muscle weakness or paralysis and vision loss. This form affects men and women equally. The onset of either form of neuromyelitis optica can occur anytime from childhood to adulthood, although the condition most frequently begins in a person's forties. Approximately one-quarter of individuals with neuromyelitis optica have signs or symptoms of another autoimmune disorder such as myasthenia gravis, systemic lupus erythematosus, or Sjögren syndrome. Some scientists believe that a condition described in Japanese patients as optic-spinal multiple sclerosis (or opticospinal multiple sclerosis) that affects the nerves of the eyes and central nervous system is the same as neuromyelitis optica. ## Frequency Neuromyelitis optica affects approximately 1 to 2 per 100,000 people worldwide. Women are affected by this condition more frequently than men. ## Causes No genes associated with neuromyelitis optica have been identified. However, a small percentage of people with this condition have a family member who is also affected, which indicates that there may be one or more genetic changes that increase susceptibility. It is thought that the inheritance of this condition is complex and that many environmental and genetic factors are involved in the development of the condition. The aquaporin-4 protein (AQP4), a normal protein in the body, plays a role in neuromyelitis optica. The aquaporin-4 protein is found in several body systems but is most abundant in tissues of the central nervous system. Approximately 70 percent of people with this disorder produce an immune protein called an antibody that attaches (binds) to the aquaporin-4 protein. Antibodies normally bind to specific foreign particles and germs, marking them for destruction, but the antibody in people with neuromyelitis optica attacks a normal human protein; this type of antibody is called an autoantibody. The autoantibody in this condition is called NMO-IgG or anti-AQP4. The binding of the NMO-IgG autoantibody to the aquaporin-4 protein turns on (activates) the complement system, which is a group of immune system proteins that work together to destroy pathogens, trigger inflammation, and remove debris from cells and tissues. Complement activation leads to the inflammation of the optic nerve and spinal cord that is characteristic of neuromyelitis optica, resulting in the signs and symptoms of the condition. The levels of the NMO-IgG autoantibody are high during episodes of neuromyelitis optica, and the levels decrease between episodes with treatment of the disorder. However, it is unclear what triggers episodes to begin or end. ## Inheritance Pattern Neuromyelitis optica is usually not inherited. Rarely, this condition is passed through generations in families, but the inheritance pattern is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Neuromyelitis optica	c0027873	3,196	medlineplus	https://medlineplus.gov/genetics/condition/neuromyelitis-optica/	2021-01-27T08:25:11	{"gard": ["6267"], "mesh": ["D009471"], "omim": ["600308"], "synonyms": []}
A number sign (#) is used with this entry because Ehlers-Danlos syndrome classic type 1 (EDSCL1) is caused by heterozygous mutation in the collagen alpha-1(V) gene (COL5A1; 120215) on chromosome 9q34. Rarely, specific mutations in the COL1A1 gene (e.g., R134C, 120150.0059) cause classic EDS. Description The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (Beighton, 1993). ### Genetic Heterogeneity of Classic Ehlers-Danlos Syndrome See EDSCL2 (130010), caused by mutation in the COL5A2 gene (120190) on chromosome 2q32. ### Classification of Ehlers-Danlos Syndrome The current OMIM classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by Malfait et al. (2017), which recognizes 13 EDS subtypes: classic, classic-like (606408, 618000), cardiac-valvular (225320), vascular (130050), hypermobile (130020), arthrochalasia (130060, 617821), dermatosparaxis (225410), kyphoscoliotic (225400, 614557), spondylodysplastic (130070, 615349), musculocontractural (601776, 615539), myopathic (616471), periodontal (130080, 617174), and brittle cornea syndrome (229200, 614170). This classification is a revision of the 'Villefranche classification' reported by Beighton et al. (1998), which was widely used in the literature and in OMIM. For a description of the Villefranche classification, see HISTORY. In an early classification of EDS, the designations EDS I and EDS II were used for severe and mild forms of classic EDS, respectively. EDS I was characterized by marked skin involvement and generalized, gross joint laxity, with musculoskeletal deformity and diverse orthopedic complications. Prematurity occurred in approximately 50% of cases. Internal complications such as aortic and bowel rupture were occasionally present. EDS II had all the stigmata of EDS I, but to a minor degree (summary by Steinmann et al., 2002). Both were considered to be forms of classic EDS. Clinical Features Graf (1965) reported a brother and sister with Ehlers-Danlos syndrome who developed 'spontaneous' carotid-cavernous fistula. Internal complications included rupture of large vessels, hiatus hernia, spontaneous rupture of the bowel, and diverticula of the bowel. Retinal detachment has been observed (Pemberton et al., 1966). Schofield et al. (1970) reported brother and sister in their 60s who suffered spontaneous rupture of the colon. They had joint laxity, and both bruised easily and sustained many lacerations from minor trauma. The father of the 2 sibs and the son of the brother may have been affected. Barabas (1966) concluded that most persons with EDS are born prematurely due to premature rupture of fetal membranes. Patients with urinary tract infection and other problems related to bladder diverticulum were reported by Eadie and Wilkins (1967) and by Zalis and Roberts (1967). Cuckow et al. (1994) described a 4-year-old boy with huge bladder diverticula complicating type I EDS. Friedman and Harrod (1982) described a severe form of EDS. The mother died of dissecting aneurysm of the aorta. Autopsy also showed myxomatous changes in the mitral and tricuspid valves with redundancy of cusps and chordae. Both mother and son had large hernias, positional foot deformities, abnormal thoracic shape, asthma, and severe eczematoid dermatitis. In an 18-year-old girl with EDS, Mishra et al. (1992) demonstrated aneurysm of the membranous ventricular septum as well as mitral valve prolapse. The patient had had lumbosacral fusion for recurrent spondylolisthesis. In a large Azerbaijanian village (population about 6,000), Kozlova et al. (1984) observed a kindred with 92 persons affected with EDS I. One patient, whose affected parents were cousins, was judged to be homozygous. The minimal diagnostic features for EDS I used in the study of Wenstrup et al. (1996) were autosomal dominant inheritance, generalized joint laxity, hyperextensible skin with doughy and velvety texture, and the presence of widened atrophic scars. The criterion used to distinguish EDS II from EDS I was the absence of widened atrophic scars in EDS II. De Felice et al. (2001) studied 4 patients with EDS II and 8 patients with EDS III (130020), the hypermobile type. They concluded that absence of the inferior labial frenulum and the lingual frenulum are characteristics of EDS. Absence of the inferior labial frenulum showed 100% sensitivity and 99.4% specificity; absence of the lingual frenulum showed 71.4% sensitivity and 100% specificity. Wenstrup et al. (2002) performed a prospective cohort study on 71 consecutive EDS patients. Twenty of 71, or 28%, had aortic root dilatation defined as greater than 2 standard deviations above population-based norms. Fourteen of 42 individuals with the classic form of EDS (types I and II) and 6 of 29 individuals with the hypermobility form (EDS III) had aortic root dilatation, with no gender differences. Wenstrup et al. (2002) concluded that aortic root dilatation is a common finding in EDS. However, rates of progression and complication were unknown. Nordschow and Marsolais (1969) could demonstrate no abnormality of shrinkage temperature thermograms of tendon collagen from a hypermobile joint of an EDS patient. They supported the suggestion of Wechsler and Fisher (1964) that the defect concerns the amount of collagen produced. Varadi and Hall (1965) concluded that elastin is normal. Borck et al. (2010) reported a 42-year-old German man with EDS and spontaneous rupture of his left common iliac artery, who was negative for mutation in COL3A1 but was found instead to carry a de novo heterozygous nonsense mutation (120215.0012) in the COL5A1 gene. The patient had a history of recurrent inguinal hernias and easy bruising since childhood; hypertension had been diagnosed 2 years earlier. Physical examination revealed pigmented scars over bony prominences, molluscoid pseudotumors at elbows and knees, skin hyperextensibility, as well as varicose veins, all consistent with EDS. He had no articular hypermobility or history of joint dislocation, no ophthalmologic involvement, and no kyphoscoliosis or periodontitis. His parents were unaffected and did not carry the mutation; however, his daughter and son, who had smooth skin with a history of easy bruising, which had raised the suspicion of child abuse by schools and social authorities, were also heterozygous for the mutation. Borck et al. (2010) stated that this was the first report of a patient with COL5A1 mutation-positive EDS and rupture of a large artery, suggesting that arterial rupture might be a rare complication of classic EDS. Skin like that in EDS has been observed with a fibrinolytic defect (134900). Other Features Deodhar and Woolf (1994) suggested that patients with Ehlers-Danlos syndrome are at unusual risk for postmenopausal osteoporosis. Voermans et al. (2009) performed a cross-sectional study on the presence of neuromuscular symptoms in 40 patients with various forms of EDS. Ten patients each were analyzed with classic EDS, vascular EDS (130050), hypermobility EDS (130020), and TNX-deficient EDS (606408). Overall, those with classic EDS and TNX-deficient EDS reported the most neuromuscular involvement, with muscle weakness, hypotonia, myalgia, easy fatigability, and intermittent paresthesias, although patients in all groups reported these features. Physical examination showed mild to moderate muscle weakness (85%) and reduction of vibration sense (60%) across all groups. Nerve conduction studies demonstrated axonal polyneuropathy in 5 (13%) of 39 patients. Needle electromyography showed myopathic EMG features in 9 (26%) and a mixed neurogenic-myopathic pattern in 21 (60%) of 35 patients. Muscle ultrasound showed increased echo intensity in 19 (48%) and atrophy in 20 (50%) of 40 patients. Mild myopathic features were seen on muscle biopsy of 5 (28%) of 18 patients. Patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected. Voermans et al. (2009) postulated that abnormalities in muscle or nerve extracellular matrix may underlie these findings. Castori et al. (2010) observed that patients with EDS reported high levels of chronic pain. Inheritance Classic EDS is an autosomal dominant disorder (Wenstrup et al., 1996; De Paepe et al., 1997). Cytogenetics Scarbrough et al. (1984) described what they considered to be EDS II in a 14-year-old male with an unbalanced t(6;13). The karyotype was designated as 45,XY,-6,-13,+der(6),t(6;13)(q27;q11). The patient was monosomic for 13pter-q11 and for a small part of 6q27 (the most distal segment of 6q). Joint hypermobility, velvety skin, several well-healed, parchment-like scars over both shins, and mild propensity for bruising were described. The patient had serious neuropsychiatric problems. Mapping Using an intragenic simple sequence repeat polymorphism of the COL5A1 gene (120215) as a linkage marker, Loughlin et al. (1995) showed linkage to EDS II; maximum lod = 8.3 at theta = 0.00 in a single large pedigree. The COL5A1 gene is located on 9q34.2-q34.3. Greenspan et al. (1995) used 3-prime untranslated region RFLPs to exclude the COL5A1 gene as a candidate in families with Ehlers-Danlos syndrome type II. The reason for inconsistency with the findings of Loughlin et al. (1995) may be the genetic heterogeneity of EDS II. In a 3-generation family with features of Ehlers-Danlos syndrome types I and II, Burrows et al. (1996) observed tight linkage to the COL5A1 gene (120215) on chromosome 9q34; a lod score of 4.07 at zero recombinations located on 9q34.2-q34.3. Greenspan et al. (1995) used 3-prime untranslated region RFLPs to exclude the COL5A1 gene as a candidate in families with Ehlers-Danlos syndrome type II. The reason for inconsistency with the findings of Loughlin et al. (1995) may be the genetic heterogeneity of EDS II. In a 3-generation family with features of Ehlers-Danlos syndrome types I and II, Burrows et al. (1996) observed tight linkage to the COL5A1 gene (120215) on chromosome 9q34; a lod score of 4.07 at zero recombination was calculated. The variation in expression in this family suggested that EDS types I and II are allelic, and the linkage data supported the hypothesis that a mutation in COL5A1 can cause both phenotypes. was calculated. The variation in expression in this family suggested that EDS types I and II are allelic, and the linkage data supported the hypothesis that a mutation in COL5A1 can cause both phenotypes. Wenstrup et al. (1996) reported 2 families in which EDS I cosegregated with the gene encoding the pro-alpha-1(V) collagen chains (COL5A1). In 2 other families with EDS I, linkage was excluded from both the COL5A1 and the COL5A2 loci. In a large Azerbaijanian family with typical clinical manifestations of EDS I, Sokolov et al. (1991) excluded linkage with 3 collagen genes: COL1A1 (120150), COL1A2 (120160), and COL3A1 (120180). At least in this family, the mutation appeared not to lie in any of these genes. Molecular Genetics Wenstrup et al. (1996) demonstrated that affected individuals in one of the EDS I COL5A1-linked families were heterozygous for a 4-bp deletion in intron 65 which led to a 234-bp deletion of exon 65 in the processed mRNA for pro-alpha-1(V) chains (120215.0002). Wenstrup et al. (1996) noted that the fact that EDS II has been reported to be linked to COL5A1 is indicative that EDS types I and II constitute a clinical and molecular spectrum. They concluded that EDS I and EDS II are genetically heterogeneous. They were unable to distinguish clinically between the COL5A1-linked and unlinked families. In 2 unrelated patients with classic EDS I, Nuytinck et al. (2000) identified a heterozygous missense mutation in the COL1A1 gene (120150.0059). Malfait et al. (2005) studied fibroblast cultures from 48 patients with classic EDS for the presence of type V collagen defects. Forty-two (88%) were heterozygous for an expressed polymorphic variant of COL5A1, and cDNA from 18 (43%) expressed only 1 COL5A1 allele. In total, 17 mutations leading to a premature stop codon and 5 structural mutations were identified in the COL5A1 and COL5A2 genes. In 3 patients with a positive COL5A1 null-allele test, no mutation was found. Overall, in 25 of the 48 patients (52%), an abnormality in type V collagen was confirmed. Variability in severity of the phenotype was observed, but no significant genotype-phenotype correlations were found. The relatively low mutation detection rate suggested that other genes are involved in classic EDS. Malfait et al. (2005) excluded COL1A1, COL1A2 (120160), and DCN (125255) as major candidate genes for classic EDS, since they could find no causal mutation in these genes in a number of patients who tested negative for COL5A1 and COL5A2. Pallotta et al. (2004) described a 2-generation family with EDS in which 2 children exhibited features suggestive of EDS I and their mother exhibited features more suggestive of EDS IV (130050), i.e., she had thin nose and thin lips, thin translucent skin with prominent vasculature, and acroosteolysis. No mutation was identified in the COL3A1 gene (120180), but a deletion mutation was detected in the COL5A1 gene (120215.0011) in all 3 affected family members. The molecular diagnosis allowed the investigators to categorize the family into the classic form of EDS, which is associated with a good long-term prognosis. Symoens et al. (2012) analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations, and 7 were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring, and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, indicating that this is the major, if not the only, cause of classic EDS. ### Reviews Molecular defects in collagen in the several forms of EDS were surveyed by Prockop and Kivirikko (1984). ### Associations Pending Confirmation For discussion of a possible association between a complex multisystem disorder with connective tissue abnormalities reminiscent of Ehlers-Danlos syndrome and variation in the LAMA5 gene, see 601033.0002. History Barabas (1967) suggested the existence of 3 distinct types of the Ehlers-Danlos syndrome. In the classic type, the patients are born prematurely because of premature rupture of fetal membranes, and have severe skin and joint involvement but no varicose veins or arterial ruptures. A second (mild or 'varicose') group is not born prematurely and, although varicose veins are severe, the skin and joint manifestations are not. In a third ('arterial') group, bruising, including spontaneous ecchymoses during menstruation, is a paramount sign. Skin is soft and transparent but not very extensible, and joint hypermobility is limited to the hands. Severe and unexplained abdominal pain is a feature. Repeated arterial ruptures occur in these patients. According to the original Beighton classification (Beighton, 1970), EDS I is the severe form of classic Ehlers-Danlos syndrome and EDS II is the mild form. According to the classification used by McKusick (1972): EDS I, or gravis type, is the severe classic form. EDS II (130010), or mitis type, is the mild classic form. EDS III (130020) is the benign hypermobility form. EDS IV (130050) is the arterial, ecchymotic or Sack form. EDS V (see 314400) was a possible X-linked form. EDS VI (225400) is the form due to deficiency of lysyl hydroxylase. EDS VII (225410) is the form due to deficiency of procollagen protease. EDS VIII (130080) is the form with accompanying periodontitis. EDS IX (304150) is the form with occipital horns. EDS X (225310) is the form with a possible fibronectin defect. EDS XI (147900) is the familial joint instability syndrome. Steinmann et al. (2002) noted that EDS IX (EDS9) and EDS XI (EDS11) have been reclassified as occipital horn syndrome and familial joint hypermobility syndrome, respectively, and that the existence of EDS V (EDS5), EDS VIII (EDS8), and EDS X (EDS10) as distinct entities is questionable. In the Villefranche classification of EDS (Beighton et al., 1998), 6 main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and EDS II, 130010), hypermobility type (EDS III, 130020), vascular type (EDS IV, 130050), kyphoscoliosis type (EDS VI, 225400), arthrochalasia type (EDS VIIA and VIIB, 130060), and dermatosparaxis type (EDS VIIC, 225410). Six other forms were listed, including a category of 'unspecified forms.' Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Face \- Narrow maxilla Ears \- Hypermobile \- Lop ears Eyes \- Myopia \- Blue sclerae \- Ectopia lentis \- Epicanthal folds Mouth \- Small, irregularly placed teeth CARDIOVASCULAR Heart \- Mitral valve prolapse \- Aortic root dilatation ABDOMEN External Features \- Inguinal hernia \- Umbilical hernia Gastrointestinal \- Spontaneous bowel rupture \- Bowel diverticula SKELETAL \- Osteoarthritis Limbs \- Joint hypermobility \- Joint dislocation (hip, shoulder, elbow, knee, or clavicle) Feet \- Pes planus SKIN, NAILS, & HAIR Skin \- Fragile skin \- Easy bruisability \- Cigarette-paper scars \- Dystrophic scarring \- Wide, thin scars \- Velvety skin \- Poor wound healing \- Molluscoid pseudotumors \- Spheroids \- Skin hyperextensibility NEUROLOGIC Central Nervous System \- Hypotonia in infancy PRENATAL MANIFESTATIONS Delivery \- Premature birth following premature rupture of fetal membranes MISCELLANEOUS \- Two unrelated patients with classic EDS and a mutation in COL1A1 ( 120150.0059 ) has been reported MOLECULAR BASIS \- Caused by mutation in the collagen V, alpha-1 polypeptide gene (COL5A1, 120215.0002 ) \- Caused by mutation in the collagen V, alpha-2 polypeptide gene (COL5A2, 120190.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	EHLERS-DANLOS SYNDROME, CLASSIC TYPE, 1	c0220679	3,197	omim	https://www.omim.org/entry/130000	2019-09-22T16:41:49	{"doid": ["14720"], "mesh": ["C562424"], "omim": ["130000"], "orphanet": ["287"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE I, FORMERLY", "EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE, FORMERLY", "EDS I, FORMERLY", "EHLERS-DANLOS SYNDROME, GRAVIS TYPE, FORMERLY"], "genereviews": ["NBK1244"]}
Degenerative brain disease caused by prions Not to be confused with Creutzfeldt–Jakob disease. Variant Creutzfeldt–Jakob disease Other namesNew variant Creutzfeldt–Jakob disease (nvCJD) Biopsy of the tonsil in variant CJD. Prion protein immunostaining. SpecialtyNeurology SymptomsInitial: Psychiatric problems, behavioral changes, painful sensations[1] Later: Poor coordination, Dementia, Involuntary movements[2] Usual onsetYears after initial exposure[3] Duration~13-month life expectancy[1] CausesPrion Risk factorsEating beef from animals with bovine spongiform encephalopathy[3][4] Diagnostic methodSuspected based on symptoms, confirmed by Brain biopsy[3] Differential diagnosisMultiple sclerosis, standard Creutzfeldt-Jakob disease PreventionNot eating contaminated beef TreatmentSupportive care[5] PrognosisAlways fatal FrequencyFewer than 250 reported cases as of 2012[6] Variant Creutzfeldt–Jakob disease (vCJD) is a type of brain disease within the transmissible spongiform encephalopathy family.[6] Initial symptoms include psychiatric problems, behavioral changes, and painful sensations.[1] In the later stages of the illness, patients may exhibit poor coordination, dementia and involuntary movements.[2] The length of time between exposure and the development of symptoms is unclear, but is believed to be years.[3] Average life expectancy following the onset of symptoms is 13 months.[1] It is caused by prions, which are misfolded proteins.[7] Spread is believed to be primarily due to eating bovine spongiform encephalopathy (BSE)-infected beef.[6][7] Infection is also believed to require a specific genetic susceptibility.[4][6] Spread may potentially also occur via blood products or contaminated surgical equipment.[8] Diagnosis is by brain biopsy but can be suspected based on certain other criteria.[3] It is different from classic Creutzfeldt–Jakob disease, though both are due to prions.[7] Treatment for vCJD involves supportive care.[5] As of 2012, about 170 cases of vCJD have been recorded in the United Kingdom, due to a 1990s outbreak, and 50 cases in the rest of the world.[6] The disease has become less common since 2000.[6] The typical age of onset is less than 30 years old.[3] It was first identified in 1996 by the National CJD Surveillance Unit in Edinburgh, Scotland.[6] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Tainted beef * 2.2 Blood products * 2.3 Sperm donation * 2.4 Other types of brains * 3 Mechanism * 4 Diagnosis * 4.1 Definitive * 4.2 Suspected * 4.3 Classification * 5 Epidemiology * 6 Society and culture * 6.1 United Kingdom * 6.2 Human BSE foundation * 7 See also * 8 References ## Signs and symptoms[edit] Initial symptoms include psychiatric problems, behavioral changes, and painful sensations.[1] In the later stages of the illness, patients may exhibit poor coordination, dementia and involuntary movements.[2] The length of time between exposure and the development of symptoms is unclear, but is believed to be years.[3] Average life expectancy following the onset of symptoms is 13 months.[1] ## Cause[edit] ### Tainted beef[edit] In the UK, the primary cause of vCJD has been eating beef tainted with bovine spongiform encephalopathy.[9] A 2012 study by the Health Protection Agency showed that around 1 in 2,000 people in the UK shows signs of abnormal prion accumulation.[10] Jonathan D. Quick, M.D. instructor of medicine at the Department of Global Health and Social Medicine at Harvard Medical School, states that bovine spongiform encephalopathy or BSE is the first man-made epidemic, or "Frankenstein" disease, because a human decision to feed meat and bone meal to previously herbivorous cattle (as a source of protein) caused what was previously an animal pathogen to enter into the human food chain, and from there to begin causing humans to contract vCJD.[11] ### Blood products[edit] As of 2018, evidence suggests that while there may be prions in the blood of individuals with vCJD, this is not the case in individuals with sporadic CJD.[9] In 2004, a report showed that vCJD can be transmitted by blood transfusions.[12] The finding alarmed healthcare officials because a large epidemic of the disease could result in the near future. A blood test for vCJD infection is possible[13] but is not yet available for screening blood donations. Significant restrictions exist to protect the blood supply. The UK government banned anyone who had received a blood transfusion since January 1980 from donating blood.[14] Since 1999 there has been a ban in the UK for using UK blood to manufacture fractional products such as albumin.[15] Whilst these restrictions may go some way to preventing a self-sustaining epidemic of secondary infections the number of infected blood donations is unknown and could be considerable. In June 2013 the government was warned that deaths—then at 176—could rise five-fold through blood transfusions.[16] On May 28, 2002, the United States Food and Drug Administration instituted a policy that excludes from donation anyone having spent at least six months in certain European countries (or three months in the United Kingdom) from 1980 to 1996. Given the large number of U.S. military personnel and their dependents residing in Europe, it was expected that over 7% of donors would be deferred due to the policy. Later changes to this policy have relaxed the restriction to a cumulative total of five years or more of civilian travel in European countries (six months or more if military). The three-month restriction on travel to the UK, however, has not been changed.[17] In New Zealand, the New Zealand Blood Service (NZBS) in 2000 introduced measures to preclude permanently donors having resided in the United Kingdom (including the Isle of Man and the Channel Islands) for a total of six months or more between January 1980 and December 1996. The measure resulted in ten percent of New Zealand's active blood donors at the time becoming ineligible to donate blood. In 2003, the NZBS further extended restrictions to permanently preclude donors having received a blood transfusion in the United Kingdom since January 1980, and in April 2006, restrictions were further extended to include the Republic of Ireland and France.[18] Similar regulations are in place where anyone having spent more than six months for Germany or one year for France living in the UK between January 1980 and December 1996 is permanently banned from donating blood.[19][20] In Canada, individuals are not eligible to donate blood or plasma if they have spent a cumulative total of three months or more in the UK or France from January 1, 1980 to December 31, 1996. They are also ineligible if they have spent a cumulative total of five years or more in Western Europe outside the UK or France since January 1, 1980 through December 31, 2007 or spent a cumulative total of six months or more in Saudi Arabia from January 1, 1980 through December 31, 1996[21] or if they have had a blood transfusion in the UK, France or Western Europe since 1980.[22] In Poland, anyone having spent cumulatively six months or longer between 1 January 1980 and 31 December 1996 in the UK, Ireland, or France is permanently barred from donating.[23] In the Czech Republic, anyone having spent more than six months in the UK or France between the years 1980 and 1996 or received transfusion in the UK after the year 1980 is not allowed to donate blood.[24] In Finland, anyone having lived or stayed in the British Isles a total of over six months between 1 January 1980 and 31 December 1996 is permanently barred from donating.[25] ### Sperm donation[edit] In the U.S., the FDA has banned import of any donor sperm, motivated by a risk of variant Creutzfeldt-Jakob disease, inhibiting the once popular[26] import of Scandinavian sperm. Despite this, the scientific consensus is that the risk is negligible, as there is no evidence Creutzfeldt–Jakob is sexually transmitted.[27][28][29] ### Other types of brains[edit] Eating other types of brains such as those from squirrels is not recommended due to potential concerns.[30] ## Mechanism[edit] Despite the consumption of contaminated beef in the UK being high, vCJD has infected a small number of people. One explanation for this can be found in the genetics of people with the disease. The human PRNP protein which is subverted in prion disease can occur with either methionine or valine at amino acid 129, without any apparent difference in normal function. Of the overall Caucasian population, about 40% have two methionine-containing alleles, 10% have two valine-containing alleles, and the other 50% are heterozygous at this position. Only a single person with vCJD tested was found to be heterozygous; most of those affected had two copies of the methionine-containing form. It is not yet known whether those unaffected are actually immune or only have a longer incubation period until symptoms appear.[31][32] ## Diagnosis[edit] Electroencephalogram of a person with suspected CJD showing typical periodic bursts of triphasic sharp waves ### Definitive[edit] Examination of brain tissue is required to confirm a diagnosis of variant CJD.[2] The following confirmatory features should be present:[2] * Numerous widespread kuru-type amyloid plaques surrounded by vacuoles in both the cerebellum and cerebrum – florid plaques.[2] * Spongiform change and extensive prion protein deposition shown by immunohistochemistry throughout the cerebellum and cerebrum.[2] ### Suspected[edit] * Current age or age at death less than 55 years (a brain autopsy is recommended, however, for all physician-diagnosed CJD cases).[2] * Psychiatric symptoms at illness onset and/or persistent painful sensory symptoms (frank pain and/or dysesthesia).[2] * Dementia, and development ≥4 months after illness onset of at least two of the following five neurologic signs: poor coordination, myoclonus, chorea, hyperreflexia, or visual signs. (If persistent painful sensory symptoms exist, ≥4 months' delay in the development of the neurologic signs is not required).[2] * A normal or an abnormal EEG, but not the diagnostic EEG changes often seen in classic CJD.[2] * Duration of illness of over 6 months.[2] * Routine investigations do not suggest an alternative, non-CJD diagnosis.[2] * No history of getting human pituitary growth hormone or a dura mater graft from a cadaver.[2] * No history of CJD in a first degree relative or prion protein gene mutation in the person.[2] ### Classification[edit] vCJD is a separate condition from classic Creutzfeldt–Jakob disease (though both are caused by PrP prions).[7] Both classic and variant CJD are subtypes of Creutzfeld–Jakob disease. There are three main categories of CJD disease: sporadic CJD, hereditary CJD, and acquired CJD, with variant CJD being in the acquired group along with iatrogenic CJD.[33][34] The classic form includes sporadic and hereditary forms.[35] Sporadic CJD is the most common type.[36] ICD-10 has no separate code for vCJD and such cases are reported under the Creutzfeldt–Jakob disease code (A81.0).[37] ## Epidemiology[edit] Dark green areas are countries that have confirmed human cases of variant Creutzfeldt–Jakob disease and light green are countries that have bovine spongiform encephalopathy cases The Lancet in 2006 suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea.[38] The reasoning behind the claim is that kuru was possibly transmitted through cannibalism in Papua New Guinea when family members would eat the body of a dead relative as a sign of mourning. In the 1950s, cannibalism was banned in Papua New Guinea.[39] In the late 20th century, however, kuru reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 20 to 50 years. A critique to this theory is that while mortuary cannibalism was banned in Papua New Guinea in the 1950s, that does not necessarily mean that the practice ended. Fifteen years later Jared Diamond was informed by Papuans that the practice continued.[39] Kuru may have passed to the Fore people through the preparation of the dead body for burial.[citation needed] These researchers noticed a genetic variation in some people with kuru that has been known to promote long incubation periods. They have also proposed that individuals having contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for bovine spongiform encephalopathy (BSE). This means that there may be many more people with vCJD with longer incubation periods, which may surface many years later.[38] Prion protein is detectable in lymphoid and appendix tissue up to two years before the onset of neurological symptoms in vCJD. Large scale studies in the UK have yielded an estimated prevalence of 493 per million, higher than the actual number of reported cases. This finding indicates a large number of asymptomatic cases and the need to monitor.[40] ## Society and culture[edit] In 1997, a number of people from Kentucky developed vCJD. It was discovered that all had consumed squirrel brains, although a coincidental relationship between the disease and this dietary practice may have been involved.[41] In 2008, UK scientists expressed concern over the possibility of a second wave of human cases due to the wide exposure and long incubation of some cases of vCJD.[42] In 2015, a man from New York developed vCJD after eating squirrel brains. From November 2017 to April 2018, four suspected cases of the disease arose in Rochester.[43] ### United Kingdom[edit] Deaths in the UK from Creutzfeldt–Jakob disease 1990–2014: while cases of vCJD have declined (green), reported cases of sporadic CJD continue to increase (blue) Researchers believe one in 2,000 people in the UK is a carrier of the disease linked to eating contaminated beef (vCJD).[44] The survey provides the most robust prevalence measure to date—and identifies abnormal prion protein across a wider age group than found previously and in all genotypes, indicating "infection" may be relatively common. This new study examined over 32,000 anonymous appendix samples. Of these, 16 samples were positive for abnormal prion protein, indicating an overall prevalence of 493 per million population, or one in 2,000 people are likely to be carriers. No difference was seen in different birth cohorts (1941–1960 and 1961–1985), in both sexes, and there was no apparent difference in abnormal prion prevalence in three broad geographical areas. Genetic testing of the 16 positive samples revealed a higher proportion of valine homozygous (VV) genotype on the codon 129 of the gene encoding the prion protein (PRNP) compared with the general UK population. This also differs from the 176 people with vCJD, all of whom to date have been methionine homozygous (MM) genotype. The concern is that individuals with this VV genotype may be susceptible to developing the condition over longer incubation periods.[45] ### Human BSE foundation[edit] Commemorative plaque in London paying tribute to people who died from vCJD In 2000 a voluntary support group was formed by families who had lost someone to vCJD. The goal was to support other families going through a similar experience. This support was provided through a National Helpline, a Carer's Guide, a website and a network of family befriending. The support groups had an internet presence at the turn of the 21st century. The driving force behind the foundation was Lester Firkins, who lost his own young son to the disease.[46][47] In October 2000 the report of the government inquiry into BSE chaired by Lord Phillips was published.[48] The BSE report criticised former Conservative Party Agriculture Ministers John Gummer, John MacGregor and Douglas Hogg.[49] The report concluded that the escalation of BSE into a crisis was the result of intensive farming, particularly with herbivore cows being fed with cow and sheep remains. Furthermore, the report was critical of the way the crisis had been handled.[50] There was a reluctance to consider the possibility that BSE could cross the species barrier. The government assured the public that British beef was safe to eat, with agriculture minister John Gummer famously feeding his daughter a beefburger. The British government were reactive more than proactive in response; the worldwide ban on all British beef exports in March 1996 was a serious economic blow.[51] The foundation had been calling for compensation to include a care package to help relatives look after those with vCJD. There have been widespread complaints of inadequate health and social services support.[52] Following the Phillips Report in October 2001, the government announced a compensation scheme for British people affected with vCJD. The multi-million-pound financial package was overseen by the vCJD Trust. A memorial plaque for persons who have died due to vCJD was installed in central London.[when?] It is located on the boundary wall of St Thomas' Hospital in Lambeth facing the Riverside Walk of Albert Embankment.[53] ## See also[edit] * Jonathan Simms, a person who died from vCJD * Mepacrine ## References[edit] 1. ^ a b c d e f "Clinical and Pathologic Characteristics \| Variant Creutzfeldt-Jakob Disease, Classic (CJD)". CDC. 10 February 2015. Retrieved 22 January 2018. 2. ^ a b c d e f g h i j k l m n o "Diagnostic Criteria \| Variant Creutzfeldt-Jakob Disease, Classic (CJD)". CDC. 10 February 2015. Retrieved 23 January 2018. 3. ^ a b c d e f g "Classic CJD versus Variant CJD". CDC. 11 February 2015. Retrieved 23 January 2018. 4. ^ a b Ironside, JW (Jul 2010). "Variant Creutzfeldt–Jakob disease". Haemophilia. 16 Suppl 5: 175–80. doi:10.1111/j.1365-2516.2010.02317.x. PMID 20590878. S2CID 24635924. 5. ^ a b "Treatment Variant Creutzfeldt-Jakob Disease". CDC. 10 February 2015. Retrieved 23 January 2018. 6. ^ a b c d e f g Ironside, JW (2012). "Variant Creutzfeldt–Jakob disease: an update". Folia Neuropathologica. 50 (1): 50–6. PMID 22505363. 7. ^ a b c d "About vCJD". CDC. 10 February 2015. Retrieved 22 January 2018. 8. ^ Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 343. ISBN 9780323529570. 9. ^ a b "Creutzfeldt-Jakob Disease Fact Sheet \| National Institute of Neurological Disorders and Stroke". NINDS. March 2003. Archived from the original on 4 July 2017. Retrieved 16 July 2017. 10. ^ HPA Press Office (August 10, 2012). "Summary results of the second national survey of abnormal prion prevalence in archived appendix specimens". Archived from the original on March 25, 2013. 11. ^ D. Quick, Jonathan; Bronwyn Fryer (2018). The End of Epidemics: The Looming Threat to Humanity and How to Stop it. St. Martin's Press. pp. 51–53. ISBN 9781250117779. 12. ^ Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW (2004). "Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient". The Lancet. 364 (9433): 527–9. doi:10.1016/S0140-6736(04)16811-6. PMID 15302196. S2CID 18617259. 13. ^ Edgeworth, JA; Farmer, M; Sicilia, A; Tavares, P; Beck, J; Campbell, T; Lowe, J; Mead, S; Rudge, P; Collinge, J; Jackson, GS (Feb 5, 2011). "Detection of prion infection in variant Creutzfeldt–Jakob disease: a blood-based assay". The Lancet. 377 (9764): 487–93. doi:10.1016/S0140-6736(10)62308-2. PMID 21295339. S2CID 39891588. 14. ^ "Variant CJD and blood donation" (PDF). National Blood Service. August 2004. Archived from the original (PDF) on October 11, 2007. Retrieved 2009-06-20. 15. ^ Regan F, Taylor C (July 2002). "Blood transfusion medicine". BMJ (Clinical Research Ed.). 325 (7356): 143–7. doi:10.1136/bmj.325.7356.143. PMC 1123672. PMID 12130612. 16. ^ Rowena Mason (April 28, 2013). "Mad cow infected blood 'to kill 1,000'". Daily Telegraph. London. Archived from the original on July 3, 2013. Retrieved July 2, 2013. 17. ^ "In-Depth Discussion of Variant Creutzfeld–Jacob Disease and Blood Donation". American Red Cross. Archived from the original on 2007-12-30. Retrieved 2009-06-20. 18. ^ "CJD (Creutzfeldt–Jakob Disease) - Information for blood donors" (PDF). New Zealand Blood Service. Archived (PDF) from the original on 10 April 2017. Retrieved 31 May 2017. 19. ^ "Permanent exclusion criteria" (in German). Blutspendedienst Hamburg. Archived from the original on 9 August 2016. Retrieved 2009-06-20. English via Google Translate 20. ^ "Les contre-indications au don de sang". Etablissement français du sang. Retrieved 20 June 2019. 21. ^ "Canada restricts blood donors from Saudi Arabia". ctv news. Archived from the original on 5 May 2016. Retrieved 14 April 2016. 22. ^ "Travel restrication". Canadian Blood Services. Archived from the original on 14 April 2016. Retrieved 14 April 2016. 23. ^ "Permanent exclusion criteria / Dyskwalifikacja stała" (in Polish). RCKiK Warszawa. Archived from the original on August 30, 2009. Retrieved 2010-03-03. 24. ^ "Blood donor guidance / Poučení dárce krve" (in Czech). Fakultní nemocnice Královské Vinohrady. Archived from the original on 2011-07-18. Retrieved 2010-03-20. 25. ^ "www.veripalvelu.fi". www.bloodservice.fi. Retrieved 2020-01-10. 26. ^ Stein, Rob (13 August 2008). "Mad Cow Rules Hit Sperm Banks' Patrons". washingtonpost.com. The Washington Post Company. Archived from the original on 26 April 2012. Retrieved 4 October 2008. 27. ^ Kotler, Steven (27 September 2007). "The God of Sperm". LA Weekly. Archived from the original on 6 July 2009. Retrieved 20 June 2009. 28. ^ Mortimer, D.; Barratt, CLR (2006). "Is there a real risk of transmitting variant Creutzfeldt-Jakob disease by donor sperm insemination?". Reproductive Biomedicine Online. 13 (6): 778–790. doi:10.1016/S1472-6483(10)61024-3. PMID 17169195. 29. ^ Lapidos, Juliet (26 September 2007). "Is Mad Cow an STD?". Slate. Archived from the original on 8 January 2017. Retrieved 7 January 2017. 30. ^ Blakeslee, Sandra (29 August 1997). "Kentucky Doctors Warn Against a Regional Dish: Squirrels' Brains". The New York Times. Retrieved 18 April 2019. 31. ^ Saba, R; Booth, SA (2013). "The genetics of susceptibility to variant Creutzfeldt–Jakob disease". Public Health Genomics. 16 (1–2): 17–24. doi:10.1159/000345203. PMID 23548713. 32. ^ Sikorska, B; Liberski, PP (2012). Human prion diseases: from Kuru to variant Creutzfeldt–Jakob disease. Subcellular Biochemistry. 65. pp. 457–96. doi:10.1007/978-94-007-5416-4_17. ISBN 978-94-007-5415-7. PMID 23225013. 33. ^ "Creutzfeldt-Jakob Disease Fact Sheet". National Institute of Neurological Disorders and Stroke. Retrieved 21 November 2018. 34. ^ Geschwind MD (December 2015). "Prion Diseases". Continuum (Minneapolis, Minn.). 21 (6): 1612–1638. doi:10.1212/CON.0000000000000251. PMC 4879966. PMID 26633779. 35. ^ "About CJD \| Creutzfeldt-Jakob Disease, Classic (CJD)". CDC. 2 October 2018. Retrieved 21 November 2018. 36. ^ Geschwind, MD (December 2015). "Prion Diseases". Continuum (Minneapolis, Minn.). 21 (6 Neuroinfectious Disease): 1612–38. doi:10.1212/CON.0000000000000251. PMC 4879966. PMID 26633779. 37. ^ "International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)-WHO Version for 2016 — A81.0". World Health Organization. 2016. Retrieved 21 November 2018. 38. ^ a b Collinge J, Whitfield J, McKintosh E (June 2006). "Kuru in the 21st century – an acquired human prion disease with very long incubation periods". Lancet. 367 (9528): 2068–74. doi:10.1016/S0140-6736(06)68930-7. PMID 16798390. S2CID 11506094. 39. ^ a b Diamond, JM (7 September 2000). "Archaeology: Talk of cannibalism". Nature. 407 (25–26): 25–26. doi:10.1038/35024175. PMID 10993054. S2CID 36954017. 40. ^ Diack, Abigail B; Head, Mark W; McCutcheon, Sandra; Boyle, Aileen; Knight, Richard; Ironside, James W; Manson, Jean C; Will, Robert G (1 November 2014). "Variant CJD". Prion. 8 (4): 286–95. doi:10.4161/pri.29237. ISSN 1933-6896. PMC 4601215. PMID 25495404. 41. ^ Berger JR, Waisman E, Weisman B (August 1997). "Creutzfeldt–Jakob disease and eating squirrel brains". Lancet. 350 (9078): 642. doi:10.1016/S0140-6736(05)63333-8. PMID 9288058. S2CID 42158648. 42. ^ "Warning over second wave of CJD cases". The Observer. 8 August 2008. Archived from the original on 28 March 2017. Retrieved 27 March 2017. 43. ^ "Man Dies from Extremely Rare Disease After Eating Squirrel Brains". Live Science. Retrieved 2018-10-18. 44. ^ "Estimate doubled for vCJD carriers in UK". BBC News. 2013-10-15. Archived from the original on 2014-02-10. 45. ^ Gill, Noel (2013). "Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey". British Medical Journal. 347: f5675. doi:10.1136/bmj.f5675. PMC 3805509. PMID 24129059. 46. ^ "Pioneer profile: Lester Firkin" (PDF). The Patient - Patient-Centered Outcomes Research. 2009-03-01. Retrieved 27 May 2020. 47. ^ "James Lind Alliance Affiliates Newsletter" (PDF). James Lind Alliance. 2012-01-01. Retrieved 27 May 2020. 48. ^ "BSE crisis: Timeline". The Guardian. London. 2019-10-26. Retrieved 2020-05-27. 49. ^ "From nannyism to public disclosure: the BSE Inquiry report". Canadian Medical Association Journal. 164 (2): 165. 23 Jan 2001. PMC 80663. PMID 11332300. 50. ^ "The BSE Inquiry Report". The Health Foundation. 2000-10-01. Retrieved 27 May 2020. 51. ^ Ainsworth, Claire; Carrington, Damian (2019-10-25). "BSE disaster: the history". New Scientist. London. Retrieved 2020-05-27. 52. ^ "BSE victims to get millions". The Guardian. 22 October 2000. Retrieved 27 May 2020. 53. ^ "memorial should be moved from listed wall, say Lambeth planners". London SE1 community website. 23 January 2016. Retrieved 27 May 2020. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Variant Creutzfeldt–Jakob disease	c0376329	3,198	wikipedia	https://en.wikipedia.org/wiki/Variant_Creutzfeldt%E2%80%93Jakob_disease	2021-01-18T18:48:21	{"gard": ["9550"], "mesh": ["D007562"], "umls": ["C0376329"], "icd-9": ["046.1"], "icd-10": ["A81.0", "F02.1"], "wikidata": ["Q2323502"]}
A number sign (#) is used with this entry because multiple types of cataract (CTRCT9) are caused by heterozygous or homozygous mutation in the CRYAA gene (123580), which encodes alpha-A-crystallin, on chromosome 21q22. Description Mutations in the CRYAA gene have been found to cause multiple types of cataract, which have been described as nuclear, zonular central nuclear, laminar, lamellar, anterior polar, posterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the CRYAA gene. Both autosomal dominant and autosomal recessive modes of inheritance have been reported. The symbol CATC1 was formerly used for the autosomal recessive form of cataract caused by mutation in the CRYAA gene. Clinical Features Litt et al. (1998) studied a 4-generation family with autosomal dominant congenital cataracts that had been described as congenital zonular central nuclear opacities. In 5 of the 13 affected family members, the cataracts were also associated with microphthalmia and microcornea. As adults in their thirties, patients developed cortical and posterior subcapsular cataracts as well. The time of surgery had varied from infancy to late childhood. Visual acuity following surgery had been as good as 20/40 in older adults, but several patients had poor vision in each eye associated with nystagmus. Other sequelae common in this family included amblyopia, strabismus, and glaucoma. Pras et al. (2000) reported 3 sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract. The patients underwent cataract extraction in the first 3 months of life, and no details of the pathologic findings in the lens were available. Mackay et al. (2003) described a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract presenting at birth or during infancy and confined to the central zone or fetal nucleus of the lens. Haplotype analysis indicated that the disease gene lay in the physical interval between 2 markers flanking the CRYAA gene. Shafie et al. (2006) examined affected members of 4 Chilean families segregating autosomal dominant cataract and found significant intrafamilial variation with respect to morphology, location within the lens, color, and density. In family 'ADC51,' affected members had cataracts in variable locations within the lens and of different densities; the authors documented interocular asymmetry of density and location and progression. The cataracts included nuclear opacities, posterior subcapsular cataracts, and combinations, and 1 individual had a dense white cataract. Two sisters in family 'ADC52' demonstrated differences in morphology and location of cataract. In family 'ADC53,' there were differences in cataract location, density of similar and disparate opacities, morphology, and color among affected members, but morphology and density were the same in each eye. Cataracts included embryonal cataract of varying densities, pulverulent cortical opacities, posterior star-shaped subcapsular cataract with pulverulent opacities in the cortical or embryonal regions, and dense embryonal cataracts. Some individuals described progression, although this was not documented by the authors. Members of family 'ADC54' exhibited significant variability in the morphology and density of the cataracts; 1 individual had interocular differences in the color of opacities. Shafie et al. (2006) concluded that significant intrafamilial variability in cataract morphology and location within the lens is common in autosomal dominant cataract. Vanita et al. (2006) examined 10 affected and 9 unaffected members of a large 4-generation family of Indian origin segregating autosomal dominant congenital cataract and microcornea. The bilateral fan-shaped cataracts were visible at birth and consisted of a round, oval, or triangular opacity with irregular margins, approximately 3 mm wide, topped by triangular opacities oriented with the base towards the periphery. In a 6-year-old patient, the base of 1 of the triangular opacities coincided with the edge of the fetal nucleus, whereas the 4 other triangular opacities extended beyond the edge of the fetal nucleus. All affected individuals also had microcornea, with corneas that were less than 10 mm in diameter. There were no other ocular abnormalities detected in this family; in particular, no posterior capsular, polar, or cortical opacities were observed in any of the affected individuals. Santhiya et al. (2006) described a 24-year-old Indian woman who had decreasing vision beginning at age 17 and who was found to have total opacity on slit-lamp examination, with severe loss of vision. There were no other associated ocular anomalies of the anterior or posterior segment. Her mother had undergone cataract surgery at age 35 years. Her 16-year-old brother denied any vision problems, but slit-lamp examination revealed a peripheral ring-like opacity; he later reported difficulty with distance vision. Beby et al. (2007) reported 12 affected members of a 4-generation French family with autosomal dominant cataract and iris coloboma. All affected individuals had bilateral early-onset cataract, either present at birth or developing during the first years of life, consisting of a single dense axial opacity of 3 mm confined to the embryonic and fetal nuclei of the lens and associated with bilateral iris coloboma in all patients. Two affected individuals also had congenital microphthalmia. No dysmorphic features, mental retardation, or developmental malformations were observed. Khan et al. (2007) studied a consanguineous Saudi Arabian family in which 2 sisters and a brother had congenital total white cataract and microcornea, with horizontal corneal diameters of approximately 8 mm at 2 years of age. Two of the 3 affected sibs developed bilateral aphakic glaucoma within a few years of cataract surgery. Their parents and 7 sibs were asymptomatic, but a cousin was reported to have a similar phenotype. None of the 3 affected sibs had any other significant medical history, and all other members of the nuclear family had normal vision and no ocular or systemic disease. Laurie et al. (2013) described a 3-generation South Australian family with lamellar cataract of variable severity. The proband was diagnosed at 2 years of age with moderate fetal nuclear lamellar cataract with no sutural involvement. His brother was diagnosed at 4.5 years of age with a more severe phenotype, described as dense white nuclear cataract. Their asymptomatic mother, maternal uncle, and maternal grandfather all displayed mild lamellar opacity consisting of fine white dots in a single lamellar shell; the uncle also had a cortical rider. These opacities did not affect visual acuity and were only discovered on examination following the children's diagnosis. The proband's 2 younger sisters had no sign of cataract. Mapping In a 4-generation family segregating autosomal dominant congenital cataracts described as congenital zonular central nuclear opacities, Litt et al. (1998) found linkage of the disorder, which they referred to as ADCC-2, to chromosome 21q22.3. In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea, Vanita et al. (2006) performed genomewide linkage analysis and obtained 2-point lod scores of 2.833 with marker D21S1260 and 1.906 with D21S1259 (theta = 0 for both). Further analysis gave a maximum lod score of 3.657 with marker D21S1411, and multipoint analysis also supported linkage in this region of chromosome 21, with a maximum lod score of 3.546 at D21S1411. Haplotype analysis revealed recombination events that narrowed the critical region to an interval on chromosome 21q22.3 that was at least 23.5 cM long. In a consanguineous Saudi Arabian family with congenital total white cataract and microcornea, Khan et al. (2007) obtained a lod score of 2.5 at chromosome 21q22.3, a region containing the candidate gene CRYAA. Molecular Genetics In affected members of a family segregating autosomal dominant congenital cataracts mapping to chromosome 21q22.3, Litt et al. (1998) sequenced the coding region of the CRYAA gene and identified a heterozygous missense mutation (R116C; 123580.0001) that segregated with the disorder. Pras et al. (2000) identified homozygosity for a nonsense mutation in the CRYAA gene (W9X; 123580.0002) in 3 sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract. In a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract presenting at birth or during infancy and confined to the central zone or fetal nucleus of the lens, Mackay et al. (2003) found by haplotype analysis that the disease locus lay in the physical interval between 2 markers flanking the CRYAA gene. Sequence analysis identified a missense mutation (R49C; 123580.0003) in the CRYAA gene in affected individuals. In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea mapping to chromosome 21q22.3, Vanita et al. (2006) identified heterozygosity for the CRYAA R116C missense mutation (123580.0001), previously found in a North American family with a zonular type of congenital cataract (Litt et al., 1998). Vanita et al. (2006) noted that despite an identical mutation, the ocular phenotype was quite different in the 2 families, with the earlier family exhibiting microphthalmia, amblyopia, strabismus, and glaucoma, as well as development of cortical and posterior subcapsular cataracts in the fourth decade of life. In a sister and brother and their mother with progressive presenile total cataract, Santhiya et al. (2006) analyzed functional candidate genes and identified heterozygosity for a missense mutation in the CRYAA gene (G98R; 123580.0005). The mutation was not found in their unaffected father or sister, in 30 random DNA samples of Indian origin, or in 96 healthy German controls. In 12 affected and 4 unaffected members of a 4-generation French family with autosomal dominant cataract and iris coloboma, Beby et al. (2007) analyzed microsatellites for 15 known cataract loci and found suggestive linkage at the CRYAA locus on chromosome 21, as well as a specific haplotype segregating with the disease. Sequence analysis of the CRYAA gene revealed that all affected family members were heterozygous for the R116C mutation; the mutation was not found in unaffected individuals. Two affected individuals also had congenital microphthalmia; the authors noted that Cryaa -/- mice have been found to have both microphthalmia and cataract (Brady et al., 1997). In 3 affected sibs from a consanguineous Saudi Arabian family with congenital total white cataract and microcornea mapping to 21q22.3, Khan et al. (2007) sequenced the candidate gene CRYAA and identified homozygosity for a missense mutation (R54C; 123580.0006). Their asymptomatic parents and 1 sib were found to be heterozygous for the mutation; on slit-lamp examination, all 3 heterozygotes had similar discernible but clinically insignificant bilateral punctate lenticular opacities that were not present in the other asymptomatic family members. In 10 Danish families segregating autosomal dominant developmental cataract and microcornea, Hansen et al. (2007) analyzed 9 candidate genes and identified 5 families with heterozygous mutations, 3 of which were in the CRYAA gene (123580.0007-123580.0009), 1 in the GJA8 gene (600897.0008), and 1 in the CRYGD gene (123690.0008). Corneal diameters varied between 8 and 10 mm. Nystagmus was present in some families and absent in others, depending primarily on the degree of visual impairment during the first months of life. Cataract phenotypes varied, but often involved the nuclei, with cortical laminar elements and anterior and posterior polar opacities to a variable extent; most cataracts had a clear peripheral zone. In some patients, cataract progression during the first years of life was noted. Richter et al. (2008) studied 14 affected and 14 unaffected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, and/or corneal opacity. Richter et al. (2008) found linkage to chromosome 21 with a maximum lod score of 4.89 at D21S171, and identified a heterozygous missense mutation in the CRYAA gene (R116H; 123580.0004) in affected members of the family. There was significant asymmetry of density, morphology, and color of the cataracts within and between affected individuals; the variable morphology included anterior polar, cortical, embryonal, fan-shaped, and anterior subcapsular cataracts. Richter et al. (2008) stated that, with the exception of iris coloboma, the clinical features of all 6 previously reported families with mutations in the CRYAA gene were found in this Chilean family. In 4 unrelated South Australian families segregating autosomal dominant cataract, Laurie et al. (2013) analyzed 10 known congenital cataract-associated crystallin genes and identified a heterozygous missense mutation in the CRYAA gene (R21Q; 123580.0010) in all affected individuals from 1 of the families. INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Eyes \- Cataract, congenital, multiple types \- Cataract, zonular central nuclear \- Cataract, nuclear \- Cataract, lamellar \- Opacities in embryonal nuclei \- Cataract, anterior subcapsular \- Cataract, anterior polar \- Cataract, posterior polar \- Cataract, fan-shaped \- Cataract, posterior subcapsular \- Cataract, cortical \- Cataract, laminar \- Cataract, progressive (in some patients) \- Cataract, total \- Cataract, presenile \- Microcornea (in some patients) \- Coloboma of the iris (in some patients) \- Microphthalmia (in some patients) \- Decreased visual acuity \- Nystagmus \- Amblyopia \- Strabismus \- Glaucoma MOLECULAR BASIS \- Caused by mutation in the alpha-A-crystallin gene (CRYAA, 123580.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CATARACT 9, MULTIPLE TYPES	c1861829	3,199	omim	https://www.omim.org/entry/604219	2019-09-22T16:12:17	{"doid": ["0110266"], "mesh": ["C538287"], "omim": ["604219"], "icd-10": ["Q12.0"], "orphanet": ["91492", "1377"], "synonyms": ["CATARACT, AUTOSOMAL DOMINANT", "Alternative titles", "CATARACT 9, MULTIPLE TYPES, WITH OR WITHOUT MICROCORNEA", "CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1"]}

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